Acta Neurol Scand 2014: 129: 420–424 DOI: 10.1111/ane.12221
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Efficacy and tolerability of add-on lacosamide in children with Lennox-Gastaut syndrome Grosso S, Coppola G, Cusmai R, Parisi P, Spalice A, Foligno S, Verrotti A, Balestri P. Efficacy and tolerability of add-on lacosamide in children with Lennox-Gastaut syndrome. Acta Neurol Scand 2014: 129: 420–424. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objective – Available data on the efficacy of lacosamide in children with Lennox-Gastaut syndrome (LGS) are scarce and controversial. We present our experience with lacosamide therapy in children affected by LGS. Material and Methods – Medical charts of all children affected by LGS receiving oral lacosamide adjunctive therapy in six paediatric neurology centres were retrospectively evaluated. Efficacy was determined according to the frequency of countable seizures during the 4 weeks prior to treatment and the frequency in the last 4 weeks of observation. Patients whose seizure frequency was reduced by at least 50% were defined as responders. Results – Eighteen children (mean age 12.3 years) were identified. After a mean follow-up period of 9 months, 33% of patients were responders. None of them was seizure-free during the study period. The overall seizure reduction rate was 29%. The percentage reductions from baseline in tonic seizures and drop-attacks rates were 31% and 20%, respectively. Adverse reactions occurred in 44% of patients. The drug was discontinued in four (22%) patients because of increased seizure frequency (three cases) and walking instability (another patient). Conclusions – A third of children with LGS were responders after lacosamide adjunctive therapy. Although caution is still necessary when the drug is used in children with LGS, our preliminary observations suggest that lacosamide might be effective and represent a possible therapeutic option in children affected by LGS.
Introduction
Lennox-Gastaut syndrome (LGS) comprises 3–10% of all childhood epilepsies. Co-morbidities, including behavioural difficulties and learning disabilities, are common (1). Lennox-Gastaut syndrome is characterized by multiple, drug-resistant seizure types, with tonic seizures during sleep as a constant feature; diffuse slow spike–wave or poly-spike–wave discharges during wakefulness, and bursts of diffuse fast rhythms at ~10–20 Hz during sleep on the EEG; and progressive mental deterioration after epilepsy onset (2). Some patients may present with absence or tonic status epilepticus (2). 420
S. Grosso1,2, G. Coppola3, R. Cusmai4, P. Parisi5, A. Spalice6, S. Foligno5, A. Verrotti7, P. Balestri2 1 Pediatric Neurology-Immunology and Endocrinology Unit, University of Siena, Siena, Italy; 2Department of Pediatrics, University of Siena, Siena, Italy; 3Institute of Child and Adolescence Neuropsychiatry, University of Salerno, Salerno, Italy; 4Neurology Unit, Bambino Gesu Children’s Hospital, Rome, Italy; 5Child Neurology, NESMOS Department, Faculty of Medicine and Psychology, Sapienza University of Rome, Italy; 6 Department of Pediatrics, Child Neurology Division, Sapienza University of Rome, Rome, Italy; 7Clinical Pediatrics, University of Perugia, Perugia, Italy
Key words: Antiepileptic drugs; drug resistant epilepsy; epileptic encephalopathy; paediatrics; seizures S. Grosso, Pediatric Neurology-Immunology and Endocrinology Unit, Department of Pediatrics, University of Siena, Viale M. Bracci, Le Scotte, 53100 Siena, Italy Tel.: +39 0577 586558 Fax: +39 0577 586143 e-mail: [email protected] Accepted for publication December 21, 2013
Lacosamide is one of the latest anti-epileptic drug (AED) available on the market (3). Potential mechanisms of action include the enhancement of slow inactivation of voltage-gated sodium channels, which leads to an increased proportion of sodium channels unavailable for depolarization. Lacosamide does not interfere with the fast inactivation of voltage-gated sodium channels (3). Lacosamide has a favourable profile as it is completely absorbed after oral administration and exhibits only 15% of protein binding (3, 4). The drug has not been shown to induce or inhibit CYP enzymes in preclinical studies or in clinical studies examining specific CYP substrates (3). Although double blind placebo-controlled
Lacosamide efficacy in children with LGS clinical trials demonstrated the efficacy of lacosamide in adults with partial onset seizures (5–8), efficacy and tolerability of lacosamide in the treatment of epileptic syndromes of childhood remain to be clarified. Here, we report on a retrospective, multicentre study which has been conducted to evaluate the efficacy and safety of lacosamide in children affected by LGS. Patients and methods
The present report is a multicentre, retrospective, open-label treatment study carried out between October 2010 and May 2013 at six Italian paediatric neurology centres. The study protocol, amendments and informed consent were reviewed by ethics committees for each site. All patients’ legal representatives gave written informed consent before study participation. Patients were selected by the following criteria: (i) age under 16 years; (ii) LGS refractory to at least three previous antiepileptic drugs (AEDs), alone or in combination; (iii) exhibiting at least four seizures a month during the 3 months before lacosamide was administered; (iv) use of at least one other AED. All seizures were classified according to the International League against Epilepsy Revised Classification of Seizures (9), while diagnostic criteria for LGS were based on the International League Against Epilepsy classification (10) as follows: (i) polymorphous seizures including tonic–axial, atonic, and absence seizures (other types such as myoclonic, GTCS or partial seizures are frequently associated); (ii) EEG abnormal background activity, slow spike-waves
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Efficacy and tolerability of add-on lacosamide in children with Lennox-Gastaut syndrome Grosso S, Coppola G, Cusmai R, Parisi P, Spalice A, Foligno S, Verrotti A, Balestri P. Efficacy and tolerability of add-on lacosamide in children with Lennox-Gastaut syndrome. Acta Neurol Scand 2014: 129: 420–424. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objective – Available data on the efficacy of lacosamide in children with Lennox-Gastaut syndrome (LGS) are scarce and controversial. We present our experience with lacosamide therapy in children affected by LGS. Material and Methods – Medical charts of all children affected by LGS receiving oral lacosamide adjunctive therapy in six paediatric neurology centres were retrospectively evaluated. Efficacy was determined according to the frequency of countable seizures during the 4 weeks prior to treatment and the frequency in the last 4 weeks of observation. Patients whose seizure frequency was reduced by at least 50% were defined as responders. Results – Eighteen children (mean age 12.3 years) were identified. After a mean follow-up period of 9 months, 33% of patients were responders. None of them was seizure-free during the study period. The overall seizure reduction rate was 29%. The percentage reductions from baseline in tonic seizures and drop-attacks rates were 31% and 20%, respectively. Adverse reactions occurred in 44% of patients. The drug was discontinued in four (22%) patients because of increased seizure frequency (three cases) and walking instability (another patient). Conclusions – A third of children with LGS were responders after lacosamide adjunctive therapy. Although caution is still necessary when the drug is used in children with LGS, our preliminary observations suggest that lacosamide might be effective and represent a possible therapeutic option in children affected by LGS.
Introduction
Lennox-Gastaut syndrome (LGS) comprises 3–10% of all childhood epilepsies. Co-morbidities, including behavioural difficulties and learning disabilities, are common (1). Lennox-Gastaut syndrome is characterized by multiple, drug-resistant seizure types, with tonic seizures during sleep as a constant feature; diffuse slow spike–wave or poly-spike–wave discharges during wakefulness, and bursts of diffuse fast rhythms at ~10–20 Hz during sleep on the EEG; and progressive mental deterioration after epilepsy onset (2). Some patients may present with absence or tonic status epilepticus (2). 420
S. Grosso1,2, G. Coppola3, R. Cusmai4, P. Parisi5, A. Spalice6, S. Foligno5, A. Verrotti7, P. Balestri2 1 Pediatric Neurology-Immunology and Endocrinology Unit, University of Siena, Siena, Italy; 2Department of Pediatrics, University of Siena, Siena, Italy; 3Institute of Child and Adolescence Neuropsychiatry, University of Salerno, Salerno, Italy; 4Neurology Unit, Bambino Gesu Children’s Hospital, Rome, Italy; 5Child Neurology, NESMOS Department, Faculty of Medicine and Psychology, Sapienza University of Rome, Italy; 6 Department of Pediatrics, Child Neurology Division, Sapienza University of Rome, Rome, Italy; 7Clinical Pediatrics, University of Perugia, Perugia, Italy
Key words: Antiepileptic drugs; drug resistant epilepsy; epileptic encephalopathy; paediatrics; seizures S. Grosso, Pediatric Neurology-Immunology and Endocrinology Unit, Department of Pediatrics, University of Siena, Viale M. Bracci, Le Scotte, 53100 Siena, Italy Tel.: +39 0577 586558 Fax: +39 0577 586143 e-mail: [email protected] Accepted for publication December 21, 2013
Lacosamide is one of the latest anti-epileptic drug (AED) available on the market (3). Potential mechanisms of action include the enhancement of slow inactivation of voltage-gated sodium channels, which leads to an increased proportion of sodium channels unavailable for depolarization. Lacosamide does not interfere with the fast inactivation of voltage-gated sodium channels (3). Lacosamide has a favourable profile as it is completely absorbed after oral administration and exhibits only 15% of protein binding (3, 4). The drug has not been shown to induce or inhibit CYP enzymes in preclinical studies or in clinical studies examining specific CYP substrates (3). Although double blind placebo-controlled
Lacosamide efficacy in children with LGS clinical trials demonstrated the efficacy of lacosamide in adults with partial onset seizures (5–8), efficacy and tolerability of lacosamide in the treatment of epileptic syndromes of childhood remain to be clarified. Here, we report on a retrospective, multicentre study which has been conducted to evaluate the efficacy and safety of lacosamide in children affected by LGS. Patients and methods
The present report is a multicentre, retrospective, open-label treatment study carried out between October 2010 and May 2013 at six Italian paediatric neurology centres. The study protocol, amendments and informed consent were reviewed by ethics committees for each site. All patients’ legal representatives gave written informed consent before study participation. Patients were selected by the following criteria: (i) age under 16 years; (ii) LGS refractory to at least three previous antiepileptic drugs (AEDs), alone or in combination; (iii) exhibiting at least four seizures a month during the 3 months before lacosamide was administered; (iv) use of at least one other AED. All seizures were classified according to the International League against Epilepsy Revised Classification of Seizures (9), while diagnostic criteria for LGS were based on the International League Against Epilepsy classification (10) as follows: (i) polymorphous seizures including tonic–axial, atonic, and absence seizures (other types such as myoclonic, GTCS or partial seizures are frequently associated); (ii) EEG abnormal background activity, slow spike-waves
