Compensated Hypogonadism Identified in Males with Cluster Headache: A Prospective Case-Controlled Study.

OBJECTIVE: Androgens have been hypothesized to be involved in the pathophysiology of cluster headache due to the male predominance, but whether androgens are altered in patients with cluster headache remains unclear. METHODS: We performed a prospective, case-controlled study in adult males with cluster headache. Sera were measured for hormones including testosterone, luteinizing hormone (LH), and sex hormone-binding globulin in 60 participants with episodic cluster headache (during a bout and in remission), 60 participants with chronic cluster headache, and 60 age- and sex-matched healthy controls. Free testosterone (fT) was calculated according to the Vermeulen equation. Shared genetic risk variants were assessed between cluster headache and testosterone concentrations. RESULTS: The mean fT/LH ratio was reduced by 35% (95% confidence interval [CI]: 21%-47%, p < 0.0001) in patients with chronic cluster headache and by 24% (95% CI: 9%-37%, p = 0.004) in patients with episodic cluster headache compared to controls after adjusting for age, sleep duration, and use of acute medication. Androgen concentrations did not differ between bouts and remissions. Furthermore, a shared genetic risk allele, rs112572874 (located in the intron of the microtubule associated protein tau (MAPT) gene on chromosome 17), between fT and cluster headache was identified. INTERPRETATION: Our results demonstrate that the male endocrine system is altered in patients with cluster headache to a state of compensated hypogonadism, and this is not an epiphenomenon associated with sleep or the use of acute medication. Together with the identified shared genetic risk allele, this may suggest a pathophysiological link between cluster headache and fT. ANN NEUROL 2024;95:1149-1161.

Reduced plasma calcitonin gene-related peptide level identified in cluster headache: A prospective and controlled study.

BACKGROUND: The role of calcitonin gene-related peptide (CGRP) in the cyclic pattern of cluster headache is unclear. To acquire biological insight and to comprehend why only episodic cluster headache responds to CGRP monoclonal antibodies, we examined whether plasma CGRP changes between disease states (i.e. bout, remission and chronic) and controls. METHODS: The present study is a prospective case-control study. Participants with episodic cluster headache were sampled twice (bout and remission). Participants with chronic cluster headache and controls were sampled once. CGRP concentrations were measured in plasma with a validated radioimmunoassay. RESULTS: Plasma was collected from 201 participants diagnosed with cluster headache according to the International Classification of Headache Disorders, 3rd edition, and from 100 age- and sex-matched controls. Overall, plasma CGRP levels were significantly lower in participants with cluster headache compared to controls (p < 0.05). In episodic cluster headache, CGRP levels were higher in bout than in remission (mean difference: 17.1 pmol/L, 95% confidence interval = 9.8-24.3, p < 0.0001). CGRP levels in bout were not different from chronic cluster headache (p = 0.266). CONCLUSIONS: Plasma CGRP is unsuitable as a diagnostic biomarker of cluster headache or its disease states. The identified reduced CGRP levels suggest that CGRPs role in cluster headache is highly complex and future investigations are needed into the modulation of CGRP and its receptors.

Current treatment options for cluster headache: limitations and the unmet need for better and specific treatments-a consensus article.

AIM: Treatment for cluster headache is currently based on a trial-and-error approach. The available preventive treatment is unspecific and based on few and small studies not adhering to modern standards. Therefore, the authors collaborated to discuss acute and preventive treatment in cluster headache, addressing the unmet need of safe and tolerable preventive medication from the perspectives of people with cluster headache and society, headache specialist and cardiologist. FINDINGS: The impact of cluster headache on personal life is substantial. Mean annual direct and indirect costs of cluster headache are more than 11,000 Euros per patient. For acute treatment, the main problems are treatment response, availability, costs and, for triptans, contraindications and the maximum use allowed. Intermediate treatment with steroids and greater occipital nerve blocks are effective but cannot be used continuously. Preventive treatment is sparsely studied and overall limited by relatively low efficacy and side effects. Neurostimulation is a relevant option for treatment-refractory chronic patients. From a cardiologist's perspective use of verapamil and triptans may be worrisome and regular follow-up is essential when using verapamil and lithium. CONCLUSION: We find that there is a great and unmet need to pursue novel and targeted preventive modalities to suppress the horrific pain attacks for people with cluster headache.

Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor.

OBJECTIVE: The 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. METHODS: A 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. RESULTS: The 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. INTERPRETATION: This 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;94:713-726.

Cluster headache polygenetic risk and known functional variants of CYP3A4 are not associated with treatment response.

BACKGROUND AND PURPOSE: The response to cluster headache treatments has a high interindividual variation. To date, treatment response has only been assessed by a candidate gene approach and no investigations into metabolic pathways have been performed. Our aim was to investigate the association between the polygenetic risk of cluster headache and treatment response to first-line cluster headache treatments as well as known functional variants of CYP3A4 and the response to verapamil. Further, it was aimed to replicate previous single nucleotide polymorphisms found to be associated with treatment response in cluster headache and/or migraine. METHODS: In, 508 cluster headache patients diagnosed according to the International Classification of Headache Disorders were genotyped and participated in a semi-structured interview to evaluate treatment response. Polygenetic risk scores were calculated by the effect retrieved from a meta-analysis of the latest two genome-wide association studies on cluster headache. RESULTS: Inferior treatment response to oxygen, triptans and verapamil is associated with chronicity of cluster headache were confirmed but no evidence was found that a response could be predicted by a high genetic risk of cluster headache. Likewise, verapamil response was not associated with functional variants of CYP3A4. No support of the genetic variants previously reported to be associated with treatment response to triptans or verapamil was found. CONCLUSION: The clinically relevant variation in treatment response for cluster headache was not influenced by genetic factors in the present study.

Transition of cluster headache phenotype: An interview-based study.

Background Cluster headache exists diagnostically in a chronic and episodic variant between which patients can convert. We aimed to describe how many patients change phenotype, elucidate possible factors associated with this transition and identify differences in clinical features between primary and secondary phenotypes.Methods 540 well-defined cluster headache patients according to current ICHD-criteria completed a cross-sectional semi-structured interview.Results Total transition-incidence for the cohort was 20.7%. Conversion from chronic to episodic was reported by 6.3% and transition from episodic to chronic by 14.4% with attack side shift as a possible predictor (p = 0.007). Compared to primary chronic patients, secondary chronic patients had more frequent (60 vs 34 per month, p = 0.0487), but shorter (60 vs 90 minutes, p = 0.041) attacks. Secondary episodic patients experienced shorter remission periods than primary episodic patients (6 vs 11 months, p = 0.010). Treatment response was poor in all groups and only one third had effective prevention.Conclusion Cluster headache is a fluctuating disorder with a fifth of our cohort having experienced at least one phenotype change during course of disease. Apart from attack side shifts, no predictors for transition were identified. Severity differed between primary and secondary subtypes. Overall, there is an urgent need for better understanding of cluster headache.

The economic and personal burden of cluster headache: a controlled cross-sectional study.

BACKGROUND: Cluster headache is a less-prevalent primary headache disorder but is overrepresented with regards to use of health care and social services. More insight into the socioeconomic impact is required. METHODS: We investigated both the personal and societal disease burden and cost in 400 patients with well-classified cluster headache according to the ICHD-criteria and 200 sex- and age matched controls. All participants completed a cross sectional questionnaire and semi-structured interview. RESULTS: Patients with chronic cluster headache constituted 146 out of 400 (37%). Overall, restriction in personal and/or professional life was reported by 94% of patients during attack periods. Even in remission, nine times as many episodic patients rated their health as poor/very poor compared to controls (9% vs 1%, p = 0.002). For chronic patients, the odds of rating health as good/very good were ten times lower compared to controls (OR:10.10, 95%CI:5.29-18.79. p < 0.001) and three times lower compared to episodic patients in remission (OR:3.22, 95%CI:1.90-5.47, p < 0.001). Additionally, chronic cluster headache patients were 5 times more likely to receive disability pension compared to episodic (OR:5.0, 95%CI:2.3-10.9, p < 0.001). The mean direct annual costs amounted to 9,158€ and 2,763€ for chronic and episodic patients, respectively (p < 0.001). We identified a substantial loss of productivity due to absence from work resulting in a higher indirect cost of 11,809 €/year/patient in the chronic population and 3,558 €/year/patient in the episodic population. Presenteeism could not be quantified but productivity was reduced in patients by 65% in periods with attacks compared to controls. CONCLUSION: Cluster headache has a major negative impact on personal life, self-perceived health, and societal cost. Patients with the chronic variant are vastly more burdened. Patients with the episodic form were still markedly affected during the remission period. This study highlights the need for more effective therapy to lighten the burden on patients and society.

Reference programme: diagnosis and treatment of headache disorders and facial pain. Danish Headache Society, 3rd edition, 2020.

Headache and facial pain are among the most common, disabling and costly diseases in Europe, which demands for high quality health care on all levels within the health system. The role of the Danish Headache Society is to educate and advocate for the needs of patients with headache and facial pain. Therefore, the Danish Headache Society has launched a third version of the guideline for the diagnosis, organization and treatment of the most common types of headaches and facial pain in Denmark. The second edition was published in Danish in 2010 and has been a great success, but as new knowledge and treatments have emerged it was timely to revise the guideline. The recommendations for the primary headaches and facial pain are largely in accordance with the European guidelines produced by the European Academy of Neurology. The guideline should be used a practical tool for use in daily clinical practice for primary care physicians, neurologists with a common interest in headache, as well as other health-care professionals treating headache patients. The guideline first describes how to examine and diagnose the headache patient and how headache treatment is organized in Denmark. This description is followed by sections on the characteristics, diagnosis and treatment of each of the most common primary and secondary headache disorders and trigeminal neuralgia. The guideline includes many tables to facilitate a quick overview. Finally, the particular challenges regarding migraine and female hormones as well as headache in children are addressed.

Real-life treatment of cluster headache in a tertiary headache center - results from the Danish Cluster Headache Survey.

BACKGROUND: Pharmacological treatment of cluster headache constitutes the core of clinical management, but evidence is sparse. We aimed to generate insight in the existing treatment and identify associations between clinical features and treatment response. METHODS: Patients aged 18-65 diagnosed with cluster headache according to the ICHD-2 completed a questionnaire followed by a structured interview. Multiple logistic regression was used to identify associations. RESULTS: The population consisted of 400 patients with an episodic: chronic ratio of 1.7:1. Episodic patients were more likely to respond to triptans (odds ratio = 1.77, confidence interval: 1.08-2.91, p = 0.023) and oxygen (odds ratio = 1.64, confidence interval: 1.05-2.57, p = 0.031) than chronic. Oxygen response was less likely if pain intensity was very severe (odds ratio = 0.53, confidence interval: 0.33-2.57, p = 0.006) and the risk of a poor response increased with disease duration (odds ratio = 0.79, confidence interval: 0.65-0.96, p = 0.016). Among current users of sumatriptan injection and oxygen, the proportion achieving 100% relief was higher with sumatriptan injection (p > 0.001) than with oxygen. No associations were identified regarding verapamil. Only 57% of current users of preventive medication responded at a 50% level. CONCLUSION: Episodic cluster headache is more responsive to acute therapy than chronic. Further, sumatriptan injection was more effective than oxygen and the responder-rate was limited with verapamil. More effective acute and preventive therapies are needed for cluster headache patients.

Diagnostic delay of cluster headache: A cohort study from the Danish Cluster Headache Survey.

AIM: To investigate the influence of clinical and demographic features on diagnostic delay in cluster headache patients, in order to discuss diagnostic pitfalls and raise disease awareness. METHODS: A large, well-characterized cohort of 400 validated cluster headache patients from the Danish Cluster Headache Survey, diagnosed according to ICHD-II, were investigated. ANOVA was applied to investigate differences in diagnostic delay between groups. Selected independent variables were assessed in relation to diagnostic delay using a gamma regression model. RESULTS: Diagnostic delay was significantly reduced for each decade of cluster headache onset from 1950-2010 (p < 0.001). Onset after 1990 was associated with shorter diagnostic delay (OR = 0.28, p < 0.001), whereas attack duration > 180 minutes (OR = 1.62, p < 0.034), migraine-like features (OR = 1.30, p < 0.043) and nocturnal attacks (OR = 1.39, p < 0.021) were associated with prolonged diagnostic delay. Further, diagnostic delay decreased with age of onset (age < 20: 13.8 years, age 20-40: 5.4 years and age > 40: 2.1 years, p < 0.001). CONCLUSION: Diagnostic delay was reduced for every decade investigated, whereas some atypical cluster headache features were associated with prolonged diagnostic delay. Better medical education and more disease awareness are needed to prevent misdiagnosis and prolonged diagnostic delay.

Episodic and Chronic Cluster Headache: Differences in Family History, Traumatic Head Injury, and Chronorisk.

OBJECTIVE AND BACKGROUND: The diagnostic criteria of episodic and chronic cluster headache (cCH) were recently modified, yet pathophysiological differences between the two are still unclear. The aim of this cross-sectional study is to identify and characterize other differences between episodic and cCH. METHODS: Data from a retrospective, questionnaire- and interview-based study were analyzed with a focus on associated factors including traumatic head injury (THI), familial history, and change of phenotype. Attack patterns were analyzed using Gaussian and spectral modeling. RESULTS: 400 patients and 200 controls participated. A positive family history was more prevalent in chronic than episodic cluster headache (eCH) (34/146 (23%) vs 33/253 (13%), respectively, P = .008). A history of THI was more common in patients than controls (173/400 (43%) vs 51/200 (26%), respectively, P < .0001) and in chronic compared to eCH (77/146 (53%) vs 96/253 (37%), respectively, P = .004). Patients with a positive family history had a unique diurnal attack pattern with twice the risk of nocturnal attacks as patients who did not report family history. Patients reporting phenotype change had a chronobiological fingerprint similar to the phenotype they had experienced a transition into. A higher attack frequency in chronic patients was the only difference in symptom manifestation across all analyzed subgroups of patients. CONCLUSIONS: cCH is associated with a positive family history and THI. In familial CH, a peak in nocturnal chronorisk may implicate genes involved in diurnal-, sleep- and homeostatic regulation. The stereotypical nature of the CH attacks themselves is confirmed and differences between subgroups should be sought in other characteristics.

Genetics of cluster headache.

BACKGROUND: Cluster headache is the most severe primary headache disorder. A genetic basis has long been suggested by family and twin studies; however, little is understood about the genetic variants that contribute to cluster headache susceptibility. METHODS: We conducted a literature search of the MEDLINE database using the PubMed search engine to identify all human genetic studies for cluster headache. In this article we provide a review of those genetic studies, along with an overview of the pathophysiology of cluster headache and a brief review of migraine genetics, which have both been significant drivers of cluster headache candidate gene selection. RESULTS: The investigation of cluster headache genetic etiology has been dominated by candidate gene studies. Candidate selection has largely been driven by the pathophysiology, such as the striking rhythmic nature of the attacks, which spurred close examination of the circadian rhythm genes CLOCK and HCRTR2. More recently, unbiased genetic approaches such as genome-wide association studies (GWAS) have yielded new genetic avenues of interest including ADCYAP1R1 and MME. CONCLUSIONS: The majority of candidate genes studied for cluster headache suffer from poor reproducibility. Broader genetic interrogation through larger unbiased GWAS, exome, and whole genome studies may provide more robust candidates, and in turn provide a clearer understanding of the causes of cluster headache.

The influence of lifestyle and gender on cluster headache.

PURPOSE OF REVIEW: Cluster headache is by many regarded as a males' disorder that is often accompanied by an unhealthy lifestyle. We aimed to study the influence of sex and lifestyle factors on clinical presentation, the diagnostic process and management. RECENT FINDINGS: Overall, the clinical presentation of cluster headache in both sexes was similar; however, chronic cluster headache may occur more frequently in women than in men. Misdiagnosis was most prevalent in women and more women than men were not correctly diagnosed until seen in a highly specialized center. In relation to lifestyle, smoking prevalence remains very high and some studies suggest that obesity and use of illegal drugs may be pronounced as well. In contrast to previous beliefs, recent findings on alcohol consumption report a lower use in patients than in controls. Overall, men and to some extent chronic patients were more prone to some unhealthy lifestyle factors than women and episodic patients. SUMMARY: Despite an overall similar clinical presentation in men and women, the diagnostic process was more problematic for women in the form of more frequent misdiagnosis and failure to diagnose women in the primary and secondary sectors. Unhealthy lifestyle factors are prevalent in cluster headache and may ultimately have consequences for the management of the disease.

Cluster headache is associated with unhealthy lifestyle and lifestyle-related comorbid diseases: Results from the Danish Cluster Headache Survey.

AIM: To compare the prevalence of unhealthy lifestyle factors and comorbid disorders in cluster headache patients with headache-free controls, in order to discuss pathophysiology and possible consequences. METHODS: Cluster headache patients from the Danish cluster headache survey aged 18-65 years, diagnosed according to ICHD-II, were compared to sex- and age-matched headache-free controls. Participants completed questionnaires and structured interviews. RESULTS: A total of 400 cluster headache patients and 200 controls participated. Patients had a more unhealthy lifestyle compared with controls in the form of current and current/former smoking (48.3% vs. 9.0%, p < 0.001 and 74.5% vs. 30.0%, p < 0.001, respectively), higher average alcohol intake per week (98.2 grams vs. 77.9 grams, p = 0.033) and BMI (26.1 vs. 24.2 kg/m2, p < 0.001), whereas coffee and energy drink consumption was equally distributed. Further, lifestyle-related, psychiatric and pain-related diseases were much more prevalent in patients compared with controls, except for diabetes. Sub-group analyses revealed that current/former smokers had a worse clinical presentation than never smokers. CONCLUSION: Unhealthy lifestyle factors and lifestyle-related diseases were more prevalent in cluster headache patients compared to controls. As lifestyle-related diseases might have serious consequences in the management of cluster headache, it is key to inform patients at an early time point about the possible risks of their lifestyle choices.

Sleep in cluster headache revisited: Results from a controlled actigraphic study.

BACKGROUND AND AIM: Cluster headache attacks exhibit a nocturnal predilection, but little is known of long-term sleep and circadian rhythm. The aim was to compare actigraphy measures, firstly in episodic cluster headache patients in bout and in remission and, secondly, to compare each disease phase with controls. METHODS: Episodic cluster headache patients (ICHD III-beta), from the Danish Headache Center and healthy, age- and sex-matched controls participated. Sleep and activity were measured using actigraphy continuously for 2 weeks, along with sleep diaries and, for patients, also attack registration. RESULTS: Patients in bout (n = 17, 2.3 attacks/day) spent more time in bed (8.4 vs. 7.7 hours, p = 0.021) and slept more (7.2 vs. 6.6 hours, p = 0.036) than controls (n = 15). In remission (n = 11), there were no differences compared with controls. Neither were there differences between patients in the two disease phases. In five patients, attacks/awakenings occurred at the same hour several nights in a row. CONCLUSION: Actigraphy offers the possibility of a continuous and long study period in a natural (non-hospital) environment. The study indicates that sleep does not differ between the bout and remission phase of episodic cluster headache. The repeated attacks/awakenings substantiate that circadian or homeostatic mechanisms are involved in the pathophysiology. The protocol was made available at ClinicalTrials.gov (NCT02853487).

Cluster headache beyond the pain phase: A prospective study of 500 attacks.

OBJECTIVE: To describe the nature, prevalence, and duration of symptoms in the preictal, ictal, and postictal phases of cluster headache (CH) attacks. METHODS: Fifty-seven patients with episodic or chronic CH participated in this prospective, observational study. In a questionnaire concerning 33 CH and migraine-related symptoms, patients reported the clinical features of up to 10 CH attacks/patient. The questionnaire was divided into 3 sections: a preictal phase, ictal phase, and postictal phase. For each phase, patients documented whether the given symptom was present, and if possible estimated the duration of the symptom. RESULTS: In total, 500 CH attack descriptions were obtained. In the preictal phase, general symptoms (most frequently concentration difficulties, restlessness, and mood changes) occurred 20 minutes prior to 46.0% of attacks. Local painful and autonomic symptoms were observed 10 minutes prior to 54.6% and 35% of attacks, respectively. Postictally, pain and autonomic symptoms resolved over 20 minutes, leaving patients with fatigue (36.2%), decreased energy (39.0%), and concentration difficulties (27.6%), lasting a median of 60 minutes. CONCLUSIONS: Preictal and postictal symptoms are very frequent in CH, demonstrating that CH attacks are not composed of a pain phase alone. Since the origin of CH attacks is unresolved, studies of preictal and postictal symptoms could contribute to the understanding of CH pathophysiology and, potentially, early, abortive treatment strategies.

Changes in medication cost observed in chronic cluster headache patients treated with sphenopalatine ganglion (SPG) stimulation: Analysis based on 1-year data from the Pathway R-1 Registry.

Background On-demand stimulation of the sphenopalatine ganglion (SPG) by means of an implantable neurostimulation system has been shown to be a safe and effective therapy for treatment-refractory cluster headache patients. Our objective was to estimate changes in cluster headache medication cost observed in SPG-treated chronic patients. Methods Detailed patient-level data of 71 chronic patients treated with the Pulsante® SPG Microstimulator System were available from the Pathway R-1 Registry through 12 months' follow-up. We used utilization data of preventive and acute medications reported at baseline, 3, 6, 9, and 12 months to estimate annualized drug costs for SPG-treated patients and compared it to baseline. Cost estimates for all drug/dosage combinations were developed based on German medication prices for 2016. Results In the base case analysis, mean annual acute and preventive medication costs decreased from €14,178 to €6924 (-€7254; -51%), and €559 to €328 (-€231; -41%), respectively, leading to total estimated annual drug cost savings of €7484, 97% of which were attributable to acute medications. Conclusions Our analysis suggests that SPG stimulation for the treatment of chronic cluster headache is associated with pronounced reductions in cluster headache medication usage that might lead to sizable annual savings in medication costs.

Chronorisk in cluster headache: A tool for individualised therapy?

BACKGROUND: The mechanisms behind the severe pain of cluster headache remain enigmatic. A distinguishing feature of the attacks is the striking rhythms with which they occur. We investigated whether statistical modelling can be used to describe 24-hour attack distributions and identify differences between subgroups. METHODS: Common hours of attacks for 351 cluster headache patients were collected. Probability distributions of attacks throughout the day (chronorisk) was calculated. These 24-hour distributions were analysed with a multimodal Gaussian fit identifying periods of elevated attack risk and a spectral analysis identifying oscillations in risk. RESULTS: The Gaussian model fit for the chronorisk distribution for all patients reporting diurnal rhythmicity (n = 286) had a goodness of fit R2 value of 0.97 and identified three times of increased risk peaking at 21:41, 02:02 and 06:23 hours. In subgroups, three to five modes of increased risk were found and goodness of fit values ranged from 0.85-0.99. Spectral analysis revealed multiple distinct oscillation frequencies in chronorisk in subgroups including a dominant circadian oscillation in episodic patients and an ultradian in chronic. CONCLUSIONS: Chronorisk in cluster headache can be characterised as a sum of individual, timed events of increased risk, each having a Gaussian distribution. In episodic cluster headache, attacks follow a circadian rhythmicity whereas, in the chronic variant, ultradian oscillations are dominant reflecting a loss of association with sleep and perhaps explaining observed differences in the effects of specific treatments. The results demonstrate the ability to accurately model chronobiological patterns in a primary headache.

Pre-attack signs and symptoms in cluster headache: Characteristics and time profile.

Introduction In contrast to the premonitory phase of migraine, little is known about the pre-attack (prodromal) phase of a cluster headache. We aimed to describe the nature, prevalence, and duration of pre-attack symptoms in cluster headache. Methods Eighty patients with episodic cluster headache or chronic cluster headache, according to ICHD-3 beta criteria, were invited to participate. In this observational study, patients underwent a semi-structured interview where they were asked about the presence of 31 symptoms/signs in relation to a typical cluster headache attack. Symptoms included previously reported cluster headache pre-attack symptoms, premonitory migraine symptoms and accompanying symptoms of migraine and cluster headache. Results Pre-attack symptoms were reported by 83.3% of patients, with an average of 4.25 (SD 3.9) per patient. Local and painful symptoms, occurring with a median of 10 minutes before attack, were reported by 70%. Local and painless symptoms and signs, occurring with a median of 10 minutes before attack, were reported by 43.8% and general symptoms, occurring with a median of 20 minutes before attack, were reported by 62.5% of patients. Apart from a dull/aching sensation in the attack area being significantly ( p < 0.05) more frequent among men and episodic patients, compared with women and chronic patients respectively, no other differences in the prevalence of pre-attack symptoms were identified between groups. Conclusion Pre-attack symptoms are frequent in cluster headache. Since the origin of cluster headache attacks is still unresolved, studies of pre-attack symptoms could contribute to the understanding of cluster headache pathophysiology. Furthermore, identification and recognition of pre-attack symptoms could potentially allow earlier abortive treatment.