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Background: Cluster headache (CH) is a debilitating condition, but current therapies leave CH patients in pain. The extent of this problem in Sweden is unknown., Methods: An anonymized questionnaire was sent to 479 Swedish CH patients to investigate patterns and perceived effects of treatments., Results: Three hundred fourteen answers were analyzed. The population was representative regarding age of onset and sex. Less than half (46%) were satisfied with their abortive treatments, 19% terminated functioning abortive treatments due to side effects. Additionally, 17% of chronic CH patients had not tried the first-line preventive drug verapamil. A small subset had tried illicit substances to treat their CH (0-8% depending on substance). Notably, psilocybin was reported effective as an abortive treatment by 100% ( n = 8), and with some level of effect as a preventive treatment by 92% ( n = 12). For verapamil, some level of preventive effect was reported among 68% ( n = 85)., Conclusions: Our descriptive data illustrate that many Swedish CH patients are undertreated, lack functional therapies, and experience side effects. Further studies are warranted to search for new treatment strategies as well as a revision of current treatment guidelines with the aim of reducing patient disease burden to the greatest extent possible.

Patients diagnosed with the primary headache disorder known as cluster headache (CH) commonly report that their headache attacks occur in patterns of both circadian and seasonal rhythmicity. Vitamin D is essential for a variety of bodily functions and vitamin D levels are largely regulated by daylight exposure in connection with seasonal variation. For this Sweden-based study, the association between CH and three single-nucleotide polymorphisms in the vitamin D receptor gene, rs2228570, rs1544410, and rs731236, were investigated, as well as CH bouts and trigger factors in relation to seasonal and weather changes. Over 600 study participants with CH and 600 controls were genotyped for rs2228570, and genotyping results for rs1544410 and rs731236 were obtained from a previous genome-wide association study. The genotyping results were combined in a meta-analysis, with data from a Greek study. No significant association was found between rs2228570 and CH or the CH subtype in Sweden, nor did the meta-analysis show significant results for any of the three markers. The most common period of the year to experience CH bouts in Sweden was autumn, and conditions linked to weather or weather changes were also identified as potential triggers for CH bouts for a quarter of the responders who reported bout triggers. Though we cannot rule out vitamin D involvement in CH, this study does not indicate any connection between CH and the three vitamin D receptor gene markers.

The trigeminal autonomic cephalalgia, cluster headache (CH), is one of the most painful disorders known to man. One of the disorder's most striking features is the reported diurnal rhythmicity of the attacks. For a majority of patients, the headache attacks occur at approximately the same time every day. Genetic variants of genes involved in the circadian rhythm such as Period Circadian Regulator 1, 2, and 3 ( PER1 , 2 and 3 ) are hypothesized to have an effect on the rhythmicity of the attacks. Six PER1 , 2 and 3 genetic markers; the indel rs57875989 and five single nucleotide polymorphisms (SNPs), rs2735611, rs2304672, rs934945, rs10462020, and rs228697, were genotyped, using TaqMan ® or regular polymerase chain reaction (PCR), in a Swedish CH case control material. Logistic regression showed no association between CH and any of the six genetic variants; rs57875989, p = 0.523; rs2735611, p = 0.416; rs2304672, p = 0.732; rs934945, p = 0.907; rs10462020, p = 0.726; and rs228697, p = 0.717. Furthermore, no difference in allele frequency was found for patients reporting diurnal rhythmicity of attacks, nor were any of the variants linked to diurnal preference. The results of this study indicate no involvement of these PER genetic variants in CH or diurnal phenotype in Sweden.

Cluster headache is characterized by activation of the autonomic-trigeminal reflex. Nitric oxide can trigger headaches in patients, and nitric oxide signaling is known to be affected in cluster headache. Based on the hypothesis of nitric oxide being involved in cluster headache pathophysiology we investigated nitric oxide synthases as potential candidate genes for cluster headache. We analyzed eight variants in the three forms of nitric oxide synthase ( NOS ) genes, inducible NOS ( iNOS ), endothelial NOS ( eNOS ) and neuronal NOS ( nNOS ), and tested for association with cluster headache. Swedish cluster headache patients ( n = 542) and controls ( n = 581) were genotyped using TaqMan ® assays on an Applied Biosystems 7500 qPCR cycler. This is the largest performed genetic study on NOS involvement in cluster headache so far. We found an association between cluster headache and one iNOS haplotype consisting of the minor alleles of rs2297518 and rs2779249 ( p = 0.022). In addition, one of the analyzed nNOS variants, rs2682826, was associated with reported triptan use ( p = 0.039). Our data suggest that genetic variants in NOS genes do not have a strong influence on cluster headache pathophysiology, but that certain combinations of genetic variants in NOS genes may influence the risk of developing the disorder or triptan use.

Cluster headache is a severe primary headache characterized by extremely painful attacks of unilateral headache. Verapamil is commonly used as a prophylactic treatment with good effect. In order to search for new pathways involved in the pathophysiology of cluster headache, we analyzed genetic variants that were previously linked to verapamil response in migraine in a Swedish cluster headache case-control sample. We used TaqMan qPCR for genetic screening and performed a gene expression analysis on associated genes in patient-derived fibroblasts, and further investigated which reference genes were suitable for analysis in fibroblasts from cluster headache patients. We discovered a significant association between anoctamin 3 , a gene encoding a calcium-activated ion channel, and cluster headache. The association was not dependent on verapamil treatment since the associated variant, rs1531394, was also overrepresented in patients not using verapamil. No difference was found in the anoctamin 3 gene expression between controls and patients. Also, we determined that TBP , IPO8 and PDHB were suitable reference genes in cluster headache fibroblasts. This finding is the first report of an association between a variant in a gene encoding an ion-channel and cluster headache, and the first significant genetic evidence of calcium involvement in cluster headache pathophysiology., Competing Interests: The authors declare no conflict of interest.