Acta Neurol Scand 2014: 130: e39–e40 DOI: 10.1111/ane.12254
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Letter to the Editor
Efficacy and tolerability of add-on Lacosamide in children with Lennox–Gastaut syndrome Dear Editor, We thank Italiano and colleagues, and AndradeMachado for their interest in our article and for providing us this opportunity to reemphasize certain findings from our study (1). All patients included in our study were affected by Lennox– Gastaut syndrome (LGS) according to the ILAE classification. All of them experienced in their epilepsy history (a mean of 6.7 years) nocturnal tonic seizures. All patients included in our study had at least one video-polygraphic EEG recording in their clinical follow-up. Four (22%) children were apparently not experiencing tonic seizures when Lacosamide was administered in add-on therapy. Italiano and colleagues, and Andrade-Machado cast some doubt upon the correct syndromic diagnosis in the above-mentioned group of four patients. Our report is a multicentre, retrospective, and open-label treatment study. This may imply some methodological weaknesses, which are common to all studies with a retrospective and multicentre nature. Italiano’s group (2) and that of Andrade-Machado (3) reported on a total of four patients with LGS who developed an apparently Lacosamide-related worsening of tonic seizures. In particular, Andrade-Machado et al. (3) observed an exacerbation of fast rhythms on EEG following Lacosamide treatment. The frequency of seizures diminished after Lacosamide was suspended. On the basis of their anecdotal observations, which were discussed in our article (1), these authors suggest that the rate of paradoxical reactions to Lacosamide treatment may have been underestimated in our study (1). Clearly, our study was not designed to successfully detect the possible Lacosamide-related seizure worsening. In fact, no systematic or prospective video-polygraphic recordings were performed. The design of our study reflects daily clinical practice and provides a more natural and realistic view of the use of Lacosamide in children affected by LGS.
Aside from all the limitations due to the study design, we observed seizure aggravation (tonic and/or drop attacks) in three patients (17%). This percentage was not dissimilar to that observed in patients with LGS taking other AEDs (4, 5). All anti-epileptic drugs may potentially have a paradoxical seizure-inducing effect under certain circumstances. We also all know that is often difficult to distinguish between the effect of an AED and the natural course of the disease. This is particularly true in LGS which tends to show a natural fluctuation of seizure frequency during the course of time. Unfortunately, to date, there exist no objective criteria for defining the extent of aggravation beyond which the suspicion of nonspontaneity is legitimately aroused. We should bear in mind that to unequivocally demonstrate AED-induced aggravation of seizures, it would be necessary to demonstrate improvement after its suspension or reduction, followed by renewed worsening secondary to its reintroduction (6). For legitimate and obvious ethical issues, neither Italiano et al. (2) nor AndradeMachado et al. (3) followed such a procedure with their patients. On this basis, it could be stated that definite proof of a direct relationship between Lacosamide treatment and tonic seizure aggravation was lacking in the patients they described (2, 3). Moreover, Italiano et al. and Andrade-Machado omitted to cite in their letters the studies that have reported very positive experiences, in terms of both efficacy and safety, with Lacosamide in patients with LGS (7, 8). In particular, Rastogi et al. (7) reported two patients with LGS who experienced almost complete seizure control under Lacosamide. Further investigations are therefore needed to define the real frequency of this possible adverse event. Of course, we agree with Italiano et al. and Andrade-Machado that caution is still necessary when the drug is used in children with LGS. We e39
Letter to the Editor have repeatedly emphasized this concept in our article (1). Acknowledgments The authors have no acknowledgements to make.
Conflict of interest and sources of funding The authors have no conflict of interests or sources of funding to declare.
S. Grosso1,2, P. Balestri2 Pediatric Neurology-Immunology and Endocrinology Unit, University of Siena, Siena, Italy; 2 Department of Pediatrics, University of Siena, Siena, Italy e-mail: [email protected]
1
References 1. GROSSO S, COPPOLA G, PARISI P et al., Efficacy and tolerability of add-on lacosamide in children with Lennox-Gastaut syndrome. Acta Neurol Scand 2014; 129:420–4.
e40
2. CUZZOLA A, FERLAZZO E, ITALIANO D, CALABRO RS, BRAMANTI P, GENTON P. Does lacosamide aggravate Lennox-Gastaut syndrome? Report on three consecutive cases. Epilepsy Behav 2010;19:650–1. 3. ANDRADE-MACHADO R, BENJUMEA-CUARTAS V, JARAMILLOJIMENEZ E. Lacosamide in Lennox-Gastaut syndrome: case report. Clin Neuropharmacol 2012;35:148–9. 4. COPPOLA G, GROSSO S, FRANZONI E et al. Rufinamide in children and adults with Lennox-Gastaut syndrome: first Italia multicenter experience. Seizure 2010;19: 587–91. 5. KIM SH, EUN SH, KANG HC et al. Rufinamide as an adjuvant treatment in children with Lennox-Gastaut syndrome. Seizure 2012;21:288–91. 6. GUERRINI R, BELMONTE A, GENTON P. Antiepileptic druginduced worsening of seizures in children. Epilepsia 1998;39(Suppl 3):S2–10. 7. RASTOGI RG, NG Y. Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study. J Child Neurol 2010;27:492–5. C, MARTINEZ-BERMEJO A, RUFO-CAMPOS 8. CASAS-FERNANDEZ M 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: 187–97.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Letter to the Editor
Efficacy and tolerability of add-on Lacosamide in children with Lennox–Gastaut syndrome Dear Editor, We thank Italiano and colleagues, and AndradeMachado for their interest in our article and for providing us this opportunity to reemphasize certain findings from our study (1). All patients included in our study were affected by Lennox– Gastaut syndrome (LGS) according to the ILAE classification. All of them experienced in their epilepsy history (a mean of 6.7 years) nocturnal tonic seizures. All patients included in our study had at least one video-polygraphic EEG recording in their clinical follow-up. Four (22%) children were apparently not experiencing tonic seizures when Lacosamide was administered in add-on therapy. Italiano and colleagues, and Andrade-Machado cast some doubt upon the correct syndromic diagnosis in the above-mentioned group of four patients. Our report is a multicentre, retrospective, and open-label treatment study. This may imply some methodological weaknesses, which are common to all studies with a retrospective and multicentre nature. Italiano’s group (2) and that of Andrade-Machado (3) reported on a total of four patients with LGS who developed an apparently Lacosamide-related worsening of tonic seizures. In particular, Andrade-Machado et al. (3) observed an exacerbation of fast rhythms on EEG following Lacosamide treatment. The frequency of seizures diminished after Lacosamide was suspended. On the basis of their anecdotal observations, which were discussed in our article (1), these authors suggest that the rate of paradoxical reactions to Lacosamide treatment may have been underestimated in our study (1). Clearly, our study was not designed to successfully detect the possible Lacosamide-related seizure worsening. In fact, no systematic or prospective video-polygraphic recordings were performed. The design of our study reflects daily clinical practice and provides a more natural and realistic view of the use of Lacosamide in children affected by LGS.
Aside from all the limitations due to the study design, we observed seizure aggravation (tonic and/or drop attacks) in three patients (17%). This percentage was not dissimilar to that observed in patients with LGS taking other AEDs (4, 5). All anti-epileptic drugs may potentially have a paradoxical seizure-inducing effect under certain circumstances. We also all know that is often difficult to distinguish between the effect of an AED and the natural course of the disease. This is particularly true in LGS which tends to show a natural fluctuation of seizure frequency during the course of time. Unfortunately, to date, there exist no objective criteria for defining the extent of aggravation beyond which the suspicion of nonspontaneity is legitimately aroused. We should bear in mind that to unequivocally demonstrate AED-induced aggravation of seizures, it would be necessary to demonstrate improvement after its suspension or reduction, followed by renewed worsening secondary to its reintroduction (6). For legitimate and obvious ethical issues, neither Italiano et al. (2) nor AndradeMachado et al. (3) followed such a procedure with their patients. On this basis, it could be stated that definite proof of a direct relationship between Lacosamide treatment and tonic seizure aggravation was lacking in the patients they described (2, 3). Moreover, Italiano et al. and Andrade-Machado omitted to cite in their letters the studies that have reported very positive experiences, in terms of both efficacy and safety, with Lacosamide in patients with LGS (7, 8). In particular, Rastogi et al. (7) reported two patients with LGS who experienced almost complete seizure control under Lacosamide. Further investigations are therefore needed to define the real frequency of this possible adverse event. Of course, we agree with Italiano et al. and Andrade-Machado that caution is still necessary when the drug is used in children with LGS. We e39
Letter to the Editor have repeatedly emphasized this concept in our article (1). Acknowledgments The authors have no acknowledgements to make.
Conflict of interest and sources of funding The authors have no conflict of interests or sources of funding to declare.
S. Grosso1,2, P. Balestri2 Pediatric Neurology-Immunology and Endocrinology Unit, University of Siena, Siena, Italy; 2 Department of Pediatrics, University of Siena, Siena, Italy e-mail: [email protected]
1
References 1. GROSSO S, COPPOLA G, PARISI P et al., Efficacy and tolerability of add-on lacosamide in children with Lennox-Gastaut syndrome. Acta Neurol Scand 2014; 129:420–4.
e40
2. CUZZOLA A, FERLAZZO E, ITALIANO D, CALABRO RS, BRAMANTI P, GENTON P. Does lacosamide aggravate Lennox-Gastaut syndrome? Report on three consecutive cases. Epilepsy Behav 2010;19:650–1. 3. ANDRADE-MACHADO R, BENJUMEA-CUARTAS V, JARAMILLOJIMENEZ E. Lacosamide in Lennox-Gastaut syndrome: case report. Clin Neuropharmacol 2012;35:148–9. 4. COPPOLA G, GROSSO S, FRANZONI E et al. Rufinamide in children and adults with Lennox-Gastaut syndrome: first Italia multicenter experience. Seizure 2010;19: 587–91. 5. KIM SH, EUN SH, KANG HC et al. Rufinamide as an adjuvant treatment in children with Lennox-Gastaut syndrome. Seizure 2012;21:288–91. 6. GUERRINI R, BELMONTE A, GENTON P. Antiepileptic druginduced worsening of seizures in children. Epilepsia 1998;39(Suppl 3):S2–10. 7. RASTOGI RG, NG Y. Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study. J Child Neurol 2010;27:492–5. C, MARTINEZ-BERMEJO A, RUFO-CAMPOS 8. CASAS-FERNANDEZ M 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: 187–97.
