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Preliminary efficacy and safety of lacosamide in children with refractory epilepsy
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 6 ( 2 0 1 2 ) 1 5 e1 9
Official Journal of the European Paediatric Neurology Society
Original article
Preliminary efficacy and safety of lacosamide in children with refractory epilepsy Eli Heyman a,c, Eli Lahat a,c, Noa Levin a, Matitiahu Berkovitch a,c, Revital Gandelman-Marton b,c,* a
Department of Pediatric Neurology, Assaf Harofeh Medical Center, Zerifin, Israel Electroencephalography Laboratory, Assaf Harofeh Medical Center, Zerifin, Israel c Sackler School of Medicine, Tel Aviv University, Israel b
article info
abstract
Article history:
Background: Despite the introduction of multiple new antiepileptic drugs (AEDs) in the past
Received 19 January 2011
20 years, about 30% of patients with epilepsy continue to experience uncontrolled seizures
Received in revised form
or significant side effects.
28 July 2011
Aims: To present our experience with lacosamide therapy in children with drug-resistant
Accepted 21 August 2011
epilepsy. Methods: We retrospectively reviewed the medical charts of all patients receiving oral
Keywords:
lacosamide until October 2010. Efficacy was determined according to seizure frequency
Drug-resistant epilepsy
during the week prior to treatment initiation and the week after the maximal dosage of
Lacosamide
lacosamide was attained.
Side effects
Results: Seventeen patients (10 boys) aged 1.5e16 (mean e 8 4.7) years were identified.
Seizure reduction
Nine patients had epilepsy attributed to a structural cause, six patients had epilepsy of unknown cause, and two had LennoxeGastaut syndrome. Mean epilepsy duration was 5.4 3.3 years. The mean number of previous AEDs was 6.6 2. Lacosamide was added to the baseline AEDs in13 patients. The mean duration of follow-up was 9.1 4.4 months. Six (35%) patients had at least a 50%.seizure reduction (mean e 76%). Social, behavioral, and/or motor improvement were noted in seven (41%) patients. Lacosamide was discontinued in six (35%) patients because of inefficacy. Side effects were reported in 10 (59%) patients. Conclusions: Lacosamide seems to be effective and safe according to the data in our small cohort. Further prospective studies on lacosamide efficacy and safety in a large number of children are warranted. ª 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
Despite the introduction of multiple new antiepileptic drugs (AEDs) in the past 20 years, about 30% of patients with epilepsy
continue to experience uncontrolled seizures or significant side effects.1 Therefore, there is a continuous need for the development of effective and well-tolerated AEDs.2 Although data regarding efficacy and safety of new AEDs can be
* Corresponding author. Department of Neurology, Assaf Harofeh Medical Center, Zerifin 70300, Israel. Tel.: þ972 8 9778134; fax: þ972 8 9779758. E-mail address: [email protected] (R. Gandelman-Marton). 1090-3798/$ e see front matter ª 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2011.08.007
16
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 6 ( 2 0 1 2 ) 1 5 e1 9
obtained from adult epilepsy trials, their application in pediatric epilepsy can be affected by differences in etiology and occurrence of comorbidities.3 Indeed, only a few of the AEDs that were effective in adults with refractory partial-onset seizures have successfully demonstrated efficacy in drugresistant children.4e8 Lacosamide ([R]-2-acetamido-N-benzyl-3-methoxyproprionamide) is a functionalized amino acid that was found to have both analgesic and anticonvulsant effects in animal models.9 Its mechanisms of action include selective facilitation of the slow inactivation of voltage-gated sodium channels, and binding to collapsin-response mediator protein 2 (CRMP-2).10 Lacosamide is negligibly bound to plasma proteins and is eliminated by metabolic biotransformation and by urinary excretion.9 Serum lacosamide concentration is reduced by 25% in the presence of enzyme-inducing AEDs but it was not found to affect serum concentrations of most AEDs, including carbamazepine, phenytoin, valproic acid, lamotrigine, topiramate, zonisamide, levetiracetam and gabapentin.9 Lacosamide was found to be effective in adults with partial-onset seizures in three randomized, double-blind, parallel-group, placebo-controlled adjunctive therapy trials.11e13 Efficacy and tolerability data of adjunctive lacosamide in pediatric patients with focal epilepsy were recently published.14,15 In this study, we present our experience with lacosamide add-on and mono-therapy in children with refractory epilepsy.
2.
Materials and methods
We retrospectively reviewed the medical charts of all patients receiving oral lacosamide until October 2010. The data collected included age, sex, epilepsy syndrome, seizure type and etiology, duration of epilepsy prior to treatment with lacosamide, previous and concomitant AEDs, highest dosage of lacosamide, seizure frequency before and after treatment initiation, changes in neurological and general function, reasons for lacosamide discontinuation, and side effects. Seizure types and epilepsy syndromes were classified based on criteria of the International League Against Epilepsy.16 Seizure frequency was determined according to seizure diaries, and cognitive or behavioral improvement e according to reports of the parents and the school teacher. Efficacy was determined according to seizure frequency during the week prior to treatment initiation and the week after the maximal dosage of lacosamide was attained. Patients were regularly evaluated for seizure response, functional status and adverse events every month by phone and every 6 months during a visit at the Epilepsy Clinic. The study was approved by the Ethics Committee at Assaf Harofeh Medical Center.
3.
in Table 1. Twelve patients had focal seizures, evolving in three to bilateral convulsive seizures, and five patients had both generalized and focal seizures. Nine patients had epilepsy attributed to a structural cause, six patients had epilepsy of unknown cause, and two had LennoxeGastaut syndrome (LGS). Mean epilepsy duration was 5.4 3.3 years (range e 1.3e11 years). The mean number of previous AEDs was 6.6 2 (range e 4e11), and five patients were previously treated with ketogenic diet. Four patients were candidates for epilepsy surgery. Lacosamide was added to a stable dosage of baseline AEDs in13 patients and was used as mono-therapy in four patients. Starting dosage was 1.4e5 mg/kg/day (mean e 3.04 1.09) given twice a day in two equal doses, and was increased every week up to a maximum of 6.7e20 mg/kg/day (meane 12.39 4.48), depending on clinical response and tolerability. The mean duration of follow-up was 9.1 4.4 months (range e 1e18 months). Six (35%) patients had a 50%.seizure reduction (mean e 76% (Table 2)). Increased seizure frequency was observed in two (12%) patients, both with LGS. There was no change in seizure frequency in seven (41%) patients. Clinical improvement was noted in seven (41%) patients, including social and behavioral aspects (n ¼ 5), motor (n ¼ 1) and both (n ¼ 1). Side effects were reported in 10 (59%) patients and included nausea (n ¼ 3) (18%), dizziness (n ¼ 3) (18%), restlessness (n ¼ 2) (12%), fatigue (n ¼ 2) (12%), headache (n ¼ 2) (12%), increased appetite (n ¼ 1) (6%), and prolonged crying (n ¼ 1) (6%). Lacosamide was discontinued in six (35%) patients because of inefficacy (n ¼ 4) and increased frequency of seizures (n ¼ 2) (Table 2).
Results
Seventeen patients (10 boys) aged 1.5e16 years (mean e 8 4.7) were identified. Clinical characteristics are presented
4.
Discussion
The safety and efficacy of add-on lacosamide were evaluated in adults with uncontrolled partial-onset seizures in three double-blind, placebo-controlled trials and two open-label studies.11e13,17,18 A favorable outcome of at least 50% seizure reduction was reported in 33%e41% of the patients treated with lacosamide 200e600 mg/day. Adverse events were observed in 84% of the patients and were responsible for withdrawal from the study in 8.7%e17%. The most common adverse events included dizziness, headache, nausea, fatigue, ataxia, vision abnormalities, vomiting, diplopia, somnolence, and nystagmus. Postmarketing experience with adjunctive lacosamide in 25 adolescent and adult patients with pharmaco-resistant focal epilepsy yielded similar results.19 Recently, pediatric experience with adjunctive lacosamide was described in two studies. Seizure reduction greater than 50% was reported in 36% of 18 patients with pharmacoresistant focal epilepsy, aged 3e18 years, after three months of treatment with adjunctive lacosamide at doses up to 10 mg/ kg/day, and in 20% one year later.14 Adverse events were reported by 39% of the patients, and included mostly somnolence and irritability. Treatment was discontinued in 50% of the patients because of unsatisfactory therapeutic effect (44%) and somnolence (6%). In another study, a 50% seizure reduction was reported in 37.5% of 16 patients with focal epilepsy, aged 8e21 years, treated with adjunctive lacosamide
Table 1 e Clinical data in patients treated with lacosamide. Patient
Age (y)
Sex
11
F
2
9
F
3
2.5
4
Seizure etiology
Seizure types
Epilepsy duration (y) 10
Previous AEDs/ other therapies
Concomitant AEDs
Epilepsy of unknown cause Epilepsy attributed to a structural cause
Unknown cause
Dyscognitive
Perinatal ischemic stroke
M
Epilepsy attributed to a structural cause
Polymicrogyria
3
M
5
10
M
Perinatal ischemic stroke Unknown cause
Dyscognitive
5
6
16
F
Unknown cause
Dyscognitive
10
7
3
M
2.7
4
M
Dyscognitive, Tonic Atonic
4
9
10
M
Epilepsy of unknown cause
Generalized cerebral hypoxia Prematurity Intraventricular hemorrhage Unknown cause
Dyscognitive, Tonic
8
Epilepsy attributed to a structural cause Epilepsy of unknown cause Epilepsy of unknown cause Epilepsy attributed to a structural cause Epilepsy attributed to a structural cause
Dyscognitive Evolving to a bilateral convulsive seizure Dyscognitive, Evolving to a bilateral convulsive seizure Dyscognitive, Tonic
Dyscognitive
3
10
6
F
Epilepsy attributed to a structural cause
Perinatal ischemic stroke
4
11
10
M
Cortical dysplasia
6.5
CBZ. OSP, OXC, PHT, VPA
LTG
12
12
M
9
CBZ, TPM
LTG, VPA
13
F
Perinatal ischemic stroke Unknown cause
Dyscognitive
13
Dyscognitive
11
8
F
HSV encephalitis
Dyscognitive
5.5
15
15
F
Unknown cause
Dyscognitive
5
16
2
M
Unknown cause
Dyscognitive, Tonic, Generalized tonic-clonic
1.5
17
1.5
M
LGS
Unknown cause
Dyscognitive, Tonic, Generalized tonic-clonic
1.3
CBZ, ETS, LEV, LTG, OXC, PB, VPA CBZ, CLB, LEV, LTG, OSP, TPM, VPA CLB, CLZ, LEV, LTG, OSP, OXC, VPA ACTH, CLB, ketogenic diet, LEV, prednison, TPM, VGB, vitamin B6, VPA FBM, ketogenic diet, LEV, PB, TPM, VGB, vitamin B6, ZNS
e
14
Epilepsy attributed to a structural cause Epilepsy attributed to a structural cause Epilepsy of unknown cause Epilepsy attributed to a structural cause Epilepsy of unknown cause LGS
Dyscognitive, Evolving to a bilateral convulsive seizure Dyscognitive
FBM, ketogenic diet, LEV, LTG, PB, PHT, TPM, VPA CLB, CLZ, FBM, ketogenic diet, LEV, LTG, MP, PB, TPM, VGB, vitamin B6, VPA CBZ, FBM, LEV, LTG, MP, OXC, PHT, TPM, vitamin B6, VPA CBZ, LEV, TPM
Maximum LCS dosage (mg/kg/day)
LTG
10
8.8
CBZ, CLB, LEV, OXC, TPM, Vitamin B6, VPA, ACTH, CLZ, VPA
VAL
11.4
2.2
LEV, TPM, ZNS
FBM, vitamin B6
16.7
2
CLZ, ketogenic diet, LEV, TPM FBM, LEV, OXC, TPM, VPA CBZ, LEV, LTG, OXC, VPA
LTG, VPA
14.3
e
6.7
e
2.9
OXC, RUF
14.1
ZNS
16.7
e
12.5
FBM, VPA
12.5
8.6 16 9.3
CLB
12.9
LEV
8
ZNS
18.2
FBM
20
17
F e female, M e male, LGS e LennoxeGastaut syndrome, AEDs e antiepileptic drugs, HSV e herpes simplex virus, ACTH e adrenocorticotrophic hormone, CBZ e carbamazepine, CLB e clobazam, CLZ e clonazepam, ETS e ethosuximide, FBM e Felbamate, LCS e lacosamide, LEV e levetiracetam, LTG e lamotrigine, MP e methylprednisolone, OSP e ospolot, OXC e oxcarbazepine, PB e phenobarbital, PHT e phenytoin, RUF e rufinamide, TPM e topiramate, VGB, e vigabatrin, VPA e valproic acid, ZNS e zonisamide.
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 6 ( 2 0 1 2 ) 1 5 e1 9
1
Epilepsy type/ syndrome
18
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 6 ( 2 0 1 2 ) 1 5 e1 9
Table 2 e Outcome in patients treated with lacosamide. Patient
Seizure frequency per week before/ after LCS
Percent seizure reduction/Seizure type improved
Improved function
LCS discontinuation
1 2 3 4 5 6
7/1 7/7 7/7 70/70 2/2 10/7
86/Dyscognitive 0 0 0 0 30/Dyscognitive
Social Behavior e e e e
e Inefficacy Inefficacy Inefficacy e e
7
4/4
0
e
8 9 10 11 12 13 14
15/15 7/4 3/0.5 7/7 7/1 7/1 105/3
0 43/Dyscognitive 83/Dyscognitive 0 86/Dyscognitive 86/Dyscognitive 97/Dyscognitive
Motor Communication e Behavior e e e Behavior Social e
15 16
7/0 7/9
100/Dyscognitive 28
Behavior Social e
17
7/10
43
Motor
Inefficacy e e e e e e e Increased seizure frequency Increased seizure frequency
Side effects
Nausea Fatigue Fatigue e Increased appetite Unsteadiness, nausea headache e e e Dizziness Dizziness e Headache Increased appetite, restlessness e Restlessness, nausea, prolonged crying e
LCS e lacosamide.
at doses up to 8.8 mg/kg/day.15 Four (25%) patients discontinued the drug because of adverse events (oral tics, severe behavioral outbursts, vomiting, ataxia, depression associated with suicidal ideation) and two (13%) had mild transient adverse events (worsening of chronic headache, nausea and blurred vision). The efficacy of lacosamide in our group of children with refractory epilepsy was generally similar to previous reports.11e15,17,18 Notably, decreased seizure frequency was limited to dyscognitive seizures. Lacosamide was ineffective in two patients with LGS despite doses up to 20 mg/kg/day. Improvement of behavioral, social, and/or motor functioning was noted in seven (41%) of our patients, including three patients with unchanged or increased seizure frequency. In previous studies, lacosamide was evaluated in adult and pediatric patients with refractory epilepsy as adjunct therapy.11e15,17,18 Four of our patients were treated with lacosamide monotherapy. One of them had a 50% seizure reduction and two other patients had up to 43% reduction in seizure frequency. Similar to previous reports,11e15,17,18 the most commonly reported side effects in our study were CNS and gastrointestinal symptoms. These occurred more frequently in our patients compared to the other pediatric groups17,18 probably because of the higher lacosamide maintenance dose taken by our patients. In conclusion, we suggest that lacosamide is well tolerated at doses up to 20 mg/kg/day and should be considered as adjunctive treatment for children with pharmaco-resistant focal epilepsy. Although only two patients were found to have an increase in seizure frequency, probably, lacosamide should not be prescribed to children with LGS. Further prospective investigation of lacosamide efficacy and safety in a large number of children is warranted.
references
1. Diaz-Arrastia R, Agostini MA, Van Ness PC. Evolving treatment strategies for epilepsy. JAMA 2002;287:2917e20. 2. Bialer M. New antiepileptic drugs currently in clinical trials: is there a strategy in their development? Ther Drug Monit 2002; 24:85e90. 3. Pellock JM. Drug treatment in children. In: Engel J, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia: Lippincott-Raven; 1997. p. 1205e10. 4. Glauser TA, Nigro M, Sachdeo R, et alThe Oxcarbazepine Pediatric Study Group. Adjunctive therapy with Oxcarbazepine in children with partial seizures. Neurology 2000;54:2237e44. 5. Appleton R, Fichtner K, LaMoreaux L, et alGabapentin Pediatric Study Group. Gabapentin as add-on therapy in children with refractory partial seizures: a 12-week, multicentre, double-blind, placebo-controlled study. Epilepsia 1999;40:1147e54. 6. Callenbach PM, Arts WF, ten Houten R, et al. Add-on levetiracetam in children and adolescents with refractory epilepsy: results of an open-label multi-centre study. Eur J Paediatr Neurol 2007;11:261e9. 7. Elterman RD, Glauser TA, Wyllie E, et alTopiramate YP Study Group. A double-blind, randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children. Neurology 1999;52:1338e44. 8. Duchowny M, Pellock JM, Graf WD, et al. A placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children. Lamictal Pediatric Partial Seizure Study Group. Neurology 1999;53:1724e31. 9. Curia G, Biagini G, Perucca E, Avoli M. Lacosamide: a new approach to target voltage-gated sodium currents in epileptic disorders. CNS Drugs 2009;23:555e68.
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10. Perucca E, Yasothan U, Clincke G, Kirpatrick P. Lacosamide. Nat Rev Drug Discov 2008;7:973e4. 11. Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia 2007;48:1308e17. ska M, et al. 12. Hala´sz P, Ka¨lvia¨inen R, Mazurkiewicz-Beldzin Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia 2009;50:443e53. 13. Chung S, Sperling MR, Biton V, etal. Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial. Epilepsia 2010;51:958e67. 14. Gavatha M, Ioannou I, Papavasiliou AS. Efficacy and tolerability of oral lacosamide as adjunctive therapy in pediatric patients with pharmacoresistant focal epilepsy. Epilepsy Behav 2011;20:691e3. 15. Guilhoto LM, Loddenkemper T, Gooty VD, et al. Experience with lacosamide in a series of children with drug-resistant focal epilepsy. Pediatr Neurol 2011;44:414e9.
19
16. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005e2009. Epilepsia 2010; 51:676e85. 17. Fountain NB, French JA, Privitera MD. Harkoseride: safety and tolerability of a new antiepileptic drug (AED) in patients with refractory partial seizures. Epilepsia 2000;41(Suppl. 7):169e70 [abstract]. 18. Sachdeo RC, Montouris GD, Beydoun A, et al. An open label, dose titration trial to evaluate tolerability and efficacy of oral SPM 927 as adjunctive therapy in patients with partial seizures. Neurology 2003;60(Suppl. 1):A433 [abstract]. 19. Wehner T, Bauer S, Hamer HM, et al. Six months of postmarketing experience with adjunctive lacosamide in patients with pharmacoresistant focal epilepsy at a tertiary epilepsy center in Germany. Epilepsy Behav 2009; 16:423e5.
Official Journal of the European Paediatric Neurology Society
Original article
Preliminary efficacy and safety of lacosamide in children with refractory epilepsy Eli Heyman a,c, Eli Lahat a,c, Noa Levin a, Matitiahu Berkovitch a,c, Revital Gandelman-Marton b,c,* a
Department of Pediatric Neurology, Assaf Harofeh Medical Center, Zerifin, Israel Electroencephalography Laboratory, Assaf Harofeh Medical Center, Zerifin, Israel c Sackler School of Medicine, Tel Aviv University, Israel b
article info
abstract
Article history:
Background: Despite the introduction of multiple new antiepileptic drugs (AEDs) in the past
Received 19 January 2011
20 years, about 30% of patients with epilepsy continue to experience uncontrolled seizures
Received in revised form
or significant side effects.
28 July 2011
Aims: To present our experience with lacosamide therapy in children with drug-resistant
Accepted 21 August 2011
epilepsy. Methods: We retrospectively reviewed the medical charts of all patients receiving oral
Keywords:
lacosamide until October 2010. Efficacy was determined according to seizure frequency
Drug-resistant epilepsy
during the week prior to treatment initiation and the week after the maximal dosage of
Lacosamide
lacosamide was attained.
Side effects
Results: Seventeen patients (10 boys) aged 1.5e16 (mean e 8 4.7) years were identified.
Seizure reduction
Nine patients had epilepsy attributed to a structural cause, six patients had epilepsy of unknown cause, and two had LennoxeGastaut syndrome. Mean epilepsy duration was 5.4 3.3 years. The mean number of previous AEDs was 6.6 2. Lacosamide was added to the baseline AEDs in13 patients. The mean duration of follow-up was 9.1 4.4 months. Six (35%) patients had at least a 50%.seizure reduction (mean e 76%). Social, behavioral, and/or motor improvement were noted in seven (41%) patients. Lacosamide was discontinued in six (35%) patients because of inefficacy. Side effects were reported in 10 (59%) patients. Conclusions: Lacosamide seems to be effective and safe according to the data in our small cohort. Further prospective studies on lacosamide efficacy and safety in a large number of children are warranted. ª 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
Despite the introduction of multiple new antiepileptic drugs (AEDs) in the past 20 years, about 30% of patients with epilepsy
continue to experience uncontrolled seizures or significant side effects.1 Therefore, there is a continuous need for the development of effective and well-tolerated AEDs.2 Although data regarding efficacy and safety of new AEDs can be
* Corresponding author. Department of Neurology, Assaf Harofeh Medical Center, Zerifin 70300, Israel. Tel.: þ972 8 9778134; fax: þ972 8 9779758. E-mail address: [email protected] (R. Gandelman-Marton). 1090-3798/$ e see front matter ª 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2011.08.007
16
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 6 ( 2 0 1 2 ) 1 5 e1 9
obtained from adult epilepsy trials, their application in pediatric epilepsy can be affected by differences in etiology and occurrence of comorbidities.3 Indeed, only a few of the AEDs that were effective in adults with refractory partial-onset seizures have successfully demonstrated efficacy in drugresistant children.4e8 Lacosamide ([R]-2-acetamido-N-benzyl-3-methoxyproprionamide) is a functionalized amino acid that was found to have both analgesic and anticonvulsant effects in animal models.9 Its mechanisms of action include selective facilitation of the slow inactivation of voltage-gated sodium channels, and binding to collapsin-response mediator protein 2 (CRMP-2).10 Lacosamide is negligibly bound to plasma proteins and is eliminated by metabolic biotransformation and by urinary excretion.9 Serum lacosamide concentration is reduced by 25% in the presence of enzyme-inducing AEDs but it was not found to affect serum concentrations of most AEDs, including carbamazepine, phenytoin, valproic acid, lamotrigine, topiramate, zonisamide, levetiracetam and gabapentin.9 Lacosamide was found to be effective in adults with partial-onset seizures in three randomized, double-blind, parallel-group, placebo-controlled adjunctive therapy trials.11e13 Efficacy and tolerability data of adjunctive lacosamide in pediatric patients with focal epilepsy were recently published.14,15 In this study, we present our experience with lacosamide add-on and mono-therapy in children with refractory epilepsy.
2.
Materials and methods
We retrospectively reviewed the medical charts of all patients receiving oral lacosamide until October 2010. The data collected included age, sex, epilepsy syndrome, seizure type and etiology, duration of epilepsy prior to treatment with lacosamide, previous and concomitant AEDs, highest dosage of lacosamide, seizure frequency before and after treatment initiation, changes in neurological and general function, reasons for lacosamide discontinuation, and side effects. Seizure types and epilepsy syndromes were classified based on criteria of the International League Against Epilepsy.16 Seizure frequency was determined according to seizure diaries, and cognitive or behavioral improvement e according to reports of the parents and the school teacher. Efficacy was determined according to seizure frequency during the week prior to treatment initiation and the week after the maximal dosage of lacosamide was attained. Patients were regularly evaluated for seizure response, functional status and adverse events every month by phone and every 6 months during a visit at the Epilepsy Clinic. The study was approved by the Ethics Committee at Assaf Harofeh Medical Center.
3.
in Table 1. Twelve patients had focal seizures, evolving in three to bilateral convulsive seizures, and five patients had both generalized and focal seizures. Nine patients had epilepsy attributed to a structural cause, six patients had epilepsy of unknown cause, and two had LennoxeGastaut syndrome (LGS). Mean epilepsy duration was 5.4 3.3 years (range e 1.3e11 years). The mean number of previous AEDs was 6.6 2 (range e 4e11), and five patients were previously treated with ketogenic diet. Four patients were candidates for epilepsy surgery. Lacosamide was added to a stable dosage of baseline AEDs in13 patients and was used as mono-therapy in four patients. Starting dosage was 1.4e5 mg/kg/day (mean e 3.04 1.09) given twice a day in two equal doses, and was increased every week up to a maximum of 6.7e20 mg/kg/day (meane 12.39 4.48), depending on clinical response and tolerability. The mean duration of follow-up was 9.1 4.4 months (range e 1e18 months). Six (35%) patients had a 50%.seizure reduction (mean e 76% (Table 2)). Increased seizure frequency was observed in two (12%) patients, both with LGS. There was no change in seizure frequency in seven (41%) patients. Clinical improvement was noted in seven (41%) patients, including social and behavioral aspects (n ¼ 5), motor (n ¼ 1) and both (n ¼ 1). Side effects were reported in 10 (59%) patients and included nausea (n ¼ 3) (18%), dizziness (n ¼ 3) (18%), restlessness (n ¼ 2) (12%), fatigue (n ¼ 2) (12%), headache (n ¼ 2) (12%), increased appetite (n ¼ 1) (6%), and prolonged crying (n ¼ 1) (6%). Lacosamide was discontinued in six (35%) patients because of inefficacy (n ¼ 4) and increased frequency of seizures (n ¼ 2) (Table 2).
Results
Seventeen patients (10 boys) aged 1.5e16 years (mean e 8 4.7) were identified. Clinical characteristics are presented
4.
Discussion
The safety and efficacy of add-on lacosamide were evaluated in adults with uncontrolled partial-onset seizures in three double-blind, placebo-controlled trials and two open-label studies.11e13,17,18 A favorable outcome of at least 50% seizure reduction was reported in 33%e41% of the patients treated with lacosamide 200e600 mg/day. Adverse events were observed in 84% of the patients and were responsible for withdrawal from the study in 8.7%e17%. The most common adverse events included dizziness, headache, nausea, fatigue, ataxia, vision abnormalities, vomiting, diplopia, somnolence, and nystagmus. Postmarketing experience with adjunctive lacosamide in 25 adolescent and adult patients with pharmaco-resistant focal epilepsy yielded similar results.19 Recently, pediatric experience with adjunctive lacosamide was described in two studies. Seizure reduction greater than 50% was reported in 36% of 18 patients with pharmacoresistant focal epilepsy, aged 3e18 years, after three months of treatment with adjunctive lacosamide at doses up to 10 mg/ kg/day, and in 20% one year later.14 Adverse events were reported by 39% of the patients, and included mostly somnolence and irritability. Treatment was discontinued in 50% of the patients because of unsatisfactory therapeutic effect (44%) and somnolence (6%). In another study, a 50% seizure reduction was reported in 37.5% of 16 patients with focal epilepsy, aged 8e21 years, treated with adjunctive lacosamide
Table 1 e Clinical data in patients treated with lacosamide. Patient
Age (y)
Sex
11
F
2
9
F
3
2.5
4
Seizure etiology
Seizure types
Epilepsy duration (y) 10
Previous AEDs/ other therapies
Concomitant AEDs
Epilepsy of unknown cause Epilepsy attributed to a structural cause
Unknown cause
Dyscognitive
Perinatal ischemic stroke
M
Epilepsy attributed to a structural cause
Polymicrogyria
3
M
5
10
M
Perinatal ischemic stroke Unknown cause
Dyscognitive
5
6
16
F
Unknown cause
Dyscognitive
10
7
3
M
2.7
4
M
Dyscognitive, Tonic Atonic
4
9
10
M
Epilepsy of unknown cause
Generalized cerebral hypoxia Prematurity Intraventricular hemorrhage Unknown cause
Dyscognitive, Tonic
8
Epilepsy attributed to a structural cause Epilepsy of unknown cause Epilepsy of unknown cause Epilepsy attributed to a structural cause Epilepsy attributed to a structural cause
Dyscognitive Evolving to a bilateral convulsive seizure Dyscognitive, Evolving to a bilateral convulsive seizure Dyscognitive, Tonic
Dyscognitive
3
10
6
F
Epilepsy attributed to a structural cause
Perinatal ischemic stroke
4
11
10
M
Cortical dysplasia
6.5
CBZ. OSP, OXC, PHT, VPA
LTG
12
12
M
9
CBZ, TPM
LTG, VPA
13
F
Perinatal ischemic stroke Unknown cause
Dyscognitive
13
Dyscognitive
11
8
F
HSV encephalitis
Dyscognitive
5.5
15
15
F
Unknown cause
Dyscognitive
5
16
2
M
Unknown cause
Dyscognitive, Tonic, Generalized tonic-clonic
1.5
17
1.5
M
LGS
Unknown cause
Dyscognitive, Tonic, Generalized tonic-clonic
1.3
CBZ, ETS, LEV, LTG, OXC, PB, VPA CBZ, CLB, LEV, LTG, OSP, TPM, VPA CLB, CLZ, LEV, LTG, OSP, OXC, VPA ACTH, CLB, ketogenic diet, LEV, prednison, TPM, VGB, vitamin B6, VPA FBM, ketogenic diet, LEV, PB, TPM, VGB, vitamin B6, ZNS
e
14
Epilepsy attributed to a structural cause Epilepsy attributed to a structural cause Epilepsy of unknown cause Epilepsy attributed to a structural cause Epilepsy of unknown cause LGS
Dyscognitive, Evolving to a bilateral convulsive seizure Dyscognitive
FBM, ketogenic diet, LEV, LTG, PB, PHT, TPM, VPA CLB, CLZ, FBM, ketogenic diet, LEV, LTG, MP, PB, TPM, VGB, vitamin B6, VPA CBZ, FBM, LEV, LTG, MP, OXC, PHT, TPM, vitamin B6, VPA CBZ, LEV, TPM
Maximum LCS dosage (mg/kg/day)
LTG
10
8.8
CBZ, CLB, LEV, OXC, TPM, Vitamin B6, VPA, ACTH, CLZ, VPA
VAL
11.4
2.2
LEV, TPM, ZNS
FBM, vitamin B6
16.7
2
CLZ, ketogenic diet, LEV, TPM FBM, LEV, OXC, TPM, VPA CBZ, LEV, LTG, OXC, VPA
LTG, VPA
14.3
e
6.7
e
2.9
OXC, RUF
14.1
ZNS
16.7
e
12.5
FBM, VPA
12.5
8.6 16 9.3
CLB
12.9
LEV
8
ZNS
18.2
FBM
20
17
F e female, M e male, LGS e LennoxeGastaut syndrome, AEDs e antiepileptic drugs, HSV e herpes simplex virus, ACTH e adrenocorticotrophic hormone, CBZ e carbamazepine, CLB e clobazam, CLZ e clonazepam, ETS e ethosuximide, FBM e Felbamate, LCS e lacosamide, LEV e levetiracetam, LTG e lamotrigine, MP e methylprednisolone, OSP e ospolot, OXC e oxcarbazepine, PB e phenobarbital, PHT e phenytoin, RUF e rufinamide, TPM e topiramate, VGB, e vigabatrin, VPA e valproic acid, ZNS e zonisamide.
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 6 ( 2 0 1 2 ) 1 5 e1 9
1
Epilepsy type/ syndrome
18
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 6 ( 2 0 1 2 ) 1 5 e1 9
Table 2 e Outcome in patients treated with lacosamide. Patient
Seizure frequency per week before/ after LCS
Percent seizure reduction/Seizure type improved
Improved function
LCS discontinuation
1 2 3 4 5 6
7/1 7/7 7/7 70/70 2/2 10/7
86/Dyscognitive 0 0 0 0 30/Dyscognitive
Social Behavior e e e e
e Inefficacy Inefficacy Inefficacy e e
7
4/4
0
e
8 9 10 11 12 13 14
15/15 7/4 3/0.5 7/7 7/1 7/1 105/3
0 43/Dyscognitive 83/Dyscognitive 0 86/Dyscognitive 86/Dyscognitive 97/Dyscognitive
Motor Communication e Behavior e e e Behavior Social e
15 16
7/0 7/9
100/Dyscognitive 28
Behavior Social e
17
7/10
43
Motor
Inefficacy e e e e e e e Increased seizure frequency Increased seizure frequency
Side effects
Nausea Fatigue Fatigue e Increased appetite Unsteadiness, nausea headache e e e Dizziness Dizziness e Headache Increased appetite, restlessness e Restlessness, nausea, prolonged crying e
LCS e lacosamide.
at doses up to 8.8 mg/kg/day.15 Four (25%) patients discontinued the drug because of adverse events (oral tics, severe behavioral outbursts, vomiting, ataxia, depression associated with suicidal ideation) and two (13%) had mild transient adverse events (worsening of chronic headache, nausea and blurred vision). The efficacy of lacosamide in our group of children with refractory epilepsy was generally similar to previous reports.11e15,17,18 Notably, decreased seizure frequency was limited to dyscognitive seizures. Lacosamide was ineffective in two patients with LGS despite doses up to 20 mg/kg/day. Improvement of behavioral, social, and/or motor functioning was noted in seven (41%) of our patients, including three patients with unchanged or increased seizure frequency. In previous studies, lacosamide was evaluated in adult and pediatric patients with refractory epilepsy as adjunct therapy.11e15,17,18 Four of our patients were treated with lacosamide monotherapy. One of them had a 50% seizure reduction and two other patients had up to 43% reduction in seizure frequency. Similar to previous reports,11e15,17,18 the most commonly reported side effects in our study were CNS and gastrointestinal symptoms. These occurred more frequently in our patients compared to the other pediatric groups17,18 probably because of the higher lacosamide maintenance dose taken by our patients. In conclusion, we suggest that lacosamide is well tolerated at doses up to 20 mg/kg/day and should be considered as adjunctive treatment for children with pharmaco-resistant focal epilepsy. Although only two patients were found to have an increase in seizure frequency, probably, lacosamide should not be prescribed to children with LGS. Further prospective investigation of lacosamide efficacy and safety in a large number of children is warranted.
references
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10. Perucca E, Yasothan U, Clincke G, Kirpatrick P. Lacosamide. Nat Rev Drug Discov 2008;7:973e4. 11. Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia 2007;48:1308e17. ska M, et al. 12. Hala´sz P, Ka¨lvia¨inen R, Mazurkiewicz-Beldzin Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia 2009;50:443e53. 13. Chung S, Sperling MR, Biton V, etal. Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial. Epilepsia 2010;51:958e67. 14. Gavatha M, Ioannou I, Papavasiliou AS. Efficacy and tolerability of oral lacosamide as adjunctive therapy in pediatric patients with pharmacoresistant focal epilepsy. Epilepsy Behav 2011;20:691e3. 15. Guilhoto LM, Loddenkemper T, Gooty VD, et al. Experience with lacosamide in a series of children with drug-resistant focal epilepsy. Pediatr Neurol 2011;44:414e9.
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16. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005e2009. Epilepsia 2010; 51:676e85. 17. Fountain NB, French JA, Privitera MD. Harkoseride: safety and tolerability of a new antiepileptic drug (AED) in patients with refractory partial seizures. Epilepsia 2000;41(Suppl. 7):169e70 [abstract]. 18. Sachdeo RC, Montouris GD, Beydoun A, et al. An open label, dose titration trial to evaluate tolerability and efficacy of oral SPM 927 as adjunctive therapy in patients with partial seizures. Neurology 2003;60(Suppl. 1):A433 [abstract]. 19. Wehner T, Bauer S, Hamer HM, et al. Six months of postmarketing experience with adjunctive lacosamide in patients with pharmacoresistant focal epilepsy at a tertiary epilepsy center in Germany. Epilepsy Behav 2009; 16:423e5.