e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 5 5 e5 9
Official Journal of the European Paediatric Neurology Society
Original article
Efficacy and safety of lacosamide in infants and young children with refractory focal epilepsy Salvatore Grosso a,e,*, Pasquale Parisi b, Alberto Spalice c, Alberto Verrotti d, Paolo Balestri e a
Child NeurologyeImmunology and Endocrinology Unit, University of Siena, Italy Child Neurology, Chair of Pediatrics, NESMOS Department, Faculty of Medicine and Psychology, “Sapienza University”, Rome, Italy c Department of Pediatrics, Child Neurology Division, Sapienza University of Rome, Italy d Clinical Pediatrics, University of Chieti, Italy e Department of Pediatrics, University of Siena, Italy b
article info
abstract
Article history:
Background: Lacosamide is effective and well-tolerated antiepileptic drug (AED) in both
Received 10 July 2013
children and adults.
Received in revised form
Aim: This multicentric, prospective study investigates the efficacy and safety of lacosamide
10 August 2013
adjunctive therapy in children aged less than four years presenting with refractory focal
Accepted 22 August 2013
seizures. Methods: Lacosamide was added to the baseline therapy at a starting dose of 1e2 mg/kg/day
Keywords:
and titrated to the final dose, ranging from 7 to 15.5 mg/kg/day. Efficacy was evaluated after
Antiepileptic drugs
a three-month period of therapy. When possible, we compared the initial efficacy and the
Partial seizures
retention after a minimum of 12 months of lacosamide, with regard to loss of efficacy
Epileptic encephalopathy
(defined as the return to the baseline seizure frequency).
Pediatrics
Results: Twenty-four children were enrolled in the study. Mean age was 2.7 years. After a
Drug resistant epilepsy
minimum three-month period of lacosamide add-on therapy, ten (42%) patients were responders (more than a 50% decrease in seizure frequency), of whom 4 (17%) became seizure free. Retention rate, after a minimum of 12 months of lacosamide, was evaluated in a group of 18 patients. In the latter group, eight patients (44%) were initial responders (three of whom seizure free). After 12 months of follow-up, four of them (22%) maintained the improvement, 2 (11%) of whom remained seizure free. A loss of efficacy was observed in 4 of the initial responders (50%). Adverse events were seen in 8 (33%) patients. Conclusion: We conclude that lacosamide is an effective and a well-tolerated antiepileptic drug in an etiologically wide range of focal seizures. Therefore, lacosamide might represent a possible therapeutic option in infants and young children affected by uncontrolled focal epilepsy. ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. ImmunologyeNeurology and Endocrinology Unit, Department of Pediatrics, University of Siena, Via M. Bracci, Le Scotte, 53100 Siena, Italy. Tel.: þ39 057 7586 546. E-mail address: [email protected] (S. Grosso). 1090-3798/$ e see front matter ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejpn.2013.08.006
56
1.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 5 5 e5 9
Introduction
Lacosamide is one of the latest antiepileptic drug (AED) available on the market.1 It is a functionalized amino acid that selectively enhances slow inactivation of voltage-gated sodium channels, increasing the proportion of sodium channels unavailable for depolarization. Unlike other anticonvulsants lacosamide does not alter fast inactivation of voltage-gated sodium channels.1 Lacosamide may also interact with collapsin response mediator protein 2 (CRMP-2); however, this binding has recently been challenged.2 Studies of the pharmacokinetic profile of lacosamide in children are under way.1 However, in adults the drug appears to have a favorable profile since it is completely absorbed after oral administration and exhibits minimal protein binding (50%). We defined responders those patients who at the last follow-up visit had more than 50% reduction in seizure frequency during a minimum period of 3 months. Physicians openly reported adverse events related to the drug administration.
2.2.
Lacosamide retention at 12 months
In a group of 18 patients, the initial lacosamide efficacy, defined as the number of responsive patients at a minimum period of three months follow-up (range 3e4 months), was compared with the retention at 12 months of lacosamide, to examine the loss of efficacy. Retention at 12 months of lacosamide, a composite measure of efficacy and adverse events in clinical practice, was defined as the percentage of patients still taking lacosamide after a 12-month period of follow-up. Loss of efficacy was defined as the return to the baseline seizure frequency.
2.3.
Statistics
Wilcoxon rank sum score test was used to compare nonparametric data (SPSS 11 software version 11.0; SPSS Inc., Chicago, IL, USA).
3.
Results
A total of 24 children (10 girls and 14 boys) aged less than four years were recruited (Table 1). Neuromotor retardation, evaluated before starting lacosamide by BruneteLezine13 or TermaneMerrill14 tests, was observed in 19 (79%) patients. It was considered to be severe in 8, moderate in 7, and mild in 2. Median seizure frequency was 38 per month (range 5e56). The mean age to the first seizure was 10.5 months (range 1e25), and mean duration of the epileptic history was 17 months (range 3e35 months). Epilepsy was symptomatic in 14 (58%) patients and cryptogenic in 10 (42%). In 5 (21%) patients, partial seizures evolved to secondary generalization. The mean number of antiepileptic drugs (AEDs) tried before starting lacosamide treatment was three (range 1e7). The median number of AEDs administered when lacosamide treatment was started was two (range 1e4) (Table 1). The mean age of patients at the time of initial lacosamide treatment was 22 months (range 14e42 months). The mean duration of treatment was 10.3 months (range 3e26 months). Mean lacosamide daily dose was 12.5 mg/kg (range 7e15.5 mg/ kg/day).
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 5 5 e5 9
Table 1 e Clinical findings of patients. Characteristics Age (year) Mean SD Range Sex M F Age at seizure onset (months) Mean Range Age lacosamide initiated (months) Mean Range Seizure types, n (%) Dyscognitive Focal versive Focal motor Focal somatosensory Secondary generalization Etiology classification, n (%) Symptomatic Cryptogenic N of AEDs when LCM initiated, n (%) 1 2 3 4 Concomitant AEDs, n (%) VPA TPM LEV BDZ CBZ OXC RUF PHT Efficacy after 3-month follow-up Symptomatic Responders n (%) Nonresponders n (%) Cryptogenic Responders n (%) Nonresponders n (%)
Value 2.7 1.1 1.9e3.9 14 10 10.5 3.2 1e25 22 5.5 14e42 16 (58%) 5 (21%) 3 (12.5%) 3 (12.5%) 5 (21%) 14 (58%) 10 (42%) 2 (12.5%) 12 (50%) 7 (25% 4 (17%) 10 (42%) 7 (30%) 6 (21%) 5 (21%) 4 (17%) 4 (17%) 3 (12.5%) 1 (4%)
3 (21%) 11 (79%) 6 (60%) 4 (40%)
Legend. M: male; F: female; AED: antiepileptic drug; VPA: valproic acid; TPM: topiramate; LEV: levetiracetam; BDZ: benzodiazepines; CBZ: carbamazepine; OXC: oxcarbazepine; RUF: rufinamide; PHT: phenytoin.
3.1.
Efficacy
After three month-period of lacosamide add-on therapy, ten (42%) patients were considered to be responders because they showed a reduction in their seizure frequency by more than 50%. Specifically, 4 (17%) children became seizure free and 6 (25%) showed a seizure reduction of more than 50%. Seizure frequency remained unchanged in 9 (37.5%) patients, and slightly increased in another one (4%) in comparison with the baseline. Adverse events prompted lacosamide discontinuation in 4 (17%) patients (Table 1). Lacosamide appeared to be effective in an etiologically wide range of epileptic disorders. However, patients with a cryptogenic etiology tended to be more responder than those with symptomatic epilepsy (21% and 60%, respectively).
57
In one patient affected by perinatal anoxic-ischemic encephalopathy, lacosamide monotherapy was successful after the previous AED was tailored-off. In a further two (8%) children, one or more concomitant drugs was reduced without affecting seizure frequency.
3.2.
Lacosamide retention at 12 months
The group of 18 patients was not different from the remaining patients in terms of age, sex, epilepsy history, seizure frequency, and number of antiepileptic drugs administered (Wilcoxon sum rank test). Efficacy retention at 12 months was observed in 4 out of 18 patients (22%), of whom 2 (8%) remained seizure free. A loss of efficacy was seen in four (50%) of the eight initial responders of whom 2 (11%) still seizure free. With respect to etiology, efficacy loss was less obvious in patients with cryptogenic focal epilepsy (Fig. 1B).
3.3.
Safety
At least one adverse event was seen in 8 (33%) patients. The most common adverse events were drowsiness (21%), nervousness (12.5%), vomiting (8%), instability and difficulty walking (4%). Five patients showed more than one side effect. No life threatening side effects were observed during the study. All side effects were either tolerable or resolved in time through dosage reduction (drowsiness in two patients and vomiting in another one) or discontinuation of the drug (in a child with walking instability). There were no significant laboratory anomalies in liver function, renal function, or hematology.
4.
Discussion
In randomized controlled trials conducted in adults, lacosamide has shown to be an effective and safe AED in treating refractory seizures, with 30%e40% of patients achieving a 50% reduction in seizure frequency at doses of 400e600 mg/ day.1,4e7 Since 2010, five studies have been published that report similar efficacy and tolerability of lacosamide in children and young adults with refractory epilepsy.8e12 Thirty-six percent of 18 children placed under lacosamide, at a mean dose of 6.3 mg/kg/day (rage 1.7e10), were found to be responder (50% in seizure reduction) for a mean period of 8 months.8 In a retrospective study, Guilhoto et al.9 evaluated the efficacy and safety of lacosamide in a series of adolescent patients (mean age 14.9 years) and reported that six of them (37.5%) were classified as responder to therapy. Similar results (35% of responders) were observed by Heyman et al.10 in seventeen younger children (mean age 8 years) placed under lacosamide for a mean follow-up period of 9.1 months. In a recent, prospective, study including 21 pediatric patients affected by refractory epilepsy with various seizure types, lacosamide demonstrated to be an effective AED.11 In particular, 62.5% of patients with localization-related epilepsy and 25% of those having generalized epilepsy were defined as responders at the last visit. Of interest, two patients with Lennox-Gastaut syndrome showed greater than 90% seizure reduction. However, none of these very refractory patients
58
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 5 5 e5 9
Fig. 1 e Study design (A). Retention rate after 12 months of follow-up (B). remained seizure free.11 In a prospective, open-label, multicenter study including 130 patients aged less than 16 years with a variety of etiologies including refractory partial epilepsies and symptomatic, generalized epilepsy syndromes. The drug was dosed at a mean of 6.8 mg/kg/day. After 3 months of lacosamide add-on therapy, 62.3% of patients achieved a 50% reduction in seizure frequency.12 Lacosamide efficacy and safety were also evaluated in two series including both children and adults.15,16 In particular, a comparison study of lacosamide efficacy and safety in pediatric and adult patients with uncontrolled focal and generalized epilepsy, showed similar response rates (47% of patients with >50% of seizure reduction) after three months of therapy.15 Novy et al.,16 recently reported that forty-five percent of the 376 people included were still taking LCM at last follow-up. Eighteen percent reported a period of improvement in terms of significant seizure reduction or seizure freedom of at least six months duration whilst on LCM, of whom four people were seizure free for at least one year. The authors concluded that long-term efficacy appeared similar to zonisamide and pregabalin when compared to historical controls. Lacosamide has been approved by the licensing authorities in the European Union and in the United States as an add-on treatment of partial seizures in patients 16 years of age or older. Although, a number of infants and young children were treated with lacosamide and reported in other studies,8e12,15,16 systematic data are not yet available. In this context, we believe this study is the first evaluation of the efficacy and safety of lacosamide in patients aged less than four years affected by focal seizures. The design of the present study
reflects daily clinical practice. Although this introduces some methodological weaknesses, it provides a more natural and realistic view of the use of lacosamide in infants and young children. All patients we studied were refractory to first line drugs. The main aim of add-on treatment in these patients was to improve their quality of life by decreasing seizure frequency as much as possible and by limiting adverse events, rather than to make them seizure free.17 Forty-two percent of patients had a more than a 50% reduction in seizure frequency after a three-month period of therapy. The percentage of responders was slightly higher than that reported in older children with focal epilepsy in previous studies8e10 and lower than that observed in studies including patients with both focal and generalized uncontrolled seizures.12,15 We compared the efficacy in 18 patients observed after a mean of three months of follow-up with retention after 12 months of lacosamide, with regard to loss of efficacy. According to Krakow et al.18 the retention rate is an important measure of the efficacy and adverse events of the drug because it is a reliable indicator over time. Twenty-two percent of our patients were still responsive to lacosamide after a minimum of 12 months of follow-up. Loss of efficacy was observed in 50% of the initial responders. Although our series is small, it seems to suggest a sustained lacosamide efficacy over time in patients with focal epilepsy. Since comedication was not (or only slightly) altered before seizure relapse, we suggest that the loss of efficacy with lacosamide was likely related to the development of tolerance to the drug. However, the percentage of responders after 12 month-period of lacosamide therapy, was lower than that observed in older
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 5 5 e5 9
children and adults in previous studies.15 In particular, Novy et al.,16 found that lacosamide retention was 62% at one year, 45% at two years and 35% at three years. The lower retention rate we observed may be because of insufficient experience with lacosamide in young children, resulting in a very strong selection bias for infants with very difficult-to-treat epilepsies This bias is further enhanced in our data which are constituted by pooled data of the first experiences with lacosamide coming from 4 pediatric neurology departments. Although the patients we investigated did not have long histories of epilepsy, up to 7 AEDs had been used before lacosamide therapy was started. Moreover, the majority of children were mentally retarded, with epilepsy being mainly related to brain injuries or brain malformations. Lacosamide has been reported to be a well-tolerated, relatively safe drug.19 Adverse reactions, such as dizziness, headache, diplopia, nausea and somnolence have an incidence varying from 29% to 61%.15,16 Similar adverse effect data have been observed in pediatric case reports and case series, with dizziness and nausea being the most commonly reported.9,10,12,19 In contrast, drowsiness was the most common adverse event we observed in our study (21% of patients), being our data congruent with those reported by Cavatha et al.,.8 Most adverse effects seen with lacosamide in adults are dose-related and are reversible upon discontinuation or dose reduction.19 In children, lacosamide doses up to 20 mg/ kg/day may be well-tolerated.19,20 The mean dose of lacosamide in our study was 12.5 mg/kg/day, with an incidence of adverse events (33%), which is similar to that reported in previous studies.8,9,11 Lacosamide was discontinued in only one patient (4%) because of severe instability. Dosage reduction was necessary in another three cases with gradual disappearance of side effects. In conclusion, although caution may still be necessary when lacosamide is used in infants and children younger than 4 years, our observations suggest that lacosamide is effective and safe and represents a possible option in treating uncontrolled focal epilepsy in this population. Of course, further clinical trials are needed to validate our data. In fact, the size of our population was not so large to enable us to draw definite conclusions.
4.
5.
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7.
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10.
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13. 14.
15.
16.
references 17. 1. Fattore C, Perucca E. Novel medications for epilepsy. Drugs 2011;71:2151e78. 2. Wolff C, Carrington B, Varrin-Doyer M, Vandendriessche A, Van der Perren C, Famelart M, et al. Drug binding assays do not reveal specific binding of lacosamide to collapsing response mediator protein 2 (CRMP-2). CNS Neurosci Ther 2012;18:493e500. 3. Cawello W, Boekens H, Bonn R. Absorption, disposition, metabolic fate and elimination of the anti-epileptic drug lacosamide in humans: mass balance following intravenous
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and oral administration. Eur J Drug Metab Pharmacokinet 2012;37:241e8. Ben-Menachem E, Biton V, Jatuzis D, Abou-Khalil B, Doty P, Rudd GD. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia 2007;48:1308e17. ska M, Hala´sz P, Ka¨lvia¨inen R, Mazurkiewicz-Beldzin Rosenow F, Doty P, Hebert D, et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia 2009;50:443e53. Chung SS. New treatment option for partial-onset seizures: efficacy and safety of lacosamide. Ther Adv Neurol Disord 2010;3:77e83. Chung S, Sperling MR, Biton V, Krauss G, Hebert D, Rudd GD, et al. Lacosamide as adjunctive therapy for partial onset seizures: a randomized controlled trial. Epilepsia 2010;51:958e67. Gavatha M, Ionnou I, Papavasiliou AS. Efficacy and tolerability of oral lacosamide as adjunctive therapy in pediatric patients with pharmacoresistant focal epilepsy. Epilepsy Behav 2011;20:691e3. Guilhoto LM, Loddenkemper T, Gooty VD, Rotenberg A, Takeoka M, Duffy FH, et al. Experience with lacosamide in a series of children with drug-resistant focal epilepsy. Pediatr Neurol 2011;44:414e9. Heyman E, Lahat E, Levin N, Berkovitch M, GandelmanMarton R. Preliminary efficacy and safety of lacosamide in children with refractory epilepsy. Eur J Paediatr Neurol 2012;16:15e9. Rastogi RG, Ng Y. Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study. J Child Neurol 2012;27:492e5. Casas-Ferna´ndez C, Martı´nez-Bermejo A, Rufo-Campos M, Smeyers-Dura´ P, Herranz-Ferna´ndez JL, Iba´n˜ez-Mico´ 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. Drugs R D 2012;12:187e97. Brunet O, Lezine I. Le developpement psychologique de la premiere enfance. Paris: Presse Universitaire de France; 1951. Terman LM, Merrill M, editors. Stanford-Binet intelligence scale: manual for the third revision. Boston: L-M. Houghton Mifflin; 1960. 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. Seizure 2013;22:210e6. Novy J, Bartolini E, Bell GS, Duncan JS, Sander JW. Long-term retention of lacosamide in a large cohort of people with medically refractory epilepsy: a single centre evaluation. Epilepsy Res 2013;106:250e6. Lagae L, Buyse G, Deconinck A, Ceulemans B. Effect of levetiracetam in refractory childhood epilepsy syndromes. Eur J Paediatr Neurol 2003;7:123e8. Krakow K, Walker M, Otoul C, Sander JW. Long-term continuation of levetiracetam in patients with refractory epilepsy. Neurology 2001;56:1772e4. Buck ML, Goodkin HP. Use of lacosamide in children with refractory epilepsy. J Pediatr Pharmacol Ther 2012;17:211e9. Vishwanath VA, Miller LM. What is the right dose of lacosamide in pediatric patients with intractable epilepsy? Epilepsy Behav 2012;23:396e7.
Official Journal of the European Paediatric Neurology Society
Original article
Efficacy and safety of lacosamide in infants and young children with refractory focal epilepsy Salvatore Grosso a,e,*, Pasquale Parisi b, Alberto Spalice c, Alberto Verrotti d, Paolo Balestri e a
Child NeurologyeImmunology and Endocrinology Unit, University of Siena, Italy Child Neurology, Chair of Pediatrics, NESMOS Department, Faculty of Medicine and Psychology, “Sapienza University”, Rome, Italy c Department of Pediatrics, Child Neurology Division, Sapienza University of Rome, Italy d Clinical Pediatrics, University of Chieti, Italy e Department of Pediatrics, University of Siena, Italy b
article info
abstract
Article history:
Background: Lacosamide is effective and well-tolerated antiepileptic drug (AED) in both
Received 10 July 2013
children and adults.
Received in revised form
Aim: This multicentric, prospective study investigates the efficacy and safety of lacosamide
10 August 2013
adjunctive therapy in children aged less than four years presenting with refractory focal
Accepted 22 August 2013
seizures. Methods: Lacosamide was added to the baseline therapy at a starting dose of 1e2 mg/kg/day
Keywords:
and titrated to the final dose, ranging from 7 to 15.5 mg/kg/day. Efficacy was evaluated after
Antiepileptic drugs
a three-month period of therapy. When possible, we compared the initial efficacy and the
Partial seizures
retention after a minimum of 12 months of lacosamide, with regard to loss of efficacy
Epileptic encephalopathy
(defined as the return to the baseline seizure frequency).
Pediatrics
Results: Twenty-four children were enrolled in the study. Mean age was 2.7 years. After a
Drug resistant epilepsy
minimum three-month period of lacosamide add-on therapy, ten (42%) patients were responders (more than a 50% decrease in seizure frequency), of whom 4 (17%) became seizure free. Retention rate, after a minimum of 12 months of lacosamide, was evaluated in a group of 18 patients. In the latter group, eight patients (44%) were initial responders (three of whom seizure free). After 12 months of follow-up, four of them (22%) maintained the improvement, 2 (11%) of whom remained seizure free. A loss of efficacy was observed in 4 of the initial responders (50%). Adverse events were seen in 8 (33%) patients. Conclusion: We conclude that lacosamide is an effective and a well-tolerated antiepileptic drug in an etiologically wide range of focal seizures. Therefore, lacosamide might represent a possible therapeutic option in infants and young children affected by uncontrolled focal epilepsy. ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. ImmunologyeNeurology and Endocrinology Unit, Department of Pediatrics, University of Siena, Via M. Bracci, Le Scotte, 53100 Siena, Italy. Tel.: þ39 057 7586 546. E-mail address: [email protected] (S. Grosso). 1090-3798/$ e see front matter ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejpn.2013.08.006
56
1.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 5 5 e5 9
Introduction
Lacosamide is one of the latest antiepileptic drug (AED) available on the market.1 It is a functionalized amino acid that selectively enhances slow inactivation of voltage-gated sodium channels, increasing the proportion of sodium channels unavailable for depolarization. Unlike other anticonvulsants lacosamide does not alter fast inactivation of voltage-gated sodium channels.1 Lacosamide may also interact with collapsin response mediator protein 2 (CRMP-2); however, this binding has recently been challenged.2 Studies of the pharmacokinetic profile of lacosamide in children are under way.1 However, in adults the drug appears to have a favorable profile since it is completely absorbed after oral administration and exhibits minimal protein binding (50%). We defined responders those patients who at the last follow-up visit had more than 50% reduction in seizure frequency during a minimum period of 3 months. Physicians openly reported adverse events related to the drug administration.
2.2.
Lacosamide retention at 12 months
In a group of 18 patients, the initial lacosamide efficacy, defined as the number of responsive patients at a minimum period of three months follow-up (range 3e4 months), was compared with the retention at 12 months of lacosamide, to examine the loss of efficacy. Retention at 12 months of lacosamide, a composite measure of efficacy and adverse events in clinical practice, was defined as the percentage of patients still taking lacosamide after a 12-month period of follow-up. Loss of efficacy was defined as the return to the baseline seizure frequency.
2.3.
Statistics
Wilcoxon rank sum score test was used to compare nonparametric data (SPSS 11 software version 11.0; SPSS Inc., Chicago, IL, USA).
3.
Results
A total of 24 children (10 girls and 14 boys) aged less than four years were recruited (Table 1). Neuromotor retardation, evaluated before starting lacosamide by BruneteLezine13 or TermaneMerrill14 tests, was observed in 19 (79%) patients. It was considered to be severe in 8, moderate in 7, and mild in 2. Median seizure frequency was 38 per month (range 5e56). The mean age to the first seizure was 10.5 months (range 1e25), and mean duration of the epileptic history was 17 months (range 3e35 months). Epilepsy was symptomatic in 14 (58%) patients and cryptogenic in 10 (42%). In 5 (21%) patients, partial seizures evolved to secondary generalization. The mean number of antiepileptic drugs (AEDs) tried before starting lacosamide treatment was three (range 1e7). The median number of AEDs administered when lacosamide treatment was started was two (range 1e4) (Table 1). The mean age of patients at the time of initial lacosamide treatment was 22 months (range 14e42 months). The mean duration of treatment was 10.3 months (range 3e26 months). Mean lacosamide daily dose was 12.5 mg/kg (range 7e15.5 mg/ kg/day).
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 5 5 e5 9
Table 1 e Clinical findings of patients. Characteristics Age (year) Mean SD Range Sex M F Age at seizure onset (months) Mean Range Age lacosamide initiated (months) Mean Range Seizure types, n (%) Dyscognitive Focal versive Focal motor Focal somatosensory Secondary generalization Etiology classification, n (%) Symptomatic Cryptogenic N of AEDs when LCM initiated, n (%) 1 2 3 4 Concomitant AEDs, n (%) VPA TPM LEV BDZ CBZ OXC RUF PHT Efficacy after 3-month follow-up Symptomatic Responders n (%) Nonresponders n (%) Cryptogenic Responders n (%) Nonresponders n (%)
Value 2.7 1.1 1.9e3.9 14 10 10.5 3.2 1e25 22 5.5 14e42 16 (58%) 5 (21%) 3 (12.5%) 3 (12.5%) 5 (21%) 14 (58%) 10 (42%) 2 (12.5%) 12 (50%) 7 (25% 4 (17%) 10 (42%) 7 (30%) 6 (21%) 5 (21%) 4 (17%) 4 (17%) 3 (12.5%) 1 (4%)
3 (21%) 11 (79%) 6 (60%) 4 (40%)
Legend. M: male; F: female; AED: antiepileptic drug; VPA: valproic acid; TPM: topiramate; LEV: levetiracetam; BDZ: benzodiazepines; CBZ: carbamazepine; OXC: oxcarbazepine; RUF: rufinamide; PHT: phenytoin.
3.1.
Efficacy
After three month-period of lacosamide add-on therapy, ten (42%) patients were considered to be responders because they showed a reduction in their seizure frequency by more than 50%. Specifically, 4 (17%) children became seizure free and 6 (25%) showed a seizure reduction of more than 50%. Seizure frequency remained unchanged in 9 (37.5%) patients, and slightly increased in another one (4%) in comparison with the baseline. Adverse events prompted lacosamide discontinuation in 4 (17%) patients (Table 1). Lacosamide appeared to be effective in an etiologically wide range of epileptic disorders. However, patients with a cryptogenic etiology tended to be more responder than those with symptomatic epilepsy (21% and 60%, respectively).
57
In one patient affected by perinatal anoxic-ischemic encephalopathy, lacosamide monotherapy was successful after the previous AED was tailored-off. In a further two (8%) children, one or more concomitant drugs was reduced without affecting seizure frequency.
3.2.
Lacosamide retention at 12 months
The group of 18 patients was not different from the remaining patients in terms of age, sex, epilepsy history, seizure frequency, and number of antiepileptic drugs administered (Wilcoxon sum rank test). Efficacy retention at 12 months was observed in 4 out of 18 patients (22%), of whom 2 (8%) remained seizure free. A loss of efficacy was seen in four (50%) of the eight initial responders of whom 2 (11%) still seizure free. With respect to etiology, efficacy loss was less obvious in patients with cryptogenic focal epilepsy (Fig. 1B).
3.3.
Safety
At least one adverse event was seen in 8 (33%) patients. The most common adverse events were drowsiness (21%), nervousness (12.5%), vomiting (8%), instability and difficulty walking (4%). Five patients showed more than one side effect. No life threatening side effects were observed during the study. All side effects were either tolerable or resolved in time through dosage reduction (drowsiness in two patients and vomiting in another one) or discontinuation of the drug (in a child with walking instability). There were no significant laboratory anomalies in liver function, renal function, or hematology.
4.
Discussion
In randomized controlled trials conducted in adults, lacosamide has shown to be an effective and safe AED in treating refractory seizures, with 30%e40% of patients achieving a 50% reduction in seizure frequency at doses of 400e600 mg/ day.1,4e7 Since 2010, five studies have been published that report similar efficacy and tolerability of lacosamide in children and young adults with refractory epilepsy.8e12 Thirty-six percent of 18 children placed under lacosamide, at a mean dose of 6.3 mg/kg/day (rage 1.7e10), were found to be responder (50% in seizure reduction) for a mean period of 8 months.8 In a retrospective study, Guilhoto et al.9 evaluated the efficacy and safety of lacosamide in a series of adolescent patients (mean age 14.9 years) and reported that six of them (37.5%) were classified as responder to therapy. Similar results (35% of responders) were observed by Heyman et al.10 in seventeen younger children (mean age 8 years) placed under lacosamide for a mean follow-up period of 9.1 months. In a recent, prospective, study including 21 pediatric patients affected by refractory epilepsy with various seizure types, lacosamide demonstrated to be an effective AED.11 In particular, 62.5% of patients with localization-related epilepsy and 25% of those having generalized epilepsy were defined as responders at the last visit. Of interest, two patients with Lennox-Gastaut syndrome showed greater than 90% seizure reduction. However, none of these very refractory patients
58
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 5 5 e5 9
Fig. 1 e Study design (A). Retention rate after 12 months of follow-up (B). remained seizure free.11 In a prospective, open-label, multicenter study including 130 patients aged less than 16 years with a variety of etiologies including refractory partial epilepsies and symptomatic, generalized epilepsy syndromes. The drug was dosed at a mean of 6.8 mg/kg/day. After 3 months of lacosamide add-on therapy, 62.3% of patients achieved a 50% reduction in seizure frequency.12 Lacosamide efficacy and safety were also evaluated in two series including both children and adults.15,16 In particular, a comparison study of lacosamide efficacy and safety in pediatric and adult patients with uncontrolled focal and generalized epilepsy, showed similar response rates (47% of patients with >50% of seizure reduction) after three months of therapy.15 Novy et al.,16 recently reported that forty-five percent of the 376 people included were still taking LCM at last follow-up. Eighteen percent reported a period of improvement in terms of significant seizure reduction or seizure freedom of at least six months duration whilst on LCM, of whom four people were seizure free for at least one year. The authors concluded that long-term efficacy appeared similar to zonisamide and pregabalin when compared to historical controls. Lacosamide has been approved by the licensing authorities in the European Union and in the United States as an add-on treatment of partial seizures in patients 16 years of age or older. Although, a number of infants and young children were treated with lacosamide and reported in other studies,8e12,15,16 systematic data are not yet available. In this context, we believe this study is the first evaluation of the efficacy and safety of lacosamide in patients aged less than four years affected by focal seizures. The design of the present study
reflects daily clinical practice. Although this introduces some methodological weaknesses, it provides a more natural and realistic view of the use of lacosamide in infants and young children. All patients we studied were refractory to first line drugs. The main aim of add-on treatment in these patients was to improve their quality of life by decreasing seizure frequency as much as possible and by limiting adverse events, rather than to make them seizure free.17 Forty-two percent of patients had a more than a 50% reduction in seizure frequency after a three-month period of therapy. The percentage of responders was slightly higher than that reported in older children with focal epilepsy in previous studies8e10 and lower than that observed in studies including patients with both focal and generalized uncontrolled seizures.12,15 We compared the efficacy in 18 patients observed after a mean of three months of follow-up with retention after 12 months of lacosamide, with regard to loss of efficacy. According to Krakow et al.18 the retention rate is an important measure of the efficacy and adverse events of the drug because it is a reliable indicator over time. Twenty-two percent of our patients were still responsive to lacosamide after a minimum of 12 months of follow-up. Loss of efficacy was observed in 50% of the initial responders. Although our series is small, it seems to suggest a sustained lacosamide efficacy over time in patients with focal epilepsy. Since comedication was not (or only slightly) altered before seizure relapse, we suggest that the loss of efficacy with lacosamide was likely related to the development of tolerance to the drug. However, the percentage of responders after 12 month-period of lacosamide therapy, was lower than that observed in older
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 5 5 e5 9
children and adults in previous studies.15 In particular, Novy et al.,16 found that lacosamide retention was 62% at one year, 45% at two years and 35% at three years. The lower retention rate we observed may be because of insufficient experience with lacosamide in young children, resulting in a very strong selection bias for infants with very difficult-to-treat epilepsies This bias is further enhanced in our data which are constituted by pooled data of the first experiences with lacosamide coming from 4 pediatric neurology departments. Although the patients we investigated did not have long histories of epilepsy, up to 7 AEDs had been used before lacosamide therapy was started. Moreover, the majority of children were mentally retarded, with epilepsy being mainly related to brain injuries or brain malformations. Lacosamide has been reported to be a well-tolerated, relatively safe drug.19 Adverse reactions, such as dizziness, headache, diplopia, nausea and somnolence have an incidence varying from 29% to 61%.15,16 Similar adverse effect data have been observed in pediatric case reports and case series, with dizziness and nausea being the most commonly reported.9,10,12,19 In contrast, drowsiness was the most common adverse event we observed in our study (21% of patients), being our data congruent with those reported by Cavatha et al.,.8 Most adverse effects seen with lacosamide in adults are dose-related and are reversible upon discontinuation or dose reduction.19 In children, lacosamide doses up to 20 mg/ kg/day may be well-tolerated.19,20 The mean dose of lacosamide in our study was 12.5 mg/kg/day, with an incidence of adverse events (33%), which is similar to that reported in previous studies.8,9,11 Lacosamide was discontinued in only one patient (4%) because of severe instability. Dosage reduction was necessary in another three cases with gradual disappearance of side effects. In conclusion, although caution may still be necessary when lacosamide is used in infants and children younger than 4 years, our observations suggest that lacosamide is effective and safe and represents a possible option in treating uncontrolled focal epilepsy in this population. Of course, further clinical trials are needed to validate our data. In fact, the size of our population was not so large to enable us to draw definite conclusions.
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