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Official Journal of the European Paediatric Neurology Society
Original article
Intravenous levetiracetam in Thai children and adolescents with status epilepticus and acute repetitive seizures Chaiyos Khongkhatithum, Lunliya Thampratankul, Natrujee Wiwattanadittakul, Anannit Visudtibhan* Division of Neurology, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Bangkok 10400, Thailand
article info
abstract
Article history:
Background: Intravenous levetiracetam is an option for treatment of status epilepticus (SE)
Received 27 January 2014
and acute repetitive seizures (ARS). However, there have been relatively few studies with
Received in revised form
children and adolescents. Also, an appropriate dosage has yet to be determined.
8 January 2015
Aim: This study investigated the safety and the efficacy of levetiracetam for intravenous
Accepted 21 February 2015
treatment of convulsive status epilepticus and acute repetitive seizures in children and adolescents.
Keywords:
Method: Retrospectively, the study reviewed the medical records of 19 male and 31 female
Levetiracetam
patients under 18 years of age who had received intravenous levetiracetam treatment
Status epilepticus
either for acute repetitive seizures or for convulsive status epilepticus. The patients were
Acute repetitive seizures
admitted between April 1st, 2010 and December 31st, 2011 to the Department of Pediatrics,
Childhood seizures
Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. Data were collected on underlying illnesses, etiology of seizures, indication for levetiracetam therapy, initial dosage, rate of infusion, untoward effects during infusion and emerged complications. Efficacy of treatment was defined as the termination of seizure within 30 min of completing levetiracetam infusion and no seizure recurrence within 6 h of initial treatment. Results: The age range of the 50 patients was from one day to 18 years (mean 79.6 months). The analysis included 52 episodes of 34 acute repetitive seizures (63.4%) and 18 convulsive status epilepticus (34.6%). Infusion rates ranged from 2 to 66 mg/kg/min (mean 29.6). Cessation of seizure was obtained in 59.6% of 52 episodes. Patients with underlying drug resistant epilepsy did not respond to levetiracetam therapy as well as patients with other etiology of seizures. There were no adverse drug reactions or untoward effects observed during the therapy. Conclusion: Intravenous administration of levetiracetam is safe and effective for treatment of acute repetitive seizures and convulsive status epilepticus in children and adolescents.
* Corresponding author. Division of Neurology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Rama 6 Road, Ratchathewee, Bangkok 10400, Thailand. Tel.: þ66 2 201 1879; fax: þ66 2 201 1850. E-mail address: [email protected] (A. Visudtibhan). http://dx.doi.org/10.1016/j.ejpn.2015.02.010 1090-3798/© 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Khongkhatithum C, et al., Intravenous levetiracetam in Thai children and adolescents with status epilepticus and acute repetitive seizures, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/ j.ejpn.2015.02.010
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Failure of treatment may be related to underlying drug resistant epilepsy. Further study of appropriate initial dosage and pharmacokinetic variations in the patients is needed as possible explanation of the unresponsiveness. © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
Levetiracetam is a broad-spectrum antiepileptic drug with proven efficacy as an adjunctive therapy for localizationrelated epilepsy in children, for juvenile myoclonic epilepsy in children and adolescents, and for primary generalized tonic-clonic seizures in adults. It has been recognized as a new generation antiepileptic drug with a favorable safety and tolerability profile, and insignificant drugedrug interaction.1 Levetiracetam has been available in tablet form since 1999 and in oral solution since 2003. The United States Food and Drug Administration (US FDA) approved the intravenous formulation in July 2006.1,2 Since then, levetiracetam has been used in the treatment of various types of seizures in children and adolescents. As of 2012 with the US FDA's approval, it has been used for drug-resistant focal-onset seizures.3 The availability of levetiracetam in the intravenous formulation provides a useful option when oral administration is temporarily unattainable in status epilepticus and acute repetitive seizures.4 There have been many reports of its favorable efficacy in treatment of adult patients presenting with status epilepticus.5e8 After being administered in the treatment of adult status epilepticus and acute repetitive seizures, its efficacy and safety for children were also reported and documented.9e17 Recently, there have been reports on levetiracetam's role in the treatment of neonatal seizures with favorable outcomes.18e23 However, the total number of patients in those studies was very small with a wide-range of initial dosage. In Thailand, there are five intravenous antiepileptic drugs available. These are phenobarbital, phenytoin, fos-phenytoin, valproate and levetiracetam. Levetiracetam was included as an option for treatment of convulsive status epilepticus in the guidelines for epilepsy treatment by the Epilepsy Society of Thailand in 2011. Nevertheless, there have been very few reports in Thailand on these drugs' efficacy and safety, especially of levetiracetam. To date, there has been only one study that examined intravenous levetiracetam in 34 adult patients presenting with convulsive status epilepticus. The study reported a seizure-control rate of 61.8%.24 This current study was therefore conducted to evaluate the efficacy and the safety of intravenous levetiracetam for treatment of convulsive status epilepticus and acute repetitive seizure in Thai children and adolescents.
2.
Methods
A retrospective review was conducted of medical records of 50 patients under the age of 18 years admitted to the Department of Pediatrics, Ramathibodi Hospital, between April 1st, 2010
and December 31st, 2011. All of these patients received the intravenous levetiracetam for treatment of either acute repetitive seizures or convulsive status epilepticus. Acute repetitive seizure was defined as repeated seizures of which each lasted less than 5 min with recovery of consciousness between each seizure and that persisted for at least 30 min. Convulsive status epilepticus was defined as convulsive type of any single and prolonged tonic-clonic seizure that persisted for over 5 min and irrespective of whether any emergency medication administered.10 The etiologies of seizures were classified according to the documented cause of seizures. The episode with definitive causes of seizures would be categorized into symptomatic group, while the episodes without definitive causes would be categorized into unknown group. The study collected data on the underlying illnesses, etiology of seizures, indication for the use of levetiracetam, initial dosage, rate of infusion, and untoward effects during infusion and during the 24 h after administration. The efficacy of the treatment was categorized into 2 groups as respond-totreatment and unresponsive. The group assignment was determined according to the cessation of seizures within 30 min after completion of infusion and no recurrence of seizures within 6 h after infusion. Patients with seizures that terminated within 30 min after levetiracetam infusion with no recurrence of seizure within 6 h were categorized as respondto-treatment. Descriptive statistical analyses were applied in this study. Demographic and clinical characteristics were analyzed with SPSS software version 21.0 (SPSS Inc., Chicago, Ill., USA). Student's t-test and chi-square analysis were applied for continuous variables and discrete variables, as appropriate. Fisher's exact test or chi-square test was employed for analysis of response to treatment according to sample size. This study was approved by the Ethics Committee of the Human Right to Research Involving Human Subjects, Faculty of Medicine Ramathibodi Hospital, Mahidol University, document number MURA2013/561.
3.
Results
Nineteen males and 31females were included in this study. Two patients had two separate admissions due to acute repetitive seizures or convulsive status epilepticus resulting in 52 total episodes for analysis. Patients' ages ranged from one day to 18 years (mean 79.6 months). The etiology of 52 episodes of acute repetitive seizures or status epilepticus consisted of 36 symptomatic etiology and 16 unknown etiology. The indication for administration of intravenous levetiracetam is shown in Table 1.
Please cite this article in press as: Khongkhatithum C, et al., Intravenous levetiracetam in Thai children and adolescents with status epilepticus and acute repetitive seizures, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/ j.ejpn.2015.02.010
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Table 1 e Indication for intravenous levetiracetam administration.
Status epilepticus (SE) SE þ organ failure SE þ Unresponsive to initial iv antiepileptic drugs SE þ Underlying drug-resistant epilepsy Acute repetitive seizure (ARS) Underlying drug-resistant epilepsy Unresponsive to initial iv antiepileptic drug Liver dysfunction/failure Multiple organ failure Avoidance of drug interactions History of allergic reaction to antiepileptic drugs Total
Number of episodes
%
18 5 8
34.6 9.6 15.4
5 34 18 2
9.6 65.4 34.6 3.8
6 4 3 1
11.6 7.7 5.8 1.9
52
Response rates according to the etiology of seizures and epilepsy are shown in Table 3. Fisher's exact test was applied to determine the efficacy of levetiracetam between the two etiologies of seizures (unknown etiology VS symptomatic etiology). Among overall 52 episodes, there was no significant difference between the etiologies (p ¼ 0.54). In subgroup analysis, there was no significant statistical difference of the response rate (p ¼ 1.297) in acute repetitive seizures. However, in convulsive status epilepticus, the response rate of levetiracetam was statistically higher in the unknown etiology than the efficacy in the symptomatic etiology (p < 0.05). Additionally, there were no statistical correlations between the efficacy of levetiracetam either to the age or to the gender of the patients. There were no adverse drug reactions or untoward effects observed during levetiracetam administration and within the following 24 h.
100
SE ¼ status epilepticus.
4. Details of intravenous administration of levetiracetam are given in Table 2. Three neonates received 20 mg/kg of levetiracetam diluted in 10 mL of 5% dextrose in water solution during 15 min. Among the 52 episodes, there were 8 episodes which levetiracetam was administered at the dose of 10 mg/ kg. This was due to the breakthrough repetitive seizures in patients who were on oral levetiracetam prior to the emerging seizures. There were 18 episodes of convulsive status epilepticus (34.6%) and 34 episodes of acute repetitive seizures (63.4%). Among 18 episodes of convulsive status epilepticus, six had received an intravenous phenobarbital and two had received an intravenous valporate prior to intravenous levetiracetam infusion. Among 34 episodes of acute repetitive seizures, two had received either intravenous phenobarbital or intravenous valproate prior to intravenous levetiracetam infusion. Regarding concomitant antiepileptic drugs, eighteen patients did not have any concomitant antiepileptic drug. These patients had acute onset of either acute repetitive seizures or convulsive status epilepticus with one of the following conditions: underlying liver failure, multiple organ failure, or avoidance of drug interaction with concomitant chemotherapy. Overall, the cessation of seizure was obtained in 59.6% of the 52 episodes. Seizure cessation after administration of levetiracetam in each subgroup, categorized according to primary indication for treatment with levetiracetam, is shown in Fig. 1. The majority (52%) of the unresponsive episodes to levetiracetam therapy occurred in 12 of the total of 23 patients with drug-resistant epilepsy.
Discussion
Convulsive status epilepticus is a life-threatening condition. In children, its mortality rate ranges from 2.7% to 8%.25 Morbidity and neurological sequalae from this condition occur in 10% and 20% respectively.26 Acute repetitive seizures, including seizure clustering, serial or crescendo seizures, have been well recognized clinically. These seizures are characterized by multiple generalized tonic-clonic or tonic-clonic seizures with or without bilateral synchronization.27 Acute repetitive seizures are strongly associated with a reported history of convulsive status epilepticus.28 Untreated acute repetitive seizures in children could also evolve into convulsive status epilepticus.29 Therefore, it is crucial to terminate seizures as soon as possible. Levetiracetam, in its intravenous form, has been evaluated for its efficacy in terminating acute seizure. Intravenous levetiracetam has been found to be a good alternative for pediatric patients who present with acute seizure and need a rapid titration of anti-seizure therapy to control seizure. The drug is little protein binding, is not extensively metabolized in humans with the major metabolic pathway of hydrolysis, does not have active metabolite, and is excreted 66% in urine.30,31 In addition, it has less drug-to-drug interaction and has less interference with other drug metabolism. There is no need for dosage adjustment for hepatic impairment. Levetiracetam is considered a suitable antiepileptic drug for patients being treated with chemotherapy such as metrotrexate, receiving organ transplantation, or having compromised liver functions.31,32 The efficacy of levetiracetam therapy in this study was 59.6%. This result was consistent with most published reports for children and
Table 2 e Details of intravenous levetiracetam administration.
Mean Median Minimum Maximum
Weight (kg)
Dosage (mg/kg)
Total (mg)
Volume (ml)
Duration (min)
Infusion rate (mg/min)
Infusion rate per weight (mg/kg/min)
23.3 15 3 50
18.6 20 10 25
443.3 250 30 1000
90 100 10 100
14.9 15.0 10.0 15.0
29.6 16.7 2.0 66.7
1.3 1.3 0.7 2.2
Please cite this article in press as: Khongkhatithum C, et al., Intravenous levetiracetam in Thai children and adolescents with status epilepticus and acute repetitive seizures, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/ j.ejpn.2015.02.010
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Fig. 1 e Efficacy of levetiracetam in each indication. SE ¼ Status epilepticus, DRE ¼ Drug-resistant epilepsy, AED ¼ Antiepileptic drug.
adolescents. Table 4 shows a summary and comparison of published reports on the use of intravenous levetiracetam in infants, children, and adolescents. Levetiracetam has few of the well-known adverse effects such as risk of sedation, vomiting, anorexia, rhinitis, pharyngitis, compromised cardio respiratory functions, acute neuropsychological impairments, decreased lymphocyte count and coagulopathy.2,33e35 Most of the reports on intravenous administration of levetiracetam in children disclosed minimal, if any, adverse effect.9,10,13,14,17 Few children had excessive sleep, fatigue, behavioral adverse effects (such as fussiness) or neuropsychiatric effects (such as agitation and restlessness).11,12 However, a decrease in white blood cell count was noted in some reports.11,12,16 A recent open-label, multicenter study reported mild to moderate treatmentemergent adverse events of pyrexia and dry mouth in 63%.15 None of the patients in this current study had aforementioned experiences, not even irritability and agitation. A subset of patients in this current study who needed a complete
Table 3 e Response rates according to etiology of ARS/SE. Etiology of ARS/SE Unknown ARS SE Symptomatic ARS SE
Number of episodes
Number of episode responded to LEV
Response rate (%)
16 10 6 36 24 12
11 6 5 20 18 2
68.7 60 83.3 55.6 75 16.7
ARS ¼ acute repetitive seizures. SE ¼ status epilepticus. LEV ¼ levetiracetam.
blood count to determine their underlying diseases was examined at 24 h after the administration of levetiracetam. The results showed no significant changes in total white blood cell count and number of platelets. Given that approximately one fourth of the patients in this study were critically ill with liver or multiple organ failure, it was possible that determination of acute adverse effects from levetiracetam infusion might not be accurate. Since there were no serious adverse effects observed in any patients administered with intravenous levetiracetam in this study, this study confirms previous published reports on children's and adolescents' tolerability of intravenous levetiracetam. Despite the favorable efficacy indicated in this study, there were patients who did not respond to the treatment. Thus may be related to an issue of initial dosage at the commencement of levetiracetam especially in patients who had drug resistant epilepsy and were naı¨ve to levetiracetam. As noted earlier, previous studies had reported a wide range of initial dosage of intravenous levetiracetam from 5 mg to 30 mg per kilogram of body weight with various methods used for escalation of dosage. In this study, among 23 episodes occurred in patients with drug-resistant epilepsy, 52% did respond to levetiracetam. Initial levetiracetam at 20 mg/ kg was given to all of these 23 episodes except one, when levetiracetam of 10 mg/kg was given. Those with status epilepticus who were previously drug-resistant did not respond to levetiracetam. Though the number of patients in this category was small, there was a possibility that the initial dosage of 20 mg/kg might not be sufficient for termination of seizures in these patients. Successful control of acute repetitive seizures with high-dose intravenous levetiracetam has been demonstrated in children with medically intractable epilepsy.36 Given the safety and tolerability of intravenous levetiracetam reported in
Please cite this article in press as: Khongkhatithum C, et al., Intravenous levetiracetam in Thai children and adolescents with status epilepticus and acute repetitive seizures, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/ j.ejpn.2015.02.010
8 50 Neonate Neonate to adolescence 2013 e Rakshasbhuvankar A.20 This study
Neonatal seizures ARS, SE
6 23 38 22 51 Neonate Neonate Neonate Neonate Infant to adolescence seizures seizures seizures seizures Neonatal Neonatal Neonatal Neonatal ARS, SE 2010 2011 2011 2011 2012 Furwentsches A.22 Abend NS.23 Ramantani G.18 Khan O.19 McTague A.10
SF ¼ seizure free, ARS ¼ acute repetitive seizure, SE ¼ status epilepticus, RSE ¼ refractory status epilepticus, NCSE ¼ non-convulsive status epilepticus.
SF all SF in 9/10 SF 1/15; 50% reduction in 3/15 SF 3/11, respond to Rx 5/11 SF 3/10, seizure terminate 5/10 Respond to Rx18/32 SF 15/30, no response 10/30 83% for single seizure, 52% of ARS, 40% of SE 31e41 wks 10e50 SF all (within 6 days) 38.7 ± 1.7 wks 16 ± 6 (max 45 ± 19) SF 7/23 (30%) 37 wk 13 10e30 SF 30/38 37.5e41.2 wks (mean 39.3 wks) 10e50 SF 14/22 (within 24 h), 22/22 (within 72 h) 2 mo18.8 yrs (mean 7.1 yrs) 5e30 (mean 14.4) SF 23/39 with ARS; 2/3 with SE; 3/4 with NCSE 22e28 wk (n ¼ 2), full-term (n ¼ 6) 5e10 mg/kg SF 6/8 1 daye18 yrs 10e20 mg/kg SF 59.6% 30e60 mean 50.8 5e50 (mean ¼ 8.8) 15e70 (mean 30) 6.5e31 25e50 50 29.4 ± 13.5 2007 2008 2008 2009 2009 2009 2010 2010 Shoemaker M.21 Goraya JS.13 Michaelides C.12 Gallentine WB.14 Abend NS.9 Kirmani BF.17 Ng YT.11 Reiter PD.16
Neonatal seizures ARS, mixed Tolerability evaluation RSE ARS/SE/NCSE Acute seizure Acute seizure Acute seizure, ARS, SE
Neonate Neonate Neonate Neonate Neonate Neonate Neonate Neonate
to to to to to to to
adolescence childhood childhood childhood adolescence childhood adolescence
3 10 15 11 10 32 30 73
2 3 3 2 1 2 6 1
dayse3 mo wkse19 yrs moe13 yrs dayse9 yrs mo12 yrs (median 5 yrs) moe18 yrs moe14.8 yrs (mean 6.3 yrs) daye17.8 yrs
Results Dosage mg/kg Age range No of patients Subjects Seizures Published year Authors
Table 4 e Published studies on the efficacy of intravenous levetiracetam for treatment of acute repetitive seizures and status epilepticus in paediatric age-group.
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 5 ) 1 e6
5
previous studies15,18,37 and in the current study, an increase in the initial dose of intravenous levetiracetam for treatment of acute seizure children, especially for those with documented intractable seizures or drug-resistant epilepsy, may be warranted. There were some limitations to this study. First is the relatively small number of convulsive status epilepticus. Second is the retrospective nature of data collection. However, it is still possible to conclude that levetiracetam is a new antiepileptic drug with favorable pharmacologic profiles. Its role in intravenous treatment of acute repetitive seizures and status epilepticus in children and adolescents has been demonstrated. To gain more information and insight in its application in acute seizure in pediatric patients, further studies should look at larger sample sizes and different age groups, should examine its pharmacokinetics in certain populations, and should prospectively compare levetiracetam with other available intravenous antiepileptic drugs.
Conflict of interest None.
Acknowledgments The authors would like to express our gratitude to Dr. Mahippathorn Chinnapha, Prof. Pat Mahachoklertwattana, and Prof. Surang Chiemchanya for reviewing the manuscript, to Prof. Amnauy Thithapandha and Prof. David T. Bussard for English editing of the manuscript.
references
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9. Abend NS, Monk HM, Licht DJ, Dlugos DJ. Intravenous levetiracetam in critically ill children with status epilepticus or acute repetitive seizures. Pediatr Crit Care Med 2009;10(4):505e10. 10. McTague A, Kneen R, Kumar R, Spinty S, Appleton R. Intravenous levetiracetam in acute repetitive seizures and status epilepticus in children: experience from a children's hospital. Seizure 2012;21(7):529e34. 11. Ng YT, Hastriter EV, Cardenas JF, Khoury EM, Chapman KE. Intravenous levetiracetam in children with seizures: a prospective safety study. J Child Neurol 2010;25(5):551e5. 12. Michaelides C, Thibert RL, Shapiro MJ, et al. Tolerability and dosing experience of intravenous levetiracetam in children and infants. Epilepsy Res 2008;81(2e3):143e7. 13. Goraya JS, Khurana DS, Valencia I, et al. Intravenous levetiracetam in children with epilepsy. Pediatr Neurol 2008;38(3):177e80. 14. Gallentine WB, Hunnicutt AS, Husain AM. Levetiracetam in children with refractory status epilepticus. Epilepsy Behav 2009;14(1):215e8. 15. Weinstock A, Ruiz M, Gerard D, et al. Prospective open-label, single-arm, multicenter, safety, tolerability, and pharmacokinetic studies of intravenous levetiracetam in children with epilepsy. J Child Neurol 2013;28(11):1423e9. 16. Reiter PD, Huff AD, Knupp KG, Valuck RJ. Intravenous levetiracetam in the management of acute seizures in children. Pediatr Neurol 2010;43(2):117e21. 17. Kirmani BF, Crisp ED, Kayani S, Rajab H. Role of intravenous levetiracetam in acute seizure management of children. Pediatr Neurol 2009;41(1):37e9. 18. Ramantani G, Ikonomidou C, Walter B, Rating D, Dinger J. Levetiracetam: safety and efficacy in neonatal seizures. Eur J Paediatr Neurol 2011;15(1):1e7. 19. Khan O, Chang E, Cipriani C, Wright C, Crisp E, Kirmani B. Use of intravenous levetiracetam for management of acute seizures in neonates. Pediatr Neurol 2011;44(4):265e9. 20. Rakshasbhuvankar A, Rao S, Kohan R, Simmer K, Nagarajan L. Intravenous levetiracetam for treatment of neonatal seizures. J Clin Neurosci 2013;20(8):1165e7. 21. Shoemaker MT, Rotenberg JS. Levetiracetam for the treatment of neonatal seizures. J Child Neurol 2007;22(1):95e8. 22. Furwentsches A, Bussmann C, Ramantani G, et al. Levetiracetam in the treatment of neonatal seizures: a pilot study. Seizure 2010;19(3):185e9.
23. Abend NS, Gutierrez-Colina AM, Monk HM, Dlugos DJ, Clancy RR. Levetiracetam for treatment of neonatal seizures. J Child Neurol 2011;26(4):465e70. 24. Thongplew S, Chawsamtong S, Suwanyawisuth K, Tiamkao S. Intergrated epilepsy research group KKU. Intravenous levetiracetam treatment in Thai adults with status epilepticus. Neurol Asia 2013;18(2):167e75. 25. Novorol CL, Chin RF, Scott RC. Outcome of convulsive status epilepticus: a review. Arch Dis Child 2007;92(11):948e51. 26. Raspall-Chaure M, Chin RF, Neville BG, Scott RC. Outcome of pediatric convulsive status epilepticus: a systematic review. Lancet Neurol 2006;5(9):769e79. 27. Martinez C, Sullivan T, Hauser WA. Prevalence of acute repetitive seizures (ARS) in the United Kingdom. Epilepsy Res 2009;87(2e3):137e43. 28. Haut SR, Shinnar S, Moshe SL. Seizure clustering: risks and outcomes. Epilepsia 2005;46(1):146e9. 29. Mitchell WG. Status epilepticus and acute repetitive seizures in children, adolescents, and young adults: etiology, outcome, and treatment. Epilepsia 1996;37(Suppl. 1):S74e80. 30. Pellock JM, Glauser TA, Bebin EM, et al. Pharmacokinetic study of levetiracetam in children. Epilepsia 2001;42(12):1574e9. 31. Wright C, Downing J, Mungall D, et al. Clinical pharmacology and pharmacokinetics of levetiracetam. Front Neurol 2013;4:192. 32. Shepard PW, St Louis EK. Seizure treatment in transplant patients. Curr Treat Options Neurol 2012;14(4):332e47. 33. Glauser TA. Behavioral and psychiatric adverse events associated with antiepileptic drugs commonly used in pediatric patients. J Child Neurol 2004;19(Suppl. 1):S25e38. 34. Glauser TA, Ayala R, Elterman RD, et al. Double-blind placebocontrolled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology 2006;66(11):1654e60. 35. Dinopoulos A, Attilakos A, Paschalidou M, et al. Short-term effect of levetiracetam monotherapy on haematological parameters in children with epilepsy: a prospective study. Epilepsy Res 2014;108(4):820e3. 36. Depositario-Cabacar DT, Peters JM, Pong AW, et al. High-dose intravenous levetiracetam for acute seizure exacerbation in children with intractable epilepsy. Epilepsia 2010;51(7):1319e22. 37. Li J, Xiao N, Chen S. Efficacy and tolerability of levetiracetam in children with epilepsy. Brain Dev 2011;33(2):145e51.
Please cite this article in press as: Khongkhatithum C, et al., Intravenous levetiracetam in Thai children and adolescents with status epilepticus and acute repetitive seizures, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/ j.ejpn.2015.02.010
Official Journal of the European Paediatric Neurology Society
Original article
Intravenous levetiracetam in Thai children and adolescents with status epilepticus and acute repetitive seizures Chaiyos Khongkhatithum, Lunliya Thampratankul, Natrujee Wiwattanadittakul, Anannit Visudtibhan* Division of Neurology, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Bangkok 10400, Thailand
article info
abstract
Article history:
Background: Intravenous levetiracetam is an option for treatment of status epilepticus (SE)
Received 27 January 2014
and acute repetitive seizures (ARS). However, there have been relatively few studies with
Received in revised form
children and adolescents. Also, an appropriate dosage has yet to be determined.
8 January 2015
Aim: This study investigated the safety and the efficacy of levetiracetam for intravenous
Accepted 21 February 2015
treatment of convulsive status epilepticus and acute repetitive seizures in children and adolescents.
Keywords:
Method: Retrospectively, the study reviewed the medical records of 19 male and 31 female
Levetiracetam
patients under 18 years of age who had received intravenous levetiracetam treatment
Status epilepticus
either for acute repetitive seizures or for convulsive status epilepticus. The patients were
Acute repetitive seizures
admitted between April 1st, 2010 and December 31st, 2011 to the Department of Pediatrics,
Childhood seizures
Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. Data were collected on underlying illnesses, etiology of seizures, indication for levetiracetam therapy, initial dosage, rate of infusion, untoward effects during infusion and emerged complications. Efficacy of treatment was defined as the termination of seizure within 30 min of completing levetiracetam infusion and no seizure recurrence within 6 h of initial treatment. Results: The age range of the 50 patients was from one day to 18 years (mean 79.6 months). The analysis included 52 episodes of 34 acute repetitive seizures (63.4%) and 18 convulsive status epilepticus (34.6%). Infusion rates ranged from 2 to 66 mg/kg/min (mean 29.6). Cessation of seizure was obtained in 59.6% of 52 episodes. Patients with underlying drug resistant epilepsy did not respond to levetiracetam therapy as well as patients with other etiology of seizures. There were no adverse drug reactions or untoward effects observed during the therapy. Conclusion: Intravenous administration of levetiracetam is safe and effective for treatment of acute repetitive seizures and convulsive status epilepticus in children and adolescents.
* Corresponding author. Division of Neurology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Rama 6 Road, Ratchathewee, Bangkok 10400, Thailand. Tel.: þ66 2 201 1879; fax: þ66 2 201 1850. E-mail address: [email protected] (A. Visudtibhan). http://dx.doi.org/10.1016/j.ejpn.2015.02.010 1090-3798/© 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Khongkhatithum C, et al., Intravenous levetiracetam in Thai children and adolescents with status epilepticus and acute repetitive seizures, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/ j.ejpn.2015.02.010
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Failure of treatment may be related to underlying drug resistant epilepsy. Further study of appropriate initial dosage and pharmacokinetic variations in the patients is needed as possible explanation of the unresponsiveness. © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
Levetiracetam is a broad-spectrum antiepileptic drug with proven efficacy as an adjunctive therapy for localizationrelated epilepsy in children, for juvenile myoclonic epilepsy in children and adolescents, and for primary generalized tonic-clonic seizures in adults. It has been recognized as a new generation antiepileptic drug with a favorable safety and tolerability profile, and insignificant drugedrug interaction.1 Levetiracetam has been available in tablet form since 1999 and in oral solution since 2003. The United States Food and Drug Administration (US FDA) approved the intravenous formulation in July 2006.1,2 Since then, levetiracetam has been used in the treatment of various types of seizures in children and adolescents. As of 2012 with the US FDA's approval, it has been used for drug-resistant focal-onset seizures.3 The availability of levetiracetam in the intravenous formulation provides a useful option when oral administration is temporarily unattainable in status epilepticus and acute repetitive seizures.4 There have been many reports of its favorable efficacy in treatment of adult patients presenting with status epilepticus.5e8 After being administered in the treatment of adult status epilepticus and acute repetitive seizures, its efficacy and safety for children were also reported and documented.9e17 Recently, there have been reports on levetiracetam's role in the treatment of neonatal seizures with favorable outcomes.18e23 However, the total number of patients in those studies was very small with a wide-range of initial dosage. In Thailand, there are five intravenous antiepileptic drugs available. These are phenobarbital, phenytoin, fos-phenytoin, valproate and levetiracetam. Levetiracetam was included as an option for treatment of convulsive status epilepticus in the guidelines for epilepsy treatment by the Epilepsy Society of Thailand in 2011. Nevertheless, there have been very few reports in Thailand on these drugs' efficacy and safety, especially of levetiracetam. To date, there has been only one study that examined intravenous levetiracetam in 34 adult patients presenting with convulsive status epilepticus. The study reported a seizure-control rate of 61.8%.24 This current study was therefore conducted to evaluate the efficacy and the safety of intravenous levetiracetam for treatment of convulsive status epilepticus and acute repetitive seizure in Thai children and adolescents.
2.
Methods
A retrospective review was conducted of medical records of 50 patients under the age of 18 years admitted to the Department of Pediatrics, Ramathibodi Hospital, between April 1st, 2010
and December 31st, 2011. All of these patients received the intravenous levetiracetam for treatment of either acute repetitive seizures or convulsive status epilepticus. Acute repetitive seizure was defined as repeated seizures of which each lasted less than 5 min with recovery of consciousness between each seizure and that persisted for at least 30 min. Convulsive status epilepticus was defined as convulsive type of any single and prolonged tonic-clonic seizure that persisted for over 5 min and irrespective of whether any emergency medication administered.10 The etiologies of seizures were classified according to the documented cause of seizures. The episode with definitive causes of seizures would be categorized into symptomatic group, while the episodes without definitive causes would be categorized into unknown group. The study collected data on the underlying illnesses, etiology of seizures, indication for the use of levetiracetam, initial dosage, rate of infusion, and untoward effects during infusion and during the 24 h after administration. The efficacy of the treatment was categorized into 2 groups as respond-totreatment and unresponsive. The group assignment was determined according to the cessation of seizures within 30 min after completion of infusion and no recurrence of seizures within 6 h after infusion. Patients with seizures that terminated within 30 min after levetiracetam infusion with no recurrence of seizure within 6 h were categorized as respondto-treatment. Descriptive statistical analyses were applied in this study. Demographic and clinical characteristics were analyzed with SPSS software version 21.0 (SPSS Inc., Chicago, Ill., USA). Student's t-test and chi-square analysis were applied for continuous variables and discrete variables, as appropriate. Fisher's exact test or chi-square test was employed for analysis of response to treatment according to sample size. This study was approved by the Ethics Committee of the Human Right to Research Involving Human Subjects, Faculty of Medicine Ramathibodi Hospital, Mahidol University, document number MURA2013/561.
3.
Results
Nineteen males and 31females were included in this study. Two patients had two separate admissions due to acute repetitive seizures or convulsive status epilepticus resulting in 52 total episodes for analysis. Patients' ages ranged from one day to 18 years (mean 79.6 months). The etiology of 52 episodes of acute repetitive seizures or status epilepticus consisted of 36 symptomatic etiology and 16 unknown etiology. The indication for administration of intravenous levetiracetam is shown in Table 1.
Please cite this article in press as: Khongkhatithum C, et al., Intravenous levetiracetam in Thai children and adolescents with status epilepticus and acute repetitive seizures, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/ j.ejpn.2015.02.010
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Table 1 e Indication for intravenous levetiracetam administration.
Status epilepticus (SE) SE þ organ failure SE þ Unresponsive to initial iv antiepileptic drugs SE þ Underlying drug-resistant epilepsy Acute repetitive seizure (ARS) Underlying drug-resistant epilepsy Unresponsive to initial iv antiepileptic drug Liver dysfunction/failure Multiple organ failure Avoidance of drug interactions History of allergic reaction to antiepileptic drugs Total
Number of episodes
%
18 5 8
34.6 9.6 15.4
5 34 18 2
9.6 65.4 34.6 3.8
6 4 3 1
11.6 7.7 5.8 1.9
52
Response rates according to the etiology of seizures and epilepsy are shown in Table 3. Fisher's exact test was applied to determine the efficacy of levetiracetam between the two etiologies of seizures (unknown etiology VS symptomatic etiology). Among overall 52 episodes, there was no significant difference between the etiologies (p ¼ 0.54). In subgroup analysis, there was no significant statistical difference of the response rate (p ¼ 1.297) in acute repetitive seizures. However, in convulsive status epilepticus, the response rate of levetiracetam was statistically higher in the unknown etiology than the efficacy in the symptomatic etiology (p < 0.05). Additionally, there were no statistical correlations between the efficacy of levetiracetam either to the age or to the gender of the patients. There were no adverse drug reactions or untoward effects observed during levetiracetam administration and within the following 24 h.
100
SE ¼ status epilepticus.
4. Details of intravenous administration of levetiracetam are given in Table 2. Three neonates received 20 mg/kg of levetiracetam diluted in 10 mL of 5% dextrose in water solution during 15 min. Among the 52 episodes, there were 8 episodes which levetiracetam was administered at the dose of 10 mg/ kg. This was due to the breakthrough repetitive seizures in patients who were on oral levetiracetam prior to the emerging seizures. There were 18 episodes of convulsive status epilepticus (34.6%) and 34 episodes of acute repetitive seizures (63.4%). Among 18 episodes of convulsive status epilepticus, six had received an intravenous phenobarbital and two had received an intravenous valporate prior to intravenous levetiracetam infusion. Among 34 episodes of acute repetitive seizures, two had received either intravenous phenobarbital or intravenous valproate prior to intravenous levetiracetam infusion. Regarding concomitant antiepileptic drugs, eighteen patients did not have any concomitant antiepileptic drug. These patients had acute onset of either acute repetitive seizures or convulsive status epilepticus with one of the following conditions: underlying liver failure, multiple organ failure, or avoidance of drug interaction with concomitant chemotherapy. Overall, the cessation of seizure was obtained in 59.6% of the 52 episodes. Seizure cessation after administration of levetiracetam in each subgroup, categorized according to primary indication for treatment with levetiracetam, is shown in Fig. 1. The majority (52%) of the unresponsive episodes to levetiracetam therapy occurred in 12 of the total of 23 patients with drug-resistant epilepsy.
Discussion
Convulsive status epilepticus is a life-threatening condition. In children, its mortality rate ranges from 2.7% to 8%.25 Morbidity and neurological sequalae from this condition occur in 10% and 20% respectively.26 Acute repetitive seizures, including seizure clustering, serial or crescendo seizures, have been well recognized clinically. These seizures are characterized by multiple generalized tonic-clonic or tonic-clonic seizures with or without bilateral synchronization.27 Acute repetitive seizures are strongly associated with a reported history of convulsive status epilepticus.28 Untreated acute repetitive seizures in children could also evolve into convulsive status epilepticus.29 Therefore, it is crucial to terminate seizures as soon as possible. Levetiracetam, in its intravenous form, has been evaluated for its efficacy in terminating acute seizure. Intravenous levetiracetam has been found to be a good alternative for pediatric patients who present with acute seizure and need a rapid titration of anti-seizure therapy to control seizure. The drug is little protein binding, is not extensively metabolized in humans with the major metabolic pathway of hydrolysis, does not have active metabolite, and is excreted 66% in urine.30,31 In addition, it has less drug-to-drug interaction and has less interference with other drug metabolism. There is no need for dosage adjustment for hepatic impairment. Levetiracetam is considered a suitable antiepileptic drug for patients being treated with chemotherapy such as metrotrexate, receiving organ transplantation, or having compromised liver functions.31,32 The efficacy of levetiracetam therapy in this study was 59.6%. This result was consistent with most published reports for children and
Table 2 e Details of intravenous levetiracetam administration.
Mean Median Minimum Maximum
Weight (kg)
Dosage (mg/kg)
Total (mg)
Volume (ml)
Duration (min)
Infusion rate (mg/min)
Infusion rate per weight (mg/kg/min)
23.3 15 3 50
18.6 20 10 25
443.3 250 30 1000
90 100 10 100
14.9 15.0 10.0 15.0
29.6 16.7 2.0 66.7
1.3 1.3 0.7 2.2
Please cite this article in press as: Khongkhatithum C, et al., Intravenous levetiracetam in Thai children and adolescents with status epilepticus and acute repetitive seizures, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/ j.ejpn.2015.02.010
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Fig. 1 e Efficacy of levetiracetam in each indication. SE ¼ Status epilepticus, DRE ¼ Drug-resistant epilepsy, AED ¼ Antiepileptic drug.
adolescents. Table 4 shows a summary and comparison of published reports on the use of intravenous levetiracetam in infants, children, and adolescents. Levetiracetam has few of the well-known adverse effects such as risk of sedation, vomiting, anorexia, rhinitis, pharyngitis, compromised cardio respiratory functions, acute neuropsychological impairments, decreased lymphocyte count and coagulopathy.2,33e35 Most of the reports on intravenous administration of levetiracetam in children disclosed minimal, if any, adverse effect.9,10,13,14,17 Few children had excessive sleep, fatigue, behavioral adverse effects (such as fussiness) or neuropsychiatric effects (such as agitation and restlessness).11,12 However, a decrease in white blood cell count was noted in some reports.11,12,16 A recent open-label, multicenter study reported mild to moderate treatmentemergent adverse events of pyrexia and dry mouth in 63%.15 None of the patients in this current study had aforementioned experiences, not even irritability and agitation. A subset of patients in this current study who needed a complete
Table 3 e Response rates according to etiology of ARS/SE. Etiology of ARS/SE Unknown ARS SE Symptomatic ARS SE
Number of episodes
Number of episode responded to LEV
Response rate (%)
16 10 6 36 24 12
11 6 5 20 18 2
68.7 60 83.3 55.6 75 16.7
ARS ¼ acute repetitive seizures. SE ¼ status epilepticus. LEV ¼ levetiracetam.
blood count to determine their underlying diseases was examined at 24 h after the administration of levetiracetam. The results showed no significant changes in total white blood cell count and number of platelets. Given that approximately one fourth of the patients in this study were critically ill with liver or multiple organ failure, it was possible that determination of acute adverse effects from levetiracetam infusion might not be accurate. Since there were no serious adverse effects observed in any patients administered with intravenous levetiracetam in this study, this study confirms previous published reports on children's and adolescents' tolerability of intravenous levetiracetam. Despite the favorable efficacy indicated in this study, there were patients who did not respond to the treatment. Thus may be related to an issue of initial dosage at the commencement of levetiracetam especially in patients who had drug resistant epilepsy and were naı¨ve to levetiracetam. As noted earlier, previous studies had reported a wide range of initial dosage of intravenous levetiracetam from 5 mg to 30 mg per kilogram of body weight with various methods used for escalation of dosage. In this study, among 23 episodes occurred in patients with drug-resistant epilepsy, 52% did respond to levetiracetam. Initial levetiracetam at 20 mg/ kg was given to all of these 23 episodes except one, when levetiracetam of 10 mg/kg was given. Those with status epilepticus who were previously drug-resistant did not respond to levetiracetam. Though the number of patients in this category was small, there was a possibility that the initial dosage of 20 mg/kg might not be sufficient for termination of seizures in these patients. Successful control of acute repetitive seizures with high-dose intravenous levetiracetam has been demonstrated in children with medically intractable epilepsy.36 Given the safety and tolerability of intravenous levetiracetam reported in
Please cite this article in press as: Khongkhatithum C, et al., Intravenous levetiracetam in Thai children and adolescents with status epilepticus and acute repetitive seizures, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/ j.ejpn.2015.02.010
8 50 Neonate Neonate to adolescence 2013 e Rakshasbhuvankar A.20 This study
Neonatal seizures ARS, SE
6 23 38 22 51 Neonate Neonate Neonate Neonate Infant to adolescence seizures seizures seizures seizures Neonatal Neonatal Neonatal Neonatal ARS, SE 2010 2011 2011 2011 2012 Furwentsches A.22 Abend NS.23 Ramantani G.18 Khan O.19 McTague A.10
SF ¼ seizure free, ARS ¼ acute repetitive seizure, SE ¼ status epilepticus, RSE ¼ refractory status epilepticus, NCSE ¼ non-convulsive status epilepticus.
SF all SF in 9/10 SF 1/15; 50% reduction in 3/15 SF 3/11, respond to Rx 5/11 SF 3/10, seizure terminate 5/10 Respond to Rx18/32 SF 15/30, no response 10/30 83% for single seizure, 52% of ARS, 40% of SE 31e41 wks 10e50 SF all (within 6 days) 38.7 ± 1.7 wks 16 ± 6 (max 45 ± 19) SF 7/23 (30%) 37 wk 13 10e30 SF 30/38 37.5e41.2 wks (mean 39.3 wks) 10e50 SF 14/22 (within 24 h), 22/22 (within 72 h) 2 mo18.8 yrs (mean 7.1 yrs) 5e30 (mean 14.4) SF 23/39 with ARS; 2/3 with SE; 3/4 with NCSE 22e28 wk (n ¼ 2), full-term (n ¼ 6) 5e10 mg/kg SF 6/8 1 daye18 yrs 10e20 mg/kg SF 59.6% 30e60 mean 50.8 5e50 (mean ¼ 8.8) 15e70 (mean 30) 6.5e31 25e50 50 29.4 ± 13.5 2007 2008 2008 2009 2009 2009 2010 2010 Shoemaker M.21 Goraya JS.13 Michaelides C.12 Gallentine WB.14 Abend NS.9 Kirmani BF.17 Ng YT.11 Reiter PD.16
Neonatal seizures ARS, mixed Tolerability evaluation RSE ARS/SE/NCSE Acute seizure Acute seizure Acute seizure, ARS, SE
Neonate Neonate Neonate Neonate Neonate Neonate Neonate Neonate
to to to to to to to
adolescence childhood childhood childhood adolescence childhood adolescence
3 10 15 11 10 32 30 73
2 3 3 2 1 2 6 1
dayse3 mo wkse19 yrs moe13 yrs dayse9 yrs mo12 yrs (median 5 yrs) moe18 yrs moe14.8 yrs (mean 6.3 yrs) daye17.8 yrs
Results Dosage mg/kg Age range No of patients Subjects Seizures Published year Authors
Table 4 e Published studies on the efficacy of intravenous levetiracetam for treatment of acute repetitive seizures and status epilepticus in paediatric age-group.
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 5 ) 1 e6
5
previous studies15,18,37 and in the current study, an increase in the initial dose of intravenous levetiracetam for treatment of acute seizure children, especially for those with documented intractable seizures or drug-resistant epilepsy, may be warranted. There were some limitations to this study. First is the relatively small number of convulsive status epilepticus. Second is the retrospective nature of data collection. However, it is still possible to conclude that levetiracetam is a new antiepileptic drug with favorable pharmacologic profiles. Its role in intravenous treatment of acute repetitive seizures and status epilepticus in children and adolescents has been demonstrated. To gain more information and insight in its application in acute seizure in pediatric patients, further studies should look at larger sample sizes and different age groups, should examine its pharmacokinetics in certain populations, and should prospectively compare levetiracetam with other available intravenous antiepileptic drugs.
Conflict of interest None.
Acknowledgments The authors would like to express our gratitude to Dr. Mahippathorn Chinnapha, Prof. Pat Mahachoklertwattana, and Prof. Surang Chiemchanya for reviewing the manuscript, to Prof. Amnauy Thithapandha and Prof. David T. Bussard for English editing of the manuscript.
references
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Please cite this article in press as: Khongkhatithum C, et al., Intravenous levetiracetam in Thai children and adolescents with status epilepticus and acute repetitive seizures, European Journal of Paediatric Neurology (2015), http://dx.doi.org/10.1016/ j.ejpn.2015.02.010
