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Efficacy of lacosamide in children and adolescents with drug-resistant epilepsy and refractory status epilepticus: A systematic review

Open ArchivePublished:February 02, 2018DOI:https://doi.org/10.1016/j.seizure.2018.01.014

      Highlights

      • Lacosamide is a good option in children with focal drug-resistant epilepsy.
      • Lacosamide is a safe and well-tolerated antiepileptic drug for refractory epilepsies.
      • The efficacy of lacosamide in generalized epilepsies shows conflicting data.
      • Seizure worsening with lacosamide is more frequent in generalized epilepsies.
      • The efficacy of lacosamide in pediatric status epilepticus shows scarce data.

      Abstract

      Purpose

      Lacosamide, is one of the newer antiepileptic drug approved for focal drug-resistant epilepsy as an add-on treatment in patients older than 16 years. However, there is growing evidence of its use, safety and efficacy in children. We aim to evaluate efficacy and tolerability of lacosamide in focal and generalized drug-resistant epilepsy and refractory status epilepticus in the pediatric population.

      Methods

      We conducted a systematic review on MEDLINE, EMBASE, COCHRANE, Google Scholar and Scielo from January 2008 to January 2017. The primary outcome was the efficacy of lacosamide in children with drug-resistant epilepsy and refractory status epilepticus. Efficacy and adverse events attributed to lacosamide were extracted from each publication and systematically reported. We performed no meta-analyses due to limited available data.

      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). The majority of studies were retrospective (69%) small series (84%). On average 51% of patients had 50% or greater seizure reduction. The mean seizure freedom rate was 24%. Adverse effects occurred in 18–59% of patients. The main events were dizziness, sedation, gastrointestinal upset, mood and behavioral changes. 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.

      Conclusion

      Current evidence shows lacosamide as a good option in pediatric patients with focal drug-resistant epilepsy and refractory status epilepticus as an add-on therapy given its efficacy on seizure control and safety profile. The use of lacosamide in Lennox-Gastaut syndrome shows conflicting data. Large randomized controlled studies in the pediatric population are necessary to substantiate these findings.

      Keywords

      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 [
      • Hirtz D.
      • Thurman D.J.
      • Gwinn-Hardy K.
      • Mohamed M.
      • Chaudhuri A.R.
      • Zalutsky R.
      How common are the common neurologic disorders?.
      ]. 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) [
      • Stephen L.J.
      • Brodie M.J.
      Pharmacotherapy of epilepsy newly approved and developmental agents.
      ]. Those patients who failed to respond to at least two properly indicated and tolerated AEDs are referred as drug-resistant [
      • Kwan P.
      • Arzimanoglou A.
      • Berg A.T.
      • Brodie M.J.
      • Perucca E.
      • Wiebe S.
      • et al.
      Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies.
      ].
      Newer AEDs have novel mechanisms of action designed to decrease drug–drug interactions and achieve seizure freedom [
      • Stephen L.J.
      • Brodie M.J.
      Pharmacotherapy of epilepsy newly approved and developmental agents.
      ]. Lacosamide is one of the newest medications and exhibits its function through selectively enhancing slow inactivation of voltage-gated sodium channels, without affecting fast inactivation; decreasing in this way pathologic neuronal hyperexcitability without affecting the physiological neuronal function [
      • Rogawski M.A.
      • Tofighy A.
      • White H.S.
      • Matagne A.
      • Wolff C.
      Current understanding of the mechanism of action of the antiepileptic drug lacosamide.
      ]. Simultaneously, 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 [
      • Wilson S.M.
      • Khanna R.
      Specific binding of lacosamide to collapsin response mediator protein 2 (CRMP2) and direct impairment of its canonical function: implications for the therapeutic potential of lacosamide.
      ].
      Currently, lacosamide is approved by the Food and Drug Administration to be used in patients older than 16 years [
      • Stephen L.J.
      • Brodie M.J.
      Pharmacotherapy of epilepsy newly approved and developmental agents.
      ,
      • Rogawski M.A.
      • Tofighy A.
      • White H.S.
      • Matagne A.
      • Wolff C.
      Current understanding of the mechanism of action of the antiepileptic drug lacosamide.
      ]. 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.

      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 aggravation, lacosamide dosing regimen, and time of follow-up. Using a standardized form data were systematically reported. Discrepancies 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 [
      • Getchius T.S.D.
      Clinical Practice Guideline Process Manual Prepared by Neurology.
      ].

      2.4 Statistical analysis

      Categorical data were expressed as percentages and quantitative 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, 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.
      Fig. 1
      Fig. 1Flowchart of the literature search and study inclusion.

      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 [
      • Rastogi R.G.
      • Ng Y.-T.
      Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study.
      ]. Two studies [
      • Pasha I.
      • Kamate M.
      • Didagi S.K.
      Efficacy and tolerability of lacosamide as an adjunctive therapy in children with refractory partial epilepsy.
      ,
      • Grosso S.
      • Parisi P.
      • Spalice A.
      • Verrotti A.
      • Balestri P.
      Efficacy and safety of lacosamide in infants and young children with refractory focal epilepsy.
      ] 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.
      Table 1Clinical evidence of Lacosamide in pediatric Population.
      Author/YearStudy TypeAAN Classification EvidenceAge (years)NSeizuresFollow-up/Outcome (Mean)Seizure freedom (%)≥50% seizure reduction (%)Dose mg/Kg/day mean (range)Side Effects
      McGinnis 2016 [
      • Mcginnis E.
      • Kessler S.K.
      Lacosamide use in children with epilepsy: retention rate and effect of concomitant sodium channel blockers in a large cohort.
      ]
      RetroIV1–20223Focal 75%7 (1–53) months40(–)6.6 (1.4–251)Total 42%: MBC 16%, drowsiness 16%, dizziness 10%, GIU 8%, ataxia 5%, rash 3%
      Generalized 5%
      Mixed 19%
      Miskin 2016 [
      • Miskin C.
      • Khurana D.S.
      • Valencia I.
      • Legido A.
      • Hasbani D.M.
      • Carvalho K.S.
      Efficacy and tolerability of lacosamide in the treatment of children with refractory generalized epilepsy.
      ]
      RetroIV4–1521Generalized 100%: LGS 38%, Other 62%: JAE, JME, Doose19 months24436.9 (1.7–14.3)Total 29%: Somnolence 33%, weight loss 17%, tremor 17%, memory fails 17%, dizziness 17%
      Toupin 2015 [
      • Toupin J.-F.
      • Lortie A.
      • Major P.
      • Diadori P.
      • Vanasse M.
      • Rossignol E.
      • et al.
      Efficacy and safety of lacosamide as an adjunctive therapy for refractory focal epilepsy in paediatric patients: a retrospective single-centre.
      ]
      RetroIV5–2122Focal12 months4.5458.4Total 50%: Dizziness 23%, drowsiness 23%, incoordination 14%, MBC 9%, insomnia 9%, headache 5%, blurred vision 5%, GIU5%
      Gulati 2015 [
      • Gulati P.
      • Cannell P.
      • Ghia T.
      • Bint L.
      • Walsh P.
      • Ghosh S.
      • et al.
      Lacosamide as adjunctive therapy in treatment-resistant epilepsy in childhood.
      ]
      ProIII2–1940Focal9 months5205.7Total 18%: drowsiness, MBC, mild transient facial pain.
      Pasha 2014b [
      • Pasha I.
      • Kamate M.
      • Didagi S.K.
      Efficacy and tolerability of lacosamide as an adjunctive therapy in children with refractory partial epilepsy.
      ]
      ProIII5–1579Focal28 days(–)9650 mg BIDTotal 51%: Hyperactivity, ataxia, drowsiness, insomnia, weight gain, headache, GIU.
      Pasha 2014 [
      • Pasha I.
      • Kamate M.
      • Didagi S.K.
      Efficacy and tolerability of lacosamide as an adjunctive therapy in children with refractory partial epilepsy.
      ](1 year follow up)
      Two prospective studies assessed the efficacy soon after the drug initiation (28 days and 3 months) and re-assessed efficacy at 12 months.
      ProIII5–1579Focal12 months41624.151%: hyperactivity, ataxia, drowsiness, insomnia, weight gain, GIU, giddiness, headache
      Grosso 2014b [
      • Grosso S.
      • Coppola G.
      • Cusmai R.
      • Parisi P.
      • Spalice A.
      • Foligno S.
      Efficacy and tolerability of add-on lacosamide in children with Lennox-Gastaut syndrome.
      ]
      RetroIV4–1518Generalized: LGS9 months03315.2 (9.8–18.1)Total 44%: 17% seizure worsening, dizziness, GIU, gait instability.
      Grosso 2014c [
      • Grosso S.
      • Parisi P.
      • Giordano L.
      • di Bartolo R.
      • Balestri P.
      Lacosamide efficacy in epileptic syndromes with continuous spike and waves during slow sleep (CSWS).
      ]
      ProIII8–158Focal: CSWS6 months377512.225% MBC
      Kim 2014 [
      • Kim J.S.
      • Kim H.
      • Lim B.C.
      • Chae J.-H.
      • Choi J.
      • Kim K.J.
      • et al.
      Lacosamide as an adjunctive therapy in pediatric patients with refractory focal epilepsy.
      ]
      RetroIV1–1721Focal10.1 months19675.4 (1.4–9.8)Total 38%: somnolence 37%, dizziness25%, MBC 25%, sleep disturbance 12%, GIU 12%
      Grosso 2013 [
      • Grosso S.
      • Parisi P.
      • Spalice A.
      • Verrotti A.
      • Balestri P.
      Efficacy and safety of lacosamide in infants and young children with refractory focal epilepsy.
      ]
      ProIII1–324Focal3 months174212.5 (7–15.5)Total 33%: drowsiness (21%), MBC (12.5%), GIU (8%), instability and difficulty walking (4%).
      Grosso 2013 [
      • Grosso S.
      • Parisi P.
      • Spalice A.
      • Verrotti A.
      • Balestri P.
      Efficacy and safety of lacosamide in infants and young children with refractory focal epilepsy.
      ] (1 year follow up)
      Two prospective studies assessed the efficacy soon after the drug initiation (28 days and 3 months) and re-assessed efficacy at 12 months.
      ProIII1–318Focal12 months112212.5 (7–15.5)Total 33%: drowsiness (21%), nervousness (12.5%), vomiting (8%), instability and difficulty walking (4%).
      Verrotti 2013 [
      • Verrotti A.
      • Loiacono G.
      • Pizzolorusso A.
      • Parisi P.
      • Bruni O.
      • Luchetti A.
      • et al.
      Lacosamide in pediatric and adult patients: comparison of efficacy and safety.
      ]
      ProIII4–1559Focal 44%

      Generalized 20%

      Mixed 36%
      3 months7473–12Total 30%: seizure worsening 12%, GIU 7%, Headache 5%, CBM 5%, dizziness 3%, drowsiness 3%
      Casas-Fernandez 2012 [
      • Casas-Fernández C.
      • Martínez-Bermejo A.
      • Rufo-Campos M.
      • Smeyers-Durá P.
      • Herranz-Fernández J.L.
      • Ibáñez-Micó S.
      • et al.
      Efficacy and tolerability of lacosamide in the concomitant treatment of 130 patients under 16 years of age with refractory epilepsy: a prospective, open-label, observational, multicenter study in Spain.
      ]
      ProIII0.5–16130Focal 91%

      Generalized 9%
      3 months14626.8Total 30%: GIU 5%, instability 5%, dizziness 4%, nystagmus 2%, somnolence 2%
      Heyman 2012 [
      • Heyman E.
      • Lahat E.
      • Levin N.
      • Berkovitch M.
      • Gandelman-Marton R.
      Preliminary efficacy and safety of lacosamide in children with refractory epilepsy.
      ]
      RetroIV1.5–1617Focal 70%

      Mixed 30%
      9 months63512.3 (6.7–20)Total 59%:GIU 18%, dizziness 18%, seizure worsening 12%, restlessness 12%, fatigue 12%, headache 12%, increased appetite 6%, prolonged crying 6%.
      Rastogi 2012 [
      • Rastogi R.G.
      • Ng Y.-T.
      Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study.
      ]
      ProIV1–1616Focal 75% Generalized 25%9.8 months0502.4–19.4GIU, dizziness, headaches, somnolence, facial edema, and increased seizures
      Yorns 2012 [
      • Yorns W.R.
      • Khurana D.S.
      • Carvalho K.S.
      • Hardison H.H.
      • Legido A.
      • Valencia I.
      Efficacy of lacosamide as adjunctive therapy in children with refractory epilepsy.
      ]
      RetroIV1–2040Focal 42%

      Generalized 58%
      9.2 months15427Total: 37%: CBM 12%, lethargy 10%, seizure worsening 7%, weight loss 5%, dizziness 5%, mild memoryimpairment 2.5%, tremor 2.5%
      Afra 2012[
      • Afra P.
      • Adamolekun B.
      Lacosamide treatment of juvenile myoclonic epilepsy.
      ]
      RetroIV193Generalized (JME)15 months100100200 mg BIDNone reported
      Zangaladze 2012 [
      • Zangaladze A.
      • Skidmore C.
      Lacosamide use in refractory idiopathic primary generalized epilepsy.
      ]
      RetroIV211Generalized (JME)18 months100100200 mg BIDNone reported
      Andrade-Machado 2012 [
      • Andrade-Machado R.
      • Benjumea-Cuartas V.
      • Jaramillo-Jimenez E.
      Lacosamide in Lennox-Gastaut syndrome.
      ]
      RetroIV201Generalized (LGS)1 week00200 mg BIDSeizure worsening
      Guilhoto 2011 [
      • Guilhoto L.M.F.F.
      • Loddenkemper T.
      • Gooty V.D.
      • Rotenberg A.
      • Takeoka M.
      • Duffy F.H.
      • et al.
      Experience with lacosamide in a series of children with drug-resistant focal epilepsy.
      ]
      RetroIV8–2116Focal4 months19374.7Total 37%: GIU 12%, oral tics 6%, MBC 6% (suicidal ideation), ataxia 6%, worsening of chronic headache 6%, blurred vision 6%, seizure worsening 6%
      Gavatha 2011 [
      • Gavatha M.
      • Ioannou I.
      • Papavasiliou A.S.
      Epilepsy & behavior efficacy and tolerability of oral lacosamide as adjunctive therapy in pediatric patients with pharmacoresistant focal epilepsy.
      ]
      ProIV3–1818Focal3 months11366 (1.7–10)Total 39%: somnolence 17%, MBC 11%, sleep 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.

      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), gastrointestinal 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 [
      • Verrotti A.
      • Loiacono G.
      • Pizzolorusso A.
      • Parisi P.
      • Bruni O.
      • Luchetti A.
      • et al.
      Lacosamide in pediatric and adult patients: comparison of efficacy and safety.
      ]. Two out of 26 studies found evidence of an association between lacosamide failure and simultaneous treatment with a sodium channel blocking AED [
      • Mcginnis E.
      • Kessler S.K.
      Lacosamide use in children with epilepsy: retention rate and effect of concomitant sodium channel blockers in a large cohort.
      ,
      • Guilhoto L.M.F.F.
      • Loddenkemper T.
      • Gooty V.D.
      • Rotenberg A.
      • Takeoka M.
      • Duffy F.H.
      • et al.
      Experience with lacosamide in a series of children with drug-resistant focal epilepsy.
      ]. 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 [
      • Mcginnis E.
      • Kessler S.K.
      Lacosamide use in children with epilepsy: retention rate and effect of concomitant sodium channel blockers in a large cohort.
      ].

      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) [
      • Rastogi R.G.
      • Ng Y.-T.
      Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study.
      ,
      • Yorns W.R.
      • Khurana D.S.
      • Carvalho K.S.
      • Hardison H.H.
      • Legido A.
      • Valencia I.
      Efficacy of lacosamide as adjunctive therapy in children with refractory epilepsy.
      ] Table 2.
      Table 2Lacosamide experience in status epilepticus in children.
      Author/YearStudy TypeAAN Classification EvidenceAge (years)NType of patientsCSE/NCSE (n)Outcome (hours)Cessation of seizures (%)≥50% seizure reduction (%)Mean loading dose

      Mg/kg (range)
      Mean total dose mg/Kg (range)Side Effects in the next 48 h
      Poddar 2016 [
      • Abarrategui B.
      • García-García M.E.
      • Toledano R.
      • Parejo-Carbonell B.
      • Gil-Nagel A.
      • García-Morales I.
      Lacosamide for refractory generalized tonic-clonic seizures of non-focal origin in clinical practice: a clinical and VEEG study.
      ]
      RetroIV1–16
      Age range: 3 months–16 years old (mean 5.7 years).
      9Refractory Status epilepticus3/62444788.713.811% bradycardia
      Arkilo 2016 [
      • Arkilo D.
      • Gustafson M.
      • Ritter F.J.
      Clinical experience of intravenous lacosamide in infants and young children.
      ]
      RetroIV1–12
      Age range: 1 month–12 years old.
      14Epilepsia partialis continua (3), status epilepticus (11)(–)12(–)577.5(–)7% Sedation
      Loomba 2015 [
      • Loomba R.S.
      • Singh A.K.
      • Kovach J.
      • Gudausky T.M.
      Lacosamide-induced atrial tachycardia in a child with hypoplastic left-heart syndrome: the importance of assessing additional proarrhythmic risks.
      ]
      RetroIV31Refractory Status epilepticus1/040(–)3.67.1Wide Complex Tachycardia
      Grosso 2014a [
      • Grosso S.
      • Zamponi N.
      • Bartocci A.
      • Cesaroni E.
      • Cappanera S.
      • Di Bartolo R.
      • et al.
      Lacosamide in children with refractory status epilepticus: a multicenter Italian experience.
      ]
      RetroIV3–16
      Age mean 9.4 years.
      11Refractory Status epilepticus6/54845
      In 4 out of 5 patients (80%) status epilepticus ceased within 1–12 h of the first intravenous administration of the drug.
      63
      In two patients (18%) lacosamide was able to control all clinical seizures but frequent electrographic seizures were still recorded on EEG.
      8.6(–)
      The mean maintenance dose was 12.3 mg/kg/day (range 8.8–13.9).
      None reported
      Jain 2012 [
      • Jain V.
      • Harvey A.S.
      Treatment of refractory tonic status epilepticus with intravenous lacosamide.
      ]
      RetroIV12–173Tonic Refractory Status epilepticus3/0121001002.252.7533% Chorea
      33% Oculogyric crisis
      Mnatsakanyan 2012 [
      • Mnatsakanyan L.
      • Chung J.M.
      • Tsimerinov E.I.
      • Eliashiv D.S.
      Intravenous Lacosamide in refractory nonconvulsive status epilepticus.
      ]
      RetroIV161Refractory Status epilepticus0/1(–)100100200–300 mg200 mg BIDNone reported
      Shiloh-Malawsky 2011 [
      • Shiloh-Malawsky Y.
      • Fan Z.
      • Greenwood R.
      • Tennison M.
      Successful treatment of childhood prolonged refractory status epilepticus with lacosamide.
      ]
      RetroIV81Prolonged Refractory Status epilepticus0/1120100100None25 mg BIDNone reported
      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).

      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 [
      • Grosso S.
      • Parisi P.
      • Giordano L.
      • di Bartolo R.
      • Balestri P.
      Lacosamide efficacy in epileptic syndromes with continuous spike and waves during slow sleep (CSWS).
      ]. 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 [
      • Casas-Fernández C.
      • Martínez-Bermejo A.
      • Rufo-Campos M.
      • Smeyers-Durá P.
      • Herranz-Fernández J.L.
      • Ibáñez-Micó S.
      • et al.
      Efficacy and tolerability of lacosamide in the concomitant treatment of 130 patients under 16 years of age with refractory epilepsy: a prospective, open-label, observational, multicenter study in Spain.
      ] Similarly, Heyman et al reported improvement in behavior in 30% of patients with DRE on lacosamide [
      • Heyman E.
      • Lahat E.
      • Levin N.
      • Berkovitch M.
      • Gandelman-Marton R.
      Preliminary efficacy and safety of lacosamide in children with refractory epilepsy.
      ].
      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 [
      • Grosso S.
      • Coppola G.
      • Cusmai R.
      • Parisi P.
      • Spalice A.
      • Foligno S.
      Efficacy and tolerability of add-on lacosamide in children with Lennox-Gastaut syndrome.
      ]. Seizure worsening with lacosamide was also reported in two patients with LGS by Heyman et al. [
      • Heyman E.
      • Lahat E.
      • Levin N.
      • Berkovitch M.
      • Gandelman-marton R.
      Preliminary efficacy and safety of lacosamide in children with refractory epilepsy.
      ], one patient by Andrade-Machado et al. [
      • Andrade-Machado R.
      • Benjumea-Cuartas V.
      • Jaramillo-Jimenez E.
      Lacosamide in Lennox-Gastaut syndrome.
      ], and one patient by Yorns et al. [
      • Yorns W.R.
      • Khurana D.S.
      • Carvalho K.S.
      • Hardison H.H.
      • Legido A.
      • Valencia I.
      Efficacy of lacosamide as adjunctive therapy in children with refractory epilepsy.
      ]. Casas [
      • Casas-Fernández C.
      • Martínez-Bermejo A.
      • Rufo-Campos M.
      • Smeyers-Durá P.
      • Herranz-Fernández J.L.
      • Ibáñez-Micó S.
      • et al.
      Efficacy and tolerability of lacosamide in the concomitant treatment of 130 patients under 16 years of age with refractory epilepsy: a prospective, open-label, observational, multicenter study in Spain.
      ], Miskin [
      • Miskin C.
      • Khurana D.S.
      • Valencia I.
      • Legido A.
      • Hasbani D.M.
      • Carvalho K.S.
      Efficacy and tolerability of lacosamide in the treatment of children with refractory generalized epilepsy.
      ] and Rastogi [
      • Rastogi R.G.
      • Ng Y.-T.
      Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study.
      ] 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 3Clinical evidence of Lacosamide in Lennox-Gastaut Syndrome.
      Author/YearLennox-Gastaut Syndrome casesResponder: ≥50% seizure reduction N (%)Non-responder N (%)Seizure Aggravation N (%)
      Miskin 2016 [
      • Miskin C.
      • Khurana D.S.
      • Valencia I.
      • Legido A.
      • Hasbani D.M.
      • Carvalho K.S.
      Efficacy and tolerability of lacosamide in the treatment of children with refractory generalized epilepsy.
      ]
      87 (87.5)1 (12.5)0
      Grosso 2014b [
      • Grosso S.
      • Coppola G.
      • Cusmai R.
      • Parisi P.
      • Spalice A.
      • Foligno S.
      Efficacy and tolerability of add-on lacosamide in children with Lennox-Gastaut syndrome.
      ]
      186 (33)9 (50)3 (17)
      Yorns 2014 [
      • Yorns W.R.
      • Khurana D.S.
      • Carvalho K.S.
      • Hardison H.H.
      • Legido A.
      • Valencia I.
      Efficacy of lacosamide as adjunctive therapy in children with refractory epilepsy.
      ]
      53 (60)1 (20)1 (20)
      Heyman 2012 [
      • Heyman E.
      • Lahat E.
      • Levin N.
      • Berkovitch M.
      • Gandelman-Marton R.
      Preliminary efficacy and safety of lacosamide in children with refractory epilepsy.
      ]
      2002 (100)
      Casas 2012 [
      • Casas-Fernández C.
      • Martínez-Bermejo A.
      • Rufo-Campos M.
      • Smeyers-Durá P.
      • Herranz-Fernández J.L.
      • Ibáñez-Micó S.
      • et al.
      Efficacy and tolerability of lacosamide in the concomitant treatment of 130 patients under 16 years of age with refractory epilepsy: a prospective, open-label, observational, multicenter study in Spain.
      ]
      22 (100)00
      Rastogi 2012 [
      • Rastogi R.G.
      • Ng Y.-T.
      Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study.
      ]
      42 (50)2 (50)0
      Andrade-Machado 2012 [
      • Andrade-Machado R.
      • Benjumea-Cuartas V.
      • Jaramillo-Jimenez E.
      Lacosamide in Lennox-Gastaut syndrome.
      ]
      1001 (100)
      Total4020 (50)13 (32)7 (17)
      Non-responders: patients without changes in the seizure frequency after lacosamide initiation and maintenance.
      Yorns et al. [
      • Yorns W.R.
      • Khurana D.S.
      • Carvalho K.S.
      • Hardison H.H.
      • Legido A.
      • Valencia I.
      Efficacy of lacosamide as adjunctive therapy in children with refractory epilepsy.
      ] published five patients with LGS, but there is no information about the response to lacosamide in those patients.

      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) [
      • Paquette V.
      • Culley C.
      • Greanya E.D.
      • Ensom M.H.H.
      Lacosamide as adjunctive therapy in refractory epilepsy in adults: a systematic review.
      ]. 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.
      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% [
      • Andrade-Machado R.
      • Benjumea-Cuartas V.
      • Jaramillo-Jimenez E.
      Lacosamide in Lennox-Gastaut syndrome.
      ,
      • Miskin C.
      • Khurana D.S.
      • Valencia I.
      • Legido A.
      • Hasbani D.M.
      • Carvalho K.S.
      Efficacy and tolerability of lacosamide in the treatment of children with refractory generalized epilepsy.
      ,
      • Afra P.
      • Adamolekun B.
      Lacosamide treatment of juvenile myoclonic epilepsy.
      ,
      • Zangaladze A.
      • Skidmore C.
      Lacosamide use in refractory idiopathic primary generalized epilepsy.
      ,
      • Jain V.
      • Harvey A.S.
      Treatment of refractory tonic status epilepticus with intravenous lacosamide.
      ,
      • Grosso S.
      • Parisi P.
      • Spalice A.
      • Verrotti A.
      • Balestri P.
      Efficacy and safety of lacosamide in infants and young children with refractory focal epilepsy.
      ]. Six studies included mixed populations [
      • Rastogi R.G.
      • Ng Y.-T.
      Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study.
      ,
      • Mcginnis E.
      • Kessler S.K.
      Lacosamide use in children with epilepsy: retention rate and effect of concomitant sodium channel blockers in a large cohort.
      ,
      • Yorns W.R.
      • Khurana D.S.
      • Carvalho K.S.
      • Hardison H.H.
      • Legido A.
      • Valencia I.
      Efficacy of lacosamide as adjunctive therapy in children with refractory epilepsy.
      ,
      • Casas-Fernández C.
      • Martínez-Bermejo A.
      • Rufo-Campos M.
      • Smeyers-Durá P.
      • Herranz-Fernández J.L.
      • Ibáñez-Micó S.
      • et al.
      Efficacy and tolerability of lacosamide in the concomitant treatment of 130 patients under 16 years of age with refractory epilepsy: a prospective, open-label, observational, multicenter study in Spain.
      ,
      • Heyman E.
      • Lahat E.
      • Levin N.
      • Berkovitch M.
      • Gandelman-marton R.
      Preliminary efficacy and safety of lacosamide in children with refractory epilepsy.
      ,
      • Grosso S.
      • Parisi P.
      • Spalice A.
      • Verrotti A.
      • Balestri P.
      Efficacy and safety of lacosamide in infants and young children with refractory focal epilepsy.
      ]. 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) [
      • Grosso S.
      • Parisi P.
      • Spalice A.
      • Verrotti A.
      • Balestri P.
      Efficacy and safety of lacosamide in infants and young children with refractory focal epilepsy.
      ]. 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%) [
      • Yorns W.R.
      • Khurana D.S.
      • Carvalho K.S.
      • Hardison H.H.
      • Legido A.
      • Valencia I.
      Efficacy of lacosamide as adjunctive therapy in children with refractory epilepsy.
      ]. Likewise, Afra and Zangaladze reported four cases of juvenile myoclonic epilepsy with excellent response to lacosamide [
      • Afra P.
      • Adamolekun B.
      Lacosamide treatment of juvenile myoclonic epilepsy.
      ,
      • Zangaladze A.
      • Skidmore C.
      Lacosamide use in refractory idiopathic primary generalized epilepsy.
      ]. Finally, Casas et al. and McGinnis et al. did not find a relationship between the response to lacosamide and any epileptic syndrome [
      • Mcginnis E.
      • Kessler S.K.
      Lacosamide use in children with epilepsy: retention rate and effect of concomitant sodium channel blockers in a large cohort.
      ,
      • Casas-Fernández C.
      • Martínez-Bermejo A.
      • Rufo-Campos M.
      • Smeyers-Durá P.
      • Herranz-Fernández J.L.
      • Ibáñez-Micó S.
      • et al.
      Efficacy and tolerability of lacosamide in the concomitant treatment of 130 patients under 16 years of age with refractory epilepsy: a prospective, open-label, observational, multicenter study in Spain.
      ]. 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% [
      • Wechsler R.T.
      • Yates S.L.
      • Messenheimer J.
      • Leroy R.
      • Beller C.
      • Doty P.
      Lacosamide for uncontrolled primary generalized tonic-clonic seizures: an open-label pilot study with 59-week extension.
      ] to 22% [
      • Abarrategui B.
      • García-García M.E.
      • Toledano R.
      • Parejo-Carbonell B.
      • Gil-Nagel A.
      • García-Morales I.
      Lacosamide for refractory generalized tonic-clonic seizures of non-focal origin in clinical practice: a clinical and VEEG study.
      ] of the population treated with lacosamide. Interestingly, some of these patients had not previously experienced an absence seizure in their life [
      • Wechsler R.T.
      • Yates S.L.
      • Messenheimer J.
      • Leroy R.
      • Beller C.
      • Doty P.
      Lacosamide for uncontrolled primary generalized tonic-clonic seizures: an open-label pilot study with 59-week extension.
      ].
      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 [
      • Cuzzola A.
      • Ferlazzo E.
      • Italiano D.
      • Salvatore R.
      • Bramanti P.
      • Genton P.
      Epilepsy & behavior does lacosamide aggravate lennox – gastaut syndrome? Report on three consecutive cases.
      ,
      • Andrade-Machado R.
      • Benjumea-Cuartas V.
      • Jaramillo-Jimenez E.
      Lacosamide in Lennox-Gastaut syndrome.
      ]. 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 [
      • Grosso S.
      • Coppola G.
      • Cusmai R.
      • Parisi P.
      • Spalice A.
      • Foligno S.
      Efficacy and tolerability of add-on lacosamide in children with Lennox-Gastaut syndrome.
      ]. 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 – [
      • Mcginnis E.
      • Kessler S.K.
      Lacosamide use in children with epilepsy: retention rate and effect of concomitant sodium channel blockers in a large cohort.
      ]. Children who came off lacosamide did so because of partial or no response [
      • Gulati P.
      • Cannell P.
      • Ghia T.
      • Bint L.
      • Walsh P.
      • Ghosh S.
      • et al.
      Lacosamide as adjunctive therapy in treatment-resistant epilepsy in childhood.
      ]. 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 [
      • Mcginnis E.
      • Kessler S.K.
      Lacosamide use in children with epilepsy: retention rate and effect of concomitant sodium channel blockers in a large cohort.
      ,
      • Casas-Fernández C.
      • Martínez-Bermejo A.
      • Rufo-Campos M.
      • Smeyers-Durá P.
      • Herranz-Fernández J.L.
      • Ibáñez-Micó S.
      • et al.
      Efficacy and tolerability of lacosamide in the concomitant treatment of 130 patients under 16 years of age with refractory epilepsy: a prospective, open-label, observational, multicenter study in Spain.
      ]. 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 [
      • Yorns W.R.
      • Khurana D.S.
      • Carvalho K.S.
      • Hardison H.H.
      • Legido A.
      • Valencia I.
      Efficacy of lacosamide as adjunctive therapy in children with refractory epilepsy.
      ]. Although lacosamide adverse effects in children have been classically associated with higher dosages and speed of titration [
      • Buck M.L.
      • Goodkin H.P.
      • Services P.
      Use of lacosamide in children with refractory epilepsy.
      ], 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 [
      • Mcginnis E.
      • Kessler S.K.
      Lacosamide use in children with epilepsy: retention rate and effect of concomitant sodium channel blockers in a large cohort.
      ,
      • Guilhoto L.M.F.F.
      • Loddenkemper T.
      • Gooty V.D.
      • Rotenberg A.
      • Takeoka M.
      • Duffy F.H.
      • et al.
      Experience with lacosamide in a series of children with drug-resistant focal epilepsy.
      ].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 [
      • Mcginnis E.
      • Kessler S.K.
      Lacosamide use in children with epilepsy: retention rate and effect of concomitant sodium channel blockers in a large cohort.
      ,
      • Buck M.L.
      • Goodkin H.P.
      • Services P.
      Use of lacosamide in children with refractory epilepsy.
      ], and other studies did not find it [
      • Yorns W.R.
      • Khurana D.S.
      • Carvalho K.S.
      • Hardison H.H.
      • Legido A.
      • Valencia I.
      Efficacy of lacosamide as adjunctive therapy in children with refractory epilepsy.
      ,
      • Gavatha M.
      • Ioannou I.
      • Papavasiliou A.S.
      Epilepsy & behavior efficacy and tolerability of oral lacosamide as adjunctive therapy in pediatric patients with pharmacoresistant focal epilepsy.
      ,
      • Sake J.K.
      • Hebert D.
      • Isojrvi J.
      • Doty P.
      • De Backer M.
      • Davies K.
      • et al.
      A Pooled Analysis of lacosamide clinical trial data grouped by mechanism of action of concomitant antiepileptic drugs.
      ]. 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 [
      • Strzelczyk A.
      • Z??llner J.P.
      • Willems L.M.
      • Jost J.
      • Paule E.
      • Schubert-Bast S.
      • et al.
      Lacosamide in status epilepticus: systematic review of current evidence.
      ], 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% [
      • Trinka E.
      • Höfler J.
      • Tilz C.
      • Kellinghaus C.
      Comment: lacosamide for the treatment of refractory status epilepticus.
      ]. 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 [
      • Zaccara G.
      • Perucca P.
      • Loiacono G.
      • Giovannelli F.
      • Verrotti A.
      The adverse event profile of lacosamide: a systematic review and meta-analysis of randomized controlled trials.
      ]. 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%) [
      • Poddar K.
      • Sharma R.
      • Ng Y.T.
      Intravenous lacosamide in pediatric status epilepticus: an open-label efficacy and safety study.
      ] and (2.5%) of tachycardia [
      • Loomba R.S.
      • Singh A.K.
      • Kovach J.
      • Gudausky T.M.
      Lacosamide-induced atrial tachycardia in a child with hypoplastic left-heart syndrome: the importance of assessing additional proarrhythmic risks.
      ] 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 [
      • Loomba R.S.
      • Singh A.K.
      • Kovach J.
      • Gudausky T.M.
      Lacosamide-induced atrial tachycardia in a child with hypoplastic left-heart syndrome: the importance of assessing additional proarrhythmic risks.
      ]. A recent publication has reported a possible interaction between lacosamide and valproic acid resulting in hyperammonemic encephalopathy [
      • Do G.L.J.
      • Popli G.S.
      • Silvia M.T.
      Pediatric neurology lacosamide-induced valproic acid toxicity.
      ]. 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 [
      • Moavero R.
      • Santarone M.E.
      • Galasso C.
      • Curatolo P.
      Cognitive and behavioral effects of new antiepileptic drugs in pediatric epilepsy.
      ]. By contrast, several articles have reported cases of mild negative mood and behavioral changes (5–25%) [
      • Verrotti A.
      • Loiacono G.
      • Pizzolorusso A.
      • Parisi P.
      • Bruni O.
      • Luchetti A.
      • et al.
      Lacosamide in pediatric and adult patients: comparison of efficacy and safety.
      ,
      • Mcginnis E.
      • Kessler S.K.
      Lacosamide use in children with epilepsy: retention rate and effect of concomitant sodium channel blockers in a large cohort.
      ,
      • Grosso S.
      • Parisi P.
      • Giordano L.
      • di Bartolo R.
      • Balestri P.
      Lacosamide efficacy in epileptic syndromes with continuous spike and waves during slow sleep (CSWS).
      ,
      • Gulati P.
      • Cannell P.
      • Ghia T.
      • Bint L.
      • Walsh P.
      • Ghosh S.
      • et al.
      Lacosamide as adjunctive therapy in treatment-resistant epilepsy in childhood.
      ,
      • Gavatha M.
      • Ioannou I.
      • Papavasiliou A.S.
      Epilepsy & behavior efficacy and tolerability of oral lacosamide as adjunctive therapy in pediatric patients with pharmacoresistant focal epilepsy.
      ,
      • Kim J.S.
      • Kim H.
      • Lim B.C.
      • Chae J.H.
      • Choi J.
      • Kim K.J.
      • Hwang Y.S.
      • Hwang H.
      Lacosamide as an adjunctive therapy in pediatric patients with refractory focal epilepsy.
      ,
      • Toupin J.-F.
      • Lortie A.
      • Major P.
      • Diadori P.
      • Vanasse M.
      • Rossignol E.
      • et al.
      Efficacy and safety of lacosamide as an adjunctive therapy for refractory focal epilepsy in paediatric patients: a retrospective single-centre.
      ]. In few special cases, lacosamide was discontinued because of severe hyperactivity, aggression, and inattention [
      • Pasha I.
      • Kamate M.
      • Didagi S.K.
      Efficacy and tolerability of lacosamide as an adjunctive therapy in children with refractory partial epilepsy.
      ,
      • Yorns W.R.
      • Khurana D.S.
      • Carvalho K.S.
      • Hardison H.H.
      • Legido A.
      • Valencia I.
      Efficacy of lacosamide as adjunctive therapy in children with refractory epilepsy.
      ]. One concerning case described a patient who manifested depression and suicidal ideation [
      • Guilhoto L.M.F.F.
      • Loddenkemper T.
      • Gooty V.D.
      • Rotenberg A.
      • Takeoka M.
      • Duffy F.H.
      • et al.
      Experience with lacosamide in a series of children with drug-resistant focal epilepsy.
      ]. 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.

      Conflicts of interest

      The authors have no conflict of interest.

      Ethical publication statement

      We confirm that we have read the Journals position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

      Founding sources

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Acknowledgment

      We would like to thank Dr. Sandra Riveros for her support and commentaries regarding methodology of searching.

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