CNS Drugs (2013) 27:321–329
DOI 10.1007/s40263-013-0049-y
ORIGINAL RESEARCH ARTICLE
Safety and Efficacy of Intravenous Lacosamide for Adjunctive
Treatment of Refractory Status Epilepticus: A Comparative
Cohort Study
Raoul Sutter • Stephan Marsch • Stephan Rüegg
Published online: 27 March 2013
Ó Springer International Publishing Switzerland 2013
Abstract
Background Refractory status epilepticus (RSE) is an
emergency with high mortality requiring neurointensive
care. Treatment paradigms include first-generation antiep-
ileptic drugs (AEDs) and anesthetics. Lacosamide (LCM)
is a new AED, holding promise as a potent treatment
option for RSE. High-level evidence regarding safety and
efficacy in the treatment of RSE is lacking.
Objective The objective of the study was to evaluate the
safety profile and efficacy of intravenous (i.v.) LCM as an
add-on treatment in adult RSE patients.
Methods All consecutive RSE patients treated in the
intensive care units (ICUs) of an academic tertiary care
center between 2005 and 2011 were included. Severity of
Electronic supplementary material The online version of this
article (doi:10.1007/s40263-013-0049-y) contains supplementary
material, which is available to authorized users.
R. Sutter
S. Marsch
Clinic for Intensive Care Medicine, University Hospital Basel,
Basel, Switzerland
Present Address:
R. Sutter (&)
Division of Neurosciences Critical Care, Departments of
Anesthesiology, Critical Care Medicine and Neurology, Johns
Hopkins University School of Medicine, 600 N. Wolfe Street,
Meyer 8-140, Baltimore, MD 21287, USA
e-mail: SutterR@uhbs.ch
R. Sutter
S. Rüegg
Division of Clinical Neurophysiology, Department of
Neurology, and Intensive Care Unit, University Hospital Basel,
Basel, Switzerland
status epilepticus (SE) was graded by the SE Severity Scale
(STESS), and SE etiology was categorized according to the
guidelines of the International League Against Epilepsy
(ILAE). Outcomes were seizure control, RSE duration, and
death.
Results Of 111 RSE patients, 53 % were treated with
LCM. Twenty-five patients with hypoxic-ischemic
encephalopathy were excluded. Mortality was 30 %. Mean
number of AEDs, duration, severity, and etiology of SE, as
well as critical medical conditions did not differ between
patients with and without LCM. While age tended to be
higher, critical interventions, such as the use of anesthetics
and mechanical ventilation, tended to be less frequent in
patients with LCM. Seizure control tended to be achieved
more frequently in patients with LCM (odds ratio, OR 2.34,
95 % CI 0.5–10.1, p = 0.252). Among patients with LCM,
51 % received LCM as the last AED (including hypoxic-
ischemic encephalopathy), allowing the reasonable
assumption that LCM was responsible for seizure control,
which was achieved in 91 %. Multivariable analysis
revealed a decreased mortality in patients with LCM (OR
0.34, 95 % CI 0.1–0.9, p = 0.035). A possible confounder
in this context was the implementation of continuous
video-electroencephalography (EEG) monitoring 6 months
prior to the first use of i.v. LCM. There were no serious
LCM-related adverse events.
Conclusion LCM had a favorable safety profile as
adjunctive treatment for RSE. Its use was associated with
decreased mortality of RSE—a finding that might have
been confounded by the implementation of continuous
video-EEG monitoring in the ICU prior to the use of i.v.
LCM, leading to heightened awareness as well as earlier
diagnosis and treatment of SE. Randomized trials are
warranted to further strengthen the evidence of efficacy of
LCM for RSE treatment.
322
1 Introduction
Status epilepticus (SE) is the most severe manifestation of
epilepsy, which requires intensive care. Its incidence ran-
ges from 15 to 20 per 100,000 per year [1, 2]. Several
treatment guidelines for SE suggest a four-step algorithm
depending on the persistence of SE [3–6]. Briefly, benzo-
diazepines are recommended as first-line antiepileptic
drugs (AEDs), followed by one further intravenous (i.v.)
second-line AED if SE persists, such as phenytoin, valproic
acid, a combination of both, or levetiracetam. For further
ongoing seizure activity non-sedating third-line AEDs are
often used, followed by anesthetic drugs to induce a deep
coma titrated at least to burst-suppression or even flat-line
electroencephalography (EEG). However, the latter is only
based on recommendations [7, 8]. Without prompt inter-
ventions, ongoing seizures can cause deleterious neuronal
injury or death [9]. This causality is underscored by the
association of treatment failure and unfavorable prognosis
with increasing SE duration [10]. Failure of first-line AED
and second-line treatment with at least one i.v. AED
defines refractory status epilepticus (RSE) [11], which is
found in up to 43 % of patients with SE and is predomi-
nantly associated with fatal underlying etiologies, severe
impairment of consciousness, and a mortality rate of up to
40 % [12–14]. Therefore, rapid treatment escalation is
essential. The importance of extensive therapeutic inter-
vention in these patients is further emphasized by reported
favorable outcomes after extensive long-term RSE treat-
ment [15]. To date, treatment escalation in RSE remains
challenging as interactions and adverse effects of multiple
co-administrated drugs are hazardous, and effective add-on
treatment options are limited. Thus, novel treatment
options with new targets and additional modes of action
with less adverse effects and risks would be highly
welcome.
Lacosamide (LCM) (SPM 927, formerly harkoseride),
the R-enantiomer of 2-acetamido-N-benzyl-3-methoxy-
propionamide, is a promising new AED approved in 2009
with enteral and i.v. formulations. It has a bimodal action
and almost no interactions. The selective enhancement of
the slow inactivation of voltage-gated sodium channels
may help normalize activation thresholds and decrease
pathophysiological neuronal activity [16, 17]. Uncoupling
of the collapsin-responsive mediator protein-2 from the
presynaptic Ca2? channel complex may contribute to the
decreased neuronal loss [18, 19] and may provide some
neuroprotective effect. LCM has been shown to reduce
seizure frequency in patients with uncontrolled partial-
onset seizures [20] and i.v. LCM has a comparable safety
profile and tolerability to those of oral formulations when
used as replacement therapy for patients with partial-onset
seizures [21]. Aside from induction of atrial flutter,
R. Sutter et al.
reported PQ interval prolongation on the electrocardiogram
(ECG) in a dose-dependent manner and clinically relevant
atrioventricular block, in one case associated with high
doses of LCM [22–24], no severe adverse effects or sig-
nificant laboratory abnormalities were shown to be asso-
ciated with LCM. Interactions of LCM with plasma
concentrations of other AEDs could not be demonstrated
in vivo so far [20]. A few studies reported on LCM for the
treatment of SE [25]. The use of LCM in RSE has been
described in some case reports [26, 27] and smaller case
series [28–30]. Randomized controlled trials on the effi-
cacy of LCM in RSE are lacking and not registered in the
National Institutes of Health (NIH)-sponsored database
(clinicaltrials.org), possibly because of ethical restrictions
in these critically ill patients.
The aim of this study was to explore the feasibility,
efficacy, safety profile, and effect on outcome of i.v. LCM
in a large cohort of critically ill adult patients suffering
from RSE.
2 Methods
2.1 Setting and Study Design
This retrospective comparative cohort study was performed
at the University Hospital Basel (Switzerland), a tertiary
care center with more than 4,000 intensive care unit (ICU)
admissions per year. On the basis of the hospital’s policy,
all patients with SE were treated in the ICU. The study was
approved by the local ethics committee in accordance with
the standards laid down in the 1975 Declaration of Hel-
sinki, as revised in 2000 (World Medical Association
Declaration of Helsinki 2000). The requirement for
informed consent was waived.
2.2 Patients and Data Collection
We identified all consecutive adult patients with RSE in the
medical, cardiac, and surgical ICUs between January 2005
and December 2011 by searching the medical records and
the EEG database of the University Hospital Basel. All
RSE patients had to have no prior treatment with i.v. LCM.
We decided to present the individual detailed information
of all patients who received LCM, including patients with
hypoxic-ischemic encephalopathy as electronic supple-
mental material, as we believe that treatment experience in
this distinct group should not be withheld. However, we
excluded them from all multivariable analyses, as this
etiology of RSE is considered to be different from other
causes, owing to the largely irreversible brain damage and
poor outcome [31–34]. At our institution, treatment of SE
was standardized according to the guidelines of the Swiss
Lacosamide for Refractory Status Epilepticus
Status Epilepticus Consensus Conference from 2005 [3,
35]. Briefly, benzodiazepines were applied as first-line
AEDs when there was high suspicion of SE or immediately
after SE diagnosis, followed by one further i.v. second-line
AED if SE persisted, such as phenytoin, valproic acid, a
combination of both, or levetiracetam. Anesthetics or non-
sedating third-line AEDs were applied after failure of first-
and second-line AEDs. LCM was administered after failure
of first- and second-line AEDs and in selected patients as
the second drug, based on the treating neurologist’s judg-
ment. In 2009 i.v. LCM was introduced as an add-on AED
for the treatment of SE in our hospital. No patients with SE
were treated with LCM before April 2009. Of note, while
not all patients with SE were treated with LCM, all con-
secutive patients with RSE were treated with LCM as an
add-on AED from May 2009 to December 2011. i.v. LCM
twice a day with 200 mg per application without an initial
‘loading dose’. Patients with renal failure received 150 mg
twice daily (b.i.d.) (creatinine clearance 30–50 ml) or
100 mg b.i.d. (creatinine clearance less than 30 ml); one
obese patient (110 kg) was treated with 600 mg per day.
Aside from characteristics that allow gradation of SE
severity and duration (as mentioned in Sect. 2.3), etiologies
of RSE [including hypoxic-ischemic encephalopathy],
critical medical conditions, such as infections during SE,
information from continuous ECG monitoring during the
ICU stay, mechanical ventilation, and the use of anesthetic
drugs during SE were compiled for all patients. Data on the
exact sequential arrangement of all AEDs and i.v. anes-
thetic drugs were assessed for all patients treated with and
without LCM.
2.3 Status Epilepticus: Definition, Categorization,
and Graduation of Severity
SE was diagnosed if seizures lasted at least 5 min or if a
series of seizures emerged without recovery of mental
status in between [36–38]. RSE was defined as SE refrac-
tory to first-line AEDs and second-line treatment with at
least one i.v. AED [11]. These widely accepted definitions
allow a comparison with previous works on RSE treatment.
Regarding etiologies of SE, seizures were categorized as
recommended by the International League Against Epi-
lepsy (ILAE) [39] as follows: acute symptomatic seizures,
remote symptomatic unprovoked seizures, symptomatic
seizures due to progressive CNS disorders, and unprovoked
seizures of unknown etiology. Severity of SE was graded
using the validated Status Epilepticus Severity Score
(STESS) [40, 41]. According to this, the following integral
components of STESS were used and categorized as fol-
lows: worst seizure types at presentation (simple partial,
complex partial, and absence seizures = 0 points;
323
generalized convulsive seizures = 1 point; and noncon-
vulsive status epilepticus (NCSE) in coma = 2 points),
history of prior seizures (0 points) or no history of seizures
(1 point), age of at least 65 years (2 points) and less than
65 years (0 points), and level of consciousness at SE onset
(awake or somnolent = 0 points; stuporous or coma-
tose = 1 point). Duration of SE was defined as the period
from the time of SE diagnosis to the time when SE stopped.
Seizure control was confirmed if there was no evidence of
clinical manifestations and seizure activity on EEG. All
patients had at least one routine EEG at admission, and
follow-up recordings with at least two conventional EEGs
in 24 h or continuous EEG monitoring were performed in
all patients without seizure control.
2.4 Outcomes
Primary outcomes were SE duration, seizure control, and
death. Secondary outcomes included destination at dis-
charge. Safety was defined as the absence of adverse
events, signs, or symptoms like rash, blood dyscrasias,
impairment of cardiovascular, renal, liver, and pulmonary
function closely related to the administration of LCM and
requiring acute medical intervention.
2.5 Statistics
Patients with hypoxic-ischemic encephalopathy were
excluded from all comparative analyses, as mentioned
above [31–34]. Patients were categorized into the follow-
ing two groups: with and without treatment with i.v. LCM
during RSE. Categorical variables were summarized as
counts and proportions and continuous variables as means
and standard deviations. The Shapiro–Wilk test was used to
distinguish between normal and non-normal distributions.
Continuous variables were analyzed with the Student’s
t test if normally distributed, or the Mann–Whitney U test
if non-normally distributed. For comparisons of propor-
tions, Chi-square and Fisher’s exact test were applied
where appropriate. Robust multiple linear regression
models were fitted using bootstrapped interactively re-
weighted least squares with 1,000 replications to reduce the
effects of extreme or non-normal ‘RSE duration’ data.
Univariable logistic regression was used to determine dif-
ferences in categorical outcomes for patients with and
without treatment with i.v. LCM. A multivariable logistic
regression model was used to adjust for age. Hosmer–
Lemeshow goodness-of-fit tests were applied to check the
multivariable logistic regression models. p values of 0.05
and less were considered significant. Statistical analysis
was performed with STATAÒ version 12.0 (Stata Corpo-
ration, College Station, TX, USA).
324 R. Sutter et al.

3 Results Table 1 Demographics and clinical characteristics (including

patients with hypoxic-ischemic encephalopathy; n = 111)
Two hundred and sixty consecutive patients were identified n (%)
with SE in our tertiary care center and 111 (43 %) devel-
oped RSE. From January 2005 to April 2009, 52 patients Demographics
(47 %) had no adjunctive treatment with i.v. LCM. While Gender
from May 2009 to December 2011 i.v. LCM was not Female 51 (46)
administered in all patients with SE, i.v. LCM was used as Male 60 (54)
an add-on AED in all consecutive 59 RSE patients (53 %). Age (mean ± SD), years 62 ± 16
LCM was mostly administered as a third or fourth AED. Clinical features
Demographics and clinical characteristics of the cohort are SE severity (STESS characteristics)
summarized in Table 1. Comparisons of demographics and Awake or somnolent 27 (24)
clinical characteristics including SE severity gradation by Stuporous or comatose 84 (76)
STESS and categorization of SE etiology according to the Worst seizure type
ILAE guidelines in patients with and without i.v. LCM is Simple partial/complex/absence 29 (26)
presented in Table 2 after excluding patients with hypoxic- Generalized convulsive 10 (9)
ischemic encephalopathy. Overall, there were no signifi- NCSE in coma 72 (65)
cant differences in SE severity and etiology or critical Age \65 years 58 (52)
medical conditions between both groups. Presumed RSE Age C65 years 53 (48)
etiologies categorized according to the ILAE guidelines History of seizures 32 (29)
and SE severity graded by STESS did not differ signifi- No history of seizures 79 (71)
cantly between patients with and without i.v. LCM. While Presumed RSE etiology
age tended to be higher in patients receiving i.v. LCM, Brain tumor 15 (14)
critical interventions tended to be less frequent in patients Uncontrolled epilepsy 11 (10)
with i.v. LCM. Ischemic stroke 9 (8)
The mean number of administered AEDs did not differ Meningitis/encephalitis 8 (7)
significantly between patients treated with and without i.v. Traumatic brain injury 7 (6)
LCM (4.3 ± 1.0 vs. 4.9 ± 1.7; Table 3). i.v. LCM was Intracerebral hemorrhage 6 (5)
used as an add-on treatment after 1 to 5 (mean 3 ± 0.9) Metabolic problem 4 (4)
prior administered AEDs had failed. The antiepileptic Alcohol withdrawal 3 (3)
treatment of RSE is summarized in Table 3. Detailed, Neurodegenerative 3 (3)
individual characteristics and sequential AED arrange- Others 10 (9)
ments of all patients with i.v. LCM are presented as elec- Not known 10 (9)
tronic supplemental material. Among all patients with i.v. Hypoxic-ischemic encephalopathya 25 (23)
LCM, 51 % (23/45) received LCM as the last AED
(including RSE in hypoxic-ischemic encephalopathy). NCSE nonconvulsive status epilepticus, RSE refractory status epi-
lepticus, SE status epilepticus, STESS Status Epilepticus Severity
Among those, seizure control was achieved in 91 % (21/ Score,
23). One or more AEDs were needed after beginning LCM a
Excluded from further analyses
with topiramate, lamotrigine and oxcarbazepine as the
most frequent following AEDs. even more pronounced after adjustment for age (OR 0.34,
Overall mortality was 30 % (26/86; Table 4). Analysis 95 % CI 0.1–0.9). Hosmer–Lemeshow goodness-of-fit tests
regarding significant differences in outcome in dependence revealed insignificant p values for the multivariable logistic
of sequential arrangement of AEDs was not performed regression models, indicating an adequate model fit
because of the small sample sizes in these subgroups. Uni- (Table 5).
and multivariable comparisons of continuous and categor- As stated, patients with hypoxic-ischemic encephalop-
ical outcomes in patients with and without i.v. LCM are athy were excluded from all comparative analyses. Only
presented in Table 5. In the univariable analysis, patients descriptive analyses were performed for patients with
with i.v. LCM tended to have both shorter SE duration hypoxic-ischemic encephalopathy. Of the 14 patients with
(regression coefficient -47.2, 95 % CI -122.4 to 28.0) and hypoxic-ischemic encephalopathy who were treated with
more often seizure control (OR 2.34, 95 % CI 0.5–10.1); i.v. LCM for RSE, 9 received LCM as the last AED with a
however, these trends did not reach statistical significance. resulting seizure control in 78 % (7/9). Overall, 7 patients
Administration of i.v. LCM was associated with lower odds died, 5 of them after seizure control following LCM as the
for death (OR 0.39, 95 % CI 0.2–1.0)—a result that was last AED.
Lacosamide for Refractory Status Epilepticus 325

Table 2 Demographics and clinical characteristics in patients with and without intravenous (i.v.) lacosamide (excluding patients with hypoxic-
ischemic encephalopathy; n = 86)
Patients with i.v. Patients without i.v. p values
lacosamide (n = 45) lacosamide (n = 41)
n (%) n (%)

Demographics
Gender
Female 25 (56) 16 (39) 0.125
Male 20 (44) 25 (61)
Age (mean ± SD), years 64.7 ± 15.2 59.8 ± 17.1 0.124*
Clinical features
SE severity (STESS characteristics)a
Awake or somnolent 18 (40) 9 (22) 0.103**
Stuporous or comatose 27 (60) 32 (78)
Worst seizure type
Simple partial/complex/absence 17 (38) 12 (29) 0.288**
Generalized convulsive 1 (2) 4 (10)
NCSE in coma 27 (60) 25 (61)
Age \65 years 20 (44) 25 (61) 0.125
Age C65 years 25 (56) 16 (39)
History of seizures 15 (33) 17 (41) 0.436
No history of seizures 30 (67) 24 (59)
STESS \3 indicating favorable outcome 12 (27) 11 (27) 0.986
STESS C3 indicating unfavorable outcome 33 (73) 30 (73)
RSE etiology grouped according to the ILAEb
Acute symptomatic seizures 25 (56) 21 (51) 0.687
Remote symptomatic unprovoked seizures 17 (38) 12 (29) 0.404
Symptomatic seizures due to progressive CNS disorders 0 (0) 3 (7) 0.104**
Unprovoked seizures of unknown etiology 3 (7) 5 (12) 0.470**
Critical medical conditions
Infections during SE 17 (38) 20 (49) 0.303
Coronary heart disease/cardiopathy 8 (18) 9 (22) 0.627
Pulmonary diseases/acute lung injury/acute respiratory distress syndrome 4 (9) 2 (5) 0.678**
Metabolic derangements 8 (18) 9 (22) 0.627
Tumors 13 (29) 9 (22) 0.461
Interventions
Mechanical ventilation 34 (76) 34 (83) 0.438**
Use of continuous i.v. anesthetic drugs 31 (69) 35 (85) 0.080**
ILAE International League Against Epilepsy, NCSE nonconvulsive status epilepticus, RSE refractory status epilepticus, SE status epilepticus
* Mann–Whitney U test
** Fisher’s exact test
a
Status Epilepticus Severity Score (STESS) [40, 41]
b
Grouping of etiologies according to the guidelines of the International League Against Epilepsy (ILAE) [39]

In the entire cohort, there were no adverse events due to 4 Discussion

antiepileptic treatment except for 1 patient with a rash
related to the use of lamotrigine and severe hypotension in This study explored the efficacy and safety of i.v. LCM as
3 patients, most likely caused by the use of i.v. anesthetic an antiepileptic add-on treatment for critically ill adult
drugs. patients suffering from RSE in the ICUs of a single tertiary
326 R. Sutter et al.

Table 3 Antiepileptic treatment in patients with and without intra- Table 4 Continuous and categorical outcomes in patients with
venous (i.v.) lacosamide (LCM) (excluding patients with hypoxic- refractory status epilepticus with and without intravenous (i.v.)
ischemic encephalopathy; n = 86) lacosamide (excluding patients with hypoxic-ischemic encephalopa-
thy; n = 86)
Patients Patients
with i.v. without i.v. Patients with i.v. Patients without i.v.
LCM (n = 45) LCM (n = 41) lacosamide (n = 45) lacosamide (n = 41)
n (%) n (%) n (%) n (%)

Number of AEDs (mean ± SD) 4.3 ± 1.0 4.9 ± 1.7 Duration of SE 87.2 ± 159.4 134.3 ± 188.7
AEDs during RSE (mean ± SD), h
First-line Seizure control 41 (93) 35 (85)
MDL (via bolus) 25 (61) 25 (61) Death 9 (20) 16 (39)
LZP 16 (39) 16 (39) Discharge (secondary outcome)
CLB 0 (0) 0 (0) Back home 5 (11) 3 (7)
CLP 3 (7) 3 (7) Rehabilitation 21 (47) 14 (34)
Second-line Other hospital 2 (4) 5 (12)
(for palliative
VPA 27 (66) 27 (66)
care)
LEV 36 (88) 36 (88)
Nursing home 7 (16) 3 (7)
PHT 27 (66) 27 (66) (for palliative
Third-line care)
TPM 18 (44) 18 (44) SE status epilepticus
LTG 6 (15) 6 (15)
OXC 1 (2) 1 (2) 51 % received LCM as the last AED, allowing the reasonable
CZP 2 (5) 2 (5) assumption that LCM was responsible for seizure control,
MSX 0 (0) 0 (0) which was achieved in 91 % of these patients. No adverse
Order in which i.v. lacosamide was administered events could be related to the administration of i.v. LCM,
Started simultaneously 3 (7) indicating a favorable safety profile.
with 2nd AED The experience of LCM for SE treatment in adults is
3rd AED 22 (49) limited to a few reports on LCM [25, 42] and even more
4th AED 14 (31) restricted for the treatment of patients with RSE to a few
5th AED 3 (7) case reports and recent case series [27–30]. Although LCM
6th AED 3 (7) is not a ‘broad spectrum’ AED, successful adjunctive
treatment with LCM has been recently reported in two
AED(s) antiepileptic drug(s), CLB clobazam, CLP clonazepam, CZP
carbamazepine, LTG lamotrigine, LEV levetiracetam, LZP lorazepam,
young women with refractory idiopathic generalized epi-
MDL midazolam, MSX mesuximide, OXC oxcarbazepine, PHT phe- lepsy (IGE) [43]. In our study, only one patient with
nytoin, PRO propofol, RSE refractory status epilepticus, TPM topi- hypoxic-ischemic encephalopathy also had IGE. Patients’
ramate, VPA valproate demographics, clinical characteristics, and presumed eti-
ologies of RSE were similar to those in previous studies on
care center. To our knowledge, this is the largest compar- the treatment of RSE [28–30]. In contrast to prior reports
ative cohort study of i.v. LCM for the treatment of RSE to on the use of i.v. LCM in SE, LCM was not administered
date. After adjustment for age, mortality was significantly with a ‘loading bolus’ of 400 mg [25, 42], an important
lower in patients with i.v. LCM—a finding that might have difference that might have reduced its efficacy.
been confounded by the implementation of continuous In this study, overall mortality was 30 %, i.e., higher
video-EEG monitoring in the ICU prior to the use of i.v. LCM than observed in one prior study (up to 17 %) [44], but
leading to heightened awareness as well as earlier diagnosis lower than in others (39–65 %) [9, 14, 45]. Overall,
and treatment of SE possibly contributing to a better outcome decreased mortality in patients with i.v. LCM might still be
and decreased mortality. In patients with i.v. LCM, RSE the result of multiple effects, such as improvement of
ceased in the vast majority and tended to be more frequently critical care in general, which is difficult to address. The
controlled than in patients without i.v. LCM. No significant implementation of continuous video-EEG monitoring in
differences regarding SE severity and etiology or critical the ICU in 2008 might have led to heightened awareness
medical conditions and interventions between patients with and subsequent earlier diagnosis and treatment of SE as
and without i.v. LCM could be identified as possible con- reported earlier [46], possibly contributing to a better
founders of this association in our cohort—underscoring the outcome and decreased mortality in patients treated with
strength of this finding. Among all patients with i.v. LCM, i.v. LCM. Except for the introduction of i.v. LCM and
Lacosamide for Refractory Status Epilepticus
Table 5 Uni- and multivariable
Treatment with lacosamide
analysis of outcomes in patients
with refractory status Univariable analysis
epilepticus in dependence of
treatment with lacosamide Duration
(excluding patients with of SE (h)
hypoxic-ischemic Seizure
encephalopathy; n = 86) control
Death
Multivariable analysisa
H–L X2 Hosmer–Lemeshow Duration
statistics, OR odds ratio, SE of SE (h)
status epilepticus
a Seizure control
Adjusted for age
b Death
Regression coefficient
continuous video-EEG monitoring, further changes in the
treatment strategies for RSE or changes in the team of
epileptologists involved in critical care were not imple-
mented at our institution during the entire study. In addi-
tion, there was no significant difference in underlying
etiologies and SE duration—both important determinants
for outcome [45, 47–50]. However, SE duration tended to
be longer in patients who did not receive LCM and
therefore might have influenced outcome.
Clinical monitoring of LCM-related adverse effects in
patients with RSE was challenging, because all patients
were in a stuporous or comatose state. There were no i.v.
LCM-related changes observed in cardiopulmonary, renal,
hepatic, or hematological parameters. In particular, new
onsets of atrial flutter or fibrillation (which were recently
reported in association with LCM [24]) were not identified
in the continuous ECG monitoring during their ICU stay.
Overall, this study demonstrates that i.v. LCM as an add-on
treatment in patients with RSE is safe and the potential
benefits might outweigh the risks by far, underscoring
findings from recent case series on patients with seizure
clusters and SE, where seizure control was achieved in
100 % of patients with LCM as the first or second drug [42].
4.1 Strengths and Limitations
The strengths of this study are the large cohort, the com-
parison to controls with similar SE etiologies categorized
according to the guidelines of the ILAE [39], SE severity
graded by STESS (with the integral components of age,
prior history of seizures, worst seizure type, and level of
consciousness at SE onset) [40, 41], and finally critical
medical conditions and interventions to exclude possible
confounding by indication. The last of these seems par-
ticularly important, as physicians may tend to use newer
AEDs more frequently in patients with particular clinical
and EEG characteristics.
Limitations of the study include its retrospective data
collection and single-center source. The use of historical
327
OR 95 % CI p values H–L X2 p values
-47.2b -122.4 to 28.0 0.216
2.34 0.5 to 10.1 0.252
0.39 0.2 to 1.0 0.054
-35.9b -111.2 to 39.4 0.346
2.40 0.6 to 10.5 0.246 4.34 0.825
0.34 0.1 to 0.9 0.035 15.1 0.062
controls impedes the interpretation, as patients enrolled in
recent times may benefit from more effective treatment
facilities resulting in more favorable outcomes. Therefore,
we cannot rule out the potential of residual confounding
and only assumptions could be made regarding the cause
for termination of RSE. Owing to the retrospective nature
of this study only the sequential order of AEDs and not the
exact timing relative to the diagnosis of RSE could be
assessed. In addition, all patients had several AEDs, a fact
that hampers analyses regarding isolated effects of LCM.
Furthermore, the sequential order in which i.v. LCM was
administered was mainly determined by the treating phy-
sicians, thereby impeding further analysis regarding the
efficacy of i.v. LCM. However, as the clinical character-
istics of the two compared groups were very similar (as
mentioned above), a direct association of i.v. LCM with
decreased mortality in RSE seems likely.
5 Conclusion
To conclude, i.v. LCM was well tolerated and had a
favorable safety profile as adjunctive treatment for RSE. Its
use was associated with decreased mortality of RSE—a
finding that might have been confounded by the imple-
mentation of continuous video-EEG monitoring in the ICU
prior to the use of i.v. LCM leading to heightened aware-
ness as well as earlier diagnosis and treatment of SE.
Prospective randomized trials with larger sample sizes are
warranted to further strengthen the evidence of efficacy of
LCM for the treatment of RSE.
Acknowledgments There was no financial support of this study.
This study was performed and designed independently of any
pharmaceutical company or other commercial interest. It was spon-
sored by the institution and explicitly not funded by the manufacturer
of lacosamide.
We thank Dr. S. Tschudin-Sutter for her statistical work.
We confirm that all persons who contributed significantly to the
work are listed as authors. Dr. R. Sutter and Dr. S. Rüegg conceived
and planned the work, acquired, analyzed and interpreted the data,
328
and wrote the first draft of the manuscript. Dr. S. Marsch interpreted
the data, edited, and revised the manuscript. All authors approved the
final submitted version.
Dr. R. Sutter is supported by the Research Fund of the University of
Basel, the Scientific Society Basel, and the Gottfried Julia Bangerter-
Rhyner Foundation.
Dr. S. Marsch reports no disclosures.
Dr. S. Rüegg received unconditional research grants from UCB
(Union Chimique Belge). He received honoraria from serving on the
scientific advisory boards of Desitin, Eisai, GlaxoSmithKline, and
UCB, travel grants from GlaxoSmithKline, Janssen-Cilag, and UCB,
speaker fees from UCB and from serving as a consultant for Eisai,
GlaxoSmithKline, Janssen-Cilag, Pfizer, Novartis, and UCB. He does
not hold any stocks of any pharmaceutical industries or manufacturers
of medical devices.
References
1. Knake S, Rosenow F, Vescovi M, et al. Incidence of status epi-
lepticus in adults in Germany: a prospective, population-based
study. Epilepsia. 2001;42(6):714–8.
2. Hesdorffer DC, Logroscino G, Cascino G, et al. Incidence of
status epilepticus in Rochester, Minnesota, 1965–1984. Neurol-
ogy. 1998;50(3):735–41.
3. Leppert D, Stöckli HR, Fuhr P. Richtlinien zur Behandlung des
Status epilepticus. Schweiz Ärztetzeitung. 2005;86:1–14.
4. Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the
management of status epilepticus in adults. Eur J Neurol.
2010;17(3):348–55.
5. Shorvon S, Ferlisi M. The treatment of super-refractory status
epilepticus: a critical review of available therapies and a clinical
treatment protocol. Brain. 2011;134(Pt 10):2802–18.
6. Rossetti AO, Lowenstein DH. Management of refractory status
epilepticus in adults: still more questions than answers. Lancet
Neurol. 2011;10(10):922–30.
7. Holtkamp M, Masuhr F, Harms L, et al. The management of
refractory generalised convulsive and complex partial status
epilepticus in three European countries: a survey among epilep-
tologists and critical care neurologists. J Neurol Neurosurg Psy-
chiatry. 2003;74(8):1095–9.
8. Kaplan PW. Nonconvulsive status epilepticus. Neurology.
2003;61(8):1035–6.
9. Cooper AD, Britton JW, Rabinstein AA. Functional and cognitive
outcome in prolonged refractory status epilepticus. Arch Neurol.
2009;66(12):1505–9.
10. Towne AR, Pellock JM, Ko D, et al. Determinants of mortality in
status epilepticus. Epilepsia. 1994;35(1):27–34.
11. Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med.
1998;338(14):970–6.
12. Holtkamp M, Othman J, Buchheim K, et al. A ‘‘malignant’’
variant of status epilepticus. Arch Neurol. 2005;62(9):1428–31.
13. Rossetti AO, Logroscino G, Bromfield EB. Refractory status
epilepticus: effect of treatment aggressiveness on prognosis. Arch
Neurol. 2005;62(11):1698–703.
14. Novy J, Logroscino G, Rossetti AO. Refractory status epilepticus:
a prospective observational study. Epilepsia. 2010;51(2):251–6.
15. Bausell R, Svoronos A, Lennihan L, et al. Recovery after severe
refractory status epilepticus and 4 months of coma. Neurology.
2011;77(15):1494–5.
16. Fleidervish IA, Friedman A, Gutnick MJ. Slow inactivation of
Na? current and slow cumulative spike adaptation in mouse and
guinea-pig neocortical neurones in slices. J Physiol. 1996;493(Pt
1):83–97.
R. Sutter et al.
17. Mickus T, Jung H, Spruston N. Properties of slow, cumulative
sodium channel inactivation in rat hippocampal CA1 pyramidal
neurons. Biophys J. 1999;76(2):846–60.
18. Beyreuther BK, Freitag J, Heers C, et al. Lacosamide: a review of
preclinical properties. CNS Drug Rev. 2007;13(1):21–42.
19. Yoshimura T, Kawano Y, Arimura N, et al. GSK-3beta regulates
phosphorylation of CRMP-2 and neuronal polarity. Cell.
2005;120(1):137–49.
20. Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety
of oral lacosamide as adjunctive therapy in adults with partial-
onset seizures. Epilepsia. 2007;48(7):1308–17.
21. Biton V, Rosenfeld WE, Whitesides J, et al. Intravenous laco-
samide as replacement for oral lacosamide in patients with par-
tial-onset seizures. Epilepsia. 2008;49(3):418–24.
22. Krause LU, Brodowski KO, Kellinghaus C. Atrioventricular
block following lacosamide intoxication. Epilepsy Behav.
2011;20(4):725–7.
23. Nizam A, Mylavarapu K, Thomas D, et al. Lacosamide-induced
second-degree atrioventricular block in a patient with partial
epilepsy. Epilepsia. 2011;52(10):e153–5.
24. Degiorgio CM. Atrial flutter/atrial fibrillation associated with la-
cosamide for partial seizures. Epilepsy Behav. 2010;18(3):322–4.
25. Kellinghaus C, Berning S, Immisch I, et al. Intravenous lacosa-
mide for treatment of status epilepticus. Acta Neurol Scand.
2011;123(2):137–41.
26. Chen LL, Haneef Z, Dorsch A, et al. Successful treatment of
refractory simple motor status epilepticus with lacosamide and
levetiracetam. Seizure. 2011;20(3):263–5.
27. Shiloh-Malawsky Y, Fan Z, Greenwood R, et al. Successful
treatment of childhood prolonged refractory status epilepticus
with lacosamide. Seizure. 2011;20(7):586–8.
28. Mnatsakanyan L, Chung JM, Tsimerinov EI, et al. Intravenous
lacosamide in refractory nonconvulsive status epilepticus. Sei-
zure. 2012;21:198–201.
29. Rantsch K, Walter U, Wittstock M, et al. Efficacy of intravenous
lacosamide in refractory nonconvulsive status epilepticus and
simple partial status epilepticus. Seizure. 2011;20(7):529–32.
30. Fernandez EM, Franck AJ. Lacosamide for the treatment of
refractory status epilepticus. Ann Pharmacother. 2011;45(11):
1445–9.
31. Rossetti AO, Logroscino G, Liaudet L, et al. Status epilepticus:
an independent outcome predictor after cerebral anoxia. Neu-
rology. 2007;69(3):255–60.
32. Wijdicks EF, Parisi JE, Sharbrough FW. Prognostic value of
myoclonus status in comatose survivors of cardiac arrest. Ann
Neurol. 1994;35(2):239–43.
33. Young GB, Gilbert JJ, Zochodne DW. The significance of
myoclonic status epilepticus in postanoxic coma. Neurology.
1990;40(12):1843–8.
34. Hui AC, Cheng C, Lam A, et al. Prognosis following postanoxic
myoclonus status epilepticus. Eur Neurol. 2005;54(1):10–3.
35. Rüegg S, Naegelin Y, Hardmeier M, et al. Intravenous leveti-
racetam: treatment experience with the first 50 critically ill
patients. Epilepsy Behav. 2008;12(3):477–80.
36. Young GB, Jordan KG, Doig GS. An assessment of nonconvul-
sive seizures in the intensive care unit using continuous EEG
monitoring: an investigation of variables associated with mor-
tality. Neurology. 1996;47(1):83–9.
37. Lowenstein DH, Bleck T, Macdonald RL. It’s time to revise the
definition of status epilepticus. Epilepsia. 1999;40(1):120–2.
38. Brophy GM, Bell R, Claassen J, et al. Guidelines for the evalu-
ation and management of status epilepticus. Neurocrit Care.
2012;17(1):3–23.
39. Commission on Epidemiology and Prognosis ILAE. Guidelines
for epidemiologic studies on epilepsy. Epilepsia. 1993;34(4):
592–6.
Lacosamide for Refractory Status Epilepticus
40. Rossetti AO, Logroscino G, Bromfield EB. A clinical score for
prognosis of status epilepticus in adults. Neurology. 2006;66(11):
1736–8.
41. Rossetti AO, Logroscino G, Milligan TA, et al. Status Epilepticus
Severity Score (STESS): a tool to orient early treatment strategy.
J Neurol. 2008;255(10):1561–6.
42. Hofler J, Unterberger I, Dobesberger J, et al. Intravenous laco-
samide in status epilepticus and seizure clusters. Epilepsia.
2011;52(10):e148–52.
43. Zangaladze A, Skidmore C. Lacosamide use in refractory idiopathic
primary generalized epilepsy. Epilepsy Behav. 2012;23(1):79–80.
44. Holtkamp M, Othman J, Buchheim K, et al. Predictors and prognosis
of refractory status epilepticus treated in a neurological intensive
care unit. J Neurol Neurosurg Psychiatry. 2005;76(4):534–9.
45. Drislane FW, Blum AS, Lopez MR, et al. Duration of refractory
status epilepticus and outcome: loss of prognostic utility after
several hours. Epilepsia. 2009;50(6):1566–71.
329
46. Sutter R, Fuhr P, Grize L, et al. Continuous video-EEG moni-
toring increases detection rate of nonconvulsive status epilepticus
in the ICU. Epilepsia. 2011;52(3):453–7.
47. Logroscino G, Hesdorffer DC, Cascino G, et al. Short-term
mortality after a first episode of status epilepticus. Epilepsia.
1997;38(12):1344–9.
48. Claassen J, Lokin JK, Fitzsimmons BFM, et al. Predictors of
functional disability and mortality after status epilepticus. Neu-
rology. 2002;58(1):139–42.
49. Sutter R, Marsch S, Fuhr P, Rüegg S. Mortality and recovery
from refractory status epileticus in the ICU: a 7-year observa-
tional study. Epilepsia. 2013;54(3):502–11.
50. Towne AR. Epidemiology and outcomes of status epilepticus in
the elderly. Int Rev Neurobiol. 2007;81:111–27.