Abstract：
OBJECTIVE: To qualitatively and quantitatively summarize the evidence for the use of onabotulinumtoxinA injections in children and adolescents with migraine.
BACKGROUND: There are limited evidence-based treatment options for youth with migraine, especially youth with chronic migraine (CM). OnabotulinumtoxinA injections are an established evidence-based treatment for adults with CM. While several studies have assessed their safety and efficacy among adolescents with CM, there are no published systematic reviews summarizing the pediatric evidence.
METHODS: We carried out a systematic review, reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis, aiming to identify studies that included five or more children and adolescents aged ≤18 years with a diagnosis of migraine, who were treated with ≥50 units (U) of onabotulinumtoxinA and had outcomes assessed ≥4 weeks after one or more injection cycle. Both observational studies and randomized controlled trials (RCTs) were eligible for inclusion. Two investigators independently carried out the first (titles and abstracts) and second (full text) screening stages, as well as data extraction and quality appraisal. The American Academy of Neurology risk of bias grading scheme was used to assess study risk of bias. Studies with adequate data were pooled using random effects meta-analyses, and Hedge\'s g standardized mean differences with 95% confidence intervals (CIs) were generated to estimate the effect sizes of the continuous outcomes included. Studies lacking data required for meta-analysis were summarized qualitatively.
RESULTS: We screened 634 studies and included 14 studies comprising 491 participants, of whom 489 had CM. Two studies were RCTs, 12 were observational uncontrolled studies, and all but one study included only youth with CM. Five Class IV observational uncontrolled studies were amenable to pooling in meta-analyses. After a mean of 2-2.6 injection cycles, headache frequency was shown to decrease significantly after treatment with onabotulinumtoxinA (Hedge\'s g = 0.97, 95% CI 0.58-1.35; p < 0.0001), as did severity (Hedge\'s g = 1.24, 95% CI 0.55-1.94; p = 0.0005), with both estimates having a large effect size magnitude. A Class I parallel-group RCT of one injection series (155 U, 74 U, or placebo), powered to detect a change in 4 headache days per month, did not find outcome differences between the active and placebo treatment arms. A Class IV crossover RCT showed superiority of active (155 U) versus placebo injections. The remaining Class IV observational studies that were excluded from the meta-analyses all showed improved outcomes with onabotulinumtoxinA injections over time. No serious adverse events related to treatment occurred.
CONCLUSIONS: OnabotulinumtoxinA injections have established safety for use in children and adolescents with CM and are likely effective in reducing headache frequency and severity over time. However, in the absence of an adequately powered parallel-group RCT assessing the efficacy of multiple injection cycles, it remains unclear if this intervention is superior to placebo.
BACKGROUND: There are limited evidence-based treatment options for youth with migraine, especially youth with chronic migraine (CM). OnabotulinumtoxinA injections are an established evidence-based treatment for adults with CM. While several studies have assessed their safety and efficacy among adolescents with CM, there are no published systematic reviews summarizing the pediatric evidence.
METHODS: We carried out a systematic review, reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis, aiming to identify studies that included five or more children and adolescents aged ≤18 years with a diagnosis of migraine, who were treated with ≥50 units (U) of onabotulinumtoxinA and had outcomes assessed ≥4 weeks after one or more injection cycle. Both observational studies and randomized controlled trials (RCTs) were eligible for inclusion. Two investigators independently carried out the first (titles and abstracts) and second (full text) screening stages, as well as data extraction and quality appraisal. The American Academy of Neurology risk of bias grading scheme was used to assess study risk of bias. Studies with adequate data were pooled using random effects meta-analyses, and Hedge\'s g standardized mean differences with 95% confidence intervals (CIs) were generated to estimate the effect sizes of the continuous outcomes included. Studies lacking data required for meta-analysis were summarized qualitatively.
RESULTS: We screened 634 studies and included 14 studies comprising 491 participants, of whom 489 had CM. Two studies were RCTs, 12 were observational uncontrolled studies, and all but one study included only youth with CM. Five Class IV observational uncontrolled studies were amenable to pooling in meta-analyses. After a mean of 2-2.6 injection cycles, headache frequency was shown to decrease significantly after treatment with onabotulinumtoxinA (Hedge\'s g = 0.97, 95% CI 0.58-1.35; p < 0.0001), as did severity (Hedge\'s g = 1.24, 95% CI 0.55-1.94; p = 0.0005), with both estimates having a large effect size magnitude. A Class I parallel-group RCT of one injection series (155 U, 74 U, or placebo), powered to detect a change in 4 headache days per month, did not find outcome differences between the active and placebo treatment arms. A Class IV crossover RCT showed superiority of active (155 U) versus placebo injections. The remaining Class IV observational studies that were excluded from the meta-analyses all showed improved outcomes with onabotulinumtoxinA injections over time. No serious adverse events related to treatment occurred.
CONCLUSIONS: OnabotulinumtoxinA injections have established safety for use in children and adolescents with CM and are likely effective in reducing headache frequency and severity over time. However, in the absence of an adequately powered parallel-group RCT assessing the efficacy of multiple injection cycles, it remains unclear if this intervention is superior to placebo.
摘要：
目的：定性和定量地总结儿童和青少年偏头痛患者使用促性腺激素A注射的证据。
背景：青少年偏头痛的循证治疗方案有限，尤其是青年慢性偏头痛（CM）。对成人CM患者注射OnabotulinumtoxinA是一种基于证据的治疗方法。虽然一些研究已经评估了其在患有CM的青少年中的安全性和有效性，没有发表的系统评价总结儿科证据.
方法：我们进行了系统评价，根据系统评价和荟萃分析的首选报告项目报告，旨在确定包括五名或更多年龄≤18岁的儿童和青少年诊断为偏头痛的研究，患者接受≥50单位(U)的单纯碱毒素A治疗,并在一个或多个注射周期后≥4周评估结局.观察性研究和随机对照试验（RCT）均符合纳入条件。两名调查员独立进行了第一阶段（标题和摘要）和第二阶段（全文）筛选，以及数据提取和质量评估。采用美国神经病学会偏倚风险分级方案评估研究偏倚风险。有足够数据的研究使用随机效应荟萃分析进行汇总，生成Hedge的g标准化平均差和95%置信区间(CI),以估计包括的连续结局的效应大小.对缺乏荟萃分析所需数据的研究进行了定性总结。
结果：我们筛选了634项研究，包括14项研究，包括491名参与者。其中489有CM。两项研究是随机对照试验，12是观察性对照研究，除一项研究外，所有研究仅包括患有CM的年轻人。五项IV类观察性对照研究适合于荟萃分析。在平均2-2.6次注射循环后，显示头痛频率在用甲硝胺醇毒素A治疗后显著降低(Hedge\sg=0.97,95%CI0.58-1.35;p<0.0001),严重程度也是如此(对冲g=1.24，95%CI0.55-1.94；p=0.0005)，这两个估计都有很大的影响大小。一个喷射系列的I类并联组RCT(155U，74U,或安慰剂)，在每月4天的头痛中检测到变化，没有发现活性和安慰剂治疗组之间的结局差异.IV类交叉RCT显示活性（155U）相对于安慰剂注射的优越性。从荟萃分析中排除的其余IV类观察性研究均显示，随着时间的推移，注射单纯碱内毒素A的结果有所改善。未发生与治疗相关的严重不良事件。
结论：在患有CM的儿童和青少年患者中注射OnabotulinumtoxinA已经确定了安全性，并且随着时间的推移可能有效减少头痛频率和严重程度。然而,在没有足够动力的平行组RCT评估多个注射周期的疗效的情况下，目前尚不清楚这种干预是否优于安慰剂.
背景：青少年偏头痛的循证治疗方案有限，尤其是青年慢性偏头痛（CM）。对成人CM患者注射OnabotulinumtoxinA是一种基于证据的治疗方法。虽然一些研究已经评估了其在患有CM的青少年中的安全性和有效性，没有发表的系统评价总结儿科证据.
方法：我们进行了系统评价，根据系统评价和荟萃分析的首选报告项目报告，旨在确定包括五名或更多年龄≤18岁的儿童和青少年诊断为偏头痛的研究，患者接受≥50单位(U)的单纯碱毒素A治疗,并在一个或多个注射周期后≥4周评估结局.观察性研究和随机对照试验（RCT）均符合纳入条件。两名调查员独立进行了第一阶段（标题和摘要）和第二阶段（全文）筛选，以及数据提取和质量评估。采用美国神经病学会偏倚风险分级方案评估研究偏倚风险。有足够数据的研究使用随机效应荟萃分析进行汇总，生成Hedge的g标准化平均差和95%置信区间(CI),以估计包括的连续结局的效应大小.对缺乏荟萃分析所需数据的研究进行了定性总结。
结果：我们筛选了634项研究，包括14项研究，包括491名参与者。其中489有CM。两项研究是随机对照试验，12是观察性对照研究，除一项研究外，所有研究仅包括患有CM的年轻人。五项IV类观察性对照研究适合于荟萃分析。在平均2-2.6次注射循环后，显示头痛频率在用甲硝胺醇毒素A治疗后显著降低(Hedge\sg=0.97,95%CI0.58-1.35;p<0.0001),严重程度也是如此(对冲g=1.24，95%CI0.55-1.94；p=0.0005)，这两个估计都有很大的影响大小。一个喷射系列的I类并联组RCT(155U，74U,或安慰剂)，在每月4天的头痛中检测到变化，没有发现活性和安慰剂治疗组之间的结局差异.IV类交叉RCT显示活性（155U）相对于安慰剂注射的优越性。从荟萃分析中排除的其余IV类观察性研究均显示，随着时间的推移，注射单纯碱内毒素A的结果有所改善。未发生与治疗相关的严重不良事件。
结论：在患有CM的儿童和青少年患者中注射OnabotulinumtoxinA已经确定了安全性，并且随着时间的推移可能有效减少头痛频率和严重程度。然而,在没有足够动力的平行组RCT评估多个注射周期的疗效的情况下，目前尚不清楚这种干预是否优于安慰剂.
