Seizure 56 (2018) 34–40

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Seizure
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Review

Efficacy of lacosamide in children and adolescents with drug-resistant

epilepsy and refractory status epilepticus: A systematic review
1. Introduction

Epilepsy is one of the most common neurological disorders, with an estimated annual incidence of 50/100.000 population and a
prevalence of 700/100.000 population [1]. Some researchers suggest that 60% of patients might respond to standard medical treatment
and achieve remission, however, 30–40% of patients will be refractory to current anti-epileptic drugs (AEDs) [2]. Those patients who
failed to respond to at least two properly indicated and tolerated AEDs are referred as drug-resistant [3].
Newer AEDs have novel mechanisms of action designed to decrease drug–drug interactions and achieve seizure freedom [2].
Lacosamide is one of the newest medications and exhibits its function through selectively enhancing slow inactivation of voltage-
gated sodium channels, without affecting fast inactiva- tion; decreasing in this way pathologic neuronal hyperexcitability without
affecting the physiological neuronal function [4]. Simul- taneously, it seems that the drug binds to the collapsin response mediator
protein 2, which partakes in a neurotrophic signal transduction. This is hypothesized to produce a neuroprotective effect preventing
the formation of abnormal neuronal connections in the brain [5].
Currently, lacosamide is approved by the Food and Drug Administration to be used in patients older than 16 years [ 2,4]. Yet there is
growing evidence suggesting that lacosamide is safe, well tolerated and effective in the pediatric population. In this study, we aim to
evaluate the evidence regarding lacosamide use in drug- resistant epilepsy (DRE) and refractory status epilepticus (RSE) in children
and adolescents.

Articles identified through database searching (PubMed, EMBASE, Cochrane Library, Clinicaltrials.gov)
(n = 175)

Duplication of titles removed (n = 93)

Potentially relevant abstracts (n = 82)

Excluded articles
(n = 56)

Literature Reviews 23
Other Drug 10
Other Outcome 9
Adult Trial 6
Mixed population 3
Editorial 3
Guideline 2

Full-text Articles included

(n = 26)
 J.S. Ortiz de la Rosa et al. / Seizure 56 (2018) 34–40
3
2. Methods

2.1. Search methods

We performed a systematic review of the evidence on efficacy, safety and tolerability of lacosamide in pediatric epilepsy population.
Three authors (JSO, PJR, and MCR) independently performed a literature search on MEDLINE, EMBASE, COCHRANE, Google Scholar and
Scielo databases for articles published from January 2008 to January 2017. We used the following keywords: Lacosamide, “Vimpat”, children,
infants, child, childhood, focal epilepsy, generalized epilepsy, drug-resistant epilepsy, refractory epilepsy, Lennox Gastaut Syndrome,
continuous spike and waves during slow sleep, and status epilepticus. We also searched bibliographies of pertinent reviews and relevant
conference proceedings in order to find additional documents. When necessary we contacted study authors by e-mail. Additional studies
were sought by searching the Internet for ongoing trials registers with preliminary published results (clinicaltrials.gov).

2.2. Type of studies

Original retrospective and prospective cohorts, series and case reports assessing the efficacy of lacosamide in patients <21 years of
age were included, regardless of language or country of publication. For studies with multiple publications, all versions of the study
were reviewed to ensure complete access to maximal trial data. Brief abstracts; mixed population cohorts (children and adults) not
providing separate data on the pediatric participants, as well as repeated published populations were excluded. Full texts of all
remaining articles were reviewed.

2.3. Data collection

Two authors (JSO, LDL) extracted relevant data and evaluated the methodological quality of documents. The following variables
and outcomes were assessed: study design, number of patients, type of epilepsy, 50% or greater seizure reduction, seizure freedom,
status epilepticus (SE) cessation, adverse effects, seizure aggrava- tion, lacosamide dosing regimen, and time of follow-up. Using a
standardized form data were systematically reported. Discrep- ancies were solved by consensus. Included studies were ranked on the
basis of the quality of therapeutic evidence according to the American Academy of Neurology Classification of Evidence [6].

2.4. Statistical analysis

Categorical data were expressed as percentages and quantita- tive data as mean, standard deviation, and range. A weighted average
calculator computed average of seizure cessation and seizure reduction. Categorical variables were analyzed using 2 2 contingency
table using Fisher exact test. All statistical analyses were performed with SPSS statistical software package (SPSS for Mac, v.21, SPSS,
Inc., Chicago, IL). ×

3. Results

Of 175 abstracts identified by the search, 82 were reviewed as full-text. Twenty-six articles fulfilled eligibility criteria and described
outcomes in 797 patients (57% male) (Fig. 1). Majority of patients had focal epilepsy (75%), 20% had generalized epilepsy,
3 J.S. Ortiz de la Rosa et al. / Seizure 56 (2018) 34–40

Fig. 1. Flowchart of the literature search and study inclusion.

and 5% of the population was on SE. Age ranged between 4 weeks and 21 years, but the majority of patients were 16 years old or
younger (92%). All children or adolescents included in the study had DRE. All patients had failed at least to two AED trials and some
had also trailed ketogenic diet, vagal nerve stimulation or epilepsy surgery.

3.1. Drug-resistant epilepsy

Seven hundred fifty-seven (57% male) patients had DRE. Seventy-nine percent had focal epilepsy and 21% generalized epilepsy.
Forty cases had Lennox Gastaut Syndrome (LGS) and eight cases had continuous spike and waves during slow sleep (CSWS)
syndrome. Lacosamide was administered orally in the form of syrup or tablets twice daily in all patients. Children were generally
started on a low dose and titrated up weekly. The mean maintenance dose was 7.2 mg/kg/day (range 1–20 mg/kg/day).
Seizure frequency during 1–3 months preceding the drug initiation was used as baseline to calculate the seizure frequency
reduction rate. Results were highly heterogeneous. Overall, mean follow-up was 10.23 (1–53) months, 50.07% of patients had 50%
reduction in seizure frequency, and 23.62% of patients were seizure free. Rastogi et al. found a significant difference between
generalized and focal epilepsy groups, in their cohort lacosamide was effective in treating 62% focal epilepsies but only≤25%
generalized epilepsies [7]. Two studies [8,9] compared the proportion of seizure reduction in the first and 12 months of treatment in
the same population with focal epilepsy. They found a clear difference in the weighted average seizure reduction rate at 28 days
(70%) when compared with the results at one year of follow-up (38%). See Table 1.

3.2. Adverse effects

Adverse effects occurred in 18–59% of cases. Few patients had lacosamide dose reduction because of side effects, but the drug was
rarely discontinued due to side effects alone. All side effects were either tolerable or resolved in time through dosage reduction or
discontinuation of the drug. The most common adverse events included dizziness, somnolence, headache, mood and behavioral
changes (including irritability, depression, crying, behavioral outbursts, personality changes and suicidal ideation), gastrointes- tinal
upset (including nausea, dyspepsia, abdominal discomfort and/or vomiting), visual or ocular abnormalities (including diplopia,
blurred vision, nystagmus), inappetence/weight loss, and gait disorders including ataxia, instability and difficulty walking. In rare cases
(2.1%) there were reports of seizure worsening; this phenomenon was more frequent in patients with generalized epilepsy (7%) than focal
epilepsy (0.99%) p < .05. In Verrotti et al study one patient (0.1%) experienced SE [18]. Two out of 26 studies found evidence of an
association between lacosamide failure and simultaneous treatment with a sodium channel blocking AED [10,25]. Only McGinnis and
colleagues evaluated methodically the retention rate in children (223 patients); they found that the titration rate was not related to the
presence of adverse effects, yet they established that the more AEDs are taken by the patient (three
or more), the more likely they will suspend lacosamide [10].

3.3. Status epilepticus

We found seven small retrospective published papers of lacosamide use in RSE. All studies had heterogeneous SE definitions. In
total 40 patients aged between 4 weeks to 17 years (62% male) were included. The mean loading dose was 6.2 mg/kg. On average the
efficacy of lacosamide was assessed at 36 (4–120) hours. Overall, the SE cessation rate was 53% (0–100%), and 50% reduction in seizure
frequency/EEG epileptic activity was achieved in 70% (57–100%) of cases. Objective adverse events of intravenous lacosamide were
present in less than 10%. Majority of these patients were in a condition that did not allowed detection of subjective adverse events.
Some studies demonstrated that lacosamide was more effective
≤ in children when given earlier (at least second-line of treatment) [7,21]
Table 2.

3.4. Epileptic syndromes

Grosso et al conducted a study with 8 patients with CSWS that have received at least 3 AED prior to lacosamide, they measured spike and
wave index (SWI) and neuropsychological evaluation before and 6 months after treatment, 6/8 patients were considered responders
(>50% reduction of SWI) with normalization of EEG in 3 of them. Seventy five percent of parents or caregivers reported behavior
improvement and 87% of children presented better attention at school, were more alert and less anxious after lacosamide initiation
[15]. A significant improvement in conduct and the speed of response to stimuli was reported by the parents of 13% of seizure-
controlled patients in a multicenter study in Spain [19] Similarly, Heyman et al reported improvement in behavior in 30% of patients
with DRE on lacosamide [20].
An Italian group explored the use of lacosamide in patients with LGS; they published a cohort of 18 patients with a reduction of seizures
in 33% and seizure aggravation in 17% of them [14]. Seizure worsening with lacosamide was also reported in two patients with LGS by
Heyman et al. [33], one patient by Andrade-Machado et al. [24], and one patient by Yorns et al. [21]. Casas [19], Miskin [11] and Rastogi [7]
did not report seizure aggravation on patients with LGS. Overall, we found half of the patients with Lennox Gastaut syndrome showed 50%
or greater seizure reduction, 32% did not response to lacosamide and 17% suffered seizure aggravation. See Table 3.

Table 1
Clinical evidence of Lacosamide in pediatric Population.
 Author/
J.S. Ortiz de la Rosa et al. / Seizure 56 (2018) 34–40
3
Year Study AAN Age N Seizures Follow- Seizure ≤50% Dose mg/ Side Effects
Type Classification (years) up/ freedom seizure Kg/day
Evidence Outcome (%) reduction mean
(Mean) (%) (range)
McGinnis
Retro IV 1–20 223 Focal 75% 7 (1–53) 40 (–) 6.6 (1.4– Total 42%: MBC 16%, drowsiness 16%, dizziness
2016 [10] Generalized 5% months 251) 10%, GIU 8%, ataxia 5%, rash 3%
Mixed 19%
Miskin Retro IV 4–15 21 Generalized 19 24 43 6.9 (1.7– Total 29%: Somnolence 33%, weight loss 17%,
2016 [11] 100%: LGS 38%, months 14.3) tremor 17%, memory fails 17%, dizziness 17%
Other 62%: JAE,
JME, Doose
Toupin Retro IV 5–21 22 Focal 12 4.5 45 8.4 Total 50%: Dizziness 23%, drowsiness 23%,
2015 months incoordination 14%, MBC 9%, insomnia 9%,
[12] headache 5%, blurred vision 5%, GIU5%
Gulati 2015 Pro III 2–19 40 Focal 9 months 5 20 5.7 Total 18%: drowsiness, MBC, mild transient
[13] facial pain.
Pasha Pro III 5–15 79 Focal 28 days (–) 96 50 mg Total 51%: Hyperactivity, ataxia, drowsiness,
2014b [8] BID insomnia, weight gain, headache, GIU.
Pasha 2014 Pro III 5–15 79 Focal 12 41 62 4.1 51%: hyperactivity, ataxia, drowsiness,
[8](1 year months insomnia, weight gain, GIU, giddiness,
follow headache
up) 1
Grosso Retro IV 4–15 18 Generalized: LGS 9 months 0 33 15.2 (9.8– Total 44%: 17% seizure worsening, dizziness,
2014b 18.1) GIU, gait instability.
[14]
Grosso Pro III 8–15 8 Focal: CSWS 6 months 37 75 12.2 25% MBC
2014c
[15]
Kim 2014 Retro IV 1–17 21 Focal 10.1 19 67 5.4 (1.4– Total 38%: somnolence 37%, dizziness25%, MBC
[16] months 9.8) 25%, sleep disturbance 12%, GIU 12%
Grosso Pro III 1–3 24 Focal 3 months 17 42 12.5 (7– Total 33%: drowsiness (21%), MBC (12.5%), GIU
2013 [17] 15.5) (8%), instability and difficulty walking (4%).
Grosso Pro III 1–3 18 Focal 12 11 22 12.5 (7– Total 33%: drowsiness (21%), nervousness
2013 [17] months 15.5) (12.5%), vomiting (8%), instability and difficulty
(1 year walking (4%).
follow
up)1
Verrotti Pro III 4–15 59 Focal 44% 3 months 7 47 3–12 Total 30%: seizure worsening 12%, GIU 7%,
2013 [18] Generalized 20% Headache 5%, CBM 5%, dizziness 3%, drowsiness
Mixed 36% 3%
Casas- Pro III 0.5–16 130 Focal 91% 3 months 14 62 6.8 Total 30%: GIU 5%, instability 5%, dizziness 4%,
Fernandez 2012 [19] Generalized 9% nystagmus 2%, somnolence 2%
Heyman Retro IV 1.5–16 17 Focal 70% 9 months 6 35 12.3 (6.7– Total 59%:GIU 18%, dizziness 18%, seizure
2012 [20] Mixed 30% 20) worsening 12%, restlessness 12%, fatigue 12%,
headache 12%, increased appetite 6%, prolonged
crying 6%.
Rastogi Pro IV 1–16 16 Focal 75% 9.8 0 50 2.4–19.4 GIU, dizziness, headaches, somnolence, facial
2012 [7] Generalized 25% months edema, and increased seizures
Yorns 2012 Retro IV 1–20 40 Focal 42% 9.2 15 42 7 Total: 37%: CBM 12%, lethargy 10%, seizure
[21] Generalized 58% months worsening 7%, weight loss 5%, dizziness 5%,
mild memoryimpairment 2.5%, tremor 2.5%
Afra 2012 Retro IV 19 3 Generalized 15 100 100 200 mg None reported
[22] (JME) months BID
Zangaladze Retro IV 21 1 Generalized 18 100 100 200 mg None reported
2012 [23] (JME) months BID
Andrade- Retro IV 20 1 Generalized (LGS) 1 week 0 0 200 mg Seizure worsening
Machado BID
2012 [24]
Guilhoto Retro IV 8–21 16 Focal 4 months 19 37 4.7 Total 37%: GIU 12%, oral tics 6%, MBC 6%
2011 [25] (suicidal ideation), ataxia 6%, worsening of
chronic headache 6%, blurred vision 6%, seizure
worsening 6%
Gavatha Pro IV 3–18 18 Focal 3 months 11 36 6 (1.7– Total 39%: somnolence 17%, MBC 11%, sleep
2011 [26] 10) disorder 6%, pancytopenia 6%

Abbreviations: Pro: prospective, Retro: retrospective, Mixed: patients with focal and generalized seizures, MBC: Mood and behavioral changes, GIU: Gastro-Intestinal
Upset, LGS: Lennox Gastaut Syndrome, JAE: Juvenile Absence Epilepsy, JME: Juvenile Myoclonic Epilepsy, CSWS: Continuous spike and waves during slow sleep
epileptic syndromes, (–): Not measured or reported in the article.
1
Two prospective studies assessed the efficacy soon after the drug initiation (28 days and 3 months) and re-assessed efficacy at 12 months.
 4. Discussion

To the best of our knowledge, this systematic review is the first to evaluate clinical efficacy and safety of lacosamide for DRE and
RSE in children and adolescents. In total, 797 cases were extracted from the literature. In DRE patients the mean seizure free success
rate was 24%, and 50% of patients had 50% reduction in seizure frequency at a mean follow-up of 10 months. In RSE the mean
cessation rate was 53%, and 50% reduction in clinical seizure or EEG epileptic activity was achieved in 70% of cases evaluated at 36 h
of treatment. Only one out of three children reported side effects with a low rate of lacosamide discontinuation.
In regulatory randomized controlled trials conducted in adults, lacosamide has demonstrated to be an effective and safe AED, with
40% of patients with refractory focal epilepsy achieving a 50% reduction in seizure frequency at a short period of time (3 months)
[34]. In this review, both retrospective and prospective studies consistently showed efficacy of lacosamide as an add-on therapy in
DRE, indicating that the efficacy in children appears to be equivalent to that in adults. Opposite to the adults rigorous trial, the
findings from this review came from a real-world scenario and could be directly applied to ambulatory pediatric patients with focal
DRE.
Table 2
Lacosamide experience in status epilepticus in children.

Author/Year Study AAN Age N Type of patients CSE/ Outcome Cessation ≤50% Mean Mean total Side Effects in
Type Classification (years) NCSE (hours) of seizures seizure loading dose mg/Kg the next 48 h
Evidence (n) (%) reduction dose (range)
(%) Mg/kg
(range)

Poddar 2016 Retro IV 1–16a 9 Refractory Status 3/6 24 44 78 8.7 13.8 11%
[36] epilepticus bradycardia
Arkilo 2016 Retro IV 1–12 b
14 Epilepsia partialis (–) 12 (–) 57 7.5 (–) 7% Sedation
[27] continua (3), status
epilepticus (11)
Loomba 2015 Retro IV 3 1 Refractory Status 1/0 4 0 (–) 3.6 7.1 Wide
[28] epilepticus Complex
Tachycardia
Grosso 2014a Retro IV 3–16c 11 Refractory Status 6/5 48 45d 63e 8.6 (–)f None
[29] epilepticus reported
Jain 2012 [30] Retro IV 12–17 3 Tonic Refractory Status 3/0 12 100 100 2.25 2.75 33% Chorea
epilepticus 33%
Oculogyric
crisis
Mnatsakanyan Retro IV 16 1 Refractory Status 0/1 (–) 100 100 200– 200 mg BID None
2012 [31] epilepticus 300 mg reported
Shiloh- Retro IV 8 1 Prolonged Refractory 0/1 120 100 100 None 25 mg BID None
Malawsky Status epilepticus reported
2011 [32]

a
Age range: 3 months–16 years old (mean 5.7 years).
b
Age range: 1 month–12 years old.
c
Age mean 9.4 years.
d
In 4 out of 5 patients (80%) status epilepticus ceased within 1–12 h of the first intravenous administration of the drug.
e
In two patients (18%) lacosamide was able to control all clinical seizures but frequent electrographic seizures were still recorded on EEG.
f
The mean maintenance dose was 12.3 mg/kg/day (range 8.8–13.9).

Table 3
Clinical evidence of Lacosamide in Lennox-Gastaut Syndrome.

Author/Year Lennox-Gastaut Syndrome cases Responder: ≤50% seizure reduction N (%) Non-responder N (%) Seizure Aggravation N (%)
Miskin 2016 [11] 8 7 (87.5) 1 (12.5) 0
Grosso 2014b [14] 18 6 (33) 9 (50) 3 (17)
Yorns 2014 [21] 5 3 (60) 1 (20) 1 (20)
Heyman 2012 [20] 2 0 0 2 (100)
Casas 2012 [19] 2 2 (100) 0 0
Rastogi 2012 [7] 4 2 (50) 2 (50) 0
Andrade-Machado 2012 [24] 1 0 0 1 (100)
Total 40 20 (50) 13 (32) 7 (17)

Non-responders: patients without changes in the seizure frequency after lacosamide initiation and maintenance.
Yorns et al. [21] published five patients with LGS, but there is no information about the response to lacosamide in those patients.

The evidence of lacosamide efficacy in generalized epilepsy is scarce and contradictory. In this review, 5 out of 26 studies included
exclusively patients with generalized epilepsy with an average efficacy of 33–43% [24,11,22,23,30,17]. Six studies included mixed
populations [7,10,21,19,33,17]. An Italian study comparing the use of lacosamide in children and adults demonstrated poor response in all
patients with generalized epilepsies, and a higher efficacy for focal seizures in contrast with generalized ones (p < .05) [17]. By
comparison, the study from Yorns et al, in Philadelphia reported that children with generalized epilepsy had a similar reduction in
seizure frequency when compared to children with focal epilepsy (57% vs. 42%) [21]. Likewise, Afra and Zangaladze reported four cases
of juvenile myoclonic epilepsy with excellent response to lacosamide [22,23]. Finally, Casas et al. and McGinnis et al. did not find a
relationship between the response to lacosamide and any epileptic syndrome [10,19]. Recent studies in adults have shown disturbing
results supporting the mild risk of absence seizures worsening in patients with drug-resistant generalized epilepsy, occurring in 10% [35]
to 22% [36] of the population treated with lacosamide. Interestingly, some of these patients had not previously experienced an absence
seizure in their life [35].
 Although this study demonstrated a favorable effect of lacosamide in 50% of patients with LGS, we also found seizure worsening in
17% of cases. The seizure aggravation in children with an intractable syndrome is a concern. Recently four cases of seizure worsening in
young adults with LGS were reported [37,24]. Lacosamide can cause an increase in the frequency of tonic seizures during sleep and
wakefulness, even provoking tonic SE in one patient. Fortunately, all patients returned to their previous clinical condition after
lacosamide discontinuation. All AEDs may theoretically have a paradoxical seizure-inducing effect under certain conditions. It is often
difficult to distinguish between the effect of an AED and the natural course of the disease, which is particularly true in the fluctuation
course of LGS [14]. Nevertheless tonic seizures can be subtle and might not be easily detected; additionally, some studies did not specify
if video-EEG was recorded.
Retention rate or treatment persistence is an outcome measure recommended by the International League Against Epilepsy. Retention
rate has the advantage of being a composite measure of effectiveness – efficacy and tolerability – [10]. Children who came off lacosamide
did so because of partial or no response [13]. Two of the largest studies in our review (353 patients) demonstrated that the severity of the
adverse effects or their presence was not related to the dose [10,19]. Likewise, Yorns et al described a lack of association between dose
and effect. Patients who were started on lacosamide generally responded soon after treatment initiation and they did not necessarily
improve after upward titration [21]. Although lacosamide adverse effects in children have been classically associated with higher
dosages and speed of titration [38], we could not confirm those data in this review. Few studies reported evidence of an association
between lacosamide failure and simultaneous treatment with another sodium channel blocker [10,25].This failure may be due to
increased adverse effects such as somnolence and dizziness. Different findings have been reported in pediatric and adult population.
Some studies support the association [10,38], and other studies did not find it [21,26,39]. We believe combinations of AEDs with different
mechanisms of action might be more efficacious and well tolerated than combinations of AEDs with similar mechanisms of action.
Our study shows optimistic data regarding the use of lacosamide in RSE in pediatric population. The option for intravenous use in
emergency situations requiring rapid up titration is a strength of the drug [40], however, the analysis of results is complicated. Off-
label use of lacosamide in children explains the limited number of cases in the literature. Additionally, all studies used the drug as an
adjunctive therapy, which may lead to a biased estimate of the efficacy. AEDs are less effective in stopping SE when they are used as
the last choice. The success rate in adult patients with SE or seizure clusters receiving lacosamide as a first or second drug is 100%, as
third drug 80%, and as fourth or fifth drug 75% [41]. Despite the small number of published cases in pediatric population, we believe
in IV lacosamide could be an appropriate adjunctive therapy.
A range of adverse effects suggestive of vestibulocerebellar dysfunction is significantly associated with lacosamide treatment in
adults [42]. Although the adverse-event profile in our patients differs from the adult series, we have to bear in mind several of our
patients were small children and many of them had cognitive impairment and may not have been capable of reporting some
subjective side effects. Uncommon objective adverse effects were reported in the SE patients. Only one case of bradycardia (2.5%) [43]
and (2.5%) of tachycardia [28] were mentioned within the 40 cases, however not all patients were monitored by EKG at the pediatric
intensive care unit.
Lacosamide is known in the literature by the absence of pharmacokinetic interaction, nevertheless, with only one decade of use,
the potential drug–drug interactions are yet to be described. We included one case of plausible interaction between lacosamide and
flecainide as substrate for a potential lethal arrhythmia [28]. A recent publication has reported a possible interaction between
lacosamide and valproic acid resulting in hyperammonemic encephalopathy [44]. Both cases developed after lacosamide initiation
and fully recovered after its discontinuation.
Finally, our study delivered important information regarding cognition and behavior. Although achieving seizure control produces
a secondary positive impact on cognitive and behavioral functioning in children and adolescents, some authors consider lacosamide
has a specific primary cognitive enhancing effect improving information processing speed [45]. By contrast, several articles have
reported cases of mild negative mood and behavioral changes (5–25%) [18,10,15,13,26,46,12]. In few special cases, lacosamide was
discontinued because of severe hyperactivity, aggression, and inattention [8,21]. One concerning case described a patient who
manifested depression and suicidal ideation [25]. Full recovery occurred after the drug was stopped.

4.1. Strengths and limitations

Systematic reviews can reveal data that are not evident in individual studies because of their limited sample sizes. The robustness of
our results is supported by a comprehensive literature search strategy without any restrictions on date, language, or country of origin.
In the absence of randomized controlled trials evaluating the efficacy, safety, and tolerability of lacosamide in pediatric population, our
systematic review provides practical insights into the off label post marketing use of lacosamide for pediatric epilepsy; however some
study limitations needs to be addressed. The main limitation of our study pertains to the quality of the evidence due to the
retrospective nature and small sample size of the studies. The absence of randomized clinical trial brings into question the
comparability of patients having the intervention, but also the influence of confounders on observed outcomes. Different sources of
heterogeneity were identified in the selected studies such as patient selection, age, epilepsy syndrome, and DRE and RSE definitions.
There was insufficient data regarding time between SE onset, first dose of lacosamide and seizure outcome assessment. Lack of
standardized lacosamide titration method, lack of retention data, and lack of standardized follow-up may also pose problems in the
analysis of efficacy and adverse effects. Additionally, inclusion of small series and cases reports increase the potential bias in reporting
successes rather than failures. In summary, the observational studies included were not similar enough to combine, and several
confounders almost invariably affected their effect sizes. This and the lack of randomized trials in the topic made it difficult to perform
a meta-analysis.

5. Conclusions

Lacosamide is an effective and well-tolerated antiepileptic drug for the treatment of drug-resistant focal epilepsy and refractory
status epilepticus in children. The current use of lacosamide in Lennox Gastaut Syndrome and generalized genetic epilepsies shows
scarce conflicting data. A randomized controlled clinical trial in pediatric population is needed in order to confirm and validate the
efficacy and safety results observed in this systematic review.