BackgroundCluster headache (CH) is one of the most severe types of pain, yet pharmacological treatment options are limited. In the present study, we aimed to systematically evaluate the effect of treatment with monoclona...BackgroundCluster headache (CH) is one of the most severe types of pain, yet pharmacological treatment options are limited. In the present study, we aimed to systematically evaluate the effect of treatment with monoclonal antibodies (mAbs) blocking calcitonin gene-related peptide (CGRP) in the prevention of episodic cluster headache (eCH) and chronic (cCH) cluster headache.MethodsWe searched Embase, Medline, Cochrane CENTRAL and Web of Science. Included were all clinical trials, case series and single case reports that reported the effects of anti-CGRP treatment on CH. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were used for abstracting data. Risk of bias was evaluated using the Risk of Bias 2 (RoB 2) tool for randomized trials and Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) for non-randomized studies. The collected data from all studies were summarized using descriptive statistics. Data from randomized trials were additionally reported as odds ratio (OR) with 95% confidence interval (CI) using a random-effects meta-analysis. Given the variability in study design and the diverse formats of reported outcome data, we primarily focused on the ≥ 50% responder rate reported closest to the 4-week point following drug administration, which was consistently reported in almost all studies.ResultsFrom 734 identified records, 25 articles were included, comprising a total of 1587 patients. Meta-analysis of randomized, placebo-controlled trials suggests that anti-CGRP treatment had a statistically significant positive effect in eCH (OR = 1.65, 95% CI = 1.07-2.55, = 0.02), with galcanezumab 300 mg and eptinezumab 400 mg being more effective than placebo in achieving a ≥ 50% responder rate in eCH attacks at the 4-week mark following administration. Simultaneously, a significant mean reduction in weekly attack frequency at week 4 was observed only for galcanezumab 300 mg ( = 0.04). Despite findings from some non-randomized trials, the meta-analysis showed no statistically significant effect in cCH (OR = 1.07, 95% CI = 0.78-1.48, = 0.68).ConclusionsOur analysis revealed a beneficial effect of anti-CGRP mAbs in eCH, while no effect was observed in cCH. Despite these positive findings, the favourable results with galcanezumab and eptinezumab in eCH should be interpreted with caution due to discrepancies in the outcome data and the challenges associated with selecting endpoints in CH trials. The discrepancy between real-world data and findings from controlled trials further highlights the need for continued discussions among experts to develop more adequate methods for conducting CH trials.Trial RegistrationPROSPERO ID: CRD420250609351.
BackgroundPrevious studies suggest the perimenstrual phase increases migraine without aura risk, attributed to the decline of estrogen in this phase. However, the link to the decline of estrogen in the post-ovulatory pha...BackgroundPrevious studies suggest the perimenstrual phase increases migraine without aura risk, attributed to the decline of estrogen in this phase. However, the link to the decline of estrogen in the post-ovulatory phase remains unclear.MethodsWe conducted a longitudinal cohort study among 563 women with migraine and a regular natural menstrual cycle. Participants completed a validated e-headache diary also including menstrual cycle tracking. Of these women, 31 (who participated in our Women Hormones Attacks and Treatment (WHAT)-hormone study) performed urine luteinizing hormone (LH) surge tests during two menstrual cycles to validate the estimation of the post-ovulatory estrogen decline. The association between the post-ovulatory estrogen decline and migraine incidence was assessed using a mixed logistic model with patient as random effect, and the post-ovulatory and menstrual window as fixed effects. Secondary analyses included a case-crossover model and a self-controlled case series (SCCS) model to strengthen robustness and control for time-invariant confounders.ResultsE-diary data from 2627 menstrual cycles, including 58 from the WHAT-hormone subgroup, were analyzed. Across all three statistical models, the post-ovulatory window showed no higher incidence of migraine (with or without aura) than other menstrual cycle days (mixed logistic model: OR 0.95, 95% CI 0.89-1.02; WHAT-hormone subgroup: OR 0.68, 95% CI 0.38-1.16). The perimenstrual window had the highest migraine incidence (SCCS model with luteal phase as reference: OR 1.67, 95% CI 1.60-1.75), followed by the follicular phase (OR 1.31, 95% CI 1.26-1.37).DiscussionIn contrast to what many women with migraine believe, there is no increased incidence of migraine attacks (with or without aura) during the post-ovulatory window, but a higher incidence during the follicular phase compared to the luteal phase was confirmed.
BackgroundTreatment with onabotulinumtoxinA is effective in reducing migraine day frequency and duration in individuals with chronic migraine (CM), but given the severity of the disease, those with CM often need addition...BackgroundTreatment with onabotulinumtoxinA is effective in reducing migraine day frequency and duration in individuals with chronic migraine (CM), but given the severity of the disease, those with CM often need additional treatment to achieve optimal outcomes. Combining preventive treatments with distinctly different physiological targets may yield greater benefit than monotherapy. This study evaluated the safety, tolerability, and efficacy of adding atogepant to onabotulinumtoxinA for preventive treatment of CM.MethodsIn this 24-week, Phase 3, open-label, single arm, multicenter study (NCT05216263), 75 participants on a stable dose of onabotulinumtoxinA (155-200U) with baseline mean monthly migraine days (MMDs) of 8-23 (inclusive) received add-on atogepant 60 mg once daily. Primary safety endpoints included treatment-emergent adverse events (TEAEs), and exploratory efficacy endpoints included changes in MMDs, changes in mean monthly headache days (MHDs) and responder rates (RRs) (≥50%, ≥75%, and 100% MMDs) over Weeks 1-12, Weeks 13-24, and at each 4-week interval.ResultsThe mean age of study participants was 48 (13.68) years (mean (SD)); 89% were women, and 97% were white. Participants had an established CM diagnosis for 15 (13.27) years (mean (SD)) and had been treated with onabotulinumtoxinA for 4 (3.45) years (mean (SD)). In the safety population (n = 75), the incidence of TEAEs was 65.3%. TEAEs occurring in ≥5% of participants were constipation (n = 12, 16.0%), nausea (n = 10, 13.3%), and urinary tract infection (n = 6, 8.0%). An AE was considered the primary reason for drug discontinuation in 2 (2.7%) participants. Treatment-emergent serious AEs (TESAEs) occurred in 2 participants; neither were considered treatment-related by the investigators. In the modified intention-to-treat population (n = 72), the least squares (LS) mean change from baseline of 14.34 MMDs was -6.45 MMDs (95% CI: -7.7, -5.1) at Weeks 1-4, -6.89 MMDs (95% CI: -8.1, -5.6) across Weeks 1-12, and -7.20 MMDs (95% CI: -8.4, -5.9) across Weeks 13-24. The least square mean change from baseline of 17.00 MHDs was -6.57 MHDs (95% CI: -7.8, -5.3) at Weeks 1-4, -7.33 MHDs (95% CI: -8.6, -6.0) across Weeks 1-12 and -8.15 MHDs (95% CI: -9.4, -6.8) across Weeks 13-24. A ≥ 50% RR in MMD was achieved by 54.2% and 61.9% of participants across Weeks 1-12 and Weeks 13-24 of combined treatment, respectively. A ≥ 75% RR was achieved by 30.6% and 38.1% of participants.ConclusionsIn this study, combination preventive treatment for CM with onabotulinumtoxinA and atogepant was safe and generally well-tolerated. Furthermore, the addition of atogepant to those stable on onabotulinumtoxinA resulted in clinically meaningful reductions in migraine days and improvement in responder rates, suggesting a benefit of combining treatments with distinct and complementary mechanisms of action for suppression of CM.Trial RegistrationClinical Trials.gov NCT05216263.
Dahshan A, Mahfouz Khalil MI, Abdelfatah D
… +36 more, Abu Ejheisheh M, Alshammari MSH, Mekdad AK, Tiryag AM, Sherif GMA, Hallaj F, Hammooz A, Abdallah MAH, Baraka SIM, Baraka NIM, Ibrahim ANA, Noor AM, Khraisat AMS, Awad Osman Mohammed A, Eltayeb LAE, Alhadidi M, Hweissa NA, Al Buraiki HAA, Ibraheem OA, Salameh B, Al Tabbah SAA, Lawand NM, Rezq KA, Wahba NMI, Abd Al Jaleel KN, Albagoush NA, Alwahchi W, Mansor KMH, Al-Rawashdeh ABA, Al-Yafeai TM, Albalawi HMH, Hakim AHM, Mousa EFS, Sultan HMS, Abd El Fatah NK, Farrag MA
AimThis study aimed to assess the impact of online health information and AI-based tools on treatment decisions, trust, and care-seeking behaviors among migraine patients in Arab speaking countries from MENA region.Metho...AimThis study aimed to assess the impact of online health information and AI-based tools on treatment decisions, trust, and care-seeking behaviors among migraine patients in Arab speaking countries from MENA region.MethodsA multinational, cross-sectional online survey was conducted among 4276 adults with migraine across 13 MENA countries. Data collected included sociodemographic characteristics, migraine history, digital health literacy (eHEALS), AI tool usage, and trust in health information sources.ResultsThe mean eHealth literacy score was 29.9 ± 6.2. Overall, 75.6% demonstrated adequate digital health literacy. Neurologists and physicians were the most trusted sources, whereas social media influencers were the least trusted. Approximately one-third of participants reported modifying migraine treatment or delaying medical consultation based on online information. In multivariable analyses, higher trust in online information was strongly associated with delayed medical consultation (aOR 6.48, 95% CI 5.53-7.58, p < 0.001). In contrast, use of AI tools was associated with lower odds of reporting treatment modification based on online advice (aOR 0.29, 95% CI 0.17-0.49, p < 0.001). Higher trust in online information was consistently associated with both delayed care and treatment changes. Younger age, male sex, and active online information-seeking independently predicted AI use.ConclusionDigital health engagement, including trust in online sources and AI tool use, was significantly associated with migraine-related decision behaviors in this multinational MENA cohort. While AI use was linked to more cautious treatment behaviors, higher trust in online information was associated with delayed medical consultation and treatment modification. These findings highlight the importance of strengthening digital health literacy and promoting reliable online resources.
Papetti L, Guarnera A, Longo D
… +13 more, Napolitano A, Baldassari G, Pirani G, Sforza G, Monte G, Ursitti F, Dellepiane F, Vaccaro M, Carboni A, Rossi-Espagnet MC, Moltoni G, Gandolfo C, Valeriani M
BackgroundMigraine accounts for most primary headaches in children and adolescents and is related to cortical and connectivity changes. However, the underlying mechanisms remain unclear. Morphometric similarity mapping h...BackgroundMigraine accounts for most primary headaches in children and adolescents and is related to cortical and connectivity changes. However, the underlying mechanisms remain unclear. Morphometric similarity mapping has not yet been applied to children and adolescents with migraine.MethodsEighty-three patients (6-17 years) with migraine without aura and 81 age- and sex-matched controls were retrospectively included. High-resolution 3D T1-weighted and diffusion-weighted magnetic resonance imaging scans were processed to extract cortical morphometric parameters and compute morphometric similarity networks (MSN). Global and regional MSN differences were assessed between patients and controls, and across subgroups defined by sex, attack frequency and migraine-associated symptoms.ResultsPatients showed significant MSN alterations, particularly in temporal and cingulate regions. Sex emerged as the strongest factor influencing MSN architecture, with additional modulations linked to attack frequency and clinical symptoms. Affected pathways encompassed the executive control, nociceptive and default mode networks.ConclusionsMigraine in children and adolescents is associated with widespread MSN abnormalities, likely reflecting cortical reorganization mechanisms. Male and female patients appear to engage distinct neural "orchestras", each emphasizing different network sections (sensory-affective in males and cognitive-attentive in females) to produce a shared clinical experience. These findings highlight sex as a key determinant of migraine neurobiology in developmental age.
ObjectiveTo investigate whether blockade of hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels modifies migraine induced by activation of vascular ATP-sensitive potassium (K) channels.MethodsWe conducted...ObjectiveTo investigate whether blockade of hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels modifies migraine induced by activation of vascular ATP-sensitive potassium (K) channels.MethodsWe conducted a single-centre, randomised, double-blind, placebo-controlled, two-way crossover study in adults with migraine without aura. On two separate days, participants received intravenous levcromakalim followed immediately by either oral ivabradine or placebo in a balanced order. The primary endpoint was the 12-h incidence of levcromakalim-induced migraine. Secondary endpoints included the area under the curve (AUC) for headache intensity and haemodynamic responses. Parallel preclinical experiments were performed in a validated mouse model using von Frey-based tactile sensitivity to assess whether ivabradine, given as pretreatment or as rescue medication, alters levcromakalim-induced hypersensitivity.ResultsTwenty seven of 31 individuals completed the human study and provided data for the final analysis. Ivabradine did not modify the incidence of levcromakalim-induced migraine (22 of 27 after ivabradine and 22 of 27 after placebo; > 0.99) or the AUC for headache intensity ( = 0.11). Haemodynamic responses did not differ between study days. In mice, ivabradine at multiple doses neither prevented nor reversed tactile hypersensitivity induced by repeated levcromakalim administration.ConclusionsHCN channel blockade does not influence migraine or nociceptive behaviour provoked by vascular K channel activation. These convergent human and preclinical findings indicate that HCN channels are not essential for the downstream transformation of vascular K channel activation into migraine pain and support a model in which migraine initiation arises from signalling at the vessel-to-neuron interface.Trial registrationClinicalTrials.gov; NCT04853797; Registered: 16-03-2021. Preclinical experiments were not preregistered beyond the animal ethical license (2017-15-0201-01358) from the Danish Animal Experiments Inspectorate.
BackgroundMigraine aura reflects transient neurological disturbances attributed to cortical spreading depolarization (CSD), yet the upstream molecular events that promote or precipitate this phenomenon remain uncertain....BackgroundMigraine aura reflects transient neurological disturbances attributed to cortical spreading depolarization (CSD), yet the upstream molecular events that promote or precipitate this phenomenon remain uncertain. Human pharmacological provocation models provide a controlled approach to identifying endogenous signaling pathways capable of triggering aura and thereby clarifying their mechanistic role in migraine pathogenesis.MethodsThis systematic review was pre-registered in PROSPERO (ID: CRD420250636266) and conducted in accordance with the Synthesis Without Meta-Analysis (SWiM) guideline. PubMed and Embase were searched from database inception through January 1, 2026, without language restrictions, to identify experimental studies administering pharmacological agents to individuals with migraine with aura under controlled lab conditions. Two reviewers independently performed study selection, data extraction, and methodological assessment. Extracted variables included participant characteristics, study design, pharmacological trigger, dosing protocol, and the incidence, timing, and phenotype of provoked aura and headache. Because of substantial heterogeneity, findings were synthesized qualitatively.ResultsFourteen studies met inclusion criteria, examining seven pharmacological agents: calcitonin gene-related peptide (CGRP), levcromakalim (ATP-sensitive potassium (K) channels opener), glyceryl trinitrate (GTN), sildenafil, cilostazol, endothelin-1, and histamine. Across studies, aura induction occurred far less frequently than headache induction. CGRP provoked aura in 17 (32%) of 53 participants across three studies, with latencies ranging from 10 to 360 min. Pharmacological opening of vascular K channels by levcromakalim elicited aura in 14 (27%) of 52 participants in randomized crossover trials, with onset between 20 and 120 min. Other agents produced minimal or no aura responses.ConclusionsHuman pharmacological provocation provides a reproducible framework for dissecting molecular pathways that can trigger migraine aura. Current evidence implicates CGRP signaling and vascular ATP-sensitive potassium channel activation as the most plausible associated candidate pathways. However, standardized protocols and larger controlled studies are required to confirm these mechanisms and refine experimental models of aura biology.Trial RegistrationPROSPERO (ID: CRD420250636266).
Gago-Veiga AB, Lopez-Rodriguez AB, Sanchez Jimenez M
… +28 more, Iglesias Rubio A, Montes N, Camiña Muñiz J, Dominguez Gallego M, Calle de Miguel C, Latorre G, Rodriguez-Vico J, Jaimes A, Gomez Garcia A, Urtiaga S, Gonzalez Salaices M, Dileone M, Gonzalez-García N, Porta-Etessam J, Cuadrado ML, Herrero San-Martin A, Guerrero-Peral ÁL, Gonzalez-Osorio Y, Casas-Limón J, Sánchez-Soblechero A, Lozano-Ros A, Díaz-De-Terán J, Portocarrero-Sánchez L, Molina-Martínez FJ, Santos-Lasaosa S, Martín-Ávila G, Riva E, Fernández-Lázaro I
AimAtogepant is a novel oral calcitonin gene-related peptide (CGRP) receptor antagonist approved for migraine prevention. This study primarily evaluated its effectiveness and safety in real-world clinical practice, focus...AimAtogepant is a novel oral calcitonin gene-related peptide (CGRP) receptor antagonist approved for migraine prevention. This study primarily evaluated its effectiveness and safety in real-world clinical practice, focusing on patients with treatment-resistant migraine, defined according to the European Headache Federation (EHF) criteria as failure of at least three classes of preventive medications, including onabotulinumtoxinA or anti-CGRP monoclonal antibodies (mAbs).MethodsThis prospective multicentre study was conducted across 15 tertiary Headache Units in Spain. Demographic and clinical data, prior preventives, monthly headache days (MHD), monthly migraine days (MMD), and adverse events (AEs) were systematically collected at baseline, 3 months (primary endpoint), and/or 6 months (secondary endpoint).ResultsA total of 513 patients were enrolled (mean age 48 years; 88% women). The 3-month analysis included 455 patients, with median MHD decreasing from 21 (IQR 15-30) to 14 (IQR 6-30) and MMD from 14 (IQR 10-20) to 8 (IQR 3-15) (both p < 0.0001). A ≥ 50% reduction was achieved by 34% (MHD) and 29% (MMD), with ≥75% responses in 16% and 13%. Adverse events were mostly mild, mainly constipation (30%) and nausea (18%), and the 3-month discontinuation rate was 11.8%. Responders had shorter migraine chronicity, less analgesic overuse, and fewer prior preventive failures. Although prior inadequate response to anti-CGRP mAbs reduced the likelihood of improvement, it did not prevent meaningful benefit. At analysis, 151 patients had reached the 6-month visit, showing further improvement (MHD 10 [IQR 5-20]; MMD 6 [IQR 4-12]) and fewer adverse events.ConclusionsAtogepant showed robust real-world effectiveness and good tolerability in a large, treatment-resistant migraine cohort, with clinically meaningful improvement at 3 months and incremental benefit in the subgroup evaluated at 6 months. Lower migraine chronicity and fewer prior preventive failures were associated with better outcomes, supporting the earlier introduction of anti-CGRP therapies in clinical practice.Trial RegistrationClinical Trials.gov NCT06241313.
Peres MFP, Lucchetti G, Vallada H
… +25 more, Riso IL, Westenhofen GK, Valença MM, de Andrade JR, Brennan KC, Levin M, Takizawa T, Dong Z, Wang Y, Rattanawong W, Sofyan HR, Leone M, Dodd-Glover F, Yuan H, Albilali A, Alsaadi T, Caixeta L, Andreou AP, Goadsby PJ, MaassenVanDenBrink A, Ashina S, Burstein R, Pozo-Rosich P, Ahmed F, Wang SJ
Headache disorders are among the most disabling neurological conditions, affecting over 1.5 billion people globally. Despite advances in pharmacological therapies, major inequities persist due to underdiagnosis, undertre...Headache disorders are among the most disabling neurological conditions, affecting over 1.5 billion people globally. Despite advances in pharmacological therapies, major inequities persist due to underdiagnosis, undertreatment and limited access to effective care, particularly in low- and middle-income countries. Social determinants of health, including cultural meanings, language and health beliefs, are increasingly recognized as key drivers of disparities in burden, diagnosis and treatment outcomes. Traditional medicine, used by more than 80% of the global population, remains first-line care in many regions and continues to influence therapeutic choices in high-income settings. Major systems such as Ayurveda, Traditional Chinese Medicine, Unani and Tibetan medicine, as well as diverse indigenous traditions, emphasize holistic approaches that integrate mental and physical symptoms into diagnosis and management. Additionally, religious and spiritual practices are commonly used to relieve suffering and pain. These culturally grounded explanatory models not only strongly shape health-seeking behavior, treatment adherence and patient narratives, but also may delay biomedical care when misconceptions or unsafe practices predominate. This paper introduces Transcultural Headache Medicine as an emerging framework that integrates cultural contexts, linguistic diversity and traditional practices into headache research, clinical care and policy. We review global traditions and therapeutic modalities including herbal, physical, mental and spiritual approaches, and propose a research agenda combining ethnography, culturally adapted diagnostic tools, experimental studies and clinical trials to evaluate benefits, risks, and contextual effects. We conclude with a call to action from the International Headache Society, aiming to map and evaluate culturally embedded practices, strengthen rigorous evidence and build a global learning network that supports culturally safe integration of effective, affordable and safe headache care.
Masuda H, Uzawa A, Shibata M
… +39 more, Mori M, Miyazaki Y, Niino M, Fujimori J, Nakashima I, Takai Y, Yamazaki N, Misu T, Kinoshita M, Okuno T, Sekiguchi K, Nakahara J, Takeuchi H, Mizutani K, Matsuyoshi A, Kira YI, Iwao K, Tanaka E, Shinoda K, Watanabe M, Masaki K, Isobe N, Muto M, Ohtani R, Aoyama S, Misawa S, Shibuya K, Suichi T, Yasuda M, Aotsuka Y, Morooka M, Otani R, Onishi Y, Akamine H, Handa H, Ogaya E, Ogushi M, Kurumada K, Kuwabara S
Cephalalgia
· 2026 Mar · PMID 41883304
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AimSeveral studies have reported a higher prevalence of migraine in patients with multiple sclerosis (MS) than in healthy controls (HCs). The aim of this study was to elucidate the headache prevalence in patients with MS...AimSeveral studies have reported a higher prevalence of migraine in patients with multiple sclerosis (MS) than in healthy controls (HCs). The aim of this study was to elucidate the headache prevalence in patients with MS or other neuroimmunological disorders, as well as to investigate the associations between headache characteristics and disease activity.MethodsIn this multicenter study in Japan, a headache questionnaire was distributed to patients with MS (n = 338), aquaporin-4 IgG-positive neuromyelitis optica spectrum disorder (NMOSD; n = 106), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD; n = 51) or acetylcholine receptor antibody-positive myasthenia gravis (MG; n = 104), and healthy controls (HCs; n = 407). We included only participants aged 18-65 years in this study. The questionnaire responses were classified according to the International Classification of Headache Disorders, 3rd edition. The questionnaire was designed to systematically capture headache characteristics based on established diagnostic criteria.ResultsIn total, any type of headache was found for 54.1% in MS, 63.2% in NMOSD, 43.1% in MOGAD, 43.3% in MG and 43.5% in HCs. After Holm-Bonferroni correction for comparisons among the five groups, the MS ( = 0.015) and NMOSD ( < 0.001) groups had significantly higher odds of any headache compared to the HC group. No difference was observed for migraine (MS 16.0%, NMOSD 16.0%, MOGAD 9.8%, MG 12.5%, HCs 17.0%). In contrast, patients with MS (24.0%) and NMOSD (37.7%) showed a significantly higher frequency of tension-type headache (TTH) than HCs (16.7%) even after adjusting for age and sex. Neither disease activity nor disease-modifying therapy displayed any association with headache severity in patients with MS, NMOSD, or MOGAD.ConclusionsOur study showed no increased prevalence of migraine in MS and other neuroimmunological disorders, whereas TTH comorbidity was higher in MS and NMOSD than in controls.
Cephalalgia
· 2026 Mar · PMID 41883292
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BackgroundIntegrating brain structure and function may help characterize neurobiological heterogeneity in migraine alongside symptom presentation.AimTo apply a multimodal, exploratory, data-driven approach to identify mi...BackgroundIntegrating brain structure and function may help characterize neurobiological heterogeneity in migraine alongside symptom presentation.AimTo apply a multimodal, exploratory, data-driven approach to identify migraine subgroups using structural and functional MRI, and to describe the clinical characteristics of the resulting subgroups.MethodsResting-state functional connectivity (FC) across cortical and subcortical regions, along with structural measures including cortical thickness, cortical volume, and subcortical volumes, were extracted from 111 individuals with migraine (75 chronic, 36 episodic) classified according to ICHD-3 criteria. After dimensionality reduction using principal component analysis, hierarchical agglomerative clustering was applied to identify multimodal imaging-derived subgroups. For comparison, secondary unimodal clustering models were constructed using functional-only and structural-only feature sets. The optimal number of clusters was determined using silhouette coefficients, and clustering concordance across models was quantified using the Adjusted Rand Index (ARI). Group differences in clinical characteristics, FC, and cortical and subcortical structure were assessed using covariate-adjusted statistical models with false discovery rate (FDR) correction.ResultsMultimodal clustering identified two subgroups with distinct clinical and imaging profiles, Migraine Cluster 1 (M1 ) and Migraine Cluster 2 (M2 ). M2 showed older age, longer disease duration, greater migraine disability, widespread increases in cortical-subcortical FC (including Dorsal Attention, Somatomotor, and Visual networks), and reduced cortical volumes across frontal, parietal, temporal, and insular regions compared with M1 . This subgroup also exhibited increased connectivity relative to controls. In contrast, M1 showed preserved cortical structure and stronger Control-network-subcortical connectivity compared to M2 , and no significant functional or structural deviations from controls. Unimodal analyses revealed that Functional-only clustering aligned moderately with the multimodal cluster solution (ARI = 0.427), showing that FC was a primary determinant of the multimodal cluster structure, whereas structural-only clustering showed negligible overlap (ARI = 0.001), reflecting an orthogonal dimension of heterogeneity captured by structural variation.ConclusionData-driven multimodal neuroimaging-based clustering in migraine identified two subgroups with distinct clinical and imaging patterns, highlighting heterogeneity and providing a framework for further investigation of imaging-informed characterization.
Iannone LF, Sebastianelli G, Santis F
… +38 more, Corrado M, Marcosano M, Ornello R, Grazzi L, Montisano DA, Cesaris F, Munafò A, Vigani G, Avino G, Trimboli M, Albanese M, Russo A, Volta GD, Romozzi M, Calabresi P, Castro FL, Boccalini A, Merlo P, Prudenzano MP, Valente MR, Rainero I, Giuliani G, Altieri M, Fofi L, Doretti A, Vaghi G, Pistoia F, Lanni C, Ferrandi D, Rufa A, Battistini S, Coppola G, Geppetti P, Sacco S, Guerzoni S, Altamura C, Vernieri F, Italian Headache Registry (RICe) Study Group
Cephalalgia
· 2026 Mar · PMID 41878762
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AimTo assess whether the timing of atogepant administration influences its tolerability and effectiveness over 12 weeks in patients with episodic and chronic migraine in a real-world setting.MethodsThis is a post-hoc ana...AimTo assess whether the timing of atogepant administration influences its tolerability and effectiveness over 12 weeks in patients with episodic and chronic migraine in a real-world setting.MethodsThis is a post-hoc analysis of the STAR study, a prospective, Italian, multicenter study evaluating atogepant 60 mg for migraine prevention. Data were collected at baseline (T0) and after the first 12 weeks (T3) of treatment. Patients were grouped by administration timing (morning vs. evening) and by administration with or without food. Changes in monthly headache days (MHDs), monthly migraine days (MMDs), and Migraine Disability Assessment (MIDAS) were measured. Tolerability was evaluated via adverse events (AEs). Linear mixed-effects models (LMMs) were used.ResultsEighty-one patients (86% females, mean age 50.8 ± 13.7 years) were included. At T3, MMDs decreased from 16.6 to 9.7 (p < 0.001) and MHDs from 19.8 to 11.9 (p < 0.001); 60% of patients achieved ≥50% reduction in MMDs. AEs occurred in 34 (42%) participants. Atogepant was taken in the morning by 57% and in the evening by 43% of patients. Fifty-seven out of 81 participants (70.4%) took atogepant with food. No significant differences in MMDs, MHDs, or AEs emerged between morning and evening users. Evening users had higher baseline MIDAS scores (estimated marginal means [EMMs]: 69.9 vs. 39.9, p = 0.034) that showed a greater reduction compared to morning users ((1,63) = 6.29, = 0.015), reaching similar final scores after 12 weeks (EMMs: 25.1 vs. 23.8). No difference in atogepant effectiveness and tolerability according to intake with or without food, except for a reduction in MHDs for patients who took atogepant without food (EMMs from 21.3 to 9.9 vs with food: EMMs from 18.4 to 12.7; (1,79) = 8.553, = 0.005).ConclusionsAtogepant significantly reduced migraine burden over 12 weeks in a real-world setting. Overall, the timing of atogepant administration did not affect its effectiveness or tolerability. However, a greater reduction in MIDAS scores was observed among evening users. Whether this reflects a pharmacological advantage or a ceiling effect remains unclear. Taking atogepant without food was associated with a significantly greater reduction in MHDs, whereas changes in MMDs and MIDAS scores did not differ between groups. Long-term and dedicated studies are needed to evaluate and confirm these findings.Trial RegistrationThe main study (STAR) was preregistered on clinicaltrial.gov, NCT06414044.
Zaranek L, Zsoldos P, Richter M
… +4 more, Brandt D, Lampe S, Gossrau G, Brenner S
Cephalalgia
· 2026 Mar · PMID 41873465
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AimHeadaches are a common complaint among children and adolescents, with prevalence rising over the past decades. This study aimed to retrospectively analyze all emergency consultations presenting with headache as the pr...AimHeadaches are a common complaint among children and adolescents, with prevalence rising over the past decades. This study aimed to retrospectively analyze all emergency consultations presenting with headache as the primary symptom at a Level 1 Pediatric Emergency Department (PED) over 7 years, encompassing the COVID-19 pandemic.MethodsAll electronic health records (EHR) of patients aged 2 to 18 years who presented to the PED with non-traumatic headache between January 2018 and December 2024 were retrospectively reviewed. In addition to primary headache diagnoses, conditions commonly associated with headaches were included to identify relevant emergency department cases. Statistical analyses included the chi-square test or Fishers exact test, calculation of Odds Ratios and ANOVA, significant at p < 0.05.ResultsA total of 1278 children and adolescents (564 males, 44.1%; 714 females, 55.9%) with acute headaches visited our PED 1447 times. Of those patients, 668 (46.2%) were diagnosed with primary headaches, 677 (46.8%) with secondary headaches, five (0.3%) with cranial neuropathies and facial pain, and 97 (6.7%) had headaches that could not be clearly classified. Acute headache cases accounted for 3.6% of all PED visits. The largest relative increase compared to the baseline year (2018) was observed in 2023 (+36.2%). Immediate neuroimaging was performed in 19.1% of cases. Red flag symptoms, including systemic symptoms with fever, neoplasm in history, progressive headache, headache associated with severe vomiting and papilledema, were significantly associated with abnormal brain MRI findings. Pharmacological analgesic therapy was administered in 31.9% of cases, and pain assessment was recorded in 46.1% of cases.ConclusionVisits to the PED for headaches are increasing, particularly following the COVID-19 pandemic. The high prevalence of primary headache diagnoses, combined with still insufficient pain management, highlights the need for enhanced education for both pediatricians and parents. For secondary headaches, a thorough headache history focusing on all red flag symptoms, along with a detailed neurological examination assessing clinical features, should form the basis for deciding whether immediate neuroimaging is necessary.Trial registrationThe study has also been officially registered on the public webpage of the German Clinical Trials Registry (GermanCTR) at https://drks.de/search/en/trial/DRKS00036917 (Clinical Trial Number/ DRKS-ID: DRKS00036917, Date of Registration: 2025-05-16, last update: 2025-07-28, registration type: retrospective, status: recruiting complete, study complete).
Johansson EW, Shaaban AN, Linde M
… +6 more, Ohlis A, Mattsson M, Gustafsson S, Holm J, Dalman C, Agardh EE
Cephalalgia
· 2026 Mar · PMID 41869776
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BackgroundResidential deprivation is a long-established risk factor for poor health outcomes including migraine, depression and anxiety that are significant public health problems in Sweden and globally. Yet the relation...BackgroundResidential deprivation is a long-established risk factor for poor health outcomes including migraine, depression and anxiety that are significant public health problems in Sweden and globally. Yet the relationship between residential deprivation and patterns of comorbidity among these three conditions is less understood. We aimed to estimate the magnitude and determinants of comorbid depression or anxiety among migraine patients in Sweden including the relationship between residential deprivation and comorbidity prevalence.MethodsA nationwide register-based cross-sectional study was conducted of persons aged ten years or older in Sweden in 2015-2023. Comorbid depression or anxiety was defined as any depression or anxiety diagnosis or treatment during the migraine-exposed period (from three months before until three months after the first and last recorded migraine exposure in the study period). Small-area deprivation was based on an Index for Multiple Deprivation in Sweden (IMDIS) applied to 5984 small geographic areas. Prevalence ratios (PR) estimated the association between comorbidity and small-area deprivation adjusted for other covariates (age, sex, area of residence, birthplace) using Poisson regression models with robust error variance. We compared sick leave utilization (over fourteen days) for any reason in the migraine-affected years among migraine patients with or without comorbidity.ResultsThere were 372,926 migraine patients in the study, and 35.7% (n = 133,219) had comorbid depression or anxiety. There was higher comorbidity prevalence among migraine patients in the most versus the least deprived areas (PR: 1.18, 95% CI: 1.17-1.20). Although the data have limitations, we found that one-third (31.9%) of migraine patients took sick leave (over fourteen days) for any reason during the migraine-exposed years, which rose to 50.9% among migraine patients with comorbid depression or anxiety.ConclusionsMore than one-third of migraine patients had comorbid depression or anxiety with higher prevalence of comorbidity in the most deprived areas. Common comorbid depression or anxiety among migraine patients underscores the need to consider all three conditions in clinical encounters especially for residents of more deprived residential areas.
Møen EN, Bjørk MH, Gilhus NE
… +9 more, Daltveit DS, Contreras D, Hagen K, Jayaraman M, Khanevski AN, Wergeland T, Stubberud A, Tronvik EA, Igland J
Cephalalgia
· 2026 Mar · PMID 41810905
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BackgroundTo investigate whether epidemiological characteristics, including comorbidities, income, and education, have changed over time in people with cluster headache compared to controls.MethodsTrends in cardiopulmona...BackgroundTo investigate whether epidemiological characteristics, including comorbidities, income, and education, have changed over time in people with cluster headache compared to controls.MethodsTrends in cardiopulmonary, neurological, and psychiatric comorbidities, and income and education categories, were assessed using linked data from Norwegian health registries for 2009-2022. Comorbidities were defined based on relevant diagnosis codes from both the primary and the specialist healthcare. Income was categorized based on the national median for each year. Education was assessed based on the International Classification Standard for Education. Each cluster headache case was matched with 20 controls without cluster headache. Prevalence rate ratios were calculated using generalized estimating equations.ResultsPeople with cluster headache had higher prevalence than matched controls without cluster headache in all examined comorbidities, particularly migraine (men: 9.8% versus 0.3%; women: 23.1% versus 1.6%), mood disorders (men: 6.7% versus 2.8%; women: 9.2% versus 4.9%), and pulmonary disorders (men: 3.0% versus 1.8%; women: 4.8% versus 2.3%). Hypertension, coronary heart disease, and psychiatric disorders in specific age- and sex groups increased more in people with cluster headache than in controls during the recording period. Low/medium income was more prevalent in people with cluster headache versus controls (men: 50.2% versus 42.2%; women: 51.4% versus 46.6%). Similarly, low/medium education was more prevalent in people with cluster headache than controls (men: 77.0% versus 65.1%; women: 65.0% versus 55.0%). The prevalence of low/medium education increased in young women during the recording period.ConclusionsPeople with cluster headache have a higher prevalence of comorbidities compared to matched controls, particularly migraine, mood disorders, and cardiopulmonary disease. Multiple comorbidities have increased in prevalence over time. Annual income and years of education were lower in people with cluster headache compared to matched controls. Cluster headache is a complex disease that requires specialist follow-up and individualized therapy.