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Background The aim of this study was to investigate clinical features of a cluster headache cohort in Sweden and to construct and test a new scale for grading severity. Methods Subjects were identified by screening medical records for the ICD 10 code G44.0, that is, cluster headache. Five hundred participating research subjects filled in a questionnaire including personal, demographic and medical aspects. We constructed a novel scale for grading cluster headache in this cohort: The Cluster Headache Severity Scale, which included number of attacks per day, attack and period duration. The lowest total score was three and the highest 12, and we used the Cluster Headache Severity Scale to grade subjects suffering from cluster headache. We further implemented the scale by defining a cluster headache maximum severity subgroup with a high Cluster Headache Severity Scale score ≥ 9. Results A majority (66.7%) of the patients reported that attacks appear at certain time intervals. In addition, cluster headache patients who were current tobacco users or had a history of tobacco consumption had a later age of disease onset (31.7 years) compared to non-tobacco users (28.5 years). The Cluster Headache Severity Scale score was higher in the patient group reporting sporadic or no alcohol intake than in the groups reporting an alcohol consumption of three to four standard units per week or more. Maximum severity cluster headache patients were characterised by higher age at disease onset, greater use of prophylactic medication, reduced hours of sleep, and lower alcohol consumption compared to the non-cluster headache maximum severity group. Conclusion There was a wide variation of severity grade among cluster headache patients, with a very marked impact on daily living for the most profoundly affected.

Objective This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. Methods We carried out a genome‐wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene‐set enrichment, functional variant annotation, prediction and pathway analyses, were performed. Results Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10−17, odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37–1.66) and rs4519530 (p = 6.98 × 10−17, OR = 1.47, 95% CI = 1.34–1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10−8, OR = 1.36, 95% CI = 1.22–1.52), and rs11153082 (p = 1.85 × 10−8, OR = 1.30, 95% CI = 1.19–1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. Interpretation We identified and replicated several genome‐wide significant associations supporting a genetic predisposition in cluster headache in a genome‐wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype–phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193–202

Background Cluster headache is characterized by recurrent unilateral headache attacks of severe intensity. One of the main features in a majority of patients is a striking rhythmicity of attacks. The CLOCK ( Circadian Locomotor Output Cycles Kaput) gene encodes a transcription factor that serves as a basic driving force for circadian rhythm in humans and is therefore particularly interesting as a candidate gene for cluster headache. Methods We performed an association study on a large Swedish cluster headache case-control sample (449 patients and 677 controls) screening for three single nucleotide polymorphisms (SNPs) in the CLOCK gene implicated in diurnal preference (rs1801260) or sleep duration (rs11932595 and rs12649507), respectively. We further wanted to investigate the effect of identified associated SNPs on CLOCK gene expression. Results We found a significant association with rs12649507 and cluster headache ( p = 0.0069) and this data was strengthened when stratifying for reported diurnal rhythmicity of attacks ( p = 0.0009). We investigated the effect of rs12649507 on CLOCK gene expression in human primary fibroblast cultures and identified a significant increase in CLOCK mRNA expression ( p = 0.0232). Conclusions Our results strengthen the hypothesis of the involvement of circadian rhythm in cluster headache.

Background and Objectives:Cluster headache is considered a male-dominated disorder, but we have previously suggested that females may display a more severe phenotype. Studies on sex differences in cluster headache have been conflicting, therefore this study, with the largest validated cluster headache material at present, gives more insights into sex-specific characteristics of the disease. The objective with this study was to describe sex differences in patient demographics, clinical phenotype, chronobiology, triggers, treatment, and lifestyle in a Swedish cluster headache population.Methods:Study participants were identified by screening medical records from 2014 – 2020, requested from hospitals and neurology clinics in Sweden for the International Classification of Diseases 10 code G44.0 for cluster headache. Each study participant answered a detailed questionnaire on clinical information and lifestyle and all variables were compared with regards to sex.Results:874 study participants with a verified cluster headache diagnosis were included. 575 (66%) were male and 299 (34%) were female and biological sex matched self-reported sex for all. Females were to a greater extent diagnosed with the chronic cluster headache subtype compared to males (18% vs 9%,P=0.0002). In line with this observation, female participants report longer bouts than male participants (P=0.003) and used prophylactic treatment more often (60% vs 48%,P=0.0005). Regarding associated symptoms, females experienced ptosis (61% vs 47%,P=0.0002) and restlessness (54% vs 46%,P=0.02) more frequently compared to males. More female than male study participants had a positive family history for cluster headache (15% vs 7%,P=0.0002). In addition, females reported diurnal rhythmicity of their attacks more often than males (74% vs 63%,P=0.002). Alcohol as a trigger occurred more frequently in males (54% vs 48%,P=0.01), while lack of sleep triggering an attack was more common in females (31% vs 20%,P=0.001).Discussion:With this in-depth analysis of a well-characterized cluster headache population, we could demonstrate that there are significant differences between males and females with cluster headache which should be regarded at time of diagnosis and when choosing treatment options. The data suggests that females generally may be more gravely affected by cluster headache than males.