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. 2023 Jun 28;270(10):4713–4728. doi: 10.1007/s00415-023-11834-8

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

Hongyuan Chu 3,#, Xinyu Zhang 4,#, Jie Shi 5, Zhirui Zhou 2,✉, Xu Yang 1,✉
PMCID: PMC10511599  PMID: 37378757

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.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00415-023-11834-8.

Keywords: Antiseizure medications, Idiopathic generalized epilepsy, Absence, Myoclonic, Tonic–Clonic

Introduction

Historically, idiopathic generalized epilepsies (IGEs) have included juvenile myoclonic epilepsy (JME), childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), and generalized tonic–clonic seizures alone (GTCA) [1]. The term “idiopathic” refers to “self-originating” or “spontaneously arising” and implies that the condition is genetic [2]. Characterized by 2.5–6 Hz generalized spike waves, IGEs account for approximately 15–20% of all epilepsies, as well as 55% of newly diagnosed generalized epilepsy in children and adolescents [3, 4]. Because IGEs have a strong underlying genetic basis, the updated classification from the International League Against Epilepsy suggested that IGEs should be a subgroup of “genetic generalized epilepsies,” but reserved the term to describe the aforementioned four overlapping syndromes [1].

The diagnosis of IGEs has important implications for their treatment and prognosis. In patients with IGEs, development, neurological examinations, and radiographic results are typically normal [5]. Additionally, because most cases arise in children and adolescents, IGEs are often emphasized to be of pediatric importance only; however, considerable psychosocial symptoms—such as mood disorders, attention deficits, and learning disabilities—can be observed until adulthood [6, 7]. Long-term follow-up studies have revealed correlations between IGEs and outcomes such as poorer employment/financial conditions, decreased interactions with families, and unplanned pregnancies [8]. Thus, although IGEs may seem easier to manage than symptomatic or partial epilepsies, they should not receive less attention than these other epilepsies.

Antiseizure medications (ASMs) are the cornerstone of treatment for IGE syndromes. A good response rate, at 60–80% of seizure control (i.e., more than 1 year without seizure), can be achieved with appropriate ASM selection [9, 10]. First-line monotherapy controls symptoms in the majority of patients with IGEs. Among the first-line treatments, valproate (rather than lamotrigine or topiramate) monotherapy is the recommended first choice for IGEs in boys and men because it was shown to have better efficacy and tolerability in the SANAD study (Level I evidence) [11]. By contrast, levetiracetam monotherapy is favored in women able to have children; it seldom induces drug–drug interactions. Although levetiracetam was inferior to valproate in the SANAD II study [12], it has shown good efficacy in seizure control in cohort studies [13]. The choice of optimal initial monotherapy in IGEs is very important. Management decisions are different for JME, CAE, JAE, and CTSA, and need to be individualized. However, a limited number of randomized controlled trials (RCTs) have compared various ASMs head-to-head as initial monotherapies for IGEs and related subsyndromes. For example, some ASMs, such as carbamazepine or oxcarbazepine, may exacerbate absence seizures, whereas lamotrigine and gabapentin can exacerbate some myoclonic seizures [14]. A comprehensive integration of the evidence is thus needed so that a tailored plan can be developed for each patient.

Adjunctive therapy should be started when two different monotherapies have been unable to successfully control IGEs. The drug of choice generally depends on the main seizure subtype. Lamotrigine and levetiracetam are recommended as adjunctive therapies to valproate, except in JME. Topiramate, zonisamide, and perampanel have also demonstrated efficacy in RCTs or observational studies and are recommended adjunctive options (e.g., in myoclonic seizures). However, the majority of adjunctive medications do not have proof of efficacy in placebo-controlled RCTs. Hence, a comparison of the efficacy and tolerability of adjunctive ASMs remains lacking; clinically, the choice of adjunctive drug often relies on class III or IV evidence. Furthermore, with numerous established and new medications currently available, physicians face difficult decisions when choosing the most appropriate adjunctive drugs because of the limited high-quality evidence [15].

To the best of our knowledge, no previous review has compared the efficacy and tolerability of ASMs for IGEs (neither as monotherapies nor as adjunctive therapies). This network meta-analysis (NMA) aims to provide comprehensive evidence for the relative efficacy and safety of ASMs for controlling IGEs.

Methods

This NMA was conducted following a protocol that was prospectively registered with PROSPERO (No. CRD42022372358) and adhered to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement for network meta-analysis [16].

Search strategy

Reviewers searched PubMed, Embase, and the Cochrane Library for relevant RCTs. Search terms were limited to the type of epilepsy, antiseizure medication, type of study, and year of publication (Appendix Table S1); there were no limitations on language. The reference lists of relevant RCTs and reviews were searched manually. The search procedure was conducted from December 2022 to February 2023, and EndNote X9 was used for reference management.

Study selection

In the first stage of review, two authors independently selected studies by screening the titles, abstracts, and content according to the inclusion and exclusion criteria. Differences in opinion were discussed to obtain consensus, as necessary; disagreements were arbitrated by the senior reviewer.

Inclusion criteria

(1) Population: patients of any age or sex who were diagnosed with IGEs, JME, CAE, JAE, or GTCA. (2) Intervention: monotherapy or adjunctive therapy with ASMs. (3) Outcomes: efficacy outcomes (the proportion of participants with seizure reduction or freedom after 1, 3, 6, or 12 months) and safety outcomes (the proportion of patients who experienced any treatment-emergent adverse event [TEAE], or serious TEAEs leading to discontinuation).

Exclusion criteria

(1) Patients with a diagnosis of another type of epilepsy. (2) Animal or cellular research. (3) Observational study or review article. (4) Incomplete outcomes with no explanation of clinical relevance.

Data extraction and quality evaluation

Data extraction was collected on standardized spreadsheets and double-checked. If multiple articles reported outcomes from the same population, the most comprehensive outcome was noted. When studies reported different terms of follow-up, all non-overlapping information was included. Version 2 of the Cochrane Collaboration Risk of Bias tool (RoB2) for assessing randomized trials was used to evaluate the included studies [17].

Statistical analysis

Statistical analysis was primarily conducted using R software (version 4.2.1, http://www.r-project.org). The gemtc package was used in JAGS 4.3.0 for the analysis (https://CRAN.R-project.org/package=R2jags). Pairwise meta-analyses were performed using a random-effects model for outcomes of the included studies to obtain odds ratios (ORs) and 95% confidence intervals (CIs). The NMA was conducted within a Bayesian framework that assumed a binomial likelihood for the number of events per medication [18, 19]. For outcomes with two or more treatment arms, the arms were pooled to form a single node for the corresponding ASM. The Markov chain Monte Carlo method was used to compare multiple ASMs by synthesizing the results of direct and indirect comparisons [20]. Each model used four Markov chains; the initial interaction value was set to 5000 and the adjusted interaction number was 10,000. The I2 statistic was calculated to quantify heterogeneity; I2 > 50% was defined as high-grade heterogeneity [21]. The local inconsistency model was assessed using a node-splitting method in which significance was set at a two-tailed p value of 0.05. The surface under the cumulative ranking (SUCRA) curves and the mean ranks were used to evaluate different ASMs, with a higher SUCRA representing superior efficacy.

Results

Identification and description of studies

Of the 2790 abstracts that were identified from PubMed, Embase, and the Cochrane Library, 113 were assessed for eligibility by full-text review, of which 87 were excluded. Finally, 28 RCTs containing 4282 patients were included in the NMA (Fig. 1).

Fig. 1.

Fig. 1

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Flow chart of data retrieval

The demographic characteristics of patients, such as sex and age of entrance and onset, were noted. Detailed information is provided in Table 1. All 28 RCTs assessed the efficacy and safety of ASMs in IGEs or the related entities CAE, JAE, JME, or GTCA (arm of: valproate n = 14, lamotrigine n = 13, levetiracetam n = 6, perampanel n = 5, topiramate n = 3, ethosuximide n = 5, lacosamide n = 1). The number of patients assigned to each ASM, the initial and maximum dose of daily use, and the time of follow-up are shown in Table 2. Study designs—including region, blinding, conflict of interest, and register—were carefully checked to ensure the reliability of results (Table 3). Furthermore, RoB2 assessments were conducted to evaluate bias (Appendix Table S2).

Table 1.

Characteristics of the Included Studies

Participant information
Study ID Number Randomized Seizure type description Mean age Newly diagnosed Refractory Male Age at onset
Arm1 Arm2 Arm1 Arm2 Arm1 Arm2
AE
 Basu 2005 [22] 30 Typical AE Range 5–14 No No 16 / /
 Callaghan 1982 [23] 28 Typical AE 8.00 9.00 No No 8 5 Range 2–5 Range 3–6
 Cnaan 2017 [24] 208 CAE 7.60 No Yes 84 / /
 Coppola 2004 [25] 38 CAE or JAE 7.50 Yes No 17 7.5
 Fattore 2011 [26] 59 CAE or JAE Range 4–15 Yes No 15 12 / /
 Frank 1999 [27] 29 Typical AE Range 2–16 Yes No 5 5
 Glauser 2010, 2013 [28, 29] 453 CAE Range 2.5–13 Yes No 195
 Huang 2009 [30] 45 CAE 7.00 6.00 Yes No 10 16 8-month 7-month
 Shinnar 2017 [6] 382 CAE 7.60 Yes No 43% / /
 Hwang 2011 [31] 128 AE Range 4–10 Yes No 19 20 6.3 6.4
 Brandt 2020 [32] 60 AE and ME 28.50 27.40 No No 18 16 / /
ME
 Machado 2013 [33] 72 JME 26.80 27.30 No No 15 10 16.3 15.3
 Nejad 2009 [34] 42 JME / / No No / / / /
 Noachtar 2008 [35] 120

iIGEs with myoclonic

seizures

 25.00 26.80 No No 22 22 11.9 14.1
 Levisohn 2007 [36] 28 JME 15.00 16.00 No No 6 5 Range 8–26
 Brandt 2020 [37] 47 AE and ME 28.50 27.40 No No 18 16 / /
IGEs
 Berkovic 2007 [38] 164 GTCA associated with IGEs 26.90 30.60 No No 34 39 11.6
 SANAD arm B 2007 [11] 716 Mainly IGEs, some unclassified 22.80 22.50 No No 142 143 / /
 SANAD arm B 2007 716 Mainly IGEs, some unclassified 22.30 / No No 142 / /
 SANAD II arm B 2021 [39] 520 Mainly IGEs, some unclassified 14.10 13.60 Yes No 170 167 13 12
GTCA
 Driscoll 2020 [40] 144 Primary GTCA 25.40 26.20 No No 33 32 11.6 10.3
 French 2015 [41] 162 idiopathic GTCA 27.30 29.50 No Yes 35 36 11.7 10.9
 French 2020 [42] 138 GTCA 26.60 29.10 No Yes 29 30 11.8 10.3
 Prakash 2016 [43] 60 idiopathic GTCA 31.70 33.60 Yes No 20 17 31 33
 Vossler 2020 [44] 242 GTCA 27.80 27.60 No Yes 55 45 12.9 12.9
 Wu 2018 [45] 251 GTCA 31.50 32.80 No No 79 76 14.5 16.5
 Biton 2010 [46] 117 Primary GTCA 26.90 24.90 No Yes 21 18 11.9 12.1
 Beran 1998 [47] 26 AE, ME, and GTCA 29.00 No Yes 15 7.4
 Biton 1999 [48] 80 Primary GTCA 26.80 25.60 No No 24 21 26 25
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AE absence epilepsy, CAE childhood absence epilepsy, JAE juvenile absence epilepsy, ME myoclonic epilepsy, JME juvenile myoclonic epilepsy, IGEs idiopathic generalized epilepsies, GTCA generalized tonic–clonic seizures alone

“/” represents not mentioned or not taken down for reasons

Table 2.

Description of Intervention in the included studies

Intervention information
Study ID Monotherapy Arm Initial daily dose Maximum daily dose Follow-up
Arm 1 (number) Arm 2 (number) Arm1 Arm 2 Arm1 Arm 2
AE
 Basu 2005 Yes VPA 15 LTG 15 / / / 10 mg/kg/day 12 months
 Callaghan 1982 Yes ESM 14 VPA 14 250 mg/d 1500 mg/d 400 mg/d 2400 mg/d 18 months-4 years
 Cnaan 2017 (arm 1 2) Yes ESM 75 LTG 55 / / 2000 mg/d 600 mg/d 12 months
 Cnaan 2017 (arm 3) VPA 78 / 3000 mg/d
 Coppola 2004 Yes LTG19 VPA19 0.5 mg/kg/d 10 mg/kg/d 12 mg/kg/d 30 mg/kg/d 12 months
 Fattore 2011 Yes LEV38 Placebo21 10 mg/kg/day / 30 mg/kg/day / 602 days
 Frank 1999 Yes LTG15 Placebo14 0.5 mg/kg/day 15 mg/kg/day 25 weeks
 Glauser 2010, 2013 (arm 1 2) Yes ESM156 LTG 149 10 mg/kg/d 0.3 mg/kg/d 60 mg/kg/d 12 mg/kg/d 12 months
 Glauser 2010, 2013 (arm 3) VPA148 10 mg/kg/d 60 mg/kg/d 12 months
 Huang 2009 Yes VPA23 LTG 22 15 mg/kg/d 0.15 mg/kg/d 30 mg/kg/d 10 mg/kg/d 12 months
 Shinnar 2017 (arm 1 2) Yes ESM91 LTG 91 10 mg/kg/d 0.3 mg/kg/d 60 mg/kg/d 12 mg/kg/d 12 months
 Shinnar 2017 (arm 3) VPA96 10 mg/kg/d 60 mg/kg/d
 Hwang 2011 Yes ESM48 VPA59 10 mg/kg/d 10 mg/kg/d 23 mg/kg/d 26 mg/kg/d 3.4 years(1-17 years)
 Brandt 2020 no PER 51 Placebo56 2 mg/day / 8 mg/day / 136 weeks
ME
 Machado 2013 yes LTG41 VPA31 25 mg/d 200 mg/d 300 mg/d 3000 mg/d 24 months
 Nejad 2009 yes LTG22 VPA20 500 mg/d 200 mg/d 1500-2000 mg/d 800 mg/d 28 weeks
 Noachtar 2008 No LEV60 Placebo62 1000 mg/d / 3000 mg/d / 30 weeks
 Levisohn 2007 Yes TPM19 VPA9 3–4 mg/kg/day 10 mg/kg/day 9 mg/kg/day 60 mg/kg/day 26 weeks
 Brandt 2020 No PER 24 Placebo 23 2 mg/day / 8 mg/day / 136 weeks
IGEs
 Berkovic 2007 Yes LEV80 Placebo84 Adults: 1000 mg/day children:20 mg/kg/day / Adults: 3000 mg/day children: 60 mg/kg/day / 20 weeks
 SANAD arm B 2007 (arm 1 2) Yes LTG 239 VPA 238 Decided by clinician 83.5 months
 SANAD arm B 2007 (arm 3) Yes TPM 239 Decided by clinician 83.5 months
 SANAD II arm B 2021 Yes LEV260 VPA260 250 mg/d 500 mg/d 500 mg/d 500 mg/d 67.9 months
GTCA
 Driscoll 2020 No Adjunctive PER 72 Placebo 72 10 mg/kg/day / 10 mg/kg/day / 12 weeks
 French 2015 No Adjunctive PER 81 Placebo81 2 mg/day / 8 mg/day / 21 weeks
 French 2020 No Adjunctive PER 68 Placebo70 2 mg/day / 8 mg/day / 2 years
 Prakash 2016 Yes VPA30 LTG30 10 mg/kg/day 0.5 mg/kg/day 30 mg/kg/day 12 mg/kg/day 12 months
 Vossler 2020 No Adjunctive LCM 121 Placebo121 100 mg/day / 300–400 mg/day / 28 weeks
 Wu 2018 No Adjunctive LEV126 Placebo125 1000 mg/day / 3000 mg/day / 36 weeks
 Biton 2010 No Adjunctive LTG58 Placebo59 12.5-50 mg/day / 150-500 mg/day / 24 weeks
 Beran 1998 No Adjunctive LTG26 Placebo26 50 mg/day / 150 mg/day / 24 weeks
 Biton 1999 No Adjunctive TPM39 Placebo41 50 mg/day / 400 mg/day / 20 weeks
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AE absence epilepsy, ME myoclonic epilepsy, IGEs idiopathic generalized epilepsies, GTCA generalized tonic–clonic seizures alone, VPA valproate, LTG lamotrigine, TPM topiramate, LEV levetiracetam, ESM ethosuximide, PER perampanel, LCM lacosamide

“/” represents not mentioned or not taken down for reasons

Table 3.

Design information of included studies

Study Design Information
Study ID Region Multicenter Double-blind Conflict of interest/disclosure Children/elderly/pregnancy Register
AE
 Basu 2005 India No Not stated Not stated Children Not stated
 Callaghan 1982 Eire No Yes Not stated Children Not stated
 Cnaan 2017 The USA 32 sites Open-label None Children NCT00088452
 Coppola 2004 Italy No Open-label Not stated Children Not stated
 Fattore 2011 Italy 11center Open-label Consultancy fees and/or research grants from the manufacturers of ASMs disclosed Children EudraCT 2005–003520-18,2005–003520-26
 Frank 1999 The USA Unclear Yes Stated Children Protocol 105–044
 Glauser 2010&2013 The USA 32 sites Open-label Study medications were provided free of charge by Pfizer, Abbott Laboratories, and GlaxoSmithKline Children NCT00088452
 Huang 2009 China No Open-label Not stated Children /
 Shinnar 2017 The USA 32 sites Open-label Stated Children NCT00088452
 Hwang 2011 Japan No Open-label Not stated Children Not stated
ME
 Machado 2013 Cuba Tertiary center No Stated Children /
 Nejad 2009 Iran No Open-label Not stated No /
 Noachtar 2008 14 countries 37 centers Yes Study medications were provided free of charge by Pfizer, Janssen-Cilag, Desitin, Eisai, and Sanofi-Synthelab No NCT00150774-N166
 Levisohn 2007 The USA No Open-label Not stated No Not stated
IGEs
 SANAD arm B 2007 The UK Yes No Stated No SP0993
 SANAD II arm B 2021 The UK Yes No Stated No ISRCTN30294119
 Berkovic 2007

Europe, North America, Mexico,

Australia, and New Zealand

 50 centers Yes Grants from manufacturers of ASMs disclosed / NCT00150748
 Brandt 2020 In 16 countries 78 sites Yes Funded by Eisai Inc / NCT01393743
GTCA
 Driscoll 2020 21 countries Yes Yes Several authors are full-time employees of Pfizer Children and adults NCT01747915
 French 2015 In 16 countries 78 sites Yes Funded by Eisai Inc / NCT01393743
 French 2020 In 16 countries 78 sites Yes Funded by Eisai Inc / NCT01393743
 Prakash 2016 India No No Not stated / /
 Vossler 2020 North America, Latin America, Europe and the Asia–Pacific region Yes Yes Speaker honoraria from Eisai, Greenwich Biosciences, Lundbeck, Sunovion and UCB Pharma etc / SP0982, NCT02408523
 Wu 2018 China and Japan 115sites Yes Sponsored by UCB Pharma / N01159; NCT01228747)
 Biton 2010 International (not detailed) 38 sites Yes Funded by GlaxoSmithKline, manufacturer of lamotrigine / Glaxo-SmithKline protocol LAM40097
 Beran 1998 Australia 5sites No Not stated / /
 Biton 1999 The United States and Costa Rica 8 sites Yes Not stated / /
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AE absence epilepsy, ME myoclonic epilepsy, IGEs idiopathic generalized epilepsies, GTCA generalized tonic–clonic seizures alone

“/” represents not mentioned or not taken down for reasons

A favorable consistency of the included studies was identified using the node-splitting method (all p > 0.05). Moreover, heterogeneity was low in the included studies (all I2 < 27%).

Efficacy outcomes

The included RCTs provided outcomes regarding the proportion of patients who achieved seizure freedom for 1, 3, 6, and 12 months after ASM treatment. The majority of studies reported the intention-to-treat population; intention-to-treat outcomes were thus analyzed rather than per-protocol outcomes. The network-evidence map plots of seizure-free outcomes for ASMs as monotherapies and adjunctive therapies are shown in Fig. 2A–F. Both short-term seizure-free outcomes (3–6 months) and relatively long-term outcomes (12 months) were analyzed.

Fig. 2.

Fig. 2

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Network of treatment comparisons for efficacy and safety. A Seizure free for 3–6 months after monotherapy in overall idiopathic generalized epilepsies (IGEs). B Seizure free for 3–6 months after adjunctive therapy in overall IGEs. C Seizure free for 12 months after monotherapy in overall IGEs (long-term follow-up). D Seizure free for 3–6 months after monotherapy in absence epilepsies (AE). E Seizure free for 3–6 months after adjunctive therapy in myoclonic epilepsies (ME). F Seizure free for 3–6 months after adjunctive therapy in generalized tonic–clonic seizures alone (GTCA). G Any adverse event after adjunctive therapy in overall IGEs. H Any adverse event after monotherapy in overall IGEs. I Adverse events leading to discontinuation after adjunctive therapy in overall IGEs. J Adverse events leading to discontinuation after monotherapy in overall IGEs (part 1). K Adverse events leading to discontinuation after monotherapy in overall IGEs (part 2). AE absence epilepsy, ME myoclonic epilepsy, IGEs idiopathic generalized epilepsies, GTCA generalized tonic–clonic seizures alone, VPA valproate, LTG lamotrigine, TPM topiramate, LEV levetiracetam, ESM ethosuximide, PER perampanel, LCM lacosamide, ad adjunctive

The forest plot of the NMA revealed that all ASMs were associated with a higher rate of either short- or long-term seizure-free outcomes compared with placebo (Fig. 3). In the monotherapy analysis for overall IGEs, ethosuximide had a higher 3- to 6-month seizure-free rate than valproate (OR = 1.3, 95% CI = 0.66–2.8), whereas lamotrigine had a significantly lower rate than valproate (OR = 0.40, 95% CI = 0.23–0.77; Fig. 3A).

Fig. 3.

Fig. 3

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Forest plots of treatment comparisons for efficacy. A Seizure free for 3–6 months after monotherapy in overall idiopathic generalized epilepsies (IGEs). B Seizure free for 3–6 months after adjunctive therapy in overall IGEs. C Seizure free for 12 months after monotherapy in overall IGEs (long-term follow-up). D Seizure free for 3–6 months after monotherapy in absence epilepsies (AE). E Seizure free for 3–6 months after adjunctive therapy in myoclonic epilepsies (ME). F Seizure free for 3–6 months after adjunctive therapy in generalized tonic–clonic seizures alone (GTCA). AE absence epilepsy, ME myoclonic epilepsy, IGEs idiopathic generalized epilepsies, GTCA generalized tonic–clonic seizures alone, VPA valproate, LTG lamotrigine, TPM topiramate, LEV levetiracetam, ESM ethosuximide, PER perampanel, LCM lacosamide, ad adjunctive

In the adjunctive therapy analysis, all ASMs showed superior efficacy to placebo; the effects of levetiracetam (OR = 7, 95% CI = 0.07–14) and topiramate (OR = 8.9, 95% CI = 1.9–39) were significant (Fig. 3B). There were no significant differences in long-term (12-month) follow-up outcomes between adjunctive valproate and adjunctive ethosuximide (OR = 1.3, 95% CI = 0.77–2.1), levetiracetam (OR = 0.82, 95% CI = 0.37–1.8), or topiramate (OR = 0.83, 95% CI = 0.39–1.7); however, adjunctive lamotrigine had significantly lower efficacy than adjunctive valproate (OR = 0.54, 95% CI = 0.37–0.8; Fig. 3C).

Subsyndromes of IGEs were also independently analyzed. In absence epilepsies, ethosuximide (OR = 3.1, 95% CI = 1.4–6.9) and valproate (OR = 2.4, 95% CI = 1.1–4.3) had significantly superior efficacy to lamotrigine as monotherapies (Fig. 3D). However, in the analysis of adjunctive therapies in myoclonic epilepsies (Fig. 3E) and GTCA (Fig. 3F), there were no significant differences between ASMs and placebo, likely because the 95% CIs were very broad.

Safety outcomes

In overall IGEs, adjunctive lamotrigine (OR 4.4, 95% CI = 1.0–24) had a significantly increased risk of any TEAEs compared with adjunctive placebo (Fig. 4A). There were no significant differences in safety between ASMs as either adjunctive therapies (Fig. 4A) or monotherapies (Fig. 4B).

Fig. 4.

Fig. 4

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Forest plots of treatment comparisons for safety. A Any adverse event after adjunctive therapy in overall idiopathic generalized epilepsies (IGEs). B Any adverse event after monotherapy in overall IGEs. IGEs idiopathic generalized epilepsies, VPA valproate, LTG lamotrigine, TPM topiramate, LEV levetiracetam, ESM ethosuximide, PER perampanel, LCM lacosamide, ad adjunctive

SUCRA

According to the SUCRA, the efficacy ranking for monotherapies was ethosuximide > valproate > topiramate > placebo > lamotrigine in overall IGEs, and the efficacy ranking for adjunctive therapies was topiramate > levetiracetam > lacosamide > perampanel > lamotrigine > placebo. For 12-month seizure-free efficacy, the ranking was ethosuximide > valproate > topiramate > levetiracetam > lamotrigine (Fig. 5A–C and Appendix Table S2A–C). In absence epilepsies, the SUCRA efficacy ranking for monotherapies was ethosuximide > valproate > placebo > lamotrigine. In myoclonic seizures, the efficacy ranking for adjunctive therapies was levetiracetam > lamotrigine > perampanel > placebo. Moreover, for GTCA, the efficacy ranking for adjunctive therapies was topiramate > lacosamide > perampanel > lamotrigine > placebo (Fig. 5D–F and Appendix Table S3D–F).

Fig. 5.

Fig. 5

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Ranking of efficacy outcomes according to the surface under the cumulative ranking curve (SUCRA). A Seizure free for 3–6 months after monotherapy in overall idiopathic generalized epilepsies (IGEs). B Seizure free for 3–6 months after adjunctive therapy in overall IGEs. C Seizure free for 12 months after monotherapy in overall IGEs (long-term follow-up). D Seizure free for 3–6 months after monotherapy in absence epilepsies (AE). E Seizure free for 3–6 months after adjunctive therapy in myoclonic epilepsies (ME). F Seizure free for 3–6 months after adjunctive therapy in generalized tonic–clonic seizures alone (GTCA). AE absence epilepsy, ME myoclonic epilepsy, IGEs idiopathic generalized epilepsies, GTCA generalized tonic–clonic seizures alone, VPA valproate, LTG lamotrigine, TPM topiramate, LEV levetiracetam, ESM ethosuximide, PER perampanel, LCM lacosamide, ad adjunctive

In overall IGEs, the SUCRA ranking of associations with more total TEAEs for adjunctive therapies was placebo > levetiracetam > perampanel > lamotrigine > lacosamide; for monotherapies, it was perampanel > placebo > lamotrigine > valproate > levetiracetam > ethosuximide (Fig. 6A, B and Appendix Table S3G-H). For serious TEAEs leading to discontinuation, the safety ranking was placebo > perampanel > topiramate > levetiracetam > lacosamide > lamotrigine for adjunctive therapy (Fig. 6C and Appendix Table S3I) and topiramate > valproate > ethosuximide > lamotrigine; placebo > levetiracetam > perampanel for monotherapy (Fig. 6D–E and Appendix Table S3J–K).

Fig. 6.

Fig. 6

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Ranking of safety outcomes according to the surface under the cumulative ranking curve (SUCRA). A Any adverse event after adjunctive therapy in overall idiopathic generalized epilepsies (IGEs). B Any adverse event after monotherapy in overall IGEs. C Adverse event leading to discontinuation after adjunctive therapy in overall IGEs. D Adverse event leading to discontinuation after monotherapy in overall IGEs (part 1). E Adverse event leading to discontinuation after monotherapy in overall IGEs (part 2). AE absence epilepsy, ME myoclonic epilepsy, IGEs idiopathic generalized epilepsies, GTCA generalized tonic–clonic seizures alone, VPA valproate, LTG lamotrigine, TPM topiramate, LEV levetiracetam, ESM ethosuximide, PER perampanel, LCM lacosamide, ad adjunctive

Discussion

Our NMA indicated that all of the included ASMs were more effective than the placebo. The network forest plots compared monotherapies with valproate and adjunctive therapies with placebo. Significant superiority was identified for adjunctive levetiracetam and topiramate, while inferiority was identified for lamotrigine monotherapy. Non-significant differences were also identified. Using SUCRA, rankings of efficacy and tolerability were summarized.

The analyses of the efficacy outcomes of being seizure free for 3–6 or 12 months did not affect the status of valproate as the first-choice monotherapy for overall IGEs without contraindications. Although ethosuximide ranked first according to SUCRA, its optimal efficacy and tolerability are probably only favorable for absence epilepsies rather than for overall IGEs, and especially tonic–clonic seizures [49]. It is supported as the drug of choice for absence seizures without other seizure types, in accordance with other reviews and guidelines (April 2022, NICE guidelines, https://www.nice.org.uk/guidance/ng217).

Lamotrigine monotherapy unexpectedly had the lowest efficacy in both short- and long-term seizure-free outcomes in the SUCRA analysis and showed significant inferiority in the forest plots for overall IGEs. Although a longer duration of titration may partly account for this short-term result (because lamotrigine must be titrated very slowly to avoid unwanted side effects), this finding is in accordance with a SANAD study suggesting that lamotrigine should not be interpreted as a “broad spectrum” antiseizure medication because it provides worse seizure control than valproate or topiramate in generalized epilepsies [11]. However, these findings should be interpreted with caution. Adjunctive lamotrigine is advantageous in controlling unclassified generalized tonic–clonic seizures (i.e., those unable to be classified as IGEs or partial epilepsy) [50].

In recent years, levetiracetam has been increasingly prescribed and recommended. The present NMA supports its efficacy as a second-line monotherapy and as an ideal adjunctive choice in overall IGEs according to its efficacy ranking. Although it was not found to be a non-inferior monotherapy to valproate in a previous study [12], its favorable efficacy, fast action, and good tolerability (leading to less TEAEs than placebo in our ranking) indicate its considerable potential. However, longitudinal studies are needed in the future (for both levetiracetam and brivaracetam).

In the present study, adjunctive topiramate ranked first in adjunctive therapies according to SUCRA. As a second-generation ASM, topiramate is especially effective in JME and GTCA [51]. In a Cochrane review, the efficacy of topiramate monotherapy in JME was not significantly different from that of valproate (the current drug of choice) [51]. Although topiramate is associated with cognitive TEAEs such as dulling or memory problems [52], which are especially unfavorable in neurodevelopmental disorders, its tolerability was the best ranked in terms of TEAEs leading to discontinuation.

The head-to-head comparison of third-generation ASMs used as adjunctive therapies is of great importance because there is a lack of accumulated evidence, especially for perampanel and lacosamide. In the present analysis, SUCRA demonstrated that their efficacies seem to fall between those of levetiracetam and lamotrigine. In addition, lacosamide may be more effective than perampanel for seizure-free outcomes in GTCA. Although there was previously a lack of high-quality long-term evidence, recent unblinded controlled studies have revealed that perampanel reduces generalized seizures with a median of 90% in 52-week follow-up, and has the potential to increase seizure freedom [42, 53, 54]. Moreover, after 24 weeks of lacosamide adjunctive treatment, the freedom rate from generalized seizures was 27.5% (versus placebo 13.2%) in an RCT [44].

In the current study, perampanel was the best-ranked therapy for tolerability as both a monotherapy and an adjunctive therapy when any adverse event was considered. The characteristic TEAEs of perampanel are irritability and aggression [52, 55]. In contrast, when ranking the therapies in terms of serious TEAEs leading to discontinuation, perampanel was inferior to placebo and levetiracetam. Similarly, the PERMIT study indicated a discontinuation rate of 17.6% at 12 months, in which psychiatric TEAEs were the most common reason for discontinuation [56]. We thus predict a future in which new-generation ASMs, like perampanel, are used to control generalized seizures. However, more high-quality research is warranted to draw stronger conclusions.

We must note that, although all included ASMs significantly improved the seizure-free rate compared with placebo, ASMs can neither cure epilepsies nor treat the underlying pathology that causes them; they merely aim to stop the occurrence of seizure symptoms. A better understanding of the molecular mechanisms underlying the pathogenesis, epileptogenesis, and pharmacoresistance of epilepsies is needed to change our clinical approach. For example, genetic therapies and stem cell therapies will likely cure epilepsies in the future [57].

Despite this, the importance of ASMs should not be ignored, although many patients do not achieve or retain complete seizure freedom. Improved seizure reduction may significantly downgrade the risk of injury and unexpected death [58]; however, in the present review, the NMA of the seizure reduction rate had to be stopped because insufficient data were provided in the included studies. In addition, although some well-controlled complex epilepsies might be disrupted by a single poor night’s sleep or missing dose and breakthrough, substantial improvements have been achieved [59]. Compared with invasive options like vagus nerve stimulation or corpus callosotomies, the use of established and new ASMs may provide more tolerable, incremental benefits. Furthermore, the increase in available ASMs makes it possible to devise more individualized plans, thus benefitting patients. Longitudinal comprehensive studies are therefore warranted to evaluate efficacy in particular populations (or genotypes), more in-detail tolerability, effects on quality of life, and cost-utility for ASMs.

The present study had some limitations. Methodologically, a limited number of outcomes restrained us from analyzing other important efficacy outcomes, such as seizure reduction or electroencephalogram improvements. Furthermore, because specific TEAEs were not evaluated, the tolerability outcome analysis lacked details, and only rough results were obtained because of a lack of information. The search strategy mainly focused on the idiopathic generalized seizure type. Thus, some important ASMs (such as cenobamate, brivaracetam, etc.) most frequently used in focal epilepsies, although recently proven adjunctive use in generalized seizures, were not involved. More meaningful future studies are necessary to elucidate the efficacy of these ASMs.

Although low heterogeneity was identified according to the I2 test, differences between RCTs existed such as the inclusion criteria, time of treatment, and concomitant drugs. Furthermore, although a statistically suitable and well-known analysis was used, certain overestimations or underestimations may still exist. For example, relatively broad 95% CIs were obtained because relatively few RCTs were included. Further studies are therefore required to further confirm our conclusions.

Conclusions

Among the included ASM monotherapies, valproate ranked best for overall IGEs in efficacy and was the third best in tolerability. For the adjunctive therapies, topiramate ranked best for GTCA and overall IGEs, whereas levetiracetam ranked best for myoclonic seizures. Moreover, perampanel ranked best in tolerability measured by any TEAE when used either as a monotherapy or an adjunctive therapy. Overall, valproate is recommended as the monotherapy of choice for overall IGEs without contraindications. However, our results should be interpreted with caution considering the limited available information and the inherent methodological limitations of the NMA.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 45 KB) (44.9KB, docx)

Data availability

All the datasets generated during the study are available on reasonable request from the corresponding author Xu Yang.

Declarations

Conflicts of interest

None.

Footnotes

Hongyuan Chu and Xinyu Zhang have contributed equally to this work.

Contributor Information

Zhirui Zhou, Email: zzr3711@163.com.

Xu Yang, Email: yangxu2011@163.com.

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Supplementary Materials

Supplementary file1 (DOCX 45 KB) (44.9KB, docx)

Data Availability Statement

All the datasets generated during the study are available on reasonable request from the corresponding author Xu Yang.

Articles from Journal of Neurology are provided here courtesy of Springer

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