托吡酯治疗青少年肌阵挛性癫痫
摘要
研究背景
托吡酯是一种较新的广谱抗癫痫药（antiepileptic drug, AED）。一些研究表明托吡酯对治疗青少年肌阵挛性癫痫（juvenile myoclonic epilepsy, JME）有益。然而，目前尚无系统综述来确定托吡酯对JME患者的疗效和耐受性。
这是Cochrane综述的更新版本，综述于2015年首次发表，最后更新于2019年。
研究目的
评价托吡酯治疗JME的疗效和耐受性。
检索策略
对于此次更新，我们于2021年8月26日检索了Cochrane研究注册库（CRS Web）和MEDLINE（Ovid, 1946年至2021年8月26日）。CRS网站纳入了PubMed、Embase、美国临床试验注册平台（Clinicaltrials.gov）、世界卫生组织国际临床试验注册平台（International Clinical Trials Registry Platform, ICTRP）、Cochrane对照试验中心注册库（the Cochrane Central Register of Controlled Trials, CENTRAL）和Cochrane癫痫组专业注册库（Cochrane Epilepsy Groups Specialized Registers）的随机或半随机对照试验。
纳入排除标准
我们纳入了评价托吡酯与安慰剂或与其他AED治疗对JME患者疗效的随机对照试验（randomized controlled trials, RCT），结局为有效者比例和发生不良事件（adverse events, AE）的受试者比例。
资料收集与分析
两位系统综述作者独立筛选检索到的标题和摘要，选择纳入的研究，提取资料，交叉检查数据的准确性并评价研究的方法质量。
主要结果
我们共纳入3项研究，涉及83名受试者。就疗效而言，与安慰剂组的受试者相比，托吡酯组有更大比例的受试者的主要全身性强直阵挛发作（PGTCS）减少了50%或更多（RR=4.00, 95% CI [1.08, 14.75]，共1项研究，涉及22名受试者，极低质量证据）。对于肌阵挛发作减少50%或更多的受试者来说（RR=0.88, 95% CI [0.67, 1.15]，共1项研究，涉及23名受试者，极低质量证据）或对于PGTCS来说（RR=1.22, 95% CI [0.68, 2.21]，共1项研究，涉及16名受试者，极低质量证据），或对于无发作的受试者来说（RR=1.13, 95% CI [0.61, 2.11]，共1项研究，涉及27名受试者，极低质量证据），托吡酯和丙戊酸之间没有显著差异。关于耐受性，我们将与托吡酯相关的AE列为中度至重度AE，而将59%与丙戊酸相关的AE列为重度（共2项研究，涉及61名受试者，极低质量证据）。此外，丙戊酸组的全身毒性评分高于托吡酯组。
总体而言，我们认为3项研究都存在高损耗偏倚风险和不明确的报告偏倚风险。我们判断这些研究在其余领域（选择偏倚、实行偏倚、检测偏倚和其他偏倚）具有低偏倚风险到不明确的偏倚风险。我们使用GRADE方法判断，结局总体上为极低质量证据。
作者结论
自从本系统综述的上一版本于2019年发表以来，我们未发现新的研究。本系统综述没有提供足够的证据支持使用托吡酯治疗JME患者。基于目前有限的可用数据，托吡酯似乎比丙戊酸耐受性更好，但在疗效方面无明显优于丙戊酸之处。需要使用设计良好的大样本双盲RCT来测试托吡酯对JME患者的疗效和耐受性。
PICO
简语概要
托吡酯治疗青少年肌阵挛性癫痫
系统综述背景
青少年肌阵挛性癫痫（Juvenile myoclonic epilepsy, JME）的特点是醒来后肩部和手臂肌肉不自主（不受控制）地抽搐，且通常始于儿童时期。
研究特征
我们在科学数据库中检索了将抗癫痫药物托吡酯与安慰剂（一种假治疗）或与另一种抗癫痫药物治疗JME患者进行对比的临床试验。我们想评价托吡酯的效果以及副作用。
关键结果
我们纳入并分析了涉及83名受试者的3项随机对照试验（将患者随机分入两个或多个治疗组之一的临床研究）。根据这些试验中的信息，发现托吡酯似乎比丙戊酸耐受性更好，但并不比丙戊酸更有效。托吡酯似乎比安慰剂更有效，但这是基于对少数受试者的研究得出的结果。
证据质量
这些研究为极低质量证据，应谨慎解释结果。需要更多有大量受试者的随机对照试验来测试托吡酯对JME患者的有效性和耐受性。未来的试验应该是精心设计的和双盲的（受试者和研究人员在收集结果之前都不知道接受了哪种治疗）。
结论
本系统综述没有提供足够的证据支持使用托吡酯治疗JME患者。
证据截至2021年8月。
Authors' conclusions
Summary of findings
| Topiramate compared with placebo for juvenile myoclonic epilepsy | ||||||
| Patient or population: people with juvenile myoclonic epilepsy Settings: 18 centers in the USA; 10 centers in Europe; 1 center in Costa Rica Intervention: topiramate Comparison: placebo | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo | Topiramate | |||||
| Proportion of responders (at least 50% seizure frequency reduction in PGTCS) | 182 per 1000 | 727 per 1000 (197 to 1000) | RR 4.00 (1.08 to 14.75) | 22 (1 study) | ⊕⊝⊝⊝ | More participants taking topiramate responded with a 50% or greater reduction in PGTCS compared with placebo (P = 0.04) |
| Proportion of participants who experienced at least one AE and individual AEs | See comment | See comment | N/A | 22 (1 study) | ⊕⊝⊝⊝ | The number of participants experiencing at least one AE was not reported. Individual AEs: no significant differences were found in nausea, URTI, abnormal vision, or diarrhea between topiramate and placebo |
| Number of participants who were seizure‐free | Not reported | Not reported | N/A |
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| *The basis for the assumed risk was the event rate in the control group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect | ||||||
| 1 The included trials were reported as randomized, double‐blind trials, however the methodological information was insufficient. | ||||||
| Topiramate compared with valproate for juvenile myoclonic epilepsy | ||||||
| Patient or population: people with juvenile myoclonic epilepsy Settings: Cincinnati Children’s Hospital Medical Center, Cincinnati, USA; Haeundae Paik Hospital, Busan, Republic of Korea Intervention: topiramate Comparison: valproate | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Valproate | Topiramate | |||||
| Proportion of responders (at least 50% seizure frequency reduction in myoclonic seizures) | 1000 per 1000 | 857 per 1000 (670 to 1000) | RR 0.88 (0.67 to 1.15) | 23 | ⊕⊝⊝⊝ | No significant difference was found. |
| Proportion of responders (at least 50% seizure frequency reduction in PGTCS) | 750 per 1000 | 917 per 1000 (510 to 1000) | RR 1.22 (0.68 to 2.21) | 16 (1 study) | ⊕⊝⊝⊝ | No significant difference was found. |
| Proportion of participants who experienced at least one AE and individual AEs | See comment | See comment | NA | 61 | ⊕⊝⊝⊝ | The number of participants experiencing at least one AE was not reported. We found significantly more events of paresthesia with topiramate, and more events of weight gain and tremor with valproate. There was no significant difference between groups for headache, concentration difficulty, fatigue, alopecia, dizziness, weight loss, psychomotor slowing, somnolence, nausea, appetite increase, insomnia, abnormal vision, rash, anorexia, hallucination or diarrhea. |
| Number of participants who were seizure‐free | 563 per 1000 | 636 per 1000 (343 to 1188) | RR 1.13 (0.61 to 2.11) | 27 | ⊕⊝⊝⊝ | No significant difference was found. |
| *The basis for the assumed risk was the event rate in the control group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect | ||||||
| 1 The included trials were reported as randomized, double‐blind trials, however the methodological information was insufficient. | ||||||
Background
This is an update of a Cochrane Review previously published in 2019 (Liu 2019).
Description of the condition
Juvenile myoclonic epilepsy (JME) was first described by Janz in 1985. It is a primary generalized epilepsy which is characterized by irregular myoclonic jerks of shoulders and arms after awakening, and bilateral synchronous four‐to‐six per second spike‐wave complexes (Janz 1985). JME accounts for 5% to 11% of all epilepsy cases and its prevalence varies between 10 and 20 per 100,000 population (Jallon 2005; Panayiotopoulos 1991). The age of onset ranges from six to 22 years old, but 50% of cases present between 13 and 16 years of age. Valproate is widely regarded as the first‐line therapy in JME owing to its broad spectrum of activity. However, 20% of people with JME do not achieve satisfactory control with valproate (Calleja 2001). In addition, it is generally acknowledged that JME requires lifelong therapy and the adverse effects (AEs) in chronic valproate therapy are extensive (Sharpe 2008). Thus, alternative effective broad‐spectrum agents are required.
Description of the intervention
Topiramate is a newer broad‐spectrum agent that is effective in many seizure types, including focal onset and primarily generalized tonic‐clonic seizures (PGTCS) and Lennox‐Gastaut syndrome (Biton 1999; Guberman 2002; Sachdeo 1999). Topiramate during the first year after onset controls GTCS in 62.5% of people and myoclonic jerks in 68.8% of people, although 13.6% of people have an increase in frequency of absence seizures (Alfradique 2007). Moreover, topiramate has less risk of teratogenicity than valproate, and can be used as an alternative first‐line agent in women of childbearing age (Montouris 2009).
How the intervention might work
As a sulphamate‐substituted monosaccharide, the main mode of action of topiramate is through the inhibition of carbonic anhydrase. It also has antiepileptic activity, which is probably attributed to other mechanisms, including modulation of voltage‐dependent sodium channels, potentiation of GABAergic inhibition at a novel site on the gamma‐aminobutyric acid‐A (GABA‐A) receptor and possible action at N‐methyl‐D‐aspartate (NMDA) receptors (Hanaya 1998; White 2000; Zona 1997).
Why it is important to do this review
Some studies have found topiramate to be effective in people with JME. This review aims to evaluate the efficacy and tolerability of topiramate for people with JME.
Objectives
To evaluate the efficacy and tolerability of topiramate in the treatment of juvenile myoclonic epilepsy.
Methods
Criteria for considering studies for this review
Types of studies
We included randomized controlled trials (RCTs) of topiramate versus placebo or other antiepileptic drug (AED) treatment for people with juvenile myoclonic epilepsy (JME). We included randomized cross‐over studies in meta‐analyses using the results from paired analyses (Elbourne 2002).
Types of participants
Inclusion criteria
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People with a confirmed diagnosis of JME. Diagnostic criteria included myoclonic jerks and seizure onset in adolescence. We applied no limitation on age for enrolment.
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People with co‐existent primarily generalized tonic‐clonic seizures (PGTCS) with electroencephalogram (EEG)‐confirmed JME were also eligible.
Exclusion criteria
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Previous discontinuation of topiramate owing to an adverse event (AE)
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Co‐therapy with any other AED
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Use of an experimental medication or device within 30 days of study entry
Types of interventions
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Experimental intervention: topiramate (monotherapy and add‐on studies)
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Control intervention: placebo or other AED treatment (different control groups were separately analyzed)
Types of outcome measures
We collected and analyzed the outcomes of all the participants initially randomized by intention‐to‐treat (ITT).
Primary outcomes
Efficacy
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Proportion of responders (defined as at least 50% reduction in seizure frequency from baseline to end of treatment)
Secondary outcomes
Efficacy
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Number of participants who were seizure‐free
Tolerability
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Proportion of participants who experienced at least one AE
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Proportion of participants who experienced each individual AE, such as ataxia, dizziness, fatigue or nausea
Search methods for identification of studies
Electronic searches
Searches were run for the original review in July 2012 and subsequent searches were run on 2 November 2015, 21 February 2017, and 10 July 2018. For the latest update we searched the Cochrane Register of Studies (CRS Web) on 26 August 2021, and MEDLINE (Ovid; 1946 to 26 August 2021). See Appendix 1 and Appendix 2 for the respective search strategies.
CRS Web includes randomized or quasi‐randomized, controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups, including Cochrane Epilepsy.
Previously we also searched Embase (1 July 2015), using the search strategy set out in Appendix 3. It is no longer necessary to search Embase, because randomized and quasi‐randomized controlled trials from Embase are now included in CRS Web.
Searching other resources
We also:
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searched reference lists of articles obtained from any source;
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searched conference proceedings likely to contain trials relevant to the review;
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contacted researchers, pharmaceutical companies and relevant trial authors to seek information about unpublished or incomplete trials.
We did not impose any language restrictions on our searches, and we attempted to obtain translations of articles where necessary.
Data collection and analysis
Selection of studies
Two review authors (LJ, WL) independently evaluated titles and abstracts of identified trials to determine if they fulfilled the inclusion criteria. We obtained all potentially relevant studies for further consideration. We listed the excluded studies and reported the reasons for exclusion. We resolved any disagreements by discussion or by involving an independent party if necessary.
Data extraction and management
Two review authors (LJ, WL) independently extracted eligible data from the published reports onto standardized forms, and cross‐checked them for accuracy. We resolved disagreements regarding data extraction by discussion between the review authors.
We used checklists to record, independently, details of the following.
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Study design
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Total study duration
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Methods of generating randomization schedule
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Method of concealment of allocation
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Blinding
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Use of an ITT analysis (all participants initially randomized were included in the analyses as allocated to groups)
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AEs and dropouts for all reasons
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Participants (country, number of participants, age, gender, inclusion and exclusion criteria)
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Comparison (details of the intervention in treatment and control groups, details of co intervention(s) in both groups, duration of treatment)
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Outcomes and time points of measures (number of participants in each group and outcome, regardless of compliance)
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Factors for heterogeneity (sample size, missing participants, confidence interval (CI) and P value in measurement, subgroup analyses)
Assessment of risk of bias in included studies
Two review authors (LJ, WL) independently assessed the risk of bias for each trial using the Cochrane 'Risk of bias' tool, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We assessed six specific domains including: random sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other bias. We judged the result in each domain as low, high, or unclear risk of bias.
Measures of treatment effect
We tried to evaluate the data from all the participants initially randomized as far as practically possible. We expressed continuous outcomes as mean difference (MD) with 95% CI. For outcomes commonly reported dichotomously, such as the proportion of responders, we used risk ratio (RR) with 95% CI to express the effect size. If a trial (or group within a trial) reported no AEs or dropouts, we calculated the risk difference (RD) instead of RR, with 95% CI.
Unit of analysis issues
We dealt with any unit of analysis issues using the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011).
Dealing with missing data
We attempted to contact the principal investigator for further details if any data were missing. According to ITT analysis, all randomized participants were included. We planned to assign zero improvement of dichotomous outcomes for the withdrawals. We planned to consider different scenarios (best‐case and worst‐case) to account for missing data.
Assessment of heterogeneity
We planned to use the standard Chi² statistic and I² statistic (Higgins 2003) to measure heterogeneity (Deeks 2011), and make a judgement, along with visual inspection of forest plots. For the Chi² test, we would have rejected the hypothesis of tolerability if the P value was less than 0.10 and an I² greater than 50% would represent significant heterogeneity. In this case, we would have tried to explore factors for heterogeneity.
Assessment of reporting biases
We planned to assess the publication bias by funnel plot if we had found more than ten studies. However, we only included three studies in our review.
Data synthesis
If we found neither clinical nor statistical heterogeneity, we planned to pool results using a fixed‐effect model. We would have analyzed different controls separately. For statistical heterogeneity, we planned to incorporate the results into a random‐effects model. For heterogeneity that could not be readily explained, we would not have pooled the data but only given a description of the results.
Subgroup analysis and investigation of heterogeneity
We did not perform subgroup analyses due to the limited available data. We planned to analyze subgroups of studies categorized according to different doses and durations of topiramate. As a formal method of comparing subgroups, we planned to use the Chi² test (to test for significant differences between subgroups of participants). For all statistical analyses, we used Review Manager 5 (Review Manager 2014).
Sensitivity analysis
We were unable to perform any sensitivity analyses due to the limited available data. We planned to use best‐case and worst‐case scenarios for taking into account missing data. We also planned to undertake the following sensitivity analyses to investigate unexplained heterogeneity and to test the robustness of results.
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Exclusion of cross‐over trials from the analysis
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Exclusion studies at high risk of bias, with inadequate allocation concealment or lack of blinded outcome assessor
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Comparison of fixed‐effect versus random‐effects models
Summary of findings and assessment of the certainty of the evidence
We have presented two 'Summary of findings' tables; one for each comparison (summary of findings Table 1; summary of findings Table 2). We reported all outcomes in the tables but made a general statement about the summary of findings for individual adverse events and graded the evidence based on consideration of the evidence of all of the adverse events (Schünemann 2011).
We determined the certainty of the evidence using the GRADE approach and downgraded evidence due to the presence of high risk of bias in at least one study, indirectness of the evidence, unexplained heterogeneity or inconsistency, imprecision of results, high probability of publication bias. We downgraded evidence by one level if we considered the limitation to be serious and by two levels if very serious (Schünemann 2013).
Results
Description of studies
Results of the search
The previous version of this review included three studies. On re‐running the searches on 26 August 2021, we identified 29 papers after de‐duplicating the results (Figure 1). After screening the titles and abstracts, we obtained the full papers of four studies and assessed them for eligibility. Three of these studies were already included in the previous version of the review; we excluded the remaining study because it was non‐randomized. There were no ongoing randomized controlled trials (RCTs).
Study flow diagram
Included studies
Three randomized studies with a total of 83 participants met the inclusion criteria.
One study enrolled 22 people with juvenile myoclonic epilepsy (JME) and evaluated the efficacy and tolerability of topiramate versus placebo (Biton 2005). The starting dose of topiramate 50 mg/day or equivalent placebo tablets was maintained for four weeks, then increased at two‐week intervals to target dosages of 400 mg/day in adults or 6 mg/kg/day in children. Treatment was continued for an additional 12 weeks.
Two studies focused on the efficacy and tolerability of topiramate versus valproate in people with JME (Levisohn 2007; Park 2013). Levisohn 2007 is a pilot study, in which 28 participants were assigned at a 2:1 ratio to topiramate (19 participants) or valproate (9 participants) for 26 weeks. The topiramate target dosage was 3 mg/kg/day to 4 mg/kg/day (maximum 9 mg/kg/day) for participants aged 12 to 16 years, and 200 mg/day (maximum 600 mg/day) for participants aged over 16 years. Valproate target dosages were 10 mg/kg/day in participants aged 12 to 16 years (overall maximum 60 mg/kg/day) and 750 mg/day in participants aged over 16 years. Medications were titrated at one‐ to two‐week intervals according to clinical response, and were administered in divided doses.
In Park 2013, 33 participants were assigned at a 1:1 ratio to topiramate (16 participants) or valproate (17 participants) for 32 weeks. The assigned antiepileptic drug (AED) was titrated up to 1200 mg/day for valproate or 100 mg/day for topiramate. The dose of valproate was titrated up 300 mg/day for two weeks, whereas topiramate was increased by 25 mg/day for two weeks. In participants with a poor response to medication during the 24‐week maintenance phase, the dose of valproate was increased 300 mg/day for one month to a maximum dose of 2400 mg/day, and the dose of topiramate was increased 50 mg/day for one month to a maximum 300 mg/day. Further details of the included studies are provided in the Characteristics of included studies table.
Excluded studies
We excluded one study after full‐text evaluation (Sousa 2005). The reason for exclusion was due to the non‐randomized design (see Characteristics of excluded studies table).
Risk of bias in included studies
All three included studies were subject to an assessment of bias. The information regarding risk of bias is provided in Figure 2 and Figure 3.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Allocation
All three included studies reported the method of random sequence generation and we assessed them as being at low risk of bias. However, only one study described the details of allocation concealment (Levisohn 2007). Where studies provided no information on allocation concealment, we assessed them as being at unclear risk of bias.
Blinding
Two studies were double‐blind RCTs with low risk of bias (Biton 2005; Levisohn 2007). One study was open‐label, without information of blinding; we evaluated the study as being at high risk of bias for this domain (Park 2013).
Incomplete outcome data
All three studies had incomplete outcome data. The proportion of participants who discontinued was more than 10% in all the studies. Therefore, we assessed all three studies as being at high risk of attrition bias.
Selective reporting
We intended to use the table of 'Outcome Reporting Bias In Trials' (ORBIT) to evaluate selective outcome reporting (Kirkham 2010). However, the reporting bias could not be assessed as none of pre‐published protocols were available.
Other potential sources of bias
We found no other potential sources of bias. Insufficient numbers of trials were available for a funnel plot analysis.
Effects of interventions
See: Summary of findings 1 Topiramate compared with placebo for juvenile myoclonic epilepsy; Summary of findings 2 Topiramate compared with valproate for juvenile myoclonic epilepsy
Topiramate versus placebo
Efficacy
Proportion of responders (at least 50% reduction in seizure frequency)
In Biton 2005, significantly more participants taking topiramate responded with a 50% or more reduction in primarily generalized tonic‐clonic seizures (PGTCS) compared with placebo (73% with topiramate versus 18% with placebo; risk ratio (RR) 4.00, 95% confidence interval (CI) 1.08 to 14.75, P = 0.04) (Analysis 1.1). The median PGTCS reduction after 20 weeks was 64% in the topiramate group and 38% in the placebo group, which was not significantly different.
Three participants taking topiramate had no PGTCS and one had no myoclonic seizures, and two participants taking placebo had no PGTCS. Seizure frequency increased more than 50% from baseline was found in five participants taking placebo and two participants taking topiramate.
Number of participants who were seizure‐free
Not reported.
Tolerability
Proportion of participants who experienced at least one adverse event
Not reported.
Proportion of participants who experienced each individual adverse event
In Biton 2005, we found no significant difference between topiramate and placebo for the AEs of nausea (Analysis 1.2), upper respiratory tract infection (Analysis 1.3), abnormal vision (Analysis 1.4), or diarrhoea (Analysis 1.5).
Topiramate versus valproate
Efficacy
Proportion of responders (at least 50% reduction in seizure frequency)
Myoclonic seizures
In Levisohn 2007, using intention‐to‐treat (ITT) analysis, there was no significant difference between groups (85% with topiramate versus 100% with valproate, RR 0.88, 95% CI 0.67 to 1.15) (Analysis 2.1).
Primarily generalized tonic‐clonic seizures
There was no significant difference between groups (91% with topiramate versus 75% with valproate, RR 1.22, 95% CI 0.68 to 2.21) (Analysis 2.2).
Number of participants who were seizure‐free
For Park 2013, 11/16 (68.9%) participants in the topiramate group completed 24‐week maintenance therapy, in which 7/11 (64%) were seizure‐free. Meanwhile 16/17 (94.1%) participants in the valproate group completed 24‐week follow‐up, in which 9/16 (56%) were seizure‐free. This was not significantly different (RR 1.13, 95% CI 0.61 to 2.11) (Analysis 2.3).
In Levisohn 2007, eight out of 12 participants (67%) in the topiramate group and four out of seven participants (57%) in the valproate group had no seizures during the 12‐week maintenance period.
Tolerability
Proportion of participants who experienced at least one adverse event
None of the studies reported the number of participants who experienced at least one adverse event (AE).
Proportion of participants who experienced each individual adverse event
In Levisohn 2007 and Park 2013, we found significantly more events of paresthesia with topiramate (Analysis 2.4), and more events of weight gain (Analysis 2.5) and tremor with valproate (Analysis 2.6). There was no significant difference between groups for the AEs of headache (Analysis 2.7), concentration difficulty (Analysis 2.8), fatigue (Analysis 2.9), alopecia (Analysis 2.10), dizziness (Analysis 2.11), weight loss (Analysis 2.12), psychomotor slowing (Analysis 2.13), somnolence (Analysis 2.14), nausea (Analysis 2.15), appetite increase (Analysis 2.16), insomnia (Analysis 2.17), abnormal vision (Analysis 2.18), rash (Analysis 2.19), anorexia (Analysis 2.20), hallucination (Analysis 2.21) or diarrhea (Analysis 2.22).
In Levisohn 2007, systemic toxicity scores were higher in participants taking valproate at each evaluation (at four, eight, 14 and 26 weeks). Neurotoxicity scores did not substantially differ between treatment groups.
Discussion
Summary of main results
For efficacy, there were significantly more participants in the topiramate group with a 50% or greater reduction in primarily generalized tonic‐clonic seizures (PGTCS) than in the placebo group, however this was based on only 22 randomized participants (Biton 2005). There were no significant differences between topiramate and valproate in participants who responded with a 50% or greater reduction in myoclonic seizures or in PGTCS (28 randomized participants) (Levisohn 2007), or who were seizure‐free (33 randomized participants) (Park 2013).
Concerning tolerability, 23 adverse events (AEs) occurred in 11 participants taking topiramate, and seven AEs occurred in 11 participants taking placebo (Biton 2005). AEs associated with topiramate were ranked as moderate to severe, while 59% of AEs linked to valproate were ranked as severe complaints (Park 2013). Moreover, systemic toxicity scores were higher in the valproate group than in the topiramate group (Levisohn 2007).
Overall completeness and applicability of evidence
The evidence for topiramate in the treatment of juvenile myoclonic epilepsy (JME) was insufficient. Because of the limited number of included studies and substantial heterogeneity in comparison (different controls) and outcomes design, meta‐analysis was not applicable in the majority of cases. We found high risk of bias for incomplete outcome data in all the three randomized controlled trials (RCTs). Furthermore, the sample size of randomized participants was too small to reach a robust conclusion. For the comparison of topiramate versus placebo, 22 participants were randomized, while there were 61 participants randomized in the comparison of topiramate versus valproate. Therefore, studies of high quality and with large samples are required to strengthen the applicability of evidence.
Quality of the evidence
We found limitations in the methodology of all the included studies. Two RCTs did not provide any information on allocation concealment, therefore we assessed them as having unclear risk of bias (Biton 2005; Park 2013). One RCT was not of double‐blind design and so had high risk of bias in terms of blinding (Park 2013). All three RCTs had a high risk of attrition bias (Biton 2005; Levisohn 2007; Park 2013). We could not assess reporting bias as none of the pre‐published protocols were available. We regard the quality of evidence to be very low and so the limited findings should be interpreted with caution.
Potential biases in the review process
The search for trials was rigorously performed based on the strategies in different electronic databases. To identify unpublished or incomplete trials, we also searched for protocols, but found no eligible studies. In addition, due to the inclusion of only three RCTs, we could not assess publication bias using funnel plots. Therefore, we could not exclude the possibility that we did not identify unpublished trials.
Agreements and disagreements with other studies or reviews
There is still lack of peer systematic reviews on the treatment of topiramate for JME. However, the recent review on the treatment of JME in patients of child‐bearing potential believed that valproate remained an essential and life‐changing agent in patients with JME (Serafini 2019).
Study flow diagram
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Comparison 1: Topiramate versus placebo, Outcome 1: Proportion of responders (at least 50% seizure frequency reduction in PGTCS)
Comparison 1: Topiramate versus placebo, Outcome 2: Nausea
Comparison 1: Topiramate versus placebo, Outcome 3: Upper respiratory tract infection
Comparison 1: Topiramate versus placebo, Outcome 4: Abnormal vision
Comparison 1: Topiramate versus placebo, Outcome 5: Diarrhea
Comparison 2: Topiramate versus valproate, Outcome 1: Proportion of responders (at least 50% seizure frequency reduction in myoclonic seizures)
Comparison 2: Topiramate versus valproate, Outcome 2: Proportion of responders (at least 50% seizure frequency reduction in PGTCS)
Comparison 2: Topiramate versus valproate, Outcome 3: Number of participants who were seizure‐free
Comparison 2: Topiramate versus valproate, Outcome 4: Paresthesia
Comparison 2: Topiramate versus valproate, Outcome 5: Weight gain
Comparison 2: Topiramate versus valproate, Outcome 6: Tremor
Comparison 2: Topiramate versus valproate, Outcome 7: Headache
Comparison 2: Topiramate versus valproate, Outcome 8: Concentration difficulty
Comparison 2: Topiramate versus valproate, Outcome 9: Fatigue
Comparison 2: Topiramate versus valproate, Outcome 10: Alopecia
Comparison 2: Topiramate versus valproate, Outcome 11: Dizziness
Comparison 2: Topiramate versus valproate, Outcome 12: Weight loss
Comparison 2: Topiramate versus valproate, Outcome 13: Psychomotor slowing
Comparison 2: Topiramate versus valproate, Outcome 14: Somnolence
Comparison 2: Topiramate versus valproate, Outcome 15: Nausea
Comparison 2: Topiramate versus valproate, Outcome 16: Appetite increase
Comparison 2: Topiramate versus valproate, Outcome 17: Insomnia
Comparison 2: Topiramate versus valproate, Outcome 18: Abnormal vision
Comparison 2: Topiramate versus valproate, Outcome 19: Rash
Comparison 2: Topiramate versus valproate, Outcome 20: Anorexia
Comparison 2: Topiramate versus valproate, Outcome 21: Hallucination
Comparison 2: Topiramate versus valproate, Outcome 22: Diarrhea
| Topiramate compared with placebo for juvenile myoclonic epilepsy | ||||||
| Patient or population: people with juvenile myoclonic epilepsy Settings: 18 centers in the USA; 10 centers in Europe; 1 center in Costa Rica Intervention: topiramate Comparison: placebo | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo | Topiramate | |||||
| Proportion of responders (at least 50% seizure frequency reduction in PGTCS) | 182 per 1000 | 727 per 1000 (197 to 1000) | RR 4.00 (1.08 to 14.75) | 22 (1 study) | ⊕⊝⊝⊝ | More participants taking topiramate responded with a 50% or greater reduction in PGTCS compared with placebo (P = 0.04) |
| Proportion of participants who experienced at least one AE and individual AEs | See comment | See comment | N/A | 22 (1 study) | ⊕⊝⊝⊝ | The number of participants experiencing at least one AE was not reported. Individual AEs: no significant differences were found in nausea, URTI, abnormal vision, or diarrhea between topiramate and placebo |
| Number of participants who were seizure‐free | Not reported | Not reported | N/A |
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| *The basis for the assumed risk was the event rate in the control group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect | ||||||
| 1 The included trials were reported as randomized, double‐blind trials, however the methodological information was insufficient. | ||||||
| Topiramate compared with valproate for juvenile myoclonic epilepsy | ||||||
| Patient or population: people with juvenile myoclonic epilepsy Settings: Cincinnati Children’s Hospital Medical Center, Cincinnati, USA; Haeundae Paik Hospital, Busan, Republic of Korea Intervention: topiramate Comparison: valproate | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Valproate | Topiramate | |||||
| Proportion of responders (at least 50% seizure frequency reduction in myoclonic seizures) | 1000 per 1000 | 857 per 1000 (670 to 1000) | RR 0.88 (0.67 to 1.15) | 23 | ⊕⊝⊝⊝ | No significant difference was found. |
| Proportion of responders (at least 50% seizure frequency reduction in PGTCS) | 750 per 1000 | 917 per 1000 (510 to 1000) | RR 1.22 (0.68 to 2.21) | 16 (1 study) | ⊕⊝⊝⊝ | No significant difference was found. |
| Proportion of participants who experienced at least one AE and individual AEs | See comment | See comment | NA | 61 | ⊕⊝⊝⊝ | The number of participants experiencing at least one AE was not reported. We found significantly more events of paresthesia with topiramate, and more events of weight gain and tremor with valproate. There was no significant difference between groups for headache, concentration difficulty, fatigue, alopecia, dizziness, weight loss, psychomotor slowing, somnolence, nausea, appetite increase, insomnia, abnormal vision, rash, anorexia, hallucination or diarrhea. |
| Number of participants who were seizure‐free | 563 per 1000 | 636 per 1000 (343 to 1188) | RR 1.13 (0.61 to 2.11) | 27 | ⊕⊝⊝⊝ | No significant difference was found. |
| *The basis for the assumed risk was the event rate in the control group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect | ||||||
| 1 The included trials were reported as randomized, double‐blind trials, however the methodological information was insufficient. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Proportion of responders (at least 50% seizure frequency reduction in PGTCS) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.2 Nausea Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.3 Upper respiratory tract infection Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.4 Abnormal vision Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.5 Diarrhea Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Proportion of responders (at least 50% seizure frequency reduction in myoclonic seizures) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.2 Proportion of responders (at least 50% seizure frequency reduction in PGTCS) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.3 Number of participants who were seizure‐free Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.4 Paresthesia Show forest plot | 2 | 61 | Risk Difference (M‐H, Fixed, 95% CI) | 0.19 [0.02, 0.35] |
| 2.5 Weight gain Show forest plot | 2 | 61 | Risk Difference (M‐H, Fixed, 95% CI) | ‐0.30 [‐0.49, ‐0.10] |
| 2.6 Tremor Show forest plot | 1 | Risk Difference (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.7 Headache Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.8 Concentration difficulty Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.9 Fatigue Show forest plot | 2 | 61 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.17, 2.21] |
| 2.10 Alopecia Show forest plot | 2 | 61 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.24 [0.06, 1.02] |
| 2.11 Dizziness Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.12 Weight loss Show forest plot | 1 | Risk Difference (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.13 Psychomotor slowing Show forest plot | 1 | Risk Difference (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.14 Somnolence Show forest plot | 2 | 61 | Risk Difference (M‐H, Fixed, 95% CI) | 0.08 [‐0.05, 0.21] |
| 2.15 Nausea Show forest plot | 2 | 61 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.21 [0.04, 1.18] |
| 2.16 Appetite increase Show forest plot | 1 | Risk Difference (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.17 Insomnia Show forest plot | 1 | Risk Difference (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.18 Abnormal vision Show forest plot | 1 | Risk Difference (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.19 Rash Show forest plot | 1 | Risk Difference (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.20 Anorexia Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.21 Hallucination Show forest plot | 1 | Risk Difference (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.22 Diarrhea Show forest plot | 1 | Risk Difference (M‐H, Fixed, 95% CI) | Totals not selected | |
