Epilepsy & Behavior 36 (2014) 144–152

Contents lists available at ScienceDirect

Epilepsy & Behavior

journal homepage: www.elsevier.com/locate/yebeh

Factors influencing response to intravenous lacosamide in emergency

situations: LACO-IV study
Mercedes Garcés a, Vicente Villanueva a,⁎, José Angel Mauri b, Ana Suller b, Carolina García b,
Franscisco Javier López González c, Xiana Rodríguez Osorio c, Gustavo Fernández Pajarín c, Anna Piera d,
Edelmira Guillamón d, Consuelo Santafé d, Ascensión Castillo e, Pau Giner f, Nerea Torres f, Inés Escalza g,
Ana del Villar h, Maria Carmen García de Casasola i, Macarena Bonet j, Enrique Noé k, Nuria Olmedilla l
a
Hospital Universitario y Politécnico La Fe, Valencia, Spain
b
Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
c
Complejo Hospitalario Universitario, Santiago, Spain
d
Hospital Clínico Universitario, Valencia, Spain
e
Hospital General Universitario Valencia, Spain
f
Hospital Universitario Dr. Peset, Valencia, Spain
g
Hospital Galdakao, Vizcaya, Spain
h
Hospital General Universitario, Castellón, Spain
i
Hospital Sur Santa Cruz Tenerife, Spain
j
Hospital Universitario Arnau de Vilanova, Valencia, Spain
k
Hospital NISA Valencia al Mar, Valencia, Spain
l
Hospital Gomez Ulla, Madrid, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Status epilepticus (SE) and acute repetitive seizures (ARSs) frequently result in emergency visits. Wide variations in
Received 20 January 2014 response are seen with standard antiepileptic drugs (AEDs). Oral and intravenous (IV) formulations of lacosamide
Revised 14 April 2014 are approved as adjunctive therapy in the treatment of partial-onset seizures in adults and adolescents. The aim of
Accepted 18 May 2014
the retrospective multicenter observational study (LACO-IV) was to analyze data from a large cohort of patients
Available online 10 June 2014
with SE or ARSs of varying severity and etiology, who received IV lacosamide in the emergency setting. Patient clin-
Keywords:
ical data were entered into a database; lacosamide use and efficacy and tolerability variables were analyzed. In SE, IV
Intravenous (IV) lacosamide lacosamide tended to be used mainly in nonconvulsive status epilepticus as second- or third-line treatment. The
Acute repetitive seizures proportion of patients with no seizures when IV lacosamide was the last drug administered was 76.5% (70.9% SE
Status epilepticus and 83.7% ARSs). The rate of seizure cessation ≤24 h after IV lacosamide administration was 57.1% (49.1% SE and
Retrospective study 67.4% ARSs). Of the factors analyzed, a shorter latency from seizure onset to IV lacosamide infusion influenced treat-
Emergency setting ment response significantly. A nonsignificant tendency towards a higher response was seen with lacosamide dose
N 200 mg versus ≤200 mg. Analysis of response according to mechanism of action showed no significant differences
in response to IV lacosamide in patients receiving prior sodium channel blocker (SCB) or non-SCB AEDs in the over-
all or SE population; however, in ARSs, a tendency towards a higher response was observed in those receiving non-
SCB AEDs. The frequency and nature of adverse events observed were in line with those reported in other studies
(somnolence being the most frequent). In the absence of randomized prospective controlled studies of IV
lacosamide, our observations suggest that IV lacosamide may be a potential alternative for treatment of SE/ARSs
when seizures fail to improve with standard AEDs or when AEDs are contraindicated or not recommended.
© 2014 Elsevier Inc. All rights reserved.

Abbreviations: ARSs, acute repetitive seizures; AED, antiepileptic drug; AVB, atrioventricular block; BZD, benzodiazepine; CPSs, complex partial seizures; CSE, convulsive status epilep-
ticus; ECG, electrocardiogram; EEG, electroencephalogram; GTCSs, generalized tonic–clonic seizures; IV, intravenous; LEV, levetiracetam; MoA, mechanism of action; NCSE, nonconvulsive
status epilepticus; PHT, phenytoin; SPSs, simple partial seizures; SCB, sodium channel blocker; SD, standard deviation; SE, status epilepticus; TPM, topiramate; VPA, valproic acid.
⁎ Corresponding author at: Multidisciplinary Epilepsy Unit/Neurology Service, Hospital Universitario y Politécnico La Fe, Bulevard Sur, s/n, Carretera de Malilla, 46026 Valencia, Spain.
Fax: +34 961244330.
E-mail addresses: mergarces@gmail.com (M. Garcés), vevillanuevah@yahoo.es (V. Villanueva), jamauri@telefonica.net (J.A. Mauri), anasm98@gmail.com (A. Suller),
carolariza@hotmail.com (C. García), javieritol@yahoo.com (F.J. López González), xiana.ro@gmail.com (X. Rodríguez Osorio), gferpaj@hotmail.com (G. Fernández Pajarín),
annapiera77@gmail.com (A. Piera), e_guillamon@hotmail.com (E. Guillamón), santafe_mar@gva.es (C. Santafé), s_castillo_ruiz@yahoo.es (A. Castillo), giner_pau@gva.es (P. Giner),
netorres84@gmail.com (N. Torres), M.INES.ESCALZACORTINA@osakidetza.net (I. Escalza), ana_delvi@yahoo.es (A. del Villar), carmen.casasola@hospiten.com (M.C. García de Casasola),
bonet_mac@gva.es (M. Bonet), enoe@comv.es (E. Noé), nurolmedilla@hotmail.com (N. Olmedilla).

http://dx.doi.org/10.1016/j.yebeh.2014.05.015
1525-5050/© 2014 Elsevier Inc. All rights reserved.
 M. Garcés et al. / Epilepsy & Behavior 36 (2014) 144–152
1. Introduction
Status epilepticus (SE) is the second most frequent neurological
emergency (acute stroke being the first) with a risk of major morbid-
ity or mortality [1]. The annual incidence rate is around 10–41/
100,000 individuals per year. The incidence rate is higher among
children b1 year of age and adults N65 years of age [2,3]. In total,
22.6% had seizures refractory to first- and second-line antiepileptic
treatment in a hospital-based cohort [4]. When convulsive SE was
analyzed in a population-based study, it was refractory in 27% [5],
and, in a retrospective study in an intensive care unit, 43% of the pa-
tients had seizures refractory to first-line anticonvulsants [6]. Acute
repetitive seizures (ARSs) are usually defined as multiple seizures
occurring in a short period of time. Sometimes, it is termed a cluster,
although there is no definitive clinical definition for a cluster or se-
ries of epilepsy seizures. Acute repetitive seizures frequently result
in emergency room visits and, if left untreated, may evolve into
full-blown SE [7].
The current European Federation of Neurological Societies (EFNS)
guidelines for management of SE [8,9] support the use of benzodiaze-
pine (BZD) (lorazepam or diazepam) followed by phenytoin (PHT), as
also supported by the results of a double-blind study conducted at
Veteran Centers [10]; however, the risk of serious side effects associated
with this approach can outweigh advantages, especially in patients
without generalized tonic–clonic seizures (GTCSs). In the treatment
of ARSs, the standard therapy is a BZD [11]; other drugs tried in SE,
as well as in ARSs, including valproic acid (VPA) [12], levetiracetam
(LEV) [13], and topiramate (TPM) [14], have demonstrated a range
of response rates and tolerability issues. The variation in efficacy and
tolerability observed supports the need for studies assessing the efficacy
and safety of new antiepileptic drugs (AEDs) to increase the therapy
options in these patients.
Lacosamide is an AED that selectively enhances sodium channel
slow inactivation. The oral formulation (Vimpat®, UCB Pharma SA,
Brussels, Belgium) is approved in the US and EU for use in adult and ad-
olescent (16–18 years) patients with epilepsy as adjunctive therapy in
the treatment of partial-onset seizures with or without secondary gen-
eralization [15]. The efficacy and tolerability of oral lacosamide added to
existing AED therapy were established in three pivotal phase III trials in
patients with drug/treatment-refractory partial-onset seizures [16–18].
However, as patients in emergency situations are often unable to
swallow, formulation is particularly important, and administration
must be via IV in most of the cases. As a result of this need, intravenous
(IV) lacosamide (Vimpat® 10-mg/mL solution for infusion) was devel-
oped and has been approved as replacement therapy for oral
lacosamide in patients with partial-onset seizures [19,20].
In the absence of controlled or randomized studies, collecting data
on existing practice seems to be the best way of improving the quality
of evidence of the new AEDs. Recently, papers have reported positive
clinical experience of lacosamide in SE and ARSs [21–31]. These are
mainly from case reports, case series, shorter retrospective studies [21,
22,27], or larger retrospective studies [23,24,28–30]; moreover, two
were prospective observational studies: one in 25 patients with
drug/treatment-refractory SE or seizure clusters (ARSs) in which
two doses of IV lacosamide (200 and 400 mg) were compared [25]
and another in 34 patients with drug/treatment-refractory SE in
which lacosamide was added to standard therapy of BZD plus PHT
or VPA [26]. In addition, a comparison of lacosamide and phenytoin
for treatment of refractory SE has been reported [31]. Finally, a
meta-analysis of lacosamide in SE collating most of these studies has
been published [32]. Overall, the clinical data from these uncontrolled
studies suggest that IV lacosamide is effective and well tolerated in
these patients. However, most of these studies were performed in a re-
fractory setting. Our aim was to analyze retrospective data from a larger
cohort of patients with SE or ARSs of varying severity and etiology, who
were administered IV lacosamide in the emergency clinical setting.
145
2. Material and methods
2.1. Study design and patients
The LACO-IV study was a multicenter, retrospective, observational
study of intravenous lacosamide in emergency situations. Twelve
Spanish hospital centers participated in the study.
The inclusion criteria were as follows: 1) written informed consent
by the patients or their legal representative (to permit the collection
of the information from clinical records), 2) patients older than
18 years of age, and 3) diagnosis of SE or ARSs for which IV lacosamide
was used. The exclusion criteria were as follows: 1) patients actively
enrolled in other studies of AEDs or medical devices at the moment of
inclusion, 2) a history of alcoholism or drug abuse in the prior year,
and 3) inaccurate or unreliable clinical records according to participat-
ing physicians.
The study protocol was approved by the Ethics Committee of Hospi-
tal Universitario y Politécnico La Fe and was conducted according to the
code of ethics set out in the Declaration of Helsinki.
2.2. Procedures
In all patients, IV lacosamide was used as add-on therapy to standard
AEDs (BZD, PHT, VPA, and LEV) in the treatment of established SE/
refractory ARSs or as first-line therapy in early stages of SE/ARSs if it
was deemed suitable by the participating physician because other ap-
proved AEDs were contraindicated or not recommended by the patient
profile (comorbidity, side effect risk, and allergy).
2.3. Definitions
For the purposes of this study, ARS was defined as ≥2 seizures in
b1 h, considering that situation as infrequent for the patient. Seizures
were self-limited, and patients recovered their normal state after each
seizure (a postictal phase was permitted).
Types of epilepsy, seizure types, and etiology were taken from the
patient records. Classification of seizures was assigned according to
standard definitions issued by the International League Against Epilepsy
in the 1981 classification (ILAE) [33]. Convulsive status epilepticus
(CSE) was defined as continuous convulsive seizures lasting N 5 min or
≥2 seizures during which the patient does not return to baseline con-
sciousness [34]. Generalized tonic–clonic seizures (GTCSs) or motor
simple partial seizures (SPSs) were included in the definition.
Nonconvulsive status epilepticus (NCSE) was defined as a change in
mental status from baseline for ≥30 min with ictal discharge on electro-
encephalogram (EEG) [35]. Aphasic status and dyscognitive seizures
were considered to be NCSE, as suggested by Beniczky et al. [36]. No pa-
tients with auras (without motor symptoms) were included in the study.
Seizure cessation was considered when all types of clinical and elec-
troencephalographic seizures disappeared. Seizures in patients were
deemed to have a positive response to lacosamide when it was the
last drug administered before seizure cessation (although it should be
considered that when lacosamide was given as third-line or higher,
the effect might be due to a combination of all medications given).
The response rate was defined as the percentage of patients in whom
seizures were stopped, with lacosamide being the last AED to be used.
The response rate in b24 h was the percentage of patients in whom
seizures were stopped in b24 h, with lacosamide being the last AED to
be used.
2.4. Data source and collection
The source of data was the individual patient records of clinical
information collected at each center by the participating physicians.
The following data were entered into a database: demographic data,
seizure type, etiology, for patients with previous epilepsy — age at onset
146 M. Garcés et al. / Epilepsy & Behavior 36 (2014) 144–152

and AEDs used at the moment of admission, treatment given for SE or
ARSs (specific AEDs and the order used if more than one), latency
time from seizure onset (defined as first clinical or electroencephalo-
graphic seizure recorded in the clinical chart) to treatment initiation
(any AED), latency time from seizure onset to IV lacosamide infusion,
time from IV lacosamide initiation to seizure cessation, IV lacosamide
dosage (loading and maintenance), and side effects.
Electroencephalogram and blood tests were performed routinely in
clinical practice in these patients throughout the treatment process. In
all patients, an electrocardiogram (ECG) was also performed before IV
lacosamide infusion in order to identify and exclude those with existing
second- or third-degree atrioventricular block (AVB) in whom
lacosamide was contraindicated.
2.5. Data analysis
The primary study objective was to assess the effectiveness of IV
lacosamide in emergency situations and in patients with SE or ARSs,
and the secondary study objective was to assess the tolerability of IV
lacosamide in the same situation.
The primary efficacy variable was seizure cessation with lacosamide
assessed by response rate (the percentage of patients with SE or ARSs in
whom seizures were controlled [i.e., stopped], with lacosamide being
the last AED to be used). The secondary efficacy variable was seizure
cessation within 24 h with lacosamide, assessed as response rate
b24 h (percentage of patients with SE and ARSs in whom seizures
were controlled within 24 h of IV lacosamide initiation, with
lacosamide being the last AED to be used), and the association between
time from seizure onset to IV lacosamide initiation and time from IV
lacosamide initiation to seizure cessation (and seizure cessation in
b24 h).
Some exploratory analyses of efficacy data were also conducted to
determine the relationship (if any) between efficacy achieved with
lacosamide therapy and selected items: lacosamide administration
order (as first-line, second-line therapy, etc.), mechanism of action
(MoA) of concomitant AED therapy prior to lacosamide infusion, seizure
type, and lacosamide loading and maintenance doses used.

Table 1
Characteristics of the study population.

Characteristicsa All patients SE ARS

(n = 98) (n = 55) (n = 43)

Female gender n (%) 56 (57.1) 34 (61.8) 22 (51.2)

Age (years), mean (range) 59.8 (18–91) 65.1 (18–90) 53.0 (27–91)
Previous history of epilepsy, n (%) 48 (49) 23 (41.8) 25 (58.1)
Age (years) at epilepsy onset, mean (SD) 35.7 (28.3) 43.6 (29.8) 28.4 (25.4)
Time (years) since epilepsy onset, mean (SD) 18 (17.6) 15.3 (18.5) 20.4 (16.7)

Epilepsy type (in 48 patients with previous history of epilepsy)

Generalized 5 (10.4) 1 (4.3) 4 (16.0)
Focal 43 (89.6) 22 (95.7) 21 (84.0)
Frontal 5 (10.4) 3 (13.0) 2 (8.0)
Temporal 8 (16.7) 1 (4.3) 7 (28.0)
Parietal 5 (10.4) 3 (13.0) 2 (8.0)
Occipital 0 (0) 0 (0) 0 (0)
Lobe unknown 25 (52.1) 15 (6.2) 10 (40.0)
Number of AEDs before SE/ARSs in patients with preexisting epilepsy median (range) 2 (0–5) 1 (0–4) 2 (1–5)

Type of seizure (in all patients)

NCSE/CPS 56 (57.1) 43 (78.2) 13 (30.2)
CSE (GTCS)/GTCS 25 (25.5) 5 (9.1) 20 (46.5)
CSE (motor SPS)/motor SPS 17 (17.3) 7 (12.7) 10 (23.3)

Etiology, n (%)
Preexisting epilepsy 48/98 (49) 23/55 (41.8) 25/43 (58.1)
Symptomatic 37 (37.7) 21 (38.1) 15 (34.8)
Vascular 16 (16.3) 11 (20) 5 (11.6)
Brain infection 7 (7.1) 2 (3.6) 5 (11.6)
Trauma 4 (4.1) 4 (7.3) 0 (0.0)
Cortical developmental malformation 4 (4.1) 2 (3.6) 1 (2.3)
Mesial temporal sclerosis 2 (2.0) 1 (1.8) 1 (2.3)
Tumor 2 (2.0) 1 (1.8) 1 (2.3)
Encephalopathy 2 (2.0) 0 (0) 2 (4.7)
Cryptogenic 11 (11.2) 2 (3.6) 9 (21.0)
Drug withdrawal/noncompliance (regardless of etiology) 10 (10.2) 3 (5.4) 7 (16.2)
New-onset epilepsy (initial presentation) 50 (51) 32 (58.2) 18 (41.8)
Acute symptomatic 29 (29.6) 19 (34.5) 10 (23.3)
Tumor 7 (7.1) 4 (7.3) 3 (7.0)
Brain infection 6 (6.1) 4 (7.3) 2 (4.7)
Vascular 5 (5.1) 3 (5.5) 2 (4.7)
Anoxia 3 (3.1) 3 (5.5) 0 (0.0)
Metabolic 3 (3.1) 2 (3.6) 1 (2.3)
Autoimmune 2 (2.0) 2 (3.6) 0 (0.0)
Toxic 2 (2.0) 1 (1.8) 1 (2.3)
Trauma 1 (1.0) 0 (0.0) 1 (2.3)
Remote symptomatic 18 (18.4) 12 (21.8) 6 (14.0)
Vascular 15 (15.3) 11 (20.0) 4 (9.3)
Brain infection 2 (2.0) 1 (1.8) 1 (2.3)
Tumoral 1 (1.0) 0 (0.0) 1 (2.3)
Unknown 3 (3.1) 1 (1.8) 2 (4.7)

AED, antiepileptic drug; ARS, acute repetitive seizure; GTCS, generalized tonic–clonic seizure; CPS, complex partial seizure; CSE, convulsive status epilepticus; NCSE, nonconvulsive status
epilepticus; SD, standard deviation; SE, status epilepticus; SPS, simple partial seizure.
a
Data are n (%) unless stated otherwise.
 M. Garcés et al. / Epilepsy & Behavior 36 (2014) 144–152 147

For the MoA analysis, patients were divided into sodium channel
blocker groups (SCB + and non-SCB [SCB −]). SCB + included those
who took at least one sodium channel blocker (phenytoin, carbamaze-
pine, oxcarbazepine, lamotrigine, and eslicarbazepine acetate) prior to
lacosamide. SCB− included patients who took any other AED. Antiepi-
leptic drugs in patients with prior epilepsy were also considered.
For the analysis of lacosamide loading/maintenance doses used, the
population was divided into two groups: those who received a
lacosamide loading dose/maintenance dose of ≤ 200 mg and those
given doses of N 200 mg.
Safety variables included the proportion of patients with an adverse
event and the proportion with an adverse event leading to discontinua-
tion. Only adverse events considered to be related to lacosamide by
participating physicians were included in the analysis.
2.6. Statistical analysis
A descriptive analysis was performed in all the variables studied. A
chi-square test or Fisher's exact test was used to evaluate relationships
between efficacy and other variables as necessary: lacosamide adminis-
tration order, MoA of concomitant therapy, seizure type, and
lacosamide loading and maintenance dose. The Spearman correlation
coefficient was used to study the association between time from seizure
onset to lacosamide initiation and time from lacosamide initiation to
seizure cessation (and seizure cessation in b 24 h). A multivariate logis-
tic regression model analysis was performed using the response of the
patient as dependent variable and factors with a p value b0.25 in the bi-
variate analysis as the independent variables.
The Statistical Package for Social Science version 19.0 (IBM Corpora-
tion) was used. Statistical significance was defined as p b 0.05.
3. Results
3.1. Patients
Demographics and disease characteristics of the study population
are summarized in Table 1.
Ninety-eight patients met the criteria for inclusion in the study.
Fifty-five patients were diagnosed with SE, and 43 patients were di-
agnosed with ARSs. Of 98 patients in the whole group, 48 (49%) had a
previous diagnosis of epilepsy and received a median of two AEDs.
Most of the patients with SE had NCSE (78.2%), while the remaining
21.8% had CSE. From this group, 12.7% of the patients had motor simple
partial seizures (SPSs), and 9.1% of the patients had generalized tonic–
clonic seizures (GTCSs).
In patients with ARSs, 20 (46.5%) patients had GTCSs, 13 (30.2%) pa-
tients had complex partial seizures (CPSs), and 10 (23.3%) had motor
SPSs.
Regarding etiology, patients were classified into those with
preexisting epilepsy and new-onset epilepsy (i.e., the emergency situa-
tion was the onset of epilepsy). Among this latter group, patients were
classified into those with acute symptomatic etiology (seizures occur-
ring at the time of a systemic insult or in close temporal association
with a documented brain insult) and remote symptomatic etiology
(when the insult was a preexisting condition prior to seizure onset)
[37]. The different etiologies in each group are included in Table 1.
The mean latency period from seizure onset to initiation of any AED
treatment or IV lacosamide in patients with SE and ARSs is shown in
Table 2. The mean and median loading and maintenance doses of IV
lacosamide used in patients with SE and ARSs are shown in Table 2.
The order of IV lacosamide use is shown in Table 2. Drugs adminis-
tered prior to lacosamide and the doses of the two most frequent

Table 2
Lacosamide (LCM) treatment latency, dosing, order of administration, response to treatment, and mortality in patients with status epilepticus (SE) and acute repetitive seizure (ARS).

Total SE ARS
(n = 98) (n = 55) (n = 43)

Treatment latency (h) from seizure onset to start of any AED therapy
Mean (SD) 14.8 (36.1) 11.1 (14.3)
Median (range) 4 (0.1–240) 5 (0.5–640)

Latency (h) from onset of SE/ARS to start of IV LCM therapy

Mean (SD) 74.2 (122.1) 52.7 (76.7)
Median (range) 22 (0.9–552) 24 (1–365)

LCM dose, mg (mean/median, range)

Loading dose 190.9/200 (50–400) 187.2/200 (50–400)
Daily maintenance dose 217.7/200 (50–400) 202.3/200 (100–400)

Order of IV LCM, n (%)

LCM as first-line therapy 7 (7.1) 1 (1.8) 6 (14)
LCM second 41 (41.8) 22 (40) 19 (44.2)
LCM third 31 (31.6) 19 (34.5) 12 (27.9)
LCM fourth 10 (10.2) 8 (14.5) 2 (4.7)
LCM fifth 5 (5.1) 1 (1.8) 4 (9.3)
LCM sixth 4 (4.1) 4 (4.1) 0 (0)

Response data (with IV LCM as last AED administered), n (%)

Cessation of seizures after IV LCM 75 (76.5) 39 (70.9) 36 (83.7)
Cessation of seizures b24 h after IV LCM 56 (57.1) 27 (49.1) 29 (67.4)

No seizures after IV LCM by treatment order, n/N (%)

LCM as first-line therapy 5/7 (71.4) 0/1 (0) 5/6 (83.3)
LCM second 31/41 (75.6) 17/22 (77.3) 14/19 (73.7)
LCM third 22/31 (71) 11/19 (57.9) 11/12 (91.7)
LCM fourth 8/10 (80) 6/8 (75) 2/2 (100)
LCM fifth 5/5 (100) 1/1 (100) 4/4 (100)
LCM sixth 4/4 (100) 4/4 (100) –
Further AED therapy needed to control seizures 23 (23.4) 16 (29) 7 (16.2)
Seizures controlled with another AED 18 (18.4) 12 (21.8) 6 (14)
Seizures not controlled 5 (5.1) 4 (7.3) 1 (2.3)
Overall mortality 16 (16.3) 11 (20) 5 (11.6)
Mortality + seizures not controlled 5 (5.1) 4 (7.3) 1 (2.3)

AED, antiepileptic drug; ARS, acute repetitive seizure; IV, intravenous; LCM, lacosamide; SD, standard deviation; SE, status epilepticus.
148 M. Garcés et al. / Epilepsy & Behavior 36 (2014) 144–152

Table 3 Table 5
Antiepileptic drugs (AEDs) administered prior to lacosamide and the doses of the two Patients achieving a response according to latency from lacosamide administration to
most frequent AEDs used before lacosamide (levetiracetam [LEV] and benzodiazepine seizure cessation in patients with status epilepticus (SE) and acute repetitive seizure
[BZD]). (ARS).

Treatment All patients SE ARS Latency time, hours Patients achieving a response, n (%)
(n = 98) (n = 55) (n = 43)
SE ARS Total
Treatment before LCM, n (%)
≤2 10 (25.6) 14 (38.9) 24 (32.0)
Benzodiazepine 44 (44.8) 28 (50.9) 16 (37.2)
2–6 5 (12.8) 4 (11.1) 9 (12.0)
LEV 79 (80.6) 47 (85.4) 32 (74.4)
6–24 12 (30.8) 11 (30.6) 23 (30.7)
PHT 19 (19.3) 14 (25.4) 5 (11.6)
N24 12 (30.8) 7 (19.4) 19 (25.3)
VPA 18 (18.3) 9 (16.3) 9 (20.9)
Total 39 (100.0) 36 (100.0) 75 (100.0)
Other AEDs 10 (10.2) 4 (7.2) 6 (13.9)
Anesthesia 2 (2.0) 2 (3.6) 0 (0) ARS, acute repetitive seizure; SE, status epilepticus.

BZD and LEV doses before LCM, mean loading dose, mg (range)
DZP 7.6 (2–11) 7.7 (2–11) 7.5 (3–10)
CNZ 1.2 (0.5–3) 1.3 (0.5–3) 1.0 (0.5–2)
LEV 1101.2 (500–2000) 1114.5 (500–2000) 1080.6 (500–2000)
AED, antiepileptic drug; ARS, acute repetitive seizure; CNZ, clonazepam; DZP, diazepam;
LCM, lacosamide; LEV, levetiracetam; PHT, phenytoin; SE, status epilepticus; VPA, valproic
acid.
AEDs used before lacosamide (LEV and BZD) are shown in Table 3. Ac-
cording to the recommended treatment protocols for SE [38] and con-
sidering BZDs, PHT, VPA, and LEV as standard IV AEDs available in the
Spanish armamentarium, IV lacosamide was used mainly after the fail-
ure of one or two of these standard IV AEDs in patients in whom no
other IV AEDs were appropriate (not recommended or contraindi-
cated). There was a tendency to use lacosamide earlier in patients
with ARSs than in those with SE (p = 0.087). The reasons for the use
of lacosamide as first-line therapy is summarized in Table 4.
3.2. Efficacy
3.2.1. Response rates
Response rates are shown in Table 2.
The median time from IV lacosamide initiation to cessation of sei-
zures in patients in whom seizures were stopped with lacosamide
was 18 h (mean = 47.3 h, SD = 74.1) in patients with SE and 6.5 h
(mean = 22.1 h, SD = 34.1) in those with ARSs. In the group of patients
in whom seizures were stopped with lacosamide in b24 h, the median
time from IV lacosamide initiation to cessation of seizures was 6 h
(mean = 9.7 h, SD = 9.4) in SE and 3 h in ARSs (mean = 7.9 h, SD =
8.2 h). Patients were stratified by latency from lacosamide administra-
tion to seizure cessation (b2 h, 2–6 h, 6–24 h, and N 24 h). Response
rates according to latency from lacosamide administration to seizure
cessation are shown in Table 5.
3.2.2. Factors influencing response
The response rates (proportion of patients with no seizures after IV
lacosamide administration) according to IV lacosamide order are
shown in Table 2. Regarding the order of administration, in patients
receiving IV lacosamide as first-/second-line treatment versus those
receiving it as third-line or later treatment, no statistically significant
differences were observed (SE = 73.9% versus 68.8%, p = 0.678 and
ARSs = 76% versus 94%, p = 0.209). However, in the previous compar-
ison, overall results in SE were numerically better in the early stages of
the treatment.
In the 75 patients of the whole group in whom the seizures
were controlled, there is a positive association between treatment IV
lacosamide latency (time from symptom onset to IV lacosamide
initiation) and time from IV lacosamide initiation to seizure cessation
(ro = 0.310; p = 0.007). The same results were obtained when seizure
cessation within 24 h was considered (ro = 0.265; p = 0.049); ro =
Spearman correlation. Consequently, the sooner the onset of IV
lacosamide, the faster the seizure cessation.
Regarding the MoA of concomitant therapies used, SCB+ included
38 patients, and SCB − included 57 patients. Three patients in whom
lacosamide IV was used as first-line treatment were excluded from
the analysis: two patients who did not take prior AEDs and one patient
who discontinued medication prior to hospital admission. In SE, sei-
zures in 70% of the SCB+ group responded to IV lacosamide versus sei-
zures in 71.4% of the SCB− group (p = 0.911). In patients with ARSs,
there was a tendency towards a greater response rate in the SCB −
group: seizures in 72.2% of SCB+ patients responded to lacosamide ver-
sus seizures in 95.5% of SCB− patients (p = 0.073).
Regarding seizure type, of patients with SE, 1/5 (20%) with GTCSs, 6/
7 (85.7%) with motor SPSs, and 32/43 (74.4%) with NCSE achieved a re-
sponse (seizure cessation with lacosamide). When SE with GTCSs was
compared with NCSE, the difference in response rates was statistically
significant (p = 0.028) in favor of NCSE. There was a trend towards a
better response in motor SPSs compared with GTCSs (p = 0.072).
In patients with ARSs, 18/20 (90%) patients with GTCSs, 6/10 (60%)
patients with motor SPSs, and 12/13 (92.3%) patients with CPSs
achieved a response. No statistically significant differences were ob-
served among the different groups when they were compared.
The analysis according to lacosamide loading and maintenance
dose showed no statistically significant difference in response rates
(proportion of patients with seizure cessation with IV lacosamide)
with ≤ 200-mg and N 200-mg doses in SE or ARSs, although response
rates were numerically higher with the N200-mg doses (Table 6).

Table 4
Reasons for using lacosamide (LCM) and avoiding benzodiazepine (BZD) as first-line therapy.

Total SE ARS

Reasons to use LCM as first-line therapy

Treatment change (preexisting epilepsy and LCM suitability) 3 0 3
Epilepsy resistant to drugs, prior baseline treatment with high dose of BZD and failure or allergy to other IV options in the past 1 1 0
Comorbidity (age, hepatopathy, chronic serious obstructive pulmonary disease, serious psychiatric comorbidity) 3 0 3

Reasons to avoid BZD as first-line therapy

Old age and low level of consciousness 13 7 6
Serious obstructive pulmonary disease 15 10 5
Prior baseline treatment with high-dose BZD 3 3 0
Treatment change (preexisting epilepsy and LCM suitability) 3 0 3
Search of a prolonged effect 20 7 13

BZD, benzodiazepine; IV, intravenous; LCM, lacosamide.

 M. Garcés et al. / Epilepsy & Behavior 36 (2014) 144–152 149

Table 6 small percentage of patients with CSE treated with IV lacosamide. In

Responses (defined as seizure cessation with lacosamide being the last antiepileptic drug the ARS subgroup, lacosamide use was comparable among the different
to be used) achieved according to lacosamide loading dose and maintenance doses of
≤200 mg and N200 mg in patients with status epilepticus (SE) and acute repetitive
types of seizures. Intravenous lacosamide was mainly used after failure
seizure (ARS). of one or two standard IV AEDs recommended by current protocols or
when it was not possible to use standard IV AEDs because they were
Dose Response, n/N (%)
contraindicated or not recommended by the patient profile (comorbid-
SE ARS ity, allergy, and side effect risk). Consequently, lacosamide was used
≤200 mg N200 mg ≤200 mg N200 mg predominantly as second- or third-line treatment in the emergency
Loading 36/51 (70.6) 3/4 (75.0)⁎ 31/38 (81.6) 5/5 (100)⁎⁎
situation in our series.
Maintenance 31/45 (68.9) 8/10 (80.0)⁎⁎⁎ 28/35 (80.0) 8/8 (100)⁎⁎⁎⁎ Levetiracetam was the IV AED most often administered before IV
lacosamide alone or after BZD (47 (85.4%) of 55 in SE and 32 (74.4%)
ARS, acute repetitive seizure; SE, status epilepticus.
⁎ p = 1.0. of 43 in ARSs). Similar findings have been documented in previous ret-
⁎⁎ p = 0.572. rospective studies [21–24,27,30,39–41]. Pooling the results of these
⁎⁎⁎ p = 0.484. studies shows that the majority (81.2% [108/133]) used LEV before IV
⁎⁎⁎⁎ p = 0.167.
lacosamide. In other studies with a high number of patients, LEV was
used before lacosamide in 22/48 (45%) in the study by Hofler et al.
[22] and 33/39 (84%) in the study by Kellinghaus et al. [23]. Benzodiaz-
Multiple logistic regression analyses were used to identify predictive epine use was lower in our study, used in 44.8% (44 of 98) of patients
factors of patients' response. Although the effect of different factors was compared with 83.4% (111/133) in the overall population of the pooled
observed individually, the logistic regression analysis did not yield any population previously mentioned, which varied widely between 40 and
valid multivariate results. 100%. Hofler et al. [22] used BZD prior to lacosamide in 37/48 (77%) and
the corresponding number was 37/39 (94%) in the study by Kellinghaus
3.3. Adverse events et al. [23]. In our series, most of the patients in whom BZDs were not
used before lacosamide were elderly and had a low level of conscious-
The most frequent adverse events are shown in Table 7. Adverse ness, used high-dose BZDs in their prior baseline treatment, or had seri-
events associated with lacosamide were reported by or observed in 15 ous respiratory diseases. Although the guidelines recommend the use of
(15.3%) patients: 8 (14.5%) patients with SE and 7 (16.3%) patients with first-line BZDs [8], the patient characteristics together with the presence
ARSs. Four (4.1%) patients had to withdraw because of adverse events — of a less serious condition, such as NCSE or ARS, led physicians to avoid
2 (3.6%) patients in SE and 2 (4.7%) patients with ARSs. Adverse events BZDs and to choose other options in order to avoid sedation (elderly
leading to discontinuation were diplopia (1 patient), AVB (1 patient), patients with low level of consciousness or serious respiratory diseases)
PR prolongation (1 patient), and vomiting and dizziness (1 patient). or tolerance (prior high-dose BZDs) associated with BZDs [23,42]. More-
One 77-year-old patient with ischemic cardiomyopathy had asymp- over, the lack of an IV BZD such as lorazepam with a longer intracerebral
tomatic PR interval prolongation after infusion of 200 mg IV lacosamide half life in the Spanish armamentarium and the fact that a more
for NCSE. No concomitant dromotropic agents (products that affect the prolonged effect (sometimes difficult to achieve with available BZDs
conduction speed of the AV node) were administered, and BZD, LEV, without producing a higher sedation risk) was prioritized in a few
and VPA were used prior to lacosamide. The PR interval returned to nor- patients may be an additional explanation for the use of other AEDs differ-
mal after reduction of the lacosamide dose. ent from BZDs as first-line treatment in some patients. In any case, while
A third-degree AVB was detected after two 200-mg doses were ad- the lower use of BZDs compared with other series can be considered a
ministered for NCSE in a 78-year-old man with ischemic cardiopathy. limitation of the study; rather, it reflects in a retrospective way what
This patient was also treated with a beta blocker (bisoprolol) and a cal- physicians consider to be the most appropriate option in the emergency
cium channel blocker (amlodipine), and LEV was previously adminis- setting, considering guideline recommendations and patient condition.
tered. Given that lacosamide was effective in this patient, it was In the current study, the response rate was 76.5% of all patients
withdrawn and later reintroduced after a pacemaker was implanted. (70.9% in SE and 83.7% in ARSs). The response rate in b 24 h, in terms
of SE/ARS cessation within 24 h of IV lacosamide administration, was
4. Discussion 57.1% (49.1% in SE and 67.4% in ARSs). The overall efficacy of this
study is in line with previously published data. In a retrospective analy-
The current study analyzes IV lacosamide use and effectiveness in a sis of patients with epilepsy treated with IV lacosamide, the overall suc-
large cohort of patients with SE or ARSs of varying severity, type, and cess rate documented in 10 single case reports and 9 small case series
etiology in the emergency setting. Analysis of patients with SE shows was 56% (76/136) [32], with a wide range of response rates reported
a tendency to use IV lacosamide mainly in patients with NCSE, with a from 0 to 100%. Recently, Santamarina et al. reported findings from a
retrospective, single center uncontrolled observational analysis of effi-
cacy data from 31 patients with SE treated with IV lacosamide in
Table 7 which 67.7% of patients achieved SE cessation [29]. Kellinghaus et al.
Most frequent adverse events occurring with intravenous lacosamide therapy in patients in a population with more refractory seizures reported a 40% SE cessa-
with status epilepticus (SE) and acute repetitive seizure (ARS). tion rate [23] and Hofler et al. [22], in a population closer to the one an-
Adverse event, n (%) SE⁎ ARS⁎ Total⁎ alyzed in our study, showed a success rate of 88%.
In general, factors influencing response to IV lacosamide include
Somnolence 5 (9.1) 3 (7.0) 8 (8.2)
Nausea 2 (3.6) 2 (4.7) 4 (4.1) population characteristics, loading dose of lacosamide, latency from sei-
Dizziness 1 (1.8) 2 (4.7) 3 (3.1) zure onset to IV lacosamide therapy, AEDs used before IV lacosamide,
Diplopia 1 (1.8) 0 (0.0) 1 (1.0) and particular study definition of response to IV lacosamide.
Blurred vision 0 (0.0) 1 (2.3) 1 (1.0)
Loading dose and latency from seizure onset to lacosamide treat-
Vomiting 0 (0.0) 1 (2.3) 1 (1.0)
ECG PR interval prolongation 1 (1.8) 0 (0.0) 1 (1.0) ment seem to be especially important variables influencing the efficacy
AVB 1 (1.8) 0 (0.0) 1 (1.0) of treatment, and these factors may also predict an early response in
ARS, acute repetitive seizure; AVB, atrioventricular block; ECG, electrocardiogram; SE, sta-
patients with SE/ARSs. Recently, Legros et al. found that the 400-mg IV
tus epilepticus. lacosamide loading dose tended to be associated with a higher response
⁎ Multiple adverse events were possible in an individual patient. rate than the 200-mg dose (50% versus 18%; p =0.026) [25]. We also
150 M. Garcés et al. / Epilepsy & Behavior 36 (2014) 144–152
reported a slight tendency towards a higher response when lacosamide
doses N 200 mg were used; however, no significant differences were
detected compared with doses ≤ 200 mg. Furthermore, in our study,
a response was achieved with loading doses ranging from 50 to
400 mg, which is a larger range including lower dosages than the
usual 200- to 400-mg dose ranges used in most previously published
data [22,23,27,39].
The response rates in spite of a lower IV lacosamide dose observed in
our study may be explained by early administration. Patients with SE
and ARSs had a median treatment latency of 22 h and 24 h, respectively,
before they received lacosamide, and the majority (74.5% of the patients
with SE and 72.1% of the patients with ARSs) were treated with
lacosamide as the second- or the third-line AED. Other studies reported
poorer responses with lower dose ranges when associated with delayed
administration. For example, Rantsch et al. reported a responder rate of
20% with an initial dose of 50–100 mg, with lacosamide administered
with a median of 166 h after onset of symptoms [28]. Goodwin et al. re-
ported no response in all nine patients treated with a median initial me-
dian dose of 200 mg (range = 100–300 mg) and a median time from
seizure onset to lacosamide initiation in 2 days [21]. Moreover, seizures
in the population of patients included in our study could be less refrac-
tory compared with seizures in those in previous studies, and, therefore,
our patients may have responded to lower loading and maintenance
doses [26].
A clear relationship has been reported between IV lacosamide order
and response, with demonstrations of decreasing response rates as SE
progresses both in clinical studies [22,23,26] and in animal models
[43]. Results of the current study are not fully in line with these observa-
tions, and, overall, we found no worsening in response to later use of
lacosamide, although results in SE were numerically better in early
stages. However, this difference may be related to the limited number
of patients treated with fourth-, fifth-, and sixth-line lacosamide in
our analysis, which makes them noncomparable with other series.
Moreover, in our study, it remains uncertain in the later stages whether
seizure cessation was due to the new agent or the remote (delayed)
effect of the previously administered drug combined with the last
AED used.
The time from initial lacosamide loading dose to seizure cessation
was assessed in previous lacosamide studies [22,23]. A rapid response
and cessation of seizures, as quickly as possible, are critical in treating
patients with SE to prevent brain damage [44]. Legros et al. found that
a higher dose of IV lacosamide was associated with a higher proportion
of patients with drug/treatment-refractory SE achieving early SE
cessation (occurring within 3 h of lacosamide initiation) [25]. Recently,
Santamarina et al. observed that a longer time to response with
lacosamide was associated with later lacosamide use [29]. In the current
study, we report a positive association between lacosamide latency
(time from symptom onset to lacosamide initiation) and cessation of
SE/ARSs. This is important in every emergency situation, particularly
in those difficult-to-diagnose cases (for example, NCSE); the earlier
the identification and diagnosis and the quicker the application of an
effective treatment, the better the outcome [45,46].
Rational polytherapy — i.e., the rational combination of AED therapies
based on the MoA — has been studied in an animal model of severe cho-
linergic SE; combination BZD + ketamine and VPA was shown to be
more effective and better tolerated than BZD monotherapy [43]. Rational
polytherapy with adjuvant lacosamide has been previously assessed in
patients with epilepsy, suggesting a synergistic effect when lacosamide
is combined with a non-SCB AED [47].
Correspondingly, we analyzed response with IV lacosamide accord-
ing to prior AED MoA. Overall, there were no significant differences in
IV lacosamide response in patients receiving prior SCBs or non-SCBs.
Analysis of SE and ARS subgroups according to the prior AED MoA
showed a similar pattern in patients with SE versus the overall popula-
tion, but, in ARSs, a tendency towards a higher response was observed
in those receiving prior non-SCB AEDs versus SCB AEDs. Larger studies
are necessary to confirm these results and to find the most suitable com-
binations in emergency situations.
The frequency and nature of adverse events observed in our retro-
spective analysis were in line with those reported in other studies [22].
The overall rate was low and the most frequently reported adverse events
were somnolence, dizziness, and nausea. We detected one patient with
an isolated and asymptomatic PR interval prolongation. In clinical trials
of lacosamide, mild cardiac adverse events, such as dose-dependent PR
interval prolongation and first-degree AVB, have been reported with
oral lacosamide [16,48,49] and IV lacosamide [20] in patients with epilep-
sy and diabetic neuropathy. All these cases were asymptomatic and had
increases and subsequent decreases in PR interval. Major cardiac adverse
events reported with lacosamide in the literature are very infrequent
and include atrial fibrillation/flutter at relatively high dosages of oral
lacosamide at 600 mg/day [48,50] and second- and third-degree AVBs.
In particular, in a 45-year-old patient, second-degree AVB was caused
by the addition of oral lacosamide to carbamazepine [51]. Krause et al. re-
ported third-degree AVB and paroxysmal asystole after accidental
administration of high-dose IV lacosamide in an 89-year-old patient
with heart insufficiency and a low glomerular filtration rate who was tak-
ing two other negative dromotropic agents [52]. We reported one major
cardiac adverse event in a patient with a similar profile — a patient with
cardiopathy treated with the same negative dromotropic agents —
consistent with this observation. Data from two clinical trials in which pa-
tients were treated with PHT alone showed that 6.9% [10] and 14.2% [12]
of patients had cardiac rhythm disturbances, a much higher rate com-
pared with that reported with lacosamide [20]. Atrioventricular block
has also been reported with drugs with a totally different MoA, such
as pregabalin [53]. As cardiac injury is associated with severe drug/
treatment-refractory SE [54], it can be difficult, in some cases, to
separate cardiac events related to the AED from those possibly caused
by or related to the patient's condition.
Finally, mortality in our series was lower (16.3%) than that reported
by Legros et al. [25] (28%); however, seizures in the population included
in this study were less refractory and with a different baseline condition.
Limitations of this study include its retrospective observational
design, a source of many different types of potential bias due to the unse-
lected patient population, less stringent clinical management compared
with a controlled clinical study, and lack of blinding. Because of the retro-
spective nature of the study, subgroups were not homogeneous with re-
gard to sample size or demographic and clinical characteristics (i.e.,
patients in different stages of SE), and subgroup analyses were performed
on small patient numbers, thus reducing the robustness of the data and
hindering interpretation of the findings. Moreover, unexpected adverse
events could have not been fully assessed, as it is a retrospective review.
Finally a lower proportion of patients than in other studies used BZDs as a
first-line treatment, and this could have affected the results of the study.
Study strengths include the large patient population and the real-life
clinical setting patients showing IV lacosamide effectiveness and safety
in a wide range of patient types, including less refractory cases com-
pared with those included in previous papers. Moreover, factors related
to lacosamide response have been analyzed in a large series.
5. Conclusion
In conclusion, our study data show that IV lacosamide resulted in
cessation of seizures in SE and ARSs in most of the patients and was
well tolerated. The time from seizure onset to IV lacosamide influenced
treatment response significantly. Regarding the MoA of prior concomi-
tant AEDs, in patients with ARS, there was a tendency towards a better
response with IV lacosamide in those with a prior non-SCB AED.
These findings are particularly relevant given that there are still rela-
tively few suitable IV AEDs for use in some patients with acute condi-
tions, especially those allowing for tailoring of treatment to the
individual patient's condition and profile. The availability of new effec-
tive and safe AEDs is of crucial importance. In the absence of randomized
 M. Garcés et al. / Epilepsy & Behavior 36 (2014) 144–152
prospective controlled studies assessing efficacy, effective dose, and safe-
ty of IV lacosamide in these situations and considering the limitations of
this study and the varied severity of the epilepsy conditions, our observa-
tions suggest that IV lacosamide may be a potentially effective alterna-
tive for treatment of SE/ARSs when standard AEDs fail (late stages) or
are not recommended (earlier stages). Although IV lacosamide seems
to be a safe AED, caution must be exercised when administering in
patients who are also receiving dromotropic agents.
Funding
No financial support was received for this work.
Acknowledgments
Medical writing assistance was provided by Mary Hines in Science
Communications, Springer Healthcare. We also thank Patricia Santagueda
for conducting the statistical analyses.
Disclosure and conflicts of interest
Two patients included in this study were also included in the study
by Miro J, Toledo M, Santamarina E, et al. Efficacy of intravenous
lacosamide as an add-on treatment in refractory status epilepticus: a
multicentric prospective study. Seizure 2013;22(1):77-9.
Dr. Garcés has participated in pharmaceutical industry-sponsored
symposia for Eisai Inc. and UCB.
Dr. Villanueva has participated in advisory boards and pharmaceuti-
cal industry-sponsored symposia for Eisai Inc., UCB, Merck Sharp &
Dohme, Bial, Pfizer, and GlaxoSmithKline (GSK).
Dr. Mauri has received honoraria from UCB, Bial, Eisai Inc., GSK, and
Pfizer.
Dr. López has participated in advisory boards and pharmaceutical
industry-sponsored symposia for Eisai Inc., UCB, Bial, and GSK.
Dr. Rodríguez has participated in pharmaceutical industry-
sponsored symposia for EISAI Inc., UCB, BIAL, and GSK.
Dr. Suller, Dr. Garcia, Dr. Fernández, Dr. Piera, Dr. Guillamón, Dr.
Santafé, Dr. Castillo, Dr. Giner, Dr. Torres, Dr. Escalza, Dr. del Villar, Dr.
Garcia de Casasola, Dr. Bonet, Dr. Noé, and Dr. Olmedilla have no con-
flicts of interest to declare.
References
[1] Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med 1998;338(14):970–6.
[2] Coeytaux A, Jallon P, Galobardes B, Morabia A. Incidence of status epilepticus in
French-speaking Switzerland: (EPISTAR). Neurology 2000;55(5):693–7.
[3] DeLorenzo RJ, Hauser WA, Towne AR, Boggs JG, Pellock JM, Penberthy L, et al. A pro-
spective, population-based epidemiologic study of status epilepticus in Richmond,
Virginia. Neurology 1996;46(4):1029–35.
[4] Novy J, Logroscino G, Rossetti AO. Refractory status epilepticus: a prospective obser-
vational study. Epilepsia 2010;51(2):251–6.
[5] Aranda A, Foucart G, Ducasse JL, Grolleau S, McGonigal A, Valton L. Generalized con-
vulsive status epilepticus management in adults: a cohort study with evaluation of
professional practice. Epilepsia 2010;51(10):2159–67.
[6] Holtkamp M, Othman J, Buchheim K, Meierkord H. Predictors and prognosis of
refractory status epilepticus treated in a neurological intensive care unit. J Neurol
Neurosurg Psychiatry 2005;76(4):534–9.
[7] Mitchell WG. Status epilepticus and acute repetitive seizures in children, adolescents,
and young adults: etiology, outcome, and treatment. Epilepsia 1996;37(Suppl. 1):
S74–80.
[8] Meierkord H, Boon P, Engelsen B, Gocke K, Shorvon S, Tinuper P, et al. EFNS guideline
on the management of status epilepticus in adults. Eur J Neurol 2010;17(3):348–55.
[9] Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, et al. Guidelines for
the evaluation and management of status epilepticus. Neurocrit Care 2012;17(1):
3–23.
[10] Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, et al. A compar-
ison of four treatments for generalized convulsive status epilepticus. Veterans Affairs
Status Epilepticus Cooperative Study Group. N Engl J Med 1998;339(12):792–8.
[11] Shorvon S. Clinical trials in acute repetitive seizures and status epilepticus. Epileptic
Disord 2012;14(2):138–47.
[12] Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin in status epilepticus: a
pilot study. Neurology 2006;67(2):340–2.
151
[13] Aiguabella M, Falip M, Villanueva V, de la Pena P, Molins A, Garcia-Morales I, et al.
Efficacy of intravenous levetiracetam as an add-on treatment in status epilepticus:
a multicentric observational study. Seizure 2011;20(1):60–4.
[14] Hottinger A, Sutter R, Marsch S, Ruegg S. Topiramate as an adjunctive treatment in
patients with refractory status epilepticus: an observational cohort study. CNS
Drugs 2012;26(9):761–72.
[15] UCB Pharma SA. Vimpat 10 mg/mL solution for infusion: summary of product char-
acteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_
Product_Information/human/000863/WC500050338.pdf; 2008 . [Accessed Nov 5
2013].
[16] Ben-Menachem E, Biton V, Jatuzis D, Abou-Khalil B, Doty P, Rudd GD. Efficacy and
safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures.
Epilepsia 2007;48(7):1308–17.
[17] Chung S, Sperling MR, Biton V, Krauss G, Hebert D, Rudd GD, et al. Lacosamide as ad-
junctive therapy for partial-onset seizures: a randomized controlled trial. Epilepsia
2010;51(6):958–67.
[18] Halasz P, Kalviainen R, Mazurkiewicz-Beldzinska M, Rosenow F, Doty P, Hebert D,
et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results
from a randomized controlled trial. Epilepsia 2009;50(3):443–53.
[19] Biton V, Rosenfeld WE, Whitesides J, Fountain NB, Vaiciene N, Rudd GD. Intravenous
lacosamide as replacement for oral lacosamide in patients with partial-onset sei-
zures. Epilepsia 2008;49(3):418–24.
[20] Krauss G, Ben-Menachem E, Mameniskiene R, Vaiciene-Magistris N, Brock M,
Whitesides JG, et al. Intravenous lacosamide as short-term replacement for oral
lacosamide in partial-onset seizures. Epilepsia 2010;51(6):951–7.
[21] Goodwin H, Hinson HE, Shermock KM, Karanjia N, Lewin III JJ. The use of lacosamide
in refractory status epilepticus. Neurocrit Care 2011;14(3):348–53.
[22] Hofler J, Unterberger I, Dobesberger J, Kuchukhidze G, Walser G, Trinka E. Intrave-
nous lacosamide in status epilepticus and seizure clusters. Epilepsia 2011;52(10):
e148–52.
[23] Kellinghaus C, Berning S, Immisch I, Larch J, Rosenow F, Rossetti AO, et al. Intravenous
lacosamide for treatment of status epilepticus. Acta Neurol Scand 2011;123(2):
137–41.
[24] Koubeissi MZ, Mayor CL, Estephan B, Rashid S, Azar NJ. Efficacy and safety of intra-
venous lacosamide in refractory nonconvulsive status epilepticus. Acta Neurol
Scand 2011;123(2):142–6.
[25] Legros B, Depondt C, Levy-Nogueira M, Ligot N, Mavroudakis N, Naeije G, et al. Intra-
venous lacosamide in refractory seizure clusters and status epilepticus: comparison
of 200 and 400 mg loading doses. Neurocrit Care 2013 [Epub ahead of print].
[26] Miro J, Toledo M, Santamarina E, Ricciardi AC, Villanueva V, Pato A, et al. Efficacy of
intravenous lacosamide as an add-on treatment in refractory status epilepticus: a
multicentric prospective study. Seizure 2013;22(1):77–9.
[27] Mnatsakanyan L, Chung JM, Tsimerinov EI, Eliashiv DS. Intravenous lacosamide in
refractory nonconvulsive status epilepticus. Seizure 2012;21(3):198–201.
[28] Rantsch K, Walter U, Wittstock M, Benecke R, Rosche J. Efficacy of intravenous
lacosamide in refractory nonconvulsive status epilepticus and simple partial status
epilepticus. Seizure 2011;20(7):529–32.
[29] Santamarina E, Toledo M, Sueiras M, Raspall M, Ailouti N, Lainez E, et al. Usefulness
of intravenous lacosamide in status epilepticus. J Neurol 2013;260(12):3122–8.
[30] Cherry S, Judd L, Muniz JC, Elzawahry H, LaRoche S. Safety and efficacy of lacosamide
in the intensive care unit. Neurocrit Care 2012;16(2):294–8.
[31] Kellinghaus C, Berning S, Stogbauer F. Intravenous lacosamide or phenytoin for
treatment of refractory status epilepticus. Acta Neurol Scand 2013. http://
dx.doi.org/10.1111/ane.12174.
[32] Hofler J, Trinka E. Lacosamide as a new treatment option in status epilepticus.
Epilepsia 2013;54(3):393–404.
[33] Commission on Classification and Terminology of the International League Against
Epilepsy. Proposal for revised clinical and electroencephalographic classification of
epileptic seizures. Epilepsia 1981;22(4):489–501.
[34] Lowenstein DH. Status epilepticus: an overview of the clinical problem. Epilepsia
1999;40(Suppl. 1):S3–8 [discussion S21-2].
[35] Holtkamp M, Meierkord H. Nonconvulsive status epilepticus: a diagnostic and ther-
apeutic challenge in the intensive care setting. Ther Adv Neurol Disord 2011;4(3):
169–81.
[36] Beniczky S, Hirsch LJ, Kaplan PW, Pressler R, Bauer G, Aurlien H, et al. Unified
EEG terminology and criteria for nonconvulsive status epilepticus. Epilepsia
2013;54(Suppl. 6):28–9.
[37] Beghi E, Carpio A, Forsgren L, Hesdorffer DC, Malmgren K, Sander JW, et al. Recom-
mendation for a definition of acute symptomatic seizure. Epilepsia 2010;51(4):
671–5.
[38] Shorvon S, Baulac M, Cross H, Trinka E, Walker M. The drug treatment of status
epilepticus in Europe: consensus document from a workshop at the first London
Colloquium on Status Epilepticus. Epilepsia 2008;49(7):1277–85.
[39] Albers JM, Moddel G, Dittrich R, Steidl C, Suntrup S, Ringelstein EB, et al. Intravenous
lacosamide — an effective add-on treatment of refractory status epilepticus. Seizure
2011;20(5):428–30.
[40] Jain V, Harvey AS. Treatment of refractory tonic status epilepticus with intravenous
lacosamide. Epilepsia 2012;53(4):761–2.
[41] Parkerson KA, Reinsberger C, Chou SH, Dworetzky BA, Lee JW. Lacosamide in the
treatment of acute recurrent seizures and periodic epileptiform patterns in critically
ill patients. Epilepsy Behav 2011;20(1):48–51.
[42] Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and
pharmacokinetics. Acta Neurol Scand 2008;118(2):69–86.
[43] Wasterlain CG, Baldwin R, Naylor DE, Thompson KW, Suchomelova L, Niquet J.
Rational polytherapy in the treatment of acute seizures and status epilepticus.
Epilepsia 2011;52(Suppl. 8):70–1.
152 M. Garcés et al. / Epilepsy & Behavior 36 (2014) 144–152
[44] Sutula TP, Hagen J, Pitkanen A. Do epileptic seizures damage the brain? Curr Opin
Neurol 2003;16(2):189–95.
[45] Hillman J, Lehtimaki K, Peltola J, Liimatainen S. Clinical significance of treatment
delay in status epilepticus. Int J Emerg Med 2013;6(1):6.
[46] Young GB, Jordan KG, Doig GS. An assessment of nonconvulsive seizures in the
intensive care unit using continuous EEG monitoring: an investigation of variables
associated with mortality. Neurology 1996;47(1):83–9.
[47] Villanueva V, Lopez FJ, Serratosa JM, Gonzalez-Giraldez B, Campos D, Molins A,
et al. Control of seizures in different stages of partial epilepsy: LACO-EXP,
a Spanish retrospective study of lacosamide. Epilepsy Behav 2013;29(2):
349–56.
[48] Shaibani A, Fares S, Selam JL, Arslanian A, Simpson J, Sen D, et al. Lacosamide in pain-
ful diabetic neuropathy: an 18-week double-blind placebo-controlled trial. J Pain
2009;10(8):818–28.
[49] Wymer JP, Simpson J, Sen D, Bongardt S. Efficacy and safety of lacosamide in diabetic
neuropathic pain: an 18-week double-blind placebo-controlled trial of fixed-dose
regimens. Clin J Pain 2009;25(5):376–85.
[50] Degiorgio CM. Atrial flutter/atrial fibrillation associated with lacosamide for partial
seizures. Epilepsy Behav 2010;18(3):322–4.
[51] Nizam A, Mylavarapu K, Thomas D, Briskin K, Wu B, Saluja D, et al. Lacosamide-
induced second-degree atrioventricular block in a patient with partial epilepsy.
Epilepsia 2011;52(10):e153–5.
[52] Krause LU, Brodowski KO, Kellinghaus C. Atrioventricular block following
lacosamide intoxication. Epilepsy Behav 2011;20(4):725–7.
[53] Aksakal E, Bakirci EM, Emet M, Uzkeser M. Complete atrioventricular block due to
overdose of pregabalin. Am J Emerg Med 2012;30(9):2101 [e1-4].
[54] Hocker S, Prasad A, Rabinstein AA. Cardiac injury in refractory status epilepticus.
Epilepsia 2013;54(3):518–22.