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.
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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).
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).
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.
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).
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).
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).
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).
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.
Data availability
All the datasets generated during the study are available on reasonable request from the corresponding author Xu Yang.
References
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):1475–1499
Mattson RH (2003) Overview: idiopathic generalized epilepsies. Epilepsia 44(Suppl 2):2–6
Jallon P, Latour P (2005) Epidemiology of idiopathic generalized epilepsies. Epilepsia 46(Suppl 9):10–14
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):110–118
Beydoun A, D’Souza J (2012) Treatment of idiopathic generalized epilepsy—a review of the evidence. Expert Opin Pharmacother 13(9):1283–1298
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):1698–1706
Rinaldi VE, Di Cara G, Mencaroni E, Verrotti A (2021) Therapeutic options for childhood absence epilepsy. Pediatr Rep 13(4):658–667
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):152–158
Colleran N, Connor TO, Brien JJO (2017) Anti-epileptic drug trials for patients with drug resistant idiopathic generalised epilepsy: a meta-analysis. Seizure 51:145–156
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):1256–1262
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
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):1375–1386
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):850–853
Auvin S (2007) Treatment of myoclonic seizures in patients with juvenile myoclonic epilepsy. Neuropsychiatr Dis Treat 3(6):729–734
Curatolo P, Moavero R, Lo Castro A, Cerminara C (2009) Pharmacotherapy of idiopathic generalized epilepsies. Expert Opin Pharmacother 10(1):5–17
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):777–784
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:l4898
Cipriani A, Higgins JP, Geddes JR, Salanti G (2013) Conceptual and technical challenges in network meta-analysis. Ann Intern Med 159(2):130–137
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):818–827
Lu G, Ades AE (2004) Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med 23(20):3105–3124
Higgins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560
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
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):830–836
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):182–190
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):1049–1053
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):802–809
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):973–979
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):551–563
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):790–799
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
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):344–348
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 103:106864
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):846–855
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):313–318
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):607–616
Levisohn PM, Holland KD (2007) Topiramate or valproate in patients with juvenile myoclonic epilepsy: a randomized open-label comparison. Epilepsy Behav 10(4):547–552
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 80:115–123
Berkovic SF, Knowlton RC, Leroy RF, Schiemann J, Falter U (2007) Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology 69(18):1751–1760
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):1–134
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):381–393
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
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):393–405
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–FC04
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):1067–1075
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):474–484
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):352–358
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):1329–1333
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):1330–1337
Brigo F, Igwe SC (2017) Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents. Cochrane Database Syst Rev 2(2):Cd003032
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):1737–1743
Liu J, Tai YJ, Wang LN (2021) Topiramate for juvenile myoclonic epilepsy. Cochrane Database Syst Rev 11(11):Cd010008
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):1079–1111
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):817–827
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 102:54–60
Rugg-Gunn F (2014) Adverse effects and safety profile of perampanel: a review of pooled data. Epilepsia 55(Suppl 1):13–15
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):1957–1977
Perucca E, Brodie MJ, Kwan P, Tomson T (2020) 30 years of second-generation antiseizure medications: impact and future perspectives. Lancet Neurol 19(6):544–556
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–e877
French JA, Wechsler RT (2020) Have new antiseizure medications improved clinical care over the past 30 years? Lancet Neurol 19(6):476–478
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Chu, H., Zhang, X., Shi, J. et al. Antiseizure medications for idiopathic generalized epilepsies: a systematic review and network meta-analysis. J Neurol 270, 4713–4728 (2023). https://doi.org/10.1007/s00415-023-11834-8
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DOI: https://doi.org/10.1007/s00415-023-11834-8