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.

Objective: The objective of this cross‐sectional study was to investigate the extent of perceived sleep disturbances in a cluster headache cohort, and to compare how sleep is perceived between participants in an active headache bout to participants in a headache‐free remission period.Background: Cluster headache is a primary headache disorder characterized by extremely painful headache attacks. These attacks commonly occur with a circadian rhythm, with a majority of patients experiencing nocturnal attacks. Sleep is affected in patients with cluster headache, but there are many uncertainties regarding the pathophysiological connection between cluster headache and sleep disturbances and to what extent sleep disturbances persist into remission.Methods: A digital survey was sent out to 701 individuals with cluster headache between January and May 2024. The survey contained questions regarding general health, clinical cluster headache phenotype, and questions from the Karolinska Sleep Questionnaire, the Insomnia Severity Index, and the Dysfunctional Beliefs and Attitudes about Sleep‐10. Scores extracted from each questionnaire were compared between study participants in an active bout versus study participants in remission, and study participants in short‐term remission (<5 years) versus long‐term remission (≥5 years).Results: Of the 381 individuals who answered the survey, 325 were included in the final analysis. Participants in an active cluster headache bout reported increased sleep disturbances on all measurements compared to participants in remission (insomnia severity: adjusted odds ratio [aOR] = 1.12 [95% confidence interval (CI), 1.07–1.17] p < 0.001; sleep quality: aOR = 0.67 [95% CI, 0.53–0.83] p < 0.001; daytime sleepiness: aOR = 0.59 [95% CI, 0.44–0.78] p < 0.001; and dysfunctional beliefs: aOR = 1.03 [95% CI, 1.01–1.04] p = 0.001). Of the participants in an active bout, 46.5% scored above the Insomnia Severity Index threshold indicating moderate to severe insomnia (≥15) and 43.7% were considered as having poor sleep quality (≤3 on the Sleep Quality Index extracted from the Karolinska Sleep Questionnaire). This is in comparison to 22.0% of participants in remission being above the moderate insomnia threshold and 22.0% considered having poor sleep quality. Participants in long‐term remission had better sleep scores overall compared to participants in short‐term remission (insomnia severity: aOR = 1.09 [95% CI, 1.03–1.16] p = 0.005; daytime sleepiness: aOR = 0.67 [95% CI, 0.42–1.02] p = 0.072; and dysfunctional beliefs: aOR = 1.03 [95% CI, 1.01–1.05] p = 0.006).Conclusion: Individuals with cluster headache have a large degree of sleep disturbances that are exacerbated during an active bout and not completely alleviated during remission. Future studies are needed to determine if this gradual change in sleep disturbances after an active bout is due to physiological changes, which slowly revert to baseline levels after an active bout or connected to persisting negative behavioral or cognitive associations between sleep and headache.

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.

Background / Hypothesis: Headache attacks are reported to occur with circadian rhythmicity by 2/3 of individuals with cluster headache, hinting to potential dysfunctions of the molecular clock. The aim of this study was to investigate the contribution of genetic markers in core clock genes, alone or in combinations, to the genetic risk for cluster headache. Methods: Seven markers in core clock genes BMAL1 and NPAS2 were genotyped using TaqMan qPCR in 707 individuals with cluster headache and 682 controls. Genetic data from eleven additional markers located in six other core clock genes ( CLOCK , CRY1-2 , and PER1-3 ) was obtained from the database of the Centre for Cluster Headache at Karolinska Institutet. Genotype analysis was applied for risk analysis for combinations of up to three markers. For validation we used a cluster headache cohort from the National Hospital for Neurology and Neurosurgery, London, UK. Results and interpretation: Single marker analysis of the newly genotyped markers in BMAL1 and NPAS2 found rs3789327 and rs3768984 more frequently among individuals with cluster headache (p < 0.01 and p < 0.05 respectively). Multiallelic analysis revealed that the median number of risk alleles was eight for controls and nine for individuals with cluster headache, which justifies the analysis of combinations of markers. The analysis of combinations of up to three markers identified 258 out of 897 combinations to be associated with significant risk. Further investigation starting from the function of genes in the molecular clock transcription-translation feedback loop (TTFL) found that 80% of the combinations had >50% markers located in the positive arm of the TTFL. The comparison between Swedish and UK cohorts identified 39 concordant combinations, which confirmed the risk associated with rs3768984 ( NPAS2 ), as well as the enrichment in markers in BMAL1 , CLOCK , and NPAS2 in combinations associated with significant risk. Conclusion: Our data points to molecular clock dysfunction playing a central role in the manifestation of cluster headache.

The main hypothesis of this thesis is that cluster headache (CH) has a genetic component and by investigating this genetic component we can get insights into pathophysiological mechanisms behind CH. Clinical data can help indicate which genes can be contributing to the disease. The genetic variants can in turn help us better understand the biological mechanisms which give rise to CH. In that way we lay a foundation for developing treatment which can alleviate the suffering of millions of people around the world. This thesis focused on three major areas within CH research: sleep, treatment usage/response, and genetic links to CH pathophysiology.Sleep has long been studied in connection to CH due to the strikingly rhythmic nature of CH attacks which regularly disrupt sleep. In Paper I, we studied sleep patterns of CH participants using actigraph units to record sleep and wake times, complemented with sleep diaries. Actigraphy data showed that, although sleep time did not differ between CH participants and controls, sleep latency and time in bed was increased in CH participants. Participants with CH scored worse in almost all subjective sleep scores. Interestingly, in objective sleep measurements, CH participants in an active bout did not significantly differ to participants in remission.In Paper II, a survey investigating sleep quality, dysfunctional beliefs regarding sleep, and insomnia symptoms was sent to >700 CH participants. The survey results further established that sleep is disturbed during an active bout as compared to participants in remission and even more so to the general population. The sleep scores were additionally correlated to years since last active bout, again indicating participants in remission are still disrupted by the disease. Paper III used a similar method to investigate extent of burnout in the CH cohort. As high as 67.6% of participants in an active bout were in the risk zone for burnout. Burnout symptoms were also present in remission, but to a lesser degree and correlated to the length of time since the last active bout.To study possible biological links to the observed sleep patterns and circadian rhythm of attacks we studied genetic variants in biological clock genes. PER, CRY, BMAL1, and CLOCK are the core clock genes which drives the 24-hour rhythm. In Paper IV six genetic variants were genotyped in PER1, PER2, and PER3 which had previous links to diurnal preference or sleep. No significant difference between CH participants and controls was found. In Paper V, genetic variants in BMAL1, and NPAS2, a paralog to CLOCK, were investigated. Variants in BMAL1 (rs3789327) and NPAS2 (rs3768984) were associated with CH. Significant or trending genetic variants in the core clock genes from this study and previous studies were combined in a multi allele risk analysis. This analysis showed that CH participants carried more risk alleles than controls further strengthening the possible role of the biological clock in CH.Treatment response can vary greatly between different individuals and treatment options, and is not fully understood. In Paper VI a survey was sent out to investigate treatment response in a Swedish CH cohort. It confirmed the previously reported wide range of treatment responses observed for CH. Surprisingly, a considerable number of CH participants didn’t take any preventative medication. Side effects were common and prevented some participants with continuing their otherwise effective treatment.Since treatment response varied between participants, Paper VII investigated if genetics could partially explain this variation in the first line treatment, triptans. Five genetic variants which had previously been linked to triptan response in other diseases were genotyped and the allelic distribution was compared between triptan users and non-users. One single nucleotide polymorphism (SNP) previously linked to triptan response in migraine was significantly associated with CH triptan usage, meaning the mechanisms of action behind triptan non-response could be similar.Anecdotally, some CH patients have reported taking vitamin D supplements to improve their CH. To investigate if this was reflected in genetics, a SNP in the VDR gene was genotyped in Paper VIII. We pooled the data from the genotyped SNP and two other VDR SNPs from our previous genome-wide association study (GWAS) with data from a Greek CH cohort into a meta-analysis. No significant associations were found to CH for any of the SNPs.In the last few years genetics have increasingly shown to play an important role in CH pathology. In Paper IX, a meta-GWAS was performed on genetic material from 11 cohorts comparing CH participants to controls. When only including the 10 European cohorts, the four significant loci from previous CH GWAS were replicated, in proximity to the genes MERTK, DUSP10, FTCDNL1, and FHL5. Three new loci reached genome wide significance: WNT2, PLCE1, and LRP1.The next step was to translate the genetic findings to possible biological pathways which can contribute to the disease. MERTK is a cell-surface receptor mostly present on immune cells which plays a role in immune suppression, efferocytosis, and a range of other functions. Paper X investigated its potential role in CH. Trigeminal nerves from rats were stained with MERTK antibodies. MERTK was found to be present in Satellite cells and in Schwann cells close to the nodes of Ranvier which would allow MERTK to bind to its ligands if they were released during neuronal activation. Additionally, the protein expression levels of three of MERTK’s ligands were measured in serum. Protein levels of Galectin-3 were significantly higher in CH participants compared to controls.To further investigate a possible immunological mechanism in CH, in Paper XI cerebral spinal fluid (CSF) and serum samples were sent for an immunoassay which allowed us to look at concentrations of dozens of proteins. Eleven immune system related...