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Mads Barloese1,2 1Department of Clinical Physiology and Nuclear Medicine, Center for Functional and Diagnostic Imaging, Hvidovre Hospital, Hvidovre, Denmark; 2Department of Neurology, Danish Headache Center, Rigshospitalet-Glostrup, Glostrup, DenmarkCorrespondence: Mads BarloeseFunktions- Og Billeddiagnostisk Enhed, Hvidovre Hospital, Kettegaard Alle 30, Hvidovre, DK-2650, DenmarkEmail mbar0087@regionh.dkAbstract: Cluster headache is uniquely rhythmic in its occurrence both diurnally and annually. This has implications for the clinical approach to the patient but also for our understanding of the role of central structures in its pathological basis. Many intrinsic and extrinsic factors seem to influence CH rhythmicity, including genetics. The proclivity for attacks to occur at night and the possible association with particular sleep phenomena, including sleep apnea, have motivated a number of studies which has improved our understanding but many questions remain unanswered. The sleep-headache interaction seems to be bidirectional and possibly both direct and indirect. The latter could involve more disperse networks of homeostatic regulation, which may better encompass recent observations. Treatment of the headache patient with concurrent sleep problems can be particularly challenging, especially considering side-effects and interactions of commonly used medications. While current treatment guidelines do not incorporate chronotherapeutic thinking, some evidence may suggest that application of such principles on an individual level may be beneficial.Keywords: cluster headache, chronobiology, sleep, chronotherapy

Background and purpose: Cluster headache (CH) is characterized by severe, unilateral attacks of pain and a high nocturnal attack burden. It remains unknown whether perturbations of sleep are solely present during the CH bout. Therefore, we aimed to investigate differences in sleep between the bout and remission period in patients with episodic CH and, secondly, to compare patients in the two phases with controls. Methods: Patients with episodic CH (aged 18–65 years), diagnosed according to the International Classification of Headache Disorders 2nd edition, were admitted for polysomnography at the Danish Center for Sleep Medicine in bout and in remission. The macrostructure of sleep, including arousals, breathing parameters, limb movements and periodic limb movements, was compared with 25 age‐, sex‐ and body mass index‐matched healthy controls. Results: There were no differences in any of the sleep parameters for patients in bout (n = 32) compared with patients in remission (n = 23). Attacks were unrelated to sleep stages, presence of apnea episodes, periodic limb movements, limb movements and arousals. In bout, patients had longer sleep latency (18.8 vs. 11.7 min, P < 0.05) and rapid eye movement sleep latency (1.7 vs. 1.2 h, P < 0.05) than controls and sleep efficiency was lower (82.5% vs. 86.5%, P < 0.05). Patients in remission only had a longer sleep latency compared with controls (17.5 vs. 11.7 min, P < 0.01). Conclusions: The results support the presence of a continuing or slowly recovering disturbance of sleep outside the bout rather than a disturbance occurring secondary to attacks. Further, we confirm that there is no relation between CH attacks and specific sleep stages or between CH and breathing parameters. [ABSTRACT FROM AUTHOR]

Following publication of the original article [1], we have been notified that the name of author five was spelled incorrectly as M. Ferrili, when the correct spelling is MAN Ferilli. [ABSTRACT FROM AUTHOR]

Background: Primary headache are prevalent and debilitating disorders. Acute pain cessation is one of the key points in their treatment. Many drugs have been studied but the design of the trials is not usually homogeneous. Efficacy of the trial is determined depending on the selected primary endpoint and usually other different outcomes are measured. We aim to critically appraise which were the employed outcomes through a systematic review.Methods: We conducted a systematic review of literature focusing on studies on primary headache evaluating acute relief of pain, following the PRISMA guideline. The study population included patients participating in a controlled study about symptomatic treatment. The comparator could be placebo or the standard of care. The collected information was the primary outcome of the study and all secondary outcomes. We evaluated the studied drug, the year of publication and the type of journal. We performed a search and we screened all the potential papers and reviewed them considering inclusion/exclusion criteria.Results: The search showed 4288 clinical trials that were screened and 794 full articles were assessed for eligibility for a final inclusion of 495 papers. The studies were published in headache specific journals (58%), general journals (21.6%) and neuroscience journals (20.4%).Migraine was the most studied headache, in 87.8% studies, followed by tension type headache in 4.7%. Regarding the most evaluated drug, triptans represented 68.6% of all studies, followed by non-steroidal anti-inflammatories (25.1%). Only 4.6% of the papers evaluated ergots and 1.6% analyzed opioids.The most frequent primary endpoint was the relief of the headache at a determinate moment, in 54.1%. Primary endpoint was evaluated at 2-h in 69.9% of the studies. Concerning other endpoints, tolerance was the most frequently addressed (83%), followed by headache relief (71.1%), improvement of other symptoms (62.5%) and presence of relapse (54%). The number of secondary endpoints increased from 4.2 (SD = 2.0) before 1991 to 6.39 after 2013 (p = 0.001).Conclusion: Headache relief has been the most employed primary endpoint but headache disappearance starts to be firmly considered. The number of secondary endpoints increases over time and other outcomes such as disability, quality of life and patients’ preference are receiving attention. [ABSTRACT FROM AUTHOR]

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., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

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., Competing Interests: Declaration of conflicting interestsASP reports being a sub-investigator in trials and received a restricted research grant from Lundbeck (payed to the institution), which manufactures Eptinezumab, a monoclonal antibody targeting CGRP under investigation as a preventive treatment for cluster headache. KM reports no disclosures. SLC reports no disclosures. MB reports no disclosures. NRJ reports no disclosures. LK reports no disclosures. RHJ reports lectures for Eli-Lilly, which manufactures Galcanezumab, a monoclonal antibody targeting CGRP and FDA approved as a preventive treatment for episodic cluster headache. RHJ also reports lectures, acting as an investigator in clinical trials and receiving funding in the form of a restricted and an unrestricted research grant (paid to the institution) from Lundbeck, which manufactures Eptinezumab, a monoclonal antibody targeting CGRP under investigation as a preventive treatment for cluster headache.

Objective: To systematically investigate previously examined biomarkers in blood, urine, cerebrospinal fluid, tear fluid, and saliva of patients with cluster headache., Background: Cluster headache is a condition with extensive clinical challenges in terms of diagnosis and treatment. Identification of a biomarker with diagnostic implications or as a potential treatment target is highly warranted., Methods: We conducted a systematic review including peer reviewed full text of studies that measured biochemical compounds in either blood, urine, cerebrospinal fluid, tear fluid, or saliva of patients with cluster headache diagnosed after the implementation of the International Classification of Headache Disorders (1988) written in English, Danish, Swedish, or Norwegian. Inclusion required a minimum of five participants. The search was conducted in PubMed and EMBASE, in September 2022, and extracted data were screened by two authors. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for reporting systematic reviews were followed. The Newcastle-Ottawa Scale was used to assess the risk of bias in case-controlled studies., Results: We included 40 studies involving 832 patients with cluster headache and 872 controls, evaluating 80 potential biomarkers. The risk of bias for case-controlled studies was a median of 6 (range: 3-8) and 20 studies out of 40 (50%) were of fair or good quality. Most studies were identified within three groups: hypothalamic-regulated hormones, inflammatory markers, and neuropeptides. Among the hypothalamic hormones, cortisol was the most frequently investigated (N = 7) and was elevated in cluster headache in most of the studies. The most frequently examined inflammatory marker was interleukin 1 (N = 3), but findings were divergent. Calcitonin gene-related peptide was the most investigated neuropeptide (N = 9) and all studies found increased levels during attacks., Conclusion: Biomarker findings have been inconsistent and widely non-specific for cluster headache, which explains why none of the previous studies succeeded in identifying a unique biomarker for cluster headache, but instead contributed to substantiating the underlying pathophysiologic mechanisms. Several of the examined biomarkers could hold promise as markers for disease activity but are unfit for a clear distinction from both controls and other headaches., (© 2023 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Rationale and Objectives: There is universal interest in increasing sustainability in health care, including in imaging. We studied and characterized energy consumption in a representative imaging department in Denmark to identify and quantify the effect of specific optimizations., Methods: Protocols and energy parameters for the three main scanner modalities along with supportive systems and workflows were monitored and scrutinized. Potential savings were measured and/or calculated., Results: Only few optimizations were identified at the protocol level. However, examination of usage patterns and cooling systems revealed numerous potential optimizations which fell into three categories. 1) Optimizations requiring minimal changes in installations or workflows, for example, reduction of bed-position time, 2) optimizations requiring altered work flows such as strict adherence to timed shut-down procedures and 3) optimizations requiring retro-fitting equipment, typically at considerable monetary expense, for example fitting variable flow control on pumps. The single biggest identified optimization was raising the temperature of the circulating cooling water., Conclusion: This study highlights the complexity of increasing sustainability in health care, specifically in imaging. We identified multiple potential optimizations but also technical, monetary and organizational barriers preventing immediate implementation., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

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.

Aim: To evaluate the diagnostic accuracy of the SNNOOP10 list in the detection of high-risk headaches., Methods: Patients that visited the Hospital Clínico San Carlos (Madrid) emergency department due to headache that were allocated to a Manchester Triage System level between critical and urgent were prospectively included but retrospectively analysed. A researcher blind to the patients' diagnosis administered a standardised questionnaire and afterwards a neurologist blind to the questionnaire results diagnosed the patient according to the International Classification of Headache Disorders. The primary endpoint was to assess the sensitivity of the SNNOOP10 list in the detection of high-risk headaches. Secondary endpoints included the evaluation of the sensitivity, specificity, positive predictive value, negative predictive value and area under the curve of each SNNOOP10 item., Results: Between April 2015 and October 2021, 100 patients were included. Patients were 44 years old (inter-quartile range: 33.6-64.7) and 57% were female. We identified 37 different diagnoses. Final diagnosis was a primary headache in 33%, secondary headache in 65% and cranial neuralgia in 2%. There were 46 patients that were considered as having high-risk headache. Patients from the primary headache group were younger and more frequently female. Sensitivity of SNNOOP10 list was 100% (95% confidence interval: 90.2%-100%). The items with higher sensitivity were neurologic deficit or disfunction (75.5%), pattern change or recent onset of the headache (64.4%), onset after 50 years (64.4%). The most specific items were posttraumatic onset of headache (94.5%), neoplasm in history (89.1%) and systemic symptoms (89%). The area under the curve of the SNNOOP10 list was 0.66 (95% CI: 0.55-0.76)., Conclusion: The red flags from the SNNOOP10 list showed a 100% sensitivity in the detection of high-risk headache disorders.

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., (© 2022. The Author(s).)

Background: Early symptoms prior to a cluster headache bout have been reported to occur days or weeks before the actual beginning of the cluster headache bouts. This study aimed to describe the prevalence of pre-cluster (premonitory) symptoms and examine the predictability of an upcoming cluster headache bout., Methods: 100 patients with episodic cluster headache were included in this retrospective cross-sectional study. All patients underwent a semi-structured interview including 25 questions concerning pre-cluster symptoms., Results: Pre-cluster symptoms were reported by 86% of patients with a mean of 6.8 days (interquartile range 3-14) preceding the bout. An ability to predict an upcoming bout was reported by 57% with a mean 4.6 days (interquartile range 2-7) before the bout. Occurrence of shadow attacks was associated with increased predictability (odds ratio: 3.06, confidence interval: 1.19-7.88, p -value = 0.020). In remission periods, 58% of patients reported mild cluster headache symptoms and 53% reported occurrence of single shadow attacks., Conclusions: The majority of episodic cluster headache patients experienced pre-cluster symptoms, and more than half could predict an upcoming bout, suggesting the significant potential of early intervention. Furthermore, the experience of mild cluster headache symptoms and infrequent shadow attacks in remission periods is common and suggest an underlying pathophysiology extending beyond the cluster headache bouts.

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.

Pituitary adenylate cyclase-activating peptide (PACAP) is a ubiquitous neuropeptide with diverse functions throughout the organism. Most abundantly investigated for its role in several neurological disorders as well as in circadian rhythms, other fields of medicine, including cardiology, have recently shown interest in the role of PACAP and its potential as a biomarker. Timely diagnosis and treatment of cirrhosis and its complications is a considerable challenge for health services world-wide and development of new areas of research is warranted. Direct and indirect evidence exists of PACAP involvement in the cascade of pathological events and processes ultimately leading to cirrhosis and its complications, but its exact role remains to be determined. Studies have documented PACAP involvement in immune function, metabolism, local vasoconstriction and dilatation and systemic vascular decompensation and there is ongoing research of a possible role in liver reperfusion injury. Considering these reports, PACAP could theoretically exude influence on the disease course of cirrhosis through the hypothalamus-pituitary-adrenal axis, chronic inflammation, fibrogenesis, vasodilation and reduced vascular resistance. The paucity of literature on the specific topic of PACAP and cirrhosis reflects complex mechanisms and difficulty in accurate measurements and sample taking. This does not detract from the need to further characterize and elucidate the role PACAP plays in the underdiagnosed and undertreated condition of cirrhosis., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Knowledge of the clinical features of cluster headache is mainly based on retrospective and cross-sectional studies. Here, we present a case of a chronic cluster headache patient who prospectively recorded timing and clinical features of all attacks for 6 years, aiming to describe the clinical spectrum and timing of cluster headache symptoms experienced and to identify daily and/or seasonal rhythmicity., Methods: Registration of attack timing, duration, associated symptoms and severity was done prospectively on a smartphone application. Pain severity was recorded on a 0-10 scale. Attacks were divided into mild, moderate, severe, and very severe. We analysed diurnal rhythmicity by multimodal Gaussian analysis and spectral analysis., Results: In total, 4600 attacks were registered (mean duration 39.3 (SD 18.5) min. Mean severity 3.6 (SD 1.28)). Mild attacks accounted for 14.2%, moderate 65.7%, severe 16.9% and very severe 3.2% of all attacks. Nocturnal attacks were more severe than daytime attacks. The number of autonomic symptoms and duration of attacks increased with pain severity. Peak chronorisk (risk of attacks occurring according to hour of day) was at 12.48 in the registration period. Over time, circadian rhythmicity and attack frequency varied., Conclusion: Clinical characteristics of cluster headache attacks can vary greatly within the individual patient. Clinicians attempting to personalise the administration of preventive treatment should pay notice to the variation over time in diurnal rhythmicity. The recorded self-limiting mild attacks that do not fulfill the ICHD-3 criteria for a cluster headache attack warrant further investigation, as they could hold important information about disease activity.

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/m 2 , 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.

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 R 2 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.

Introduction: Cluster headache is characterized by attacks of severe unilateral pain accompanied by cranial and systemic autonomic changes. Our knowledge of the latter is imperfect. This study aimed to investigate the effect of low-frequency sphenopalatine ganglion stimulation on cardiac autonomic regulation., Materials and Methods: In a double-blind, randomized, sham-controlled crossover design, patients received low-frequency and sham stimulation. RR intervals were recorded, and heart rate variability was analysed (time-domain, frequency-domain, nonlinear parameters). Headache characteristics, including cranial autonomic symptoms, were recorded at baseline and every 10 min for 60 min., Results: Sixteen patients were included. Changes in heart rate variability from baseline in the analysed parameters differed significantly between low-frequency and sham stimulation. Initially, during low-frequency stimulation, there was a greater increase in heart rate compared to sham (P<0·05) and changes in the frequency, nonlinear and time domain (P<0·05) reflecting a higher sympathetic tone. These preceded the observed cranial autonomic symptoms. Ten episodes of cluster-like attacks were reported (six following low-frequency stimulation, four following sham). During these, parasympathetic tone (P<0·05) was higher compared to baseline., Conclusions: In cluster headache patients subjected to low-frequency and sham stimulation of the sphenopalatine ganglion, we found changes indicating higher sympathetic tone during low-frequency stimulation preceding cranial autonomic symptoms or cluster pain. During cluster pain, regardless of stimulation parameters, we saw increased parasympathetic activity, congruent with previous reports. The results indicate involvement of cardiac autonomic regulation before and during cluster headache attacks., (© 2017 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

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., (© 2018 American Academy of Neurology.)

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.

The interaction between sleep and primary headaches has gained considerable interest due to their strong, bidirectional, clinical relationship. Several primary headaches demonstrate either a circadian/circannual rhythmicity in attack onset or are directly associated with sleep itself. Migraine and cluster headache both show distinct attack patterns and while the underlying mechanisms of this circadian variation in attack onset remain to be fully explored, recent evidence points to clear physiological, anatomical and genetic points of convergence. The hypothalamus has emerged as a key brain area in several headache disorders including migraine and cluster headache. It is involved in homeostatic regulation, including pain processing and sleep regulation, enabling appropriate physiological responses to diverse stimuli. It is also a key integrator of circadian entrainment to light, in part regulated by pituitary adenylate cyclase-activating peptide (PACAP). With its established role in experimental headache research the peptide has been extensively studied in relation to headache in both humans and animals, however, there are only few studies investigating its effect on sleep in humans. Given its prominent role in circadian entrainment, established in preclinical research, and the ability of exogenous PACAP to trigger attacks experimentally, further research is very much warranted. The current review will focus on the role of the hypothalamus in the regulation of sleep-wake and circadian rhythms and provide suggestions for the future direction of such research, with a particular focus on PACAP.

Background: Cluster headache (CH) is a disabling primary headache disorder characterized by severe periorbital pain. A subset of patients does not respond to established pharmacological therapy. This study examines outcomes of a cohort of mainly chronic CH patients treated with sphenopalatine ganglion (SPG) stimulation., Methods: Patients were followed in an open-label prospective study for 12 months. Ninety-seven CH patients (88 chronic, 9 episodic) underwent trans-oral insertion of a microstimulator targeting the SPG. Patients recorded stimulation effect prospectively for individual attacks. Frequency, use of preventive and acute medications, headache impact (HIT-6) and quality of life measures (SF-36v2) were monitored at clinic visits. Per protocol, frequency responders experienced ≥ 50% reduction in attack frequency and acute responders treated ≥ 50% of attacks. HIT-6 responders experienced an improvement ≥ 2.3 units and SF-36 responders ≥ 4 units vs. baseline., Results: Eighty-five patients (78 chronic, 7 episodic) remained implanted and were evaluated for effectiveness at 12 months. In total, 68% of all patients were responders, 55% of chronic patients were frequency responders and 32% of all patients were acute responders. 67% of patients using acute treatments were able to reduce the use of these by 52% and 74% of chronic patients were able to stop, reduce or remain off all preventive medications. 59% of all patients were HIT-6 responders, 67% were SF-36 responders., Conclusions: This open-label registry corroborates that SPG stimulation is an effective therapy for CH patients providing therapeutic benefits and improvements in use of medication as well as headache impact and quality of life.

Objectives The sphenopalatine ganglion (SPG) plays a pivotal role in cluster headache (CH) pathophysiology as the major efferent parasympathetic relay. We evaluated the long-term effectiveness of SPG stimulation in medically refractory, chronic CH patients. Methods Thirty-three patients were enrolled in an open-label follow-up study of the original Pathway CH-1 study, and participated through 24 months post-insertion of a microstimulator. Response to therapy was defined as acute effectiveness in ≥ 50% of attacks or a ≥ 50% reduction in attack frequency versus baseline. Results In total, 5956 attacks (180.5 ± 344.8, range 2-1581 per patient) were evaluated. At 24 months, 45% ( n = 15) of patients were acute responders. Among acute responders, a total of 4340 attacks had been treated, and in 78% of these, effective therapy was achieved using only SPG stimulation (relief from moderate or greater pain or freedom from mild pain or greater). A frequency response was observed in 33% ( n = 11) of patients with a mean reduction of attack frequency of 83% versus baseline. In total, 61% (20/33) of all patients were either acute or frequency responders or both. The majority maintained their therapeutic response through the 24-month evaluation. Conclusions In the population of disabled, medically refractory chronic CH patients treated in this study, SPG stimulation is an effective acute therapy in 45% of patients, offering sustained effectiveness over 24 months of observation. In addition, a maintained, clinically relevant reduction of attack frequency was observed in a third of patients. These long-term data provide support for the use of SPG stimulation for disabled patients and should be considered after medical treatments fail, are not tolerated or are inconvenient for the patients.

Objective: To describe differences between the sexes in the phenotype of cluster headache (CH) in a large, well-characterized clinical CH population., Methods: Patients from the Danish CH survey aged 18-65 years, diagnosed with CH according to International Classification of Headache Disorders, second edition, completed questionnaires and structured interviews., Results: A total of 351 patients with CH participated, with a male:female ratio of 2:1. The diurnal variation of attacks showed moments of peak prominence in men's attack cycle to be advanced by 1 hour compared to women's, despite no difference in self-reported bedtime or chronotype ( p = 0.31). The onset of CH decreased with increasing age for both sexes. Diagnostic delay was numerically longer for men vs women (6.56 vs 5.50 years, p = 0.21); however, more women had previously been misdiagnosed (61.1% vs 45.5%, p < 0.01) and received the correct diagnosis at a tertiary headache center (38.8% vs 20.9%, p < 0.001). Only minor sex differences in clinical characteristics were found but chronic CH was more prevalent in women compared to men (44.0% vs 31.9%, p < 0.05)., Conclusions: Despite a similar clinical phenotype, diurnal attack cycle is advanced by 1 hour in men with CH compared to women. Rhythmicity is a defining characteristic of CH and these findings suggest differences in the hypothalamus' influence on attack occurrence between the sexes. In addition, women were more often misdiagnosed and diagnosis in the primary or secondary sector more often failed. Furthermore, women had chronic CH more frequently than men. A long diagnostic delay and frequent misdiagnosis emphasize the need for increased awareness of CH in both sexes., (© 2017 American Academy of Neurology.)

Background: Cluster headache (CH) is a disabling headache disorder with chronobiological features. The posterior hypothalamus is involved in CH pathophysiology and is a hub for autonomic control. We studied autonomic response to the head-up tilt table test (HUT) including heart rate variability (HRV) in CH patients and compared results to healthy controls., Methods and Materials: Twenty-seven episodic and chronic CH patients and an equal number of age-, sex- and BMI-matched controls were included. We analyzed responses to HUT in the time and frequency domain and by non-linear analysis., Results: CH patients have normal cardiovascular responses compared to controls but increased blood pressure. In the frequency analysis CH patients had a smaller change in the normalized low- (LF) (2.89 vs. 13.38, p < 0.05) and high-frequency (HF) (-2.86 vs. -13.38, p < 0.05) components as well as the LF/HF ratio (0.81 vs. 2.62, p < 0.05) in response to tilt. In the Poincaré plot, the change in ratio between long- and short-term variation was lower in patients (SD1/SD2, -0.05 vs. -0.17, p < 0.05)., Conclusions: CH patients show decreased autonomic response to HUT compared to healthy controls. This can be interpreted as dysregulation in the posterior hypothalamus and supports a theory of central autonomic mechanisms involvement in CH., (© International Headache Society 2015.)

Background: Cluster headache (CH) is a debilitating disorder characterized by unilateral, severe pain attacks with accompanying autonomic symptoms, often waking the patient from sleep. As it exhibits strong chronobiological traits and genetic studies have suggested a link with the hypocretin (HCRT) system, the objective of this study was to investigate HCRT-1 in CH patients., Methods: Cerebrospinal fluid HCRT-1 concentration was measured in 12 chronic and 14 episodic CH patients during an active bout, and in 27 healthy controls. The patients were well characterized and clinical features compared to the HCRT concentration., Results: We found significantly lower HCRT levels both in chronic (p = 0.0221) and episodic CH (p = 0.0005) patients compared with controls. No significant relationship was found with other clinical features., Conclusions: This is the first report of significantly reduced HCRT concentrations in CH patients. We speculate that decreased HCRT may reflect insufficient antinociceptive activity of the hypothalamus. The mechanism of the antinociceptive effect of HCRT is not known and requires further investigation. This study supports the hypothesis of a connection between arousal regulation and CH., (© International Headache Society 2014.)

Background and Purpose: Cluster headache (CH) is a primary headache disorder characterized by severe attacks of unilateral pain following a chronobiological pattern. There is a close connection with sleep as most attacks occur during sleep. Hypothalamic involvement and a particular association with rapid eye movement (REM) sleep have been suggested. Sleep in a large, well-characterized population of CH patients was investigated., Methods: Polysomnography (PSG) was performed on two nights in 40 CH patients during active bout and one night in 25 age, sex and body mass index matched controls in hospital. Macrostructure and other features of sleep were analyzed and related to phenotype. Clinical headache characterization was obtained by semi-structured interview., Results: Ninety-nine nights of PSG were analyzed. Findings included a reduced percentage of REM sleep (17.3% vs. 23.0%, P = 0.0037), longer REM latency (2.0 vs. 1.2 h, P = 0.0012) and fewer arousals (7.34 vs. 14.1, P = 0.003) in CH patients. There was no difference in prevalence of sleep apnea between patients (38%) and matched controls (32%, P = 0.64) although the apnea index in patients was numerically higher (mean apnea-hypopnea index 10.75 vs. 4.93). No temporal association between nocturnal attacks (n = 45) and particular sleep stages was observed., Conclusions: To date, this is the largest study of sleep in CH. It is demonstrated that REM sleep is affected which is in line with our current understanding of CH and hypothalamic involvement in the regulation of this sleep stage. Further, fewer arousals were found in CH patients but no association between apnea events or specific sleep stages. The findings support a central role of the hypothalamus and arousal systems in CH., (© 2014 EAN.)

Aims: There are no previous epidemiologic studies on concurrent headache and sleep problems (HSP). This cross-sectional study aimed to determine the prevalence of HSP in Denmark, broadly characterize those with HSP, and examine associations between HSP and socioeconomic/lifestyle factors., Methods: A total of 129,150 randomly selected individuals were invited to participate in the Danish National Health Survey 2010. Respondents were asked about headache, sleep problems, depression and anxiety in the last two weeks, health-related lifestyle and quality of life (SF-12). Socioeconomic data were retrieved from national registers. Prevalence proportions were adjusted for stratified sampling and non-response. Regression analyses examined associations between HSP and socioeconomic/lifestyle factors., Results: Of 68,518 respondents, 16.3% reported only headache, 21.1% only sleep problems, and 18.1% HSP with 2.6% being severely affected. Prevalence was higher among women and the middle-aged. Severe HSP was associated with low socioeconomic position, non-Western ethnicity, unhealthy lifestyle, high stress and anxiety/depression. Those with HSP had substantially reduced quality of life; more so than those having only headache or only sleep problems., Conclusions: HSP is a highly prevalent condition. Lifestyle modification, stress reduction, and screening for concurrent depression and anxiety may play important roles in management. The high prevalence of HSP suggests a common pathophysiological mechanism., (© International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Purpose of Review: Neurostimulation has emerged as a viable treatment for intractable chronic cluster headache. Several therapeutic strategies are being investigated including stimulation of the hypothalamus, occipital nerves and sphenopalatine ganglion. The aim of this review is to provide an overview of the rationale, methods and progress for each of these., Latest Findings: Results from a randomized, controlled trial investigating sphenopalatine ganglion stimulation have just been published. Reportedly the surgery is relatively simple and it is apparently the only therapy that provides relief acutely., Summary: The rationale behind these therapies is based on growing evidence from clinical, hormonal and neuroimaging studies. The overall results are encouraging, but unfortunately not all patients have benefited. All the mentioned therapies require weeks to months of stimulation for a prophylactic effect to occur, suggesting brain plasticity as a possible mechanism, and only stimulation of the sphenopalatine ganglion has demonstrated an acute, abortive effect. Predictors of effect for all modes of neurostimulation still need to be identified and in the future, the least invasive and most effective strategy must be preferred as first-line therapy for intractable chronic cluster headache.