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AimWe aimed to evaluate the efficacy and safety of eptinezumab for the preventive treatment of chronic migraine in a predominantly Asian population.MethodsThe multi-regional, randomized, double-blind, placebo-controlled, phase 3 SUNRISE trial randomly assigned adults with chronic migraine to receive eptinezumab 100 mg, 300 mg, or placebo. The primary endpoint was change from baseline in monthly migraine days (MMDs) during Weeks 1-12. Key secondary efficacy endpoints were 50% reduction in MMDs (Weeks 1-12) and 75% reduction in MMDs (Weeks 1-4, Weeks 1-12), and the percentage of participants experiencing migraine on Day 1.ResultsOverall, 978 participants received treatment, including 621 (63.5%) from Asia. Both eptinezumab doses met the primary and all key secondary efficacy endpoints. The mean change from baseline in MMDs (Weeks 1-12) was -7.2 for eptinezumab 100 mg, -7.5 for eptinezumab 300 mg, and -4.8 for placebo. Between-group differences were -2.4 for eptinezumab 100 mg versus placebo (p < 0.0001) and -2.7 for eptinezumab 300 mg versus placebo (p < 0.0001). Both eptinezumab doses also demonstrated an odds ratio of >2 versus placebo for all migraine responder rates (p < 0.0001), and a lower percentage of participants experiencing migraine on Day 1 versus placebo (p ≤ 0.01). Safety outcomes were similar across treatment groups.ConclusionsEptinezumab demonstrated statistically significant greater reductions in MMDs compared with placebo, beginning on Day 1 and sustained through Week 12, with a well-tolerated safety profile consistent with prior clinical trials.Trial registrationClinicalTrials.gov (Identifier: NCT04921384); EudraCT (Identifier: 2020-001657-42).

ObjectiveTo develop evidence-based clinical practice guidelines for non-invasive neuromodulation devices in acute and preventive migraine treatment.MethodsA systematic review was conducted across six databases from 1946 to April 2025. Randomized controlled trials evaluating Food and Drug Administration-cleared or Conformité Européenne (CE)-marked non-invasive neuromodulation devices were included. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, and recommendations were developed through consensus following GRADE Evidence-to-Decision frameworks. The working group comprised 15 senior members and six junior members.ResultsFrom 1536 initial records, 15 studies met the inclusion criteria and were finally used to develop evidence-based recommendations. Evidence quality ranged from very low to moderate. Weak recommendations were issued for SAVI Dual, Cefaly, Relivion, and Nerivio in the treatment of acute migraine attacks, and for gammaCore Sapphire, Cefaly, and Nerivio in the preventive migraine treatment. Other cleared devices received no recommendations or have no eligible studies for the GRADE assessment. The primary limitations across studies included imprecision due to small sample sizes and various methodological concerns. Additionally, expert consensus recommendations were developed for devices and clinical scenarios not adequately covered by randomized controlled trials, including potential applications in pediatric populations, vestibular migraine, chronic migraine, menstrual migraine, and medication overuse headache.ConclusionNon-invasive neuromodulation devices offer promising alternatives to drug treatment for migraine management. These devices are safe and generally well tolerated and devoid of drug interactions. While current evidence quality varies, ongoing research and technological advancements show encouraging potential. Future studies should adhere to International Headache Society guidelines for neuromodulation device trials, address proper sham controls and blinding assessment, and account for patient adherence challenges in device use. Expanded insurance coverage would enhance cost-effectiveness and device accessibility. These guidelines provide a framework for clinical decision-making while highlighting areas requiring further research.

Migraine is increasingly understood as a disorder of brain network dysfunction, where attack-related cognitive symptoms (attention deficits, slowed processing speed and executive dysfunction) can be as disabling as pain and may persist into the interictal period. Such symptoms are associated with functional and structural changes across the migraine cycle, involving the prefrontal cortex, thalamus, hypothalamus, hippocampus and cerebellum. Interictal deficits in working memory, visuospatial processing, verbal fluency and executive function are also documented. Rodent models show impairments in learning and memory, while humans studies suggest that cortical hyperresponsiveness and deficient sensory habituation contribute to altered attentional processing, reflecting thalamocortical dysfunction and abnormal synaptic plasticity as underlying mechanisms. Cognitive performance is modulated by disease severity, chronification, hormonal fluctuations, psychiatric comorbidities, sleep disturbances and medication use. Anxiety, depression and sleep disorders negatively affect working memory, executive function and attention, while medication overuse further impairs visuospatial skills and orientation. Dementia risk appears heightened in migraine patients with frequent and severe attacks, as clinic-based studies consistently report cognitive deficits in this cohorts, unlike population-based studies. While longitudinal cohorts find no increased dementia risk, meta-analyses suggest a modest risk elevation. Differences are likely due to methodological differences in cognitive testing and diagnostic approaches. Cognitive dysfunction in migraine is multidimensional, involving intrinsic neuronal mechanism and external modulators, supporting the need for rational management strategies and treatment interventions.

BackgroundThe impact of psychiatric comorbidities in children and adolescents with headache disorders can be more comprehensively understood through a biopsychosocial perspective, which examines the dynamic interplay of factors beyond headache attacks. Resilience and executive function emerge within this framework, playing a central role in development psychopathology and other critical domains.MethodsThis narrative review aimed to examine the impact of psychiatric comorbidity on migraine and/or high-frequency headaches (HFH) in children and adolescents through a biopsychosocial perspective centered on the role of resilience and executive function (EF), exploring their potential clinical implications. PubMed was searched for English language articles of human participants, from birth to 18 years, published up to 10 April 2025.ResultsClinical and population-based studies suggest that children and adolescents with migraine and/or HFH are at an increased risk of low resilience and EF impairments. Preliminary interaction and multivariate analyses suggest that high vulnerability (the counterpart to resilience) exerts a moderating role in the psychiatric comorbidity of migraine, as well as a mediating effect in the association of HFH with psychiatric symptoms and disorders. Candidate predictors of psychiatric comorbidity in youths with migraine and/or HFH include EF impairment, high vulnerability, female sex, low socioeconomic status, prenatal exposure to tobacco, poor academic performance and headache attacks accompanied by nausea and vomiting.ConclusionsThe multidimensional impact of psychiatric comorbidities on children and adolescents with headache disorders is clearly demonstrated by consistent evidence of their adverse effects on headache severity and chronification, as well as negative outcomes in quality of life, cognitive performance, academic achievement and overall patient well-being, leading to long-term continuity across childhood, adolescence and adulthood. Most of this impact is probably due to the interactions between reduced resilience, increased vulnerability and EF impairment. This narrative review underscore the relevance of routinely assessing psychiatric symptoms, resilience, executive function skills and school functioning in children and adolescents with headache disorders. Future studies should examine whether early interventions focused on resilience, vulnerability and EF can prevent psychiatric comorbidities and improve headache outcomes in children and adolescents with migraine and/or HFH.

AimTo prospectively determine subtype shift, relapse rate and risk factors of frequent relapse in cluster headache (CH).MethodsThis multicenter cohort study recruited patients with CH at baseline visits between September 2016 and January 2019 and planned to prospectively follow them up for up to five years. The subtype (episodic vs. chronic) was reassessed at baseline visit 2 (2-4 weeks) and serial follow-up visits if unremitted. We assessed the subtype shift of the index bout (i.e. the bout at the baseline visit) in all patients and relapse rates in those with episodic CH who were in an active bout at the time of recruitment. Relapse (i.e. bout recurrence) was prospectively collected via clinic visit or telephone interview at 3 ± 1 months, 1, 2, 3, 4 and 5 years (each ±6 months) after the baseline visit. Risk factors of frequent relapse were analyzed by comparing the incidence rate ratio (IRR) of relapse using Poisson regression analysis (model 1, static variables in all patients; model 2, time-related variables in patients with two or more lifetime bouts) accounted for different follow-up periods using an offset term.ResultsIn 295 patients (58 with first-ever bouts) enrolled, CH subtypes were episodic, chronic and unclassified in 252, 11 and 32 at baseline. At baseline V2, CH subtype was re-determined to be chronic in seven (12.1%) of 58 patients with first-onset CH ("primary chronic CH") and nine (3.8%) of 237 with a history of episodic CH ("secondary chronic CH"). When excluding known chronic CHs at baseline, the incidence of chronic CH newly found during a prospective observation was 3.8% in patients with first-onset CH and 1.4% in those with a history of episodic CH. In 244 patients with episodic CH in an active bout at the time of recruitment, the relapse rate was 0.29 (95% confidence interval (CI) = 0.27-0.32; p < 0.001) per person-year after 5.9 ± 1.37 follow-up visits over a mean duration of 4.2 ± 1.32 years. Models 1 and 2 indicated that age (adjusted IRR = 0.97; 95% CI = 0.95-0.98), longer disease duration (adjusted IRR = 0.97; 95% CI = 0.95-1.00), first-ever bout (adjusted IRR = 0.35; 95% CI = 0.20-0.57), regular (one or more per week) alcohol consumption (adjusted IRR = 0.60; 95% CI = 0.45-0.81), and longer between-bout interval of previous bouts (adjusted IRR = 0.72; 95% CI = 0.60-0.87) were associated with less relapse. Seasonal rhythmicity (adjusted IRR = 1.66; 95% CI = 1.20-2.33) and increasing attack intensity across bouts (adjusted IRR = 1.66; 95% CI = 1.06-2.59) were associated with frequent relapse.ConclusionsThe present study provides data on the subtype shift and relapse rate of CH based on the prospective observation. Although our observation is only limited to a five-year time frame, our findings may suggest that disease activity increases after onset and then regress with age and time, and that seasonal rhythmicity and increasing attack intensity across bouts indicate higher propensity to relapse.

AimCortical spreading depression (CSD), the neural correlate of migraine aura, has been shown to cause activation of dural nociceptive neurons as well as immune cells, among which macrophages (MPs) are the most abundant and reactive. OnabotulinumtoxinA (onbotA) is used to treat chronic migraine but the mechanism of action is not fully understood. Here we investigate the role of meningeal MPs in a model of migraine activation and evaluate whether onabotA has an effect on their response.MethodsWe use our previously developed method to determine meningeal MP activation based on shape changes using time-lapse in vivo multiphoton microscopy.ResultsWe found that a small subset (∼10%) of MPs contracted their processes in response to CSD induction, but only in female mice. A similar subset of MPs contracted with lipopolysaccharide injection, suggesting that this is an M1-like response. Together this may provide insight into the phenotypic differences of migraine across males and females. We also found a small subset of MPs (∼10%) that expanded their processes in response to IL-10 (presumably an M2-like response), but were not affected by CSD. In female mice, pre-treatment with onabotA (i) reduces overall MP number in the dura, (ii) reduces pro-inflammatory M1 MP response and (iii) increases anti-inflammatory M2 response post-CSD compared to pretreatment with saline.ConclusionThis suggests that the mechanism of action of onabotA may not be simply due to its effects on nociceptors, but also due to an additional anti-inflammatory effect on the environment of the dura.