Objectives To compare the clinical profiles between male and female cluster headache patients from a large cohort. Methods This hospital-based study enrolled patients diagnosed with cluster headache between 1997 to 2021. Participants completed structured questionnaires collecting information on demographics, clinical profiles, and quality of life. Treatment regimens and effectiveness were determined through medical chart review. All variables were compared between the sexes. Results In total, 798 patients (M/F:659/139) were enrolled. The male-to-female ratio was 4.7:1 for the full study period, but it declined from 5.2:1 to 4.3:1 for patients enrolled before and after 2010, respectively. The frequencies of chronic cluster headache (M:1.2%, F:1.4%) and aura (M:0.3%, F:0.7%) were low but similar between the sexes. Most headache features showed no difference between men and women. Female patients had significantly longer attack duration, shorter inter-bout duration, higher frequencies for eyelid edema, nausea and vomiting and lower frequencies for conjunctival injection and pacing. Sex difference did not influence headache-associated disability, anxiety, or depression, but poor sleep quality was significantly more common in women. Among menstruating women, 22/122 (18.0%) reported worsening headaches during menses. The effectiveness of treatment was similar between the sexes. Conclusions Despite a decline of male-to-female ratio in the past two decades, most clinical profiles were similar between the sexes.

ObjectiveThe objective of this study was to aggregate data for the first genomewide association study meta‐analysis of cluster headache, to identify genetic risk variants, and gain biological insights.MethodsA total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse‐variance genomewide association meta‐analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans‐ancestry meta‐analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome‐wide association, fine‐mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses.ResultsThe estimated single nucleotide polymorphism (SNP)‐based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta‐analysis, and one additional locus in the trans‐ethnic meta‐analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk‐taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine.InterpretationThis first genomewide association study meta‐analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023

Background We aimed to assess the differences in quantitative sensory testing between chronic migraine and healthy controls and to explore the association between pain sensitivities and outcomes in chronic migraine following preventive treatment. Methods In this prospective open-label study, preventive-naïve chronic migraine and healthy controls were recruited, and cold, heat, mechanical punctate, and pressure pain thresholds over the dermatomes of first branch of trigeminal nerve and first thoracic nerve were measured by quantitative sensory testing at baseline. Chronic migraines were treated with flunarizine and treatment response was defined as ≥50% reduction in the number of monthly headache days over the 12-week treatment period. Results Eighty-four chronic migraines and fifty age-and-sex-matched healthy controls were included in the analysis. The chronic migraine had higher cold pain thresholds over the dermatomes of the first branch of trigeminal nerve and the first thoracic nerve ( p < 0.001 and < 0.001), lower pressure pain thresholds over the dermatomes of the first thoracic nerve ( p = 0.003), heat pain thresholds over the dermatomes of the first branch of the trigeminal nerve and the first thoracic nerve ( p < 0.001 and p = 0.015) than healthy controls. After treatment, 24/84 chronic migraine had treatment response. The responders with relatively normal pain sensitivity had higher heat pain thresholds over the dermatome of the first branch of the trigeminal nerve ( p = 0.002), mechanical punctate pain thresholds over the dermatomes of the first branch of the trigeminal nerve ( p = 0.023), and pressure pain thresholds over the dermatomes of the first branch of the trigeminal nerve ( p = 0.026) than the hypersensitive non-responders. Decision tree analysis showed that patients with mechanical punctate pain threshold over the dermatomes of the first branch of the trigeminal nerve > 158 g ( p = 0.020) or heat pain threshold over the dermatome of the first branch of the trigeminal nerve > 44.9°C ( p = 0.002) were more likely to be responders. Conclusions Chronic migraine were generally more sensitive compared to healthy controls. Preventive treatment with flunarizine should be recommended particularly for chronic migraine who have relatively normal sensitivity to mechanical punctate or heat pain. Trial registration: This study was registered on ClinicalTrials.gov (Identifier: NCT02747940).