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.

Migraine is a leading cause of disability worldwide, yet it remains underrecognized and undertreated, especially in the pediatric and adolescent population. Chronic migraine occurs approximately in 1% of children and adolescents requiring preventive treatment. Topiramate is the only FDA-approved preventative treatment for children older than 12 years of age, but there is conflicting evidence regarding its efficacy. OnabotulinumtoxinA is a known and approved treatment for the management of chronic migraine in people older than 18 years. Several studies examine its role in the pediatric population with positive results; however, the clear-cut benefit is still unclear. OnabotulinumtoxinA seems not only to improve disability scores (PedMIDAS) but also to improve the quality, characteristics, and frequency of migraines in the said population. This systematic review aims to summarize the evidence on the efficacy, dosing, administration, long-term outcomes, and safety of onabotulinumtoxinA in pediatric and adolescent migraine. Eighteen studies met the eligibility criteria and were included in this review. The mean monthly migraine days (MMDs), decreased from of 21.2 days per month to 10.7 after treatment. The reported treatment-related adverse effects were mild and primarily injection site related and ranged from 0% to 47.0%. Thus, this review provides compelling evidence suggesting that OnabotulinumtoxinA may represent a safe and effective preventive treatment option for pediatric migraine.

BACKGROUND: Chronic migraine (CM) significantly impacts both the physical and mental health of patients. Current studies on the safety and effectiveness of different pharmacological prophylaxis interventions for CM are limited. To address this gap, we conducted a network meta-analysis (NMA) to compare and rank the efficacy and safety of various drugs in preventing CM.
METHODS: Two independent researchers systematically searched four databases from their inception to August 1, 2023, to identify eligible randomized controlled trials (RCTs). Subsequently, they performed data extraction and assessed the risk of bias. A NMA was then performed. Continuous outcomes and binary outcomes were displayed as weighted mean difference (WMD) and risk ratio (RR), respectively, and corresponding 95% confidence intervals (CI) were reported. The surface under the cumulative ranking curve (SUCRA) was used to rank each intervention separately.
RESULTS: 24 RCTs involving 8789 patients were included. Compared to placebo, Botulinum toxin A demonstrated the most significant effect in reducing the monthly migraine days for CM patients (MD = 3.88, 95% CI 0.48, 7.28); in terms of improving the response rate by a 50% reduction in monthly migraine days, Topiramate (RR = 50.06, 95% CI 3.18, 787.30) was the most effective; there was no statistically significant difference between all preventive drugs and placebo in improving the migraine disability assessment (MIDAS) score; in terms of the incidence of adverse events, Eptinezumab (RR = 1.09, 95% CI 0.8, 1.54) exhibited the highest safety profile.
CONCLUSIONS: Among all the drugs for the preventive drugs for CM, Botulinum toxin A has the best efficacy and safety profile, closely followed by calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs).

OBJECTIVE: Chronic headaches are a significant source of disability worldwide. Despite the development of conventional strategies, a subset of patients remain refractory and/or experience side effects following these treatments. Hence, occipital nerve stimulation (ONS) should be considered as an alternative strategy for intractable chronic headaches. This review aims to provide a comprehensive overview of the effectiveness, safety, mechanisms and practical application of ONS for the treatment of headache disorders.
RESULTS: Overall response rate of ONS is 35.7-100%, 17-100%, and 63-100% in patients with cluster headache, chronic migraine and occipital neuralgia respectively. Regarding the long-term effectivity in all groups, 41.6-88.0% of patients remain responders after ≥ 18.3 months. The most frequently reported adverse events include lead migration/fracture (13%) and local pain (7.3%). Based on our results, ONS can be considered a safe and effective treatment for chronic intractable headache disorders. To support more widespread application of ONS, additional research with larger sample sizes should be conducted.

Medication-overuse headache (MOH), which potentially involves 1-2% of the population, is defined as a headache, on ≥ 15 days a month affected, along with overuse of one or other acute attack medications. MOH presents with significant challenges in the headache community, particularly in clinical settings raising various questions about its pathophysiology. Through a review of the current literature and our clinical experience, we have explored the mechanisms through which MOH may occur, provide an understanding of the current state of treatment and detail some possible views on the understanding and treatment of this condition. We evaluate the variations in treatment methods offered globally and understanding of the disorder. Above all interventions, patient education is crucial, which is underscored by an analysis of the academic publications. Given the condition is preventable, early intervention is imperative and patient awareness is highlighted as key. Globally, there is no uniform treatment methodology, which may be advantageous as approaches need to take local circumstances into account.

OBJECTIVE: This review aimed to investigate emerging evidence regarding the effectiveness of exercise for migraines, focusing on the results of recent trials. Additionally, it explored the possibility of exercise as a treatment for migraines.
RESULTS: Between 2020 and 2023, five, four, one, and two trials were conducted regarding the effect of aerobic exercise, anaerobic exercise, Tai Chi, and yoga, respectively, on migraine; all studies showed significant effects. Two trials on aerobic exercise showed that high-intensity exercise was similar to or slightly more effective than moderate-intensity exercise as a treatment for migraines. Three trials on anaerobic exercise reported its effectiveness in preventing migraines. Regarding efficacy, side effects, and health benefits, aerobic exercises and yoga are potentially beneficial strategies for the prevention of migraines. Further studies are needed to develop evidence-based exercise programs for the treatment of migraines.

BACKGROUND: Despite recent advancements in migraine treatment, some patients continue to endure significant disease burden. Due to the controlled nature of randomized trials in migraine prevention, many real-world patients with comorbidities or prior exposure to certain therapies are excluded. Capturing evidence of the effectiveness of treatment in real-world clinical settings can further shape treatment paradigms. The objective of this study was to develop a comprehensive understanding of both patients\' and physicians\' real-world experiences with eptinezumab for chronic migraine (CM).
METHODS: REVIEW (Real-world EVidence and Insights into Experiences With eptinezumab) is an observational, multi-site (n = 4), US-based study designed to evaluate real-world experiences of patients treated with eptinezumab and their treating physicians. Patients were ≥ 18 years of age, with a diagnosis of CM, who had completed ≥ 2 consecutive eptinezumab infusion cycles (≥ 6 months of exposure). The study included a retrospective chart review, a patient survey, and a semi-structured physician interview that assessed patient and/or physician satisfaction with elements of daily living / well-being, migraine symptomology, and perspectives of the eptinezumab infusion experience.
RESULTS: Of the 94 patients enrolled, 83% (78/94) were female, the mean age was 49.2 years, and the mean time since migraine diagnosis was 15.4 years. Before eptinezumab treatment, patients experienced a mean of 8 self-reported \"good\" days/month, which increased to 18 after treatment. Most patients took, on average, ≥ 10 days/month of prescription and/or over-the-counter medication (81% [75/93] and 66% [61/93], respectively) to treat migraine attacks before eptinezumab treatment, which dropped to 26% (24/93) and 23% (21/93) following eptinezumab treatment. Prior to receiving eptinezumab, 62% (58/93) of patients indicated being at least slightly concerned about infusions; after eptinezumab infusion, this dropped to 14% (13/93). These patient survey findings were consistent with physician responses.
CONCLUSIONS: This real-world evidence study demonstrated high overall satisfaction with the effectiveness of eptinezumab treatment for CM among most patients and their physicians.

OBJECTIVE: We conducted a systematic review and meta-analysis to explore the relationship between blood pituitary adenylate cyclase-activating polypeptide (PACAP) levels and migraine.
BACKGROUND: PACAP is involved in the onset of migraine, but the results from clinical studies on PACAP level variations across different periods of migraine are conflicting.
METHODS: We systematically searched for observational studies that reported PACAP levels in people with migraine and non-migraine controls published in English from the PubMed, Web of Science, and Ovid electronic databases, or in Chinese from the Chinese National Knowledge Infrastructure and the WanFang Med database. The Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of the included studies. The quality of evidence for each outcome was assessed according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidelines.
RESULTS: Of the 514 identified studies, 8 were eligible for inclusion. There was a \"very low\" level of evidence suggesting that the PACAP level is negatively correlated with migraine disease duration in adults with migraine (summary r = -0.35, 95% confidence interval [CI] -0.49 to -0.22) and that the PACAP is higher in people with migraine during the ictal period than in the interictal period (standardized mean difference = 0.41, 95% CI 0.17 to 0.66) for both adults and children with migraine. Adult patients with episodic migraine (weighted mean difference [WMD] = -9.58 pg/mL, 95% CI -13.41 to -5.75 pg/mL) or chronic migraine (WMD = -10.93 pg/mL, 95% CI -15.57 to -6.29 pg/mL) had lower blood PACAP levels than non-migraine controls during the interictal period, supported by a \"low\" or \"very low\" quality of evidence, respectively, according to the GRADE rules.
CONCLUSIONS: There is a very low certainty of evidence suggesting that the PACAP level is negatively correlated with migraine disease duration of adults with migraine and it varies greatly among different periods of migraine of both adults and children with migraine.

BACKGROUND: Chronic migraine is a highly debilitating condition that is often difficult to manage, particularly in the presence of medication overuse headache. Drugs targeting the calcitonin gene-related peptide (CGRP), or its receptor have shown promising results in treating this disorder.
METHODS: We searched Pubmed and Embase to identify randomized clinical trials and real-world studies reporting on the use of medication targeting the calcitonin gene-related peptide in patients with chronic migraine.
RESULTS: A total of 270 records were identified. Nineteen studies qualified for the qualitative analysis. Most studies reported on monoclonal antibodies targeting CGRP (anti-CGRP mAbs), that overall prove to be effective in decreasing monthly migraine days by half in about 27.6-61.4% of the patients. Conversion from chronic to episodic migraine was seen in 40.88% of the cases, and 29-88% of the patients stopped medication overuse. Obesity seems to be the main negative predictor of response to anti-CGRP mAbs. There is no evidence to suggest the superiority of one anti-CGRP mAb. Despite the lack of strong evidence, the combination of anti-CGRP medication with onabotulinumtoxinA in chronic migraine is likely to bring benefits for resistant cases. Atogepant is the first gepant to demonstrate a significant decrease in monthly migraine days compared to placebo in a recent trial. Further, anti-CGRP mAb and gepants have a good safety profile.
CONCLUSIONS: There is strong evidence from randomized trials and real-world data to suggest that drugs targeting CGRP are a safe and effective treatment for chronic migraine.

Eptinezumab, a monoclonal antibody that targets calcitonin gene-related peptide (CGRP), was recently approved in Europe for the prophylactic treatment of migraine in adults who have at least four migraine days a month. Eptinezumab is administered by intravenous infusion every 12 weeks. During recent months, a considerable amount of evidence from eptinezumab trials has been published. The aim of this review is to describe the existing evidence on the tolerability, safety and efficacy of eptinezumab in patients with migraine. Data from randomized (PROMISE-1, PROMISE-2, RELIEF and DELIVER) and open-label (PREVAIL) phase 3 clinical trials have demonstrated the favorable effect of eptinezumab in migraine symptoms from first day of treatment. These studies showed that eptinezumab results in an overall reduction in mean monthly migraine days (MMDs), increases in the ≥50% and ≥ 75% migraine responder rates (MRRs) and improvements in patient-reported outcome measures in both patients with episodic migraine (EM) and with chronic migraine (CM), including patients who failed previous preventive treatments. The RELIEF trial also showed that eptinezumab, within 2 h of administration, reduced headache pain, migraine-associated symptoms and acute medication use when administered during a migraine attack. Eptinezumab benefits manifested as early as day 1 after dosing and with the subsequent doses lasted up to at least 2 years. Treatment-emergent adverse events reported by ≥2% of patients included upper respiratory tract infection and fatigue. Current evidence demonstrates that eptinezumab has a potent, fast-acting, sustained migraine preventive effect in patients with EM and CM. Eptinezumab has also shown to be well tolerated, supporting its use in the treatment of patients with migraine and inclusion in the current migraine therapeutic options.