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 x x x ( 2 0 1 4 ) 1 e5
Official Journal of the European Paediatric Neurology Society
Original article
Lacosamide in children with refractory status epilepticus. A multicenter Italian experience Salvatore Grosso a,d,*, Nelia Zamponi b, Arnaldo Bartocci c, Elisabetta Cesaroni b, Silvia Cappanera b, Rosanna Di Bartolo d, Paolo Balestri d a
Pediatric Neurology-Immunology and Endocrinology Unit, University of Siena, Italy Child Neuropsychiatric Unit, University of Ancona, Italy c Clinical Neurophysiology, University of Perugia, Italy d Department of Pediatrics, University of Siena, Italy b
article info
abstract
Article history:
Objective: Status epilepticus (SE) is considered a life-threatening medical emergency. First-
Received 11 June 2013
line treatment with antiepileptic drugs (AEDs) consists of intravenous benzodiazepines
Received in revised form
followed by phenytoin. SE is considered refractory (RSE) when unresponsive to standard
31 March 2014
doses of the first two AEDs. Scarce evidence is available to support specific guidelines for
Accepted 6 April 2014
the management of RSE in either adults or children. This study aimed to assess the efficacy and tolerability of intravenous (iv) lacosamide (LCM) in children affected by RSE.
Keywords:
Method: Children with RSE who were treated with ivLCM were included in the study. Effi-
Epilepsy
cacy was defined as the cessation of seizures after administration of ivLCM, with no need
Antiepileptic drugs
for any further antiepileptic drug. All patients had been unsuccessfully treated following
Antiepileptic drug
standard protocols before ivLCM was administered.
Seizure
Results: Eleven children entered the study (mean age: 9.4 years). Etiology was symptomatic
Status epilepticus
in 7 patients (63%). RSE was convulsive (focal or generalized) in 6 patients and nonconvulsive in 5. The mean initial bolus dose of LCM was 8.6 mg/kg. The drug, which was used as a fourth or later option, was effective in stopping RSE in 45% of patients, with seizures terminating within 12 h in three children. No serious adverse events attributable to LCM were reported. Conclusions: LCM might be an effective and well-tolerated AED in children with RSE. ª 2014 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.
1.
Introduction
Status epilepticus (SE) is a life-threatening emergency defined as an “acute epileptic condition characterized by continuous
seizures for at least 30 min, or by 30 min of intermittent seizures without full recovery of consciousness between seizures”.1 The therapeutic approach includes (i) life support measures, (ii) identification and treatment of the etiologic cause, and (iii) rapid treatment with intravenous antiepileptic
* Corresponding author. Pediatric Neurology-Immunology and Endocrinology Unit, University of Siena, Viale M. Bracci, Le Scotte, 53100 Siena, Italy. Tel.: þ39 0577 586546; fax: þ39 0577 586143. E-mail address: [email protected] (S. Grosso). http://dx.doi.org/10.1016/j.ejpn.2014.04.013 1090-3798/ª 2014 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.
Please cite this article in press as: Grosso S, et al., Lacosamide in children with refractory status epilepticus. A multicenter Italian experience, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.04.013
2
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 x x x ( 2 0 1 4 ) 1 e5
drugs (AEDs). First-line AEDs for SE consist of intravenous benzodiazepines (BDZ) followed by phenytoin (PHT) or fosphenytoin.2e8 Two randomized controlled trials evaluated the effectiveness of lorazepam (LZP) in the first stage of SE and noted that only 65% and 59% of seizures were adequately controlled with benzodiazepines, respectively.9 Therefore, at least one third of patients with SE could be expected to require second stage treatment with intravenous AEDs. SE is considered refractory (RSE) when unresponsive to standard doses of the first two AEDs used in therapy.10,11 RSE may persist for more than 7 days, in which case it may be referred to as prolonged RSE.12 When considered globally 10e40% of SE may evolve to a refractory state.11,12 Data on the long-term prognosis of RSE are scarce.10e12 Little evidence is available to support specific guidelines for the management of RSE.10e13 Recent recommendations for adults suggest that the aggressiveness of treatment for RSE should be tailored to the clinical situation. A conservative approach might be adopted in focal motor RSE without impairment of consciousness. In contrast, the early induction of pharmacological coma is suggested in patients with generalized convulsive forms of the disorder. In the absence of evidence from randomized controlled clinical trials no agent can be considered as certainly effective.14e17 Non-pharmacological approaches such as electroconvulsive therapy, hypothermia, or the ketogenic diet have also been used in RSE.11,12,16 Lacosamide (LCM) is a newly approved adjunctive treatment for partial onset seizures with a novel mechanism of action that may underlie its effectiveness in intractable epilepsy.18 LCM has been reported to be effective in adult SE,14,15 although data regarding pediatric patients are still scarce.
2.
Patients and methods
We retrospectively analyzed data for all pediatric patients given intravenous LCM to treat RSE in three Italian centers between January 2011 and December 2012. All patients entering the study were placed under LCM as an add-on therapy in the treatment of established RSE. The drug was added to the medications administered as part of a standard protocol, including a sequence of BZD, PHT, valproic acid (VPA) and/or phenobarbital (PB), and levetiracetam (LEV). Drugs such as propofol and sodium thiopentone were also used in some cases. Patient medical charts were carefully reviewed. Electrophysiological data and clinical findings were recorded, including: sex, age, etiology, epilepsy history, seizure type, onset and duration of SE, order in which AEDs were administered, loading and maintenance doses of intravenous and concomitant AEDs, as well as responsiveness and adverse events during LCM therapy. All patients underwent continuous EEG monitoring at the time of LCM initiation and for a minimum of 48 h following the initial dose. SE was diagnosed according to the following criteria: (a) any seizure lasting for 30 min or longer, or (b) intermittent seizures repeating within 30 min without full recuperation of consciousness.1 SE was classified according to semiology and divided into convulsive SE (focal motor or generalized) or nonconvulsive SE, based on EEG features.6e8 RSE was defined
as status epilepticus with a failure to respond to standard doses of at least two medications.9e12 Cessation of RSE was defined as the disappearance of EEG seizure activity (all patients with a diagnosis of nonconvulsive RSE underwent continuous EEG monitoring) or the disappearance of previous ictal symptoms without any suspicion of ongoing subclinical seizure, if confirmed by a subsequent EEG recording. We considered RSE as under control if no change in antiepileptic medication was needed for at least 48 h after clinical or electrographic resolution. The last AED administered before RSE cessation was defined as the termination drug, regardless of the latency between its first administration and RSE cessation. Analysis of adverse reactions included evidence of hypoventilation, hypotension, cardiac dysrhythmia, fever, and laboratory abnormalities. Routine blood tests were performed regularly. The Institutional Review Board of each epilepsy unit approved the study; no support was received from pharmaceutical companies.
3.
Results
Eleven patients were included in the study. Six (54%) patients had convulsive RSE, and five (46%) had nonconvulsive RSE. Clinical findings are reported in Table 1. When considered globally, the patients were aged 3e16 years (mean 9.4 years). Etiology was unknown in 37% of cases. Structural/metabolic causes were present in the remaining group of patients (Table 1). Nine (81%) patients had a previous history of epilepsy and had received a median of two AEDs. When SE occurred, the antiepileptic drugs administered included: VPA (5 patients, mean dose 34.1 6.2 mg/kg/day; mean plasma level 88.3 4.8 mg/ml), carbamazepine (4 patients, mean dose 8.1 1.1 mg/kg/day; mean plasma level 8.2 1.9 mg/ml), topiramate (4 patients, mean dose 5.6 0.4 mg/kg/day, plasma levels not available), vigabatrin (4 patients, mean dose
Table 1 e Clinical findings and baseline data. CRSE (n ¼ 6) Mean age (years) Sex (M/F) Prior history of epilepsy Etiology Unknown Structural/metabolic Neuronal migration disorders PRES Cerebral palsy Encephalitis LCM loading dose (mg/kg): mean (range) LCM maintenance dose (mg/kg/day): mean (range) Time from seizure onset to LCM therapy: mean (range) AEDs before RSE: mean (range)
NCRSE (n ¼ 5)
9.6 3/3 5 (83%)
9.1 2/3 4 (80%)
3
1
2 e 1 e 8.8 (6.9e9.9) 12.9 (9.1e13.9) 52.5 h (22e576) 3.1 (2e6)
e 1 2 1 8.3 (6.7e9.5) 11.9 (8.8e13.4) 63.5 h (31e90) 2.8 (2e5)
CRSE: convulsive refractory status epilepticus; NCRSE: nonconvulsive status epilepticus; PRES: posterior reversible encephalopathy syndrome; LCM: lacosamide; AED: antiepileptic drugs.
Please cite this article in press as: Grosso S, et al., Lacosamide in children with refractory status epilepticus. A multicenter Italian experience, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.04.013
3
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 x x x ( 2 0 1 4 ) 1 e5
95.6 6.4 mg/kg/day; plasma levels not available), levetiracetam (3 patients, mean dose 46.2 5.1 mg/kg/day, plasma levels not available), lamotrigine (2 patients, mean dose 4.4 1.3 mg/kg/day, plasma levels not available). RSE was the initial presentation in the remaining two children. An ictal EEG was carried out in all patients prior to LCM treatment. The median interval from SE onset to the start of SE therapy was 0.3e4 h (median 1.2 h). Before LCM administration, all patients had received at least three conventional iv AEDs: lorazepam (nine patients; mean 0.097 0.01 mg/kg) and midazolam (two patients; mean 0.18 0.05 mg/kg) were the first-line treatment and PHT (mean 18.8 0.6 mg/kg) the second medication. VPA (mean 38.2 1.2 mg/kg) or PB (mean 18.1 0.3 mg/kg) was the third- or the fourth-line treatment. The fifth drug administered was LEV (five patients, mean 52 4.1 mg/kg), propofol (three patients; mean 4.3 1.9 mg/kg/h), or LCM (three patients; for doses see below). All three patients resistant to propofol and four of those unresponsive to LEV underwent LCM therapy. One patient was placed under LCM after attempted treatment with sodium thiopental (9 mg/kg/h). LCM was therefore used as a fifth drug in 3 patients, as a sixth AED in 7 patients and as the eighth compound in another one. LCM was started after a mean latency interval of 58 h (range 22e576 h). Electrographic seizures varied in frequency from continuous episodes to one every 3 h (continuous in 4 patients; >6 hourly in 3; hourly in 2; once every 2 h in 1; once every 3 h in 1). When considered globally, the mean loading dose of LCM was 8.6 mg/kg (range 6.7e9.9). The mean maintenance dose was 12.3 mg/kg/day (range 8.8e13.9). SE cessation was observed in a total of five children (45%): specifically in three of the patients with convulsive RSE and in two with nonconvulsive RSE. In another two patients LCM was able to control clinical seizures but very frequent electrographic seizures were still recorded on EEG (Table 2). In three patients RSE ceased within 12 h of the first administration of LCM (in 1 patient within 60 min of the ivLCM loading dose). In the remaining two patients, SE ceased within 20 and 26 h of the ivLCM loading dose. Oral or ivLCM was continued at discharge from the Intensive Care Unit in 9 (81%) children. In our population no early or post-discharge adverse events were reported. LCM discontinuation was not necessary in any patient. In particular, no hemodynamic instability during the infusion, cardiac side effects, rashes, or modifications in electrolyte levels were documented.
4.
Discussion
LCM is a new AED that is capable of reducing the cumulative seizure time of self-sustaining status epilepticus and hippocampal neuronal damage, as well as preventing spontaneous recurrent seizures in animal models.19 The drug is approved by the EMA and FDA as an adjunctive therapy for partial-onset seizures in patients with epilepsy aged 16 years and over.15 It has been observed that new AEDs have no real impact on the prognosis of SE.14 In particular, Goodwin et al.19 found that LCM was ineffective in controlling SE in nine patients previously treated with two other AEDs. However, there is increased evidence of a potential role for LCM in the
Table 2 e LCM efficacy according to the type of refractory state of epilepticus. Outcome Seizure cessation Persistency of electrographic seizures LCM non-responder
CRSE (n ¼ 6)
NCRSE (n ¼ 5)
3 e 3
2 2 1
CRSE: convulsive refractory status epilepticus; NCRSE: nonconvulsive status epilepticus; LCM: lacosamide.
management of seizure clusters, nonconvulsive and convulsive SE.12,14,16 In a multicenter study involving thirty-nine patients with various types of SE in whom BDZs or other standard drugs had failed, LCM administered at a median dose of 400 mg was able to control SE in 44% of patients. The drug was found to be safe, as no serious adverse events were documented.20 LCM was also found to be effective in another study involving patients with nonconvulsive RSE.21 In a retrospective study of 48 patients concerning the efficacy and tolerability of intravenous LCM in the treatment of SE or seizure clusters, its success rate as the first or second drug was 100%, as the third drug 81%, and as the fourth or later drug 75%. No side effects were observed, except for pruritus and skin rash in two patients. The conclusion was that intravenous LCM is a potential alternative to standard AEDs for the treatment of SE.22 A success rate of 64.7% was reported in a further series of adult patients affected by RSE.23 Very few reports are available regarding the efficacy and safety of LCM in childhood RSE. In one young patient with RSE persisting for 10 weeks despite treatment with multiple AEDs and anesthetics, the seizures were aborted and EEG normalized following enteral LCM 25 mg twice daily. The drug was added to the therapy four weeks after the last addition of a new AED and had effect five days after the initiation of therapy.24 In two young patients (12 and 16 years) with refractory tonic SE unresponsive to more than three standard AEDs, an immediate clinical response was noted after a bolus dose of LCM. Interestingly, seizure control in these patients was achieved after very few doses.25 In the present series of 11 children presenting with convulsive or nonconvulsive RSE (Table 1), SE cessation was observed in 45% of patients. According to Hoefler and Trinka,15 the overall success rate for LCM in SE is 56%. The success rate we observed in our study is much lower than that reported in many adult series18,26,27 but in line with data provided by other studies.20,28 Etiology was unknown in 37% of patients and related to structural/metabolic changes in the remaining group (Table 1). Eighty percent of patients had a previous history of epilepsy and all of them were on multiple AEDs when they underwent LCM treatment. It is possible that the control of SE in our patients was unrelated to the addition of LCM. In fact, in some of our patients’ therapies were given in sequence. However, the total cessation of extremely frequent seizures after such a long mean duration and the close temporal relationship between the addition of LCM and seizure cessation may suggest a direct role for the drug. Of course, delayed responses to other drugs could also be possible. The latter phenomenon has mainly been described in patients placed under vagal nerve stimulation, immunotherapy, and the ketogenic diet.29
Please cite this article in press as: Grosso S, et al., Lacosamide in children with refractory status epilepticus. A multicenter Italian experience, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.04.013
4
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 x x x ( 2 0 1 4 ) 1 e5
However, only two of our patients had a vagal nerve stimulator implanted and none of them had been placed on the ketogenic diet or had immunotherapy. In the context of RSE ivLCM acted fast, with 3 patients responding within the first 12 h from LCM administration. There are concerns about the safety of AEDs in the treatment of status epilepticus. Preliminary reports seem to suggest that LCM may be safer than fosphenytoin,14e16 although comparison studies have not been performed. Although the current approved loading dose of ivLCM is up to 200 mg, the safety of the LCM dosage used in many reports has not been evaluated. According to Hoefler and Trinka,15 adverse events were reported in 25% of patients undergoing LCM therapy and were mainly represented by sedation, allergic skin reaction, hypotension and pruritus. Anecdotal reports of angioedema,19 atrioventricular block and paroxysmal asystole,30 as well as other non-life-threatening side effects such as acute onset chorea,25 can be found in the literature. In our pediatric patients we safely used doses of up to 14 mg/kg/day with no adverse events. A maximum weightbased dose for children has not yet been established, but doses of up to 20 mg/kg/day have recently been reported.31 However, data are scarce and our series is too small to draw definite conclusions about the safety of LCM in the treatment of status epilepticus in children. Although our study has several limitations - related to the non-randomized retrospective study design, the heterogeneous patient population and the relatively different treatment protocols - our observations may be useful for clinicians since they add to the clinical data on possible therapeutic strategies in children presenting with RSE. In conclusion, due to its favorable safety profile, the availability of an intravenous preparation, and in view of the relative success we observed in our study, we would suggest early consideration of LCM in the treatment of children with RSE.
references
1. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489e501. 2. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus, Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998;339:792e8. 3. Lowenstein DH. The management of refractory status epilepticus: an update. Epilepsia 2006;47(Suppl. 1):35e40. 4. Prasad K, Krishnan PR, Al-Roomi K, Sequeira R. Anticonvulsant therapy for status epilepticus. Br J Clin Pharmacol 2007;63:640e7. 5. Appleton R, Macleod S, Martland T. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Database Syst Rev; 2008:CD001905. 6. Shorvon S, Baulac M, Cross H, Trinka E, Walker M, TaskForce on Status Epilepticus of the ILAE Commission for European Affairs. The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London Colloquium on Status Epilepticus. Epilepsia 2008;49:1277e85.
7. Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus. Eur J Neurol 2010;17:348e55. 8. Trinka E. The use of valproate and new antiepileptic drugs in status epilepticus. Epilepsia 2007;48(Suppl. 8):49e51. 9. Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001;345:631e7. 10. Abend NS, Dlugos DJ. Treatment of refractory status epilepticus: literature review and a proposed protocol. Pediatr Neurol 2008;38:377e90. 11. Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 2011;134:2082e818. 12. Shorvon S, Ferlisi M. The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy. Brain 2012;135:2314e28. 13. Capovilla G, Beccaria F, Beghi E, Minicucci F, Sartori S, Vecchi M. Treatment of convulsive status epilepticus in childhood: recommendations of the Italian League Against Epilepsy. Epilepsia 2013;54(Suppl. 7):23e34. 14. Jaques L, Rossetti AO. Newer antiepileptic drugs in the treatment of status epilepticus: impact on prognosis. Epilepsy Behav 2012;24:70e3. 15. Ho¨fler J, Trinka E. Lacosamide as a new treatment option in status epilepticus. Epilepsia 2013;54:393e404. 16. Hocker S, Wijdicks EF, Rabinstein AA. Refractory status epilepticus: new insights in presentation, treatment, and outcome. Neurol Res 2013;35:163e8. 17. Hocker SE, Britton JW, Mandrekar JN, Wijdicks EF, Rabinstein AA. Predictors of outcome in refractory status epilepticus. JAMA Neurol 2013;70:72e7. 18. Errington A, Sto¨hr T, Heers C, Lees G. The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol 2008;73:157e69. 19. Goodwin H, Hinson HE, Shermock KM, Karanjia N, Lewin 3rd JJ. The use of lacosamide in refractory status epilepticus. Neurocrit Care 2011;14:348e53. 20. Kellinghaus C, Berning S, Besselmann M. Intravenous lacosamide as successful treatment for nonconvulsive status epilepticus after failure of first-line therapy. Epilepsy Behav 2009;14:429e31. 21. Mantsakanyan L, Chung JM, Tsimerinov EI, Elishiv DS. Intravenous lacosamide in refractory nonconvulsive status epilepticus. Seizure 2012;21:198e201. 22. Ho¨fler J, Unterberger I, Dobesberger J, Kuchukhidze G, Walser G, Trinka E. Intravenous lacosamide in status epilepticus and seizure clusters. Epilepsia 2011;52:148e52. 23. Miro´ J, Toledo M, Santamarina E, et al. Efficacy of intravenous lacosamide as an add-on treatment in refractory status epilepticus: a multicentric prospective study. Seizure 2013;22:77e9. 24. Shiloh-Malawsky Y, Fan Z, Greenwood R, Tennison M. Successful treatment of childhood prolonged refractory status epilepticus with lacosamide. Seizure 2011;20:586e8. 25. Jain V, Harvey SA. Treatment of refractory tonic status epilepticus with intravenous lacosamide. Epilepsia 2012;53:761e2. 26. Koubeissi MZ, Mayor CL, Estephan B, Rashid S, Azar NJ. Efficacy and safety of intravenous lacosamide in refractory nonconvulsive status epilepticus. Acta Neurol Scand 2011;123:142e6. 27. Albers JM, Meoddel G, Dittrich R, et al. Intravenous lacosamide e an effective add-on treatment of refractory status epilepticus. Seizure 2011;20:428e30.
Please cite this article in press as: Grosso S, et al., Lacosamide in children with refractory status epilepticus. A multicenter Italian experience, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.04.013
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 x x x ( 2 0 1 4 ) 1 e5
28. Cherry S, Judd L, Muniz JC, Elzawahry H, LaRoche S. Safety and efficacy of lacosamide in the intensive care unit. Neurocrit Care 2012;16:294e8. 29. Wusthoff C, Kranick S, Morley J, Bergqvist AG. The ketogenic diet in treatment of two adults with prolonged nonconvulsive status epilepticus. Epilepsia 2010;51:1083e5.
5
30. Krause LU, Brodowski KO, Kellinghaus C. Atrioventricular block following lacosamide intoxication. Epilepsy Behav 2011;20:725e7. 31. Buck ML, Goodkin HP. Use of lacosamide in children with refractory epilepsy. J Pediatr Pharmacol Ther 2012;17:211e9.
Please cite this article in press as: Grosso S, et al., Lacosamide in children with refractory status epilepticus. A multicenter Italian experience, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.04.013
Official Journal of the European Paediatric Neurology Society
Original article
Lacosamide in children with refractory status epilepticus. A multicenter Italian experience Salvatore Grosso a,d,*, Nelia Zamponi b, Arnaldo Bartocci c, Elisabetta Cesaroni b, Silvia Cappanera b, Rosanna Di Bartolo d, Paolo Balestri d a
Pediatric Neurology-Immunology and Endocrinology Unit, University of Siena, Italy Child Neuropsychiatric Unit, University of Ancona, Italy c Clinical Neurophysiology, University of Perugia, Italy d Department of Pediatrics, University of Siena, Italy b
article info
abstract
Article history:
Objective: Status epilepticus (SE) is considered a life-threatening medical emergency. First-
Received 11 June 2013
line treatment with antiepileptic drugs (AEDs) consists of intravenous benzodiazepines
Received in revised form
followed by phenytoin. SE is considered refractory (RSE) when unresponsive to standard
31 March 2014
doses of the first two AEDs. Scarce evidence is available to support specific guidelines for
Accepted 6 April 2014
the management of RSE in either adults or children. This study aimed to assess the efficacy and tolerability of intravenous (iv) lacosamide (LCM) in children affected by RSE.
Keywords:
Method: Children with RSE who were treated with ivLCM were included in the study. Effi-
Epilepsy
cacy was defined as the cessation of seizures after administration of ivLCM, with no need
Antiepileptic drugs
for any further antiepileptic drug. All patients had been unsuccessfully treated following
Antiepileptic drug
standard protocols before ivLCM was administered.
Seizure
Results: Eleven children entered the study (mean age: 9.4 years). Etiology was symptomatic
Status epilepticus
in 7 patients (63%). RSE was convulsive (focal or generalized) in 6 patients and nonconvulsive in 5. The mean initial bolus dose of LCM was 8.6 mg/kg. The drug, which was used as a fourth or later option, was effective in stopping RSE in 45% of patients, with seizures terminating within 12 h in three children. No serious adverse events attributable to LCM were reported. Conclusions: LCM might be an effective and well-tolerated AED in children with RSE. ª 2014 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.
1.
Introduction
Status epilepticus (SE) is a life-threatening emergency defined as an “acute epileptic condition characterized by continuous
seizures for at least 30 min, or by 30 min of intermittent seizures without full recovery of consciousness between seizures”.1 The therapeutic approach includes (i) life support measures, (ii) identification and treatment of the etiologic cause, and (iii) rapid treatment with intravenous antiepileptic
* Corresponding author. Pediatric Neurology-Immunology and Endocrinology Unit, University of Siena, Viale M. Bracci, Le Scotte, 53100 Siena, Italy. Tel.: þ39 0577 586546; fax: þ39 0577 586143. E-mail address: [email protected] (S. Grosso). http://dx.doi.org/10.1016/j.ejpn.2014.04.013 1090-3798/ª 2014 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.
Please cite this article in press as: Grosso S, et al., Lacosamide in children with refractory status epilepticus. A multicenter Italian experience, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.04.013
2
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 x x x ( 2 0 1 4 ) 1 e5
drugs (AEDs). First-line AEDs for SE consist of intravenous benzodiazepines (BDZ) followed by phenytoin (PHT) or fosphenytoin.2e8 Two randomized controlled trials evaluated the effectiveness of lorazepam (LZP) in the first stage of SE and noted that only 65% and 59% of seizures were adequately controlled with benzodiazepines, respectively.9 Therefore, at least one third of patients with SE could be expected to require second stage treatment with intravenous AEDs. SE is considered refractory (RSE) when unresponsive to standard doses of the first two AEDs used in therapy.10,11 RSE may persist for more than 7 days, in which case it may be referred to as prolonged RSE.12 When considered globally 10e40% of SE may evolve to a refractory state.11,12 Data on the long-term prognosis of RSE are scarce.10e12 Little evidence is available to support specific guidelines for the management of RSE.10e13 Recent recommendations for adults suggest that the aggressiveness of treatment for RSE should be tailored to the clinical situation. A conservative approach might be adopted in focal motor RSE without impairment of consciousness. In contrast, the early induction of pharmacological coma is suggested in patients with generalized convulsive forms of the disorder. In the absence of evidence from randomized controlled clinical trials no agent can be considered as certainly effective.14e17 Non-pharmacological approaches such as electroconvulsive therapy, hypothermia, or the ketogenic diet have also been used in RSE.11,12,16 Lacosamide (LCM) is a newly approved adjunctive treatment for partial onset seizures with a novel mechanism of action that may underlie its effectiveness in intractable epilepsy.18 LCM has been reported to be effective in adult SE,14,15 although data regarding pediatric patients are still scarce.
2.
Patients and methods
We retrospectively analyzed data for all pediatric patients given intravenous LCM to treat RSE in three Italian centers between January 2011 and December 2012. All patients entering the study were placed under LCM as an add-on therapy in the treatment of established RSE. The drug was added to the medications administered as part of a standard protocol, including a sequence of BZD, PHT, valproic acid (VPA) and/or phenobarbital (PB), and levetiracetam (LEV). Drugs such as propofol and sodium thiopentone were also used in some cases. Patient medical charts were carefully reviewed. Electrophysiological data and clinical findings were recorded, including: sex, age, etiology, epilepsy history, seizure type, onset and duration of SE, order in which AEDs were administered, loading and maintenance doses of intravenous and concomitant AEDs, as well as responsiveness and adverse events during LCM therapy. All patients underwent continuous EEG monitoring at the time of LCM initiation and for a minimum of 48 h following the initial dose. SE was diagnosed according to the following criteria: (a) any seizure lasting for 30 min or longer, or (b) intermittent seizures repeating within 30 min without full recuperation of consciousness.1 SE was classified according to semiology and divided into convulsive SE (focal motor or generalized) or nonconvulsive SE, based on EEG features.6e8 RSE was defined
as status epilepticus with a failure to respond to standard doses of at least two medications.9e12 Cessation of RSE was defined as the disappearance of EEG seizure activity (all patients with a diagnosis of nonconvulsive RSE underwent continuous EEG monitoring) or the disappearance of previous ictal symptoms without any suspicion of ongoing subclinical seizure, if confirmed by a subsequent EEG recording. We considered RSE as under control if no change in antiepileptic medication was needed for at least 48 h after clinical or electrographic resolution. The last AED administered before RSE cessation was defined as the termination drug, regardless of the latency between its first administration and RSE cessation. Analysis of adverse reactions included evidence of hypoventilation, hypotension, cardiac dysrhythmia, fever, and laboratory abnormalities. Routine blood tests were performed regularly. The Institutional Review Board of each epilepsy unit approved the study; no support was received from pharmaceutical companies.
3.
Results
Eleven patients were included in the study. Six (54%) patients had convulsive RSE, and five (46%) had nonconvulsive RSE. Clinical findings are reported in Table 1. When considered globally, the patients were aged 3e16 years (mean 9.4 years). Etiology was unknown in 37% of cases. Structural/metabolic causes were present in the remaining group of patients (Table 1). Nine (81%) patients had a previous history of epilepsy and had received a median of two AEDs. When SE occurred, the antiepileptic drugs administered included: VPA (5 patients, mean dose 34.1 6.2 mg/kg/day; mean plasma level 88.3 4.8 mg/ml), carbamazepine (4 patients, mean dose 8.1 1.1 mg/kg/day; mean plasma level 8.2 1.9 mg/ml), topiramate (4 patients, mean dose 5.6 0.4 mg/kg/day, plasma levels not available), vigabatrin (4 patients, mean dose
Table 1 e Clinical findings and baseline data. CRSE (n ¼ 6) Mean age (years) Sex (M/F) Prior history of epilepsy Etiology Unknown Structural/metabolic Neuronal migration disorders PRES Cerebral palsy Encephalitis LCM loading dose (mg/kg): mean (range) LCM maintenance dose (mg/kg/day): mean (range) Time from seizure onset to LCM therapy: mean (range) AEDs before RSE: mean (range)
NCRSE (n ¼ 5)
9.6 3/3 5 (83%)
9.1 2/3 4 (80%)
3
1
2 e 1 e 8.8 (6.9e9.9) 12.9 (9.1e13.9) 52.5 h (22e576) 3.1 (2e6)
e 1 2 1 8.3 (6.7e9.5) 11.9 (8.8e13.4) 63.5 h (31e90) 2.8 (2e5)
CRSE: convulsive refractory status epilepticus; NCRSE: nonconvulsive status epilepticus; PRES: posterior reversible encephalopathy syndrome; LCM: lacosamide; AED: antiepileptic drugs.
Please cite this article in press as: Grosso S, et al., Lacosamide in children with refractory status epilepticus. A multicenter Italian experience, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.04.013
3
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 x x x ( 2 0 1 4 ) 1 e5
95.6 6.4 mg/kg/day; plasma levels not available), levetiracetam (3 patients, mean dose 46.2 5.1 mg/kg/day, plasma levels not available), lamotrigine (2 patients, mean dose 4.4 1.3 mg/kg/day, plasma levels not available). RSE was the initial presentation in the remaining two children. An ictal EEG was carried out in all patients prior to LCM treatment. The median interval from SE onset to the start of SE therapy was 0.3e4 h (median 1.2 h). Before LCM administration, all patients had received at least three conventional iv AEDs: lorazepam (nine patients; mean 0.097 0.01 mg/kg) and midazolam (two patients; mean 0.18 0.05 mg/kg) were the first-line treatment and PHT (mean 18.8 0.6 mg/kg) the second medication. VPA (mean 38.2 1.2 mg/kg) or PB (mean 18.1 0.3 mg/kg) was the third- or the fourth-line treatment. The fifth drug administered was LEV (five patients, mean 52 4.1 mg/kg), propofol (three patients; mean 4.3 1.9 mg/kg/h), or LCM (three patients; for doses see below). All three patients resistant to propofol and four of those unresponsive to LEV underwent LCM therapy. One patient was placed under LCM after attempted treatment with sodium thiopental (9 mg/kg/h). LCM was therefore used as a fifth drug in 3 patients, as a sixth AED in 7 patients and as the eighth compound in another one. LCM was started after a mean latency interval of 58 h (range 22e576 h). Electrographic seizures varied in frequency from continuous episodes to one every 3 h (continuous in 4 patients; >6 hourly in 3; hourly in 2; once every 2 h in 1; once every 3 h in 1). When considered globally, the mean loading dose of LCM was 8.6 mg/kg (range 6.7e9.9). The mean maintenance dose was 12.3 mg/kg/day (range 8.8e13.9). SE cessation was observed in a total of five children (45%): specifically in three of the patients with convulsive RSE and in two with nonconvulsive RSE. In another two patients LCM was able to control clinical seizures but very frequent electrographic seizures were still recorded on EEG (Table 2). In three patients RSE ceased within 12 h of the first administration of LCM (in 1 patient within 60 min of the ivLCM loading dose). In the remaining two patients, SE ceased within 20 and 26 h of the ivLCM loading dose. Oral or ivLCM was continued at discharge from the Intensive Care Unit in 9 (81%) children. In our population no early or post-discharge adverse events were reported. LCM discontinuation was not necessary in any patient. In particular, no hemodynamic instability during the infusion, cardiac side effects, rashes, or modifications in electrolyte levels were documented.
4.
Discussion
LCM is a new AED that is capable of reducing the cumulative seizure time of self-sustaining status epilepticus and hippocampal neuronal damage, as well as preventing spontaneous recurrent seizures in animal models.19 The drug is approved by the EMA and FDA as an adjunctive therapy for partial-onset seizures in patients with epilepsy aged 16 years and over.15 It has been observed that new AEDs have no real impact on the prognosis of SE.14 In particular, Goodwin et al.19 found that LCM was ineffective in controlling SE in nine patients previously treated with two other AEDs. However, there is increased evidence of a potential role for LCM in the
Table 2 e LCM efficacy according to the type of refractory state of epilepticus. Outcome Seizure cessation Persistency of electrographic seizures LCM non-responder
CRSE (n ¼ 6)
NCRSE (n ¼ 5)
3 e 3
2 2 1
CRSE: convulsive refractory status epilepticus; NCRSE: nonconvulsive status epilepticus; LCM: lacosamide.
management of seizure clusters, nonconvulsive and convulsive SE.12,14,16 In a multicenter study involving thirty-nine patients with various types of SE in whom BDZs or other standard drugs had failed, LCM administered at a median dose of 400 mg was able to control SE in 44% of patients. The drug was found to be safe, as no serious adverse events were documented.20 LCM was also found to be effective in another study involving patients with nonconvulsive RSE.21 In a retrospective study of 48 patients concerning the efficacy and tolerability of intravenous LCM in the treatment of SE or seizure clusters, its success rate as the first or second drug was 100%, as the third drug 81%, and as the fourth or later drug 75%. No side effects were observed, except for pruritus and skin rash in two patients. The conclusion was that intravenous LCM is a potential alternative to standard AEDs for the treatment of SE.22 A success rate of 64.7% was reported in a further series of adult patients affected by RSE.23 Very few reports are available regarding the efficacy and safety of LCM in childhood RSE. In one young patient with RSE persisting for 10 weeks despite treatment with multiple AEDs and anesthetics, the seizures were aborted and EEG normalized following enteral LCM 25 mg twice daily. The drug was added to the therapy four weeks after the last addition of a new AED and had effect five days after the initiation of therapy.24 In two young patients (12 and 16 years) with refractory tonic SE unresponsive to more than three standard AEDs, an immediate clinical response was noted after a bolus dose of LCM. Interestingly, seizure control in these patients was achieved after very few doses.25 In the present series of 11 children presenting with convulsive or nonconvulsive RSE (Table 1), SE cessation was observed in 45% of patients. According to Hoefler and Trinka,15 the overall success rate for LCM in SE is 56%. The success rate we observed in our study is much lower than that reported in many adult series18,26,27 but in line with data provided by other studies.20,28 Etiology was unknown in 37% of patients and related to structural/metabolic changes in the remaining group (Table 1). Eighty percent of patients had a previous history of epilepsy and all of them were on multiple AEDs when they underwent LCM treatment. It is possible that the control of SE in our patients was unrelated to the addition of LCM. In fact, in some of our patients’ therapies were given in sequence. However, the total cessation of extremely frequent seizures after such a long mean duration and the close temporal relationship between the addition of LCM and seizure cessation may suggest a direct role for the drug. Of course, delayed responses to other drugs could also be possible. The latter phenomenon has mainly been described in patients placed under vagal nerve stimulation, immunotherapy, and the ketogenic diet.29
Please cite this article in press as: Grosso S, et al., Lacosamide in children with refractory status epilepticus. A multicenter Italian experience, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.04.013
4
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 x x x ( 2 0 1 4 ) 1 e5
However, only two of our patients had a vagal nerve stimulator implanted and none of them had been placed on the ketogenic diet or had immunotherapy. In the context of RSE ivLCM acted fast, with 3 patients responding within the first 12 h from LCM administration. There are concerns about the safety of AEDs in the treatment of status epilepticus. Preliminary reports seem to suggest that LCM may be safer than fosphenytoin,14e16 although comparison studies have not been performed. Although the current approved loading dose of ivLCM is up to 200 mg, the safety of the LCM dosage used in many reports has not been evaluated. According to Hoefler and Trinka,15 adverse events were reported in 25% of patients undergoing LCM therapy and were mainly represented by sedation, allergic skin reaction, hypotension and pruritus. Anecdotal reports of angioedema,19 atrioventricular block and paroxysmal asystole,30 as well as other non-life-threatening side effects such as acute onset chorea,25 can be found in the literature. In our pediatric patients we safely used doses of up to 14 mg/kg/day with no adverse events. A maximum weightbased dose for children has not yet been established, but doses of up to 20 mg/kg/day have recently been reported.31 However, data are scarce and our series is too small to draw definite conclusions about the safety of LCM in the treatment of status epilepticus in children. Although our study has several limitations - related to the non-randomized retrospective study design, the heterogeneous patient population and the relatively different treatment protocols - our observations may be useful for clinicians since they add to the clinical data on possible therapeutic strategies in children presenting with RSE. In conclusion, due to its favorable safety profile, the availability of an intravenous preparation, and in view of the relative success we observed in our study, we would suggest early consideration of LCM in the treatment of children with RSE.
references
1. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489e501. 2. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus, Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998;339:792e8. 3. Lowenstein DH. The management of refractory status epilepticus: an update. Epilepsia 2006;47(Suppl. 1):35e40. 4. Prasad K, Krishnan PR, Al-Roomi K, Sequeira R. Anticonvulsant therapy for status epilepticus. Br J Clin Pharmacol 2007;63:640e7. 5. Appleton R, Macleod S, Martland T. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Database Syst Rev; 2008:CD001905. 6. Shorvon S, Baulac M, Cross H, Trinka E, Walker M, TaskForce on Status Epilepticus of the ILAE Commission for European Affairs. The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London Colloquium on Status Epilepticus. Epilepsia 2008;49:1277e85.
7. Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus. Eur J Neurol 2010;17:348e55. 8. Trinka E. The use of valproate and new antiepileptic drugs in status epilepticus. Epilepsia 2007;48(Suppl. 8):49e51. 9. Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001;345:631e7. 10. Abend NS, Dlugos DJ. Treatment of refractory status epilepticus: literature review and a proposed protocol. Pediatr Neurol 2008;38:377e90. 11. Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 2011;134:2082e818. 12. Shorvon S, Ferlisi M. The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy. Brain 2012;135:2314e28. 13. Capovilla G, Beccaria F, Beghi E, Minicucci F, Sartori S, Vecchi M. Treatment of convulsive status epilepticus in childhood: recommendations of the Italian League Against Epilepsy. Epilepsia 2013;54(Suppl. 7):23e34. 14. Jaques L, Rossetti AO. Newer antiepileptic drugs in the treatment of status epilepticus: impact on prognosis. Epilepsy Behav 2012;24:70e3. 15. Ho¨fler J, Trinka E. Lacosamide as a new treatment option in status epilepticus. Epilepsia 2013;54:393e404. 16. Hocker S, Wijdicks EF, Rabinstein AA. Refractory status epilepticus: new insights in presentation, treatment, and outcome. Neurol Res 2013;35:163e8. 17. Hocker SE, Britton JW, Mandrekar JN, Wijdicks EF, Rabinstein AA. Predictors of outcome in refractory status epilepticus. JAMA Neurol 2013;70:72e7. 18. Errington A, Sto¨hr T, Heers C, Lees G. The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol 2008;73:157e69. 19. Goodwin H, Hinson HE, Shermock KM, Karanjia N, Lewin 3rd JJ. The use of lacosamide in refractory status epilepticus. Neurocrit Care 2011;14:348e53. 20. Kellinghaus C, Berning S, Besselmann M. Intravenous lacosamide as successful treatment for nonconvulsive status epilepticus after failure of first-line therapy. Epilepsy Behav 2009;14:429e31. 21. Mantsakanyan L, Chung JM, Tsimerinov EI, Elishiv DS. Intravenous lacosamide in refractory nonconvulsive status epilepticus. Seizure 2012;21:198e201. 22. Ho¨fler J, Unterberger I, Dobesberger J, Kuchukhidze G, Walser G, Trinka E. Intravenous lacosamide in status epilepticus and seizure clusters. Epilepsia 2011;52:148e52. 23. Miro´ J, Toledo M, Santamarina E, et al. Efficacy of intravenous lacosamide as an add-on treatment in refractory status epilepticus: a multicentric prospective study. Seizure 2013;22:77e9. 24. Shiloh-Malawsky Y, Fan Z, Greenwood R, Tennison M. Successful treatment of childhood prolonged refractory status epilepticus with lacosamide. Seizure 2011;20:586e8. 25. Jain V, Harvey SA. Treatment of refractory tonic status epilepticus with intravenous lacosamide. Epilepsia 2012;53:761e2. 26. Koubeissi MZ, Mayor CL, Estephan B, Rashid S, Azar NJ. Efficacy and safety of intravenous lacosamide in refractory nonconvulsive status epilepticus. Acta Neurol Scand 2011;123:142e6. 27. Albers JM, Meoddel G, Dittrich R, et al. Intravenous lacosamide e an effective add-on treatment of refractory status epilepticus. Seizure 2011;20:428e30.
Please cite this article in press as: Grosso S, et al., Lacosamide in children with refractory status epilepticus. A multicenter Italian experience, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.04.013
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 x x x ( 2 0 1 4 ) 1 e5
28. Cherry S, Judd L, Muniz JC, Elzawahry H, LaRoche S. Safety and efficacy of lacosamide in the intensive care unit. Neurocrit Care 2012;16:294e8. 29. Wusthoff C, Kranick S, Morley J, Bergqvist AG. The ketogenic diet in treatment of two adults with prolonged nonconvulsive status epilepticus. Epilepsia 2010;51:1083e5.
5
30. Krause LU, Brodowski KO, Kellinghaus C. Atrioventricular block following lacosamide intoxication. Epilepsy Behav 2011;20:725e7. 31. Buck ML, Goodkin HP. Use of lacosamide in children with refractory epilepsy. J Pediatr Pharmacol Ther 2012;17:211e9.
Please cite this article in press as: Grosso S, et al., Lacosamide in children with refractory status epilepticus. A multicenter Italian experience, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/j.ejpn.2014.04.013
