Top

Journal of Neurology

Published in:

Open Access 28-06-2023 | Epilepsy | Review

Antiseizure medications for idiopathic generalized epilepsies: a systematic review and network meta-analysis

Authors: Hongyuan Chu, Xinyu Zhang, Jie Shi, Zhirui Zhou, Xu Yang

Published in: Journal of Neurology | Issue 10/2023

Abstract

Objectives

To compare the efficacy and safety of antiseizure medications (ASMs), both as monotherapies and adjunctive therapies, for idiopathic generalized epilepsies (IGEs) and related entities.

Methods

Two reviewers independently searched PubMed, Embase, and the Cochrane Library for relevant randomized controlled trials from December 2022 to February 2023. Studies on the efficacy and safety of ASM monotherapies or adjunctive therapies for IGEs and related entities—including juvenile myoclonic epilepsy, childhood absence epilepsy (CAE), juvenile absence epilepsy, or generalized tonic–clonic seizures alone (GTCA)—were included. Efficacy outcomes were the proportions of patients remaining seizure free for 1, 3, 6, and 12 months; safety outcomes were the proportions of any treatment-emergent adverse event (TEAE) and TEAEs leading to discontinuation. Network meta-analyses were performed in a random-effects model to obtain odds ratios and 95% confidence intervals. Rankings of ASMs were based on the surface under the cumulative ranking curve (SUCRA). This study is registered with PROSPERO (No. CRD42022372358).

Results

Twenty-eight randomized controlled trials containing 4282 patients were included. As monotherapies, all ASMs were more effective than placebo, and valproate and ethosuximide were significantly better than lamotrigine. According to the SUCRA for efficacy, ethosuximide ranked first for CAE, whereas valproate ranked first for other types of IGEs. As adjunctive therapies, topiramate ranked best for GTCA as well as overall for IGEs, while levetiracetam ranked best for myoclonic seizures. For safety, perampanel ranked best (measured by any TEAE).

Conclusions

All of the studied ASMs were more effective than placebo. Valproate monotherapy ranked best overall for IGEs, whereas ethosuximide ranked best for CAE. Adjunctive topiramate and levetiracetam were most effective for GTCA and myoclonic seizures, respectively. Furthermore, perampanel had the best tolerability.

Available only for authorised users

Hirsch E, French J, Scheffer IE, Bogacz A, Alsaadi T, Sperling MR, Abdulla F, Zuberi SM, Trinka E, Specchio N et al (2022) ILAE definition of the idiopathic generalized epilepsy syndromes: position statement by the ILAE task force on nosology and definitions. Epilepsia 63(6):1475–1499PubMedCrossRef

Mattson RH (2003) Overview: idiopathic generalized epilepsies. Epilepsia 44(Suppl 2):2–6PubMedCrossRef

Jallon P, Latour P (2005) Epidemiology of idiopathic generalized epilepsies. Epilepsia 46(Suppl 9):10–14PubMedCrossRef

Wirrell EC, Grossardt BR, Wong-Kisiel LC, Nickels KC (2011) Incidence and classification of new-onset epilepsy and epilepsy syndromes in children in Olmsted County, Minnesota from 1980 to 2004: a population-based study. Epilepsy Res 95(1–2):110–118PubMedPubMedCentralCrossRef

Beydoun A, D’Souza J (2012) Treatment of idiopathic generalized epilepsy—a review of the evidence. Expert Opin Pharmacother 13(9):1283–1298PubMedCrossRef

Shinnar RC, Shinnar S, Cnaan A, Clark P, Dlugos D, Hirtz DG, Hu F, Liu C, Masur D, Weiss EF et al (2017) Pretreatment behavior and subsequent medication effects in childhood absence epilepsy. Neurology 89(16):1698–1706PubMedPubMedCentralCrossRef

Rinaldi VE, Di Cara G, Mencaroni E, Verrotti A (2021) Therapeutic options for childhood absence epilepsy. Pediatr Rep 13(4):658–667PubMedPubMedCentralCrossRef

Wirrell EC, Camfield CS, Camfield PR, Dooley JM, Gordon KE, Smith B (1997) Long-term psychosocial outcome in typical absence epilepsy. Sometimes a wolf in sheeps’ clothing. Arch Pediatr Adolesc Med 151(2):152–158PubMedCrossRef

Colleran N, Connor TO, Brien JJO (2017) Anti-epileptic drug trials for patients with drug resistant idiopathic generalised epilepsy: a meta-analysis. Seizure 51:145–156PubMedCrossRef

10.

Semah F, Picot MC, Adam C, Broglin D, Arzimanoglou A, Bazin B, Cavalcanti D, Baulac M (1998) Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology 51(5):1256–1262PubMedCrossRef

11.

Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, Cramp C, Cockerell OC, Cooper PN, Doughty J et al (2007) The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 369(9566):1016–1026 PubMedPubMedCentralCrossRef

12.

Marson A, Burnside G, Appleton R, Smith D, Leach JP, Sills G, Tudur-Smith C, Plumpton C, Hughes DA, Williamson P et al (2021) The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial. Lancet 397(10282):1375–1386PubMedPubMedCentralCrossRef

13.

Verrotti A, Cerminara C, Domizio S, Mohn A, Franzoni E, Coppola G, Zamponi N, Parisi P, Iannetti P, Curatolo P (2008) Levetiracetam in absence epilepsy. Dev Med Child Neurol 50(11):850–853PubMedCrossRef

14.

Auvin S (2007) Treatment of myoclonic seizures in patients with juvenile myoclonic epilepsy. Neuropsychiatr Dis Treat 3(6):729–734PubMedPubMedCentral

15.

Curatolo P, Moavero R, Lo Castro A, Cerminara C (2009) Pharmacotherapy of idiopathic generalized epilepsies. Expert Opin Pharmacother 10(1):5–17PubMedCrossRef

16.

Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, Ioannidis JP, Straus S, Thorlund K, Jansen JP et al (2015) The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med 162(11):777–784PubMedCrossRef

17.

Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, Cates CJ, Cheng HY, Corbett MS, Eldridge SM et al (2019) RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 366:l4898PubMedCrossRef

18.

Cipriani A, Higgins JP, Geddes JR, Salanti G (2013) Conceptual and technical challenges in network meta-analysis. Ann Intern Med 159(2):130–137PubMedCrossRef

19.

Turner RM, Davey J, Clarke MJ, Thompson SG, Higgins JPT (2012) Predicting the extent of heterogeneity in meta-analysis, using empirical data from the Cochrane Database of Systematic Reviews. Int J Epidemiol 41(3):818–827PubMedPubMedCentralCrossRef

20.

Lu G, Ades AE (2004) Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med 23(20):3105–3124PubMedCrossRef

21.

Higgins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560PubMedPubMedCentralCrossRef

22.

Basu S, Bhattacharyya KB, Das K, Das D (2005) Comparative study of sodium valproate and lamotrigine as monotherapy in the management of typical absence seizures. Epilepsia 46:277–277

23.

Callaghan N, O’Hare J, O’Driscoll D, O’Neill B, Daly M (1982) Comparative study of ethosuximide and sodium valproate in the treatment of typical absence seizures (petit mal). Dev Med Child Neurol 24(6):830–836PubMed

24.

Cnaan A, Shinnar S, Arya R, Adamson PC, Clark PO, Dlugos D, Hirtz DG, Masur D, Glauser TA (2017) Second monotherapy in childhood absence epilepsy. Neurology 88(2):182–190PubMedPubMedCentralCrossRef

25.

Coppola G, Auricchio G, Federico R, Carotenuto M, Pascotto A (2004) Lamotrigine versus valproic acid as first-line monotherapy in newly diagnosed typical absence seizures: an open-label, randomized, parallel-group study. Epilepsia 45(9):1049–1053PubMedCrossRef

26.

Fattore C, Boniver C, Capovilla G, Cerminara C, Citterio A, Coppola G, Costa P, Darra F, Vecchi M, Perucca E (2011) A multicenter, randomized, placebo-controlled trial of levetiracetam in children and adolescents with newly diagnosed absence epilepsy. Epilepsia 52(4):802–809PubMedCrossRef

27.

Frank LM, Enlow T, Holmes GL, Manasco P, Concannon S, Chen C, Womble G, Casale EJ (1999) Lamictal (lamotrigine) monotherapy for typical absence seizures in children. Epilepsia 40(7):973–979PubMedCrossRef

28.

Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Guerreiro C, Kälviäinen R, Mattson R, French JA, Perucca E, Tomson T (2013) Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 54(3):551–563PubMedCrossRef

29.

Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, Clark PO, Capparelli EV, Adamson PC (2010) Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med 362(9):790–799PubMedPubMedCentralCrossRef

30.

Huang TS, Zhu JL, Li B, Hu Y, Chen L, Liao JX (2009) Valproic acid versus lamotrigine as a monotherapy for absence epilepsy in children. Chinese J Contemp Pediatr 11(8):653–655

31.

Hwang H, Kim H, Kim SH, Kim SH, Lim BC, Chae JH, Choi JE, Kim KJ, Hwang YS (2012) Long-term effectiveness of ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. Brain Dev 34(5):344–348PubMedCrossRef

32.

Brandt C, Klein P, Badalamenti V, Gasalla T, Whitesides J (2020) Safety and tolerability of adjunctive brivaracetam in epilepsy: in-depth pooled analysis. Epilepsy Behav 103:106864PubMedCrossRef

33.

Machado RA, García VF, Astencio AG, Cuartas VB (2013) Efficacy and tolerability of lamotrigine in juvenile myoclonic epilepsy in adults: a prospective, unblinded randomized controlled trial. Seizure 22(10):846–855PubMedCrossRef

34.

Nejad SEM, Nikpour MRA, Rahim F, Naghibi SN, Bahrammi MA (2009) A randomized open-label comparison of lamotrigine and valproate in patients with juvenile myoclonic epilepsy. Int J Pharmacol 5(5):313–318CrossRef

35.

Noachtar S, Andermann E, Meyvisch P, Andermann F, Gough WB, Schiemann-Delgado J (2008) Levetiracetam for the treatment of idiopathic generalized epilepsy with myoclonic seizures. Neurology 70(8):607–616PubMedCrossRef

36.

Levisohn PM, Holland KD (2007) Topiramate or valproate in patients with juvenile myoclonic epilepsy: a randomized open-label comparison. Epilepsy Behav 10(4):547–552PubMedCrossRef

37.

Brandt C, Wechsler RT, O’Brien TJ, Patten A, Malhotra M, Ngo LY, Steinhoff BJ (2020) Adjunctive perampanel and myoclonic and absence seizures: post hoc analysis of data from study 332 in patients with idiopathic generalized epilepsy. Seizure 80:115–123PubMedCrossRef

38.

Berkovic SF, Knowlton RC, Leroy RF, Schiemann J, Falter U (2007) Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology 69(18):1751–1760PubMedCrossRef

39.

Marson AG, Burnside G, Appleton R, Smith D, Leach JP, Sills G, Tudur-Smith C, Plumpton CO, Hughes DA, Williamson PR et al (2021) Lamotrigine versus levetiracetam or zonisamide for focal epilepsy and valproate versus levetiracetam for generalised and unclassified epilepsy: two SANAD II non-inferiority RCTs. Health Technol Assess (Winchester, England) 25(75):1–134CrossRef

40.

Driscoll J, Almas M, Gregorian G, Kyrychenko A, Makedonska I, Liu J, Patrick J, Scavone JM, Antinew J (2021) Pregabalin as adjunctive therapy in adult and pediatric patients with generalized tonic-clonic seizures: a randomized, placebo-controlled trial. Epilepsia Open 6(2):381–393PubMedPubMedCentralCrossRef

41.

French J, Krauss G, Wechsler R, Wang X, DiVentura B, Brandt C, Trinka E, O'Brien TJ, Laurenza A, Patten A et al (2015) Adjunctive perampanel for the treatment of drug-resistant primary generalized tonic-clonic (PGTC) seizures in patients with idiopathic generalized epilepsy (IGE): a double-blind randomized placebo-controlled phase III trial. Neurology 84

42.

French JA, Wechsler RT, Trinka E, Brandt C, O’Brien TJ, Patten A, Salah A, Malhotra M (2022) Long-term open-label perampanel: generalized tonic–clonic seizures in idiopathic generalized epilepsy. Epilepsia Open 7(3):393–405PubMedPubMedCentralCrossRef

43.

Giri VP, Giri OP, Khan FA, Kumar N, Kumar A, Haque A (2016) Valproic acid versus lamotrigine as first-line monotherapy in newly diagnosed idiopathic generalized tonic—Clonic seizures in adults—a randomized controlled trial. J Clin Diagn Res 10(7):FC01–FC04PubMedPubMedCentral

44.

Vossler DG, Knake S, O’Brien TJ, Watanabe M, Brock M, Steiniger-Brach B, Williams P, Roebling R (2020) Efficacy and safety of adjunctive lacosamide in the treatment of primary generalised tonic-clonic seizures: a double-blind, randomised, placebo-controlled trial. J Neurol Neurosurg Psychiatry 91(10):1067–1075PubMedCrossRef

45.

Wu L, Yagi K, Hong Z, Liao W, Wang X, Zhou D, Inoue Y, Ohtsuka Y, Sasagawa M, Terada K et al (2018) Adjunctive levetiracetam in the treatment of Chinese and Japanese adults with generalized tonic–clonic seizures: a double-blind, randomized, placebo-controlled trial. Epilepsia Open 3(4):474–484PubMedPubMedCentralCrossRef

46.

Biton V, Di Memmo J, Shukla R, Lee YY, Poverennova I, Demchenko V, Saiers J, Adams B, Hammer A, Vuong A et al (2010) Adjunctive lamotrigine XR for primary generalized tonic-clonic seizures in a randomized, placebo-controlled study. Epilepsy Behav 19(3):352–358PubMedCrossRef

47.

Beran RG, Berkovic SF, Dunagan FM, Vajda FJ, Danta G, Black AB, Mackenzie R (1998) Double-blind, placebo-controlled, crossover study of lamotrigine in treatment-resistant generalised epilepsy. Epilepsia 39(12):1329–1333PubMedCrossRef

48.

Biton V, Montouris GD, Ritter F, Riviello JJ, Reife R, Lim P, Pledger G (1999) A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Topiramate YTC Study Group. Neurology 52(7):1330–1337PubMedCrossRef

49.

Brigo F, Igwe SC (2017) Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents. Cochrane Database Syst Rev 2(2):Cd003032PubMed

50.

Biton V, Sackellares JC, Vuong A, Hammer AE, Barrett PS, Messenheimer JA (2005) Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures. Neurology 65(11):1737–1743PubMedCrossRef

51.

Liu J, Tai YJ, Wang LN (2021) Topiramate for juvenile myoclonic epilepsy. Cochrane Database Syst Rev 11(11):Cd010008PubMed

52.

Strzelczyk A, Schubert-Bast S (2022) Psychobehavioural and cognitive adverse events of anti-seizure medications for the treatment of developmental and epileptic encephalopathies. CNS Drugs 36(10):1079–1111PubMedPubMedCentralCrossRef

53.

Hsu WW, Sing CW, He Y, Worsley AJ, Wong IC, Chan EW (2013) Systematic review and meta-analysis of the efficacy and safety of perampanel in the treatment of partial-onset epilepsy. CNS Drugs 27(10):817–827PubMedPubMedCentralCrossRef

54.

Lavu A, Aboulatta L, Abou-Setta AM, Aloud B, Askin N, Rabbani R, Shouman W, Zarychanski R, Eltonsy S (2022) Efficacy and safety of perampanel in epilepsy: a systematic review and meta-analysis of randomised controlled trials. Seizure 102:54–60PubMedCrossRef

55.

Rugg-Gunn F (2014) Adverse effects and safety profile of perampanel: a review of pooled data. Epilepsia 55(Suppl 1):13–15PubMedCrossRef

56.

Villanueva V, D’Souza W, Goji H, Kim DW, Liguori C, McMurray R, Najm I, Santamarina E, Steinhoff BJ, Vlasov P et al (2022) PERMIT study: a global pooled analysis study of the effectiveness and tolerability of perampanel in routine clinical practice. J Neurol 269(4):1957–1977PubMedCrossRef

57.

Perucca E, Brodie MJ, Kwan P, Tomson T (2020) 30 years of second-generation antiseizure medications: impact and future perspectives. Lancet Neurol 19(6):544–556PubMedCrossRef

58.

Cihan E, Devinsky O, Hesdorffer DC, Brandsoy M, Li L, Fowler DR, Graham JK, Karlovich MW, Yang JE, Keller AE et al (2020) Temporal trends and autopsy findings of SUDEP based on medico-legal investigations in the United States. Neurology 95(7):e867–e877PubMedPubMedCentralCrossRef

59.

French JA, Wechsler RT (2020) Have new antiseizure medications improved clinical care over the past 30 years? Lancet Neurol 19(6):476–478PubMedCrossRef

Title: Antiseizure medications for idiopathic generalized epilepsies: a systematic review and network meta-analysis
Authors: Hongyuan Chu
Xinyu Zhang
Jie Shi
Zhirui Zhou
Xu Yang
Publication date: 28-06-2023
Publisher: Springer Berlin Heidelberg
Keywords: Epilepsy
Lamotrigine
Perampanel
Topiramate
Valproate
Levetiracetam
Juvenile Myoclonic Epilepsy
Lacosamide
Published in: Journal of Neurology / Issue 10/2023
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-023-11834-8

2024 ASCO Annual Meeting

Springer Medicine

Antiseizure medications for idiopathic generalized epilepsies: a systematic review and network meta-analysis

Abstract

Objectives

Methods

Results

Conclusions

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Objectives

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 10/2023

Genetic risk factors of Alzheimer’s Disease disrupt resting-state functional connectivity in cognitively intact young individuals

Frequency of demyelinating disease activity following immune checkpoint inhibitor cancer immunotherapy

The rising role of cognitive reserve and associated compensatory brain networks in spinocerebellar ataxia type 2

Synergistic effects of vagus nerve stimulation and antiseizure medication

Economic evaluation of Motor Neuron Diseases: a nationwide cross-sectional analysis in Germany

Study of the relationship between onset lateralization and hemispheric white matter asymmetry in Parkinson's disease