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Purpose of Review: To describe different pitfalls in the diagnosis of primary cluster headaches (CHs) with the guidance of seven case vignettes., Recent Findings: The question of whether primary CHs and migraines are totally different entities has been long debated. Autonomic features can be detected in as many as 60% of migraine patients. Although some genetic similarities have been found, CACNA1A mutations have not been detected among CH patients with hemimotor aura in contrast to hemiplegic migraine. Recently, functional MRI studies have shown that the left thalamic network was the most discriminative MRI feature in distinguishing migraine from CH patients. Compared to migraine, CH patients showed decreased functional interaction between the left thalamus and cortical areas mediating interception and sensory integration. However, clinically the most significant feature had been the restlessness and agitation seen during headache attacks patients with CHs. This feature is also important in distinguishing cluster patients from other patients having other trigeminal autonomic cephalalgias except for a subset of patients with hemicrania continua. CH is an important member of the group of headache disorders characterized by their association with one or more autonomic features in the trigeminal nerve distribution and termed Trigeminal Autonomic Cephalalgias (TACs). Although CH is a relatively rare condition, judged by the distress it generally causes to the affected individual, early diagnosis and institution of appropriate therapy seem mandatory. Correct diagnosis of CHs needs avoidance of pitfalls. Such pitfalls generally include differentiation from migraine, differentiation from other side locked headache disorders, from other trigeminal autonomic cephalalgias (TACs), and lastly, recognition of rare presentations of cluster-like manifestations with hemiplegic aura and simulating trigeminal and glossopharyngeal neuralgias. Differentiation between primary and symptomatic CHs related to sellar pathologies and systemic medical conditions is of equal importance. In the present review such issues are discussed with the assistance of seven case vignettes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Trigeminal neuropathic pain (TNP), migraine, and cluster headache (CH) profoundly impact the quality of life and present significant clinical challenges due to their complex neurobiological underpinnings. This review delves into the pivotal role of the hypothalamus in the pathophysiology of these facial pain syndromes, highlighting its distinctive functions and potential as a primary target for research, diagnosis, and therapy. While the involvement of the hypothalamus in migraine and CH has been increasingly supported by imaging and clinical studies, the precise mechanisms of its role remain under active investigation. The role of the hypothalamus in TNP, in contrast, is less explored and represents a critical gap in our understanding. The hypothalamus's involvement varies significantly across these conditions, orchestrating a unique interplay of neural circuits and neurotransmitter systems that underlie the distinct characteristics of each pain type. We have explored advanced neuromodulation techniques, such as deep brain stimulation (DBS) and optogenetics, which show promise in targeting hypothalamic dysfunction to alleviate pain symptoms. Furthermore, we discuss the neuroplastic changes within the hypothalamus that contribute to the chronicity of these pains and the implications of these findings for developing targeted therapies. By offering a comprehensive examination of the hypothalamus's roles, this paper aims to bridge existing knowledge gaps and propel forward the understanding and management of facial neuralgias, underscoring the hypothalamus's critical position in future neurological research., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Time in headache disorders is crucial for diagnosis and gives insight into headache pathophysiology., Objective: To summarize published studies which describe timing processes in both attack presentation (onset, duration) and disease characterization (age of onset, evolution over time) in primary headache disorders and link to pathophysiology., Methods: A comprehensive search was conducted through Ovid MEDLINE(R) and PubMed, focusing on English-language articles from 1946 to 2023 to write the review. The International Classification of Headache Disorders, 3rd edition provided the framework for the review of primary headache disorders (migraine, tension-type headache and cluster headache)., Results: Attack presentation : Migraine attacks exhibit significant circadian and infradian rhythms, influenced by hormonal levels, light sensitivity, and hypothalamic activation. Tension-type headache lacks clear chronobiological patterns, with limited understanding of its underlying mechanisms. Cluster headache displays a distinct circannual pattern, with attacks often occurring at night and relevant involvement of the hypothalamus. Disease characterization : Age of onset exhibits the earliest peak in migraine; frequency and typical features of primary headache disorders decrease over time., Conclusion: This comprehensive analysis of time patterns in primary headache disorders underscores their role in phenotyping, understanding and treating primary headache disorders, offering promising avenues for advancing and tailoring headache management., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.G.M. reports that within the prior 36 months has received speaker honoraria from TEVA, Lilly and Altermedica.J.C.R reports in the last 36 months he has received honoraria for education presentations for Abbvie, Novartis and Viatris. He has served on medical advisory boards for Pfizer, Viatris and Lilly. His institution has received funding for research grants, clinical trials and projects supported by the International Headache Society, Brain Foundation, Lundbeck, Abbvie, Pfizer and Aeon.F.H., F.J.O., H.G., T.C.S., M.C.D., U.A., H.H., J.M.K., reports no conflict of interests.K.S.L reports personal fees from Teva and Acticor Biotech.E.C. has received received honoraria from Novartis, Chiesi, Lundbeck, Medscape.P.P.R. reports that within the prior 36 months, having received honoraria as a consultant and speaker for: AbbVie, Amgen, Biohaven, Chiesi, Eli Lilly, Lundbeck, Medscape, Novartis, Pfizer and Teva. Her research group has received research grants from Novartis, Teva, AbbVie, EraNET Neuron, RIS3CAT FEDER, AGAUR, ISCIII, International Headache Society; has received funding for clinical trials from Alder, Amgen, Biohaven, Eli Lilly, Lundbeck, Novartis, Teva. She is the Honorary Secretary of the International Headache Society. She is a member of the Clinical Trials Guideline Committee of the International Headache Society. She serves as an associate editor for Cephalalgia, Headache, The Journal of Headache and Pain, Neurologia, and Revista de Neurologia. She is the founder of www.midolordecabeza.org. P.P.R. does not own stocks from any pharmaceutical company.

Background:  The pathophysiology of cluster headaches (CHs) involves the trigeminovascular system, the parasympathetic nervous system, and the hypothalamus. Because of the affected hypothalamus, there may be limbic system involvement in CH., Objective:  To investigate the relationship between depression, anxiety, and alexithymia in CH, to demonstrate that the limbic system is affected., Methods:  A total of 18 patients with CHs who were outside of cluster period and 18 healthy controls were included. Participants were administered the Beck depression inventory (BDI), Beck anxiety inventory (BAI), and Toronto alexithymia scale-20 (TAS-20)., Results:  Patients with CHs had significantly higher rates of alexithymia ( p  = 0.003) and depression ( p  = 0.014) than controls. There was no significant difference in anxiety levels ( p  = 0.297) between groups., Conclusion:  It was shown that, in addition to previously identified psychiatric disorders, alexithymia can accompany CHs in patients., Competing Interests: The authors have no conflict of interest to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/).)

The objectives were 1) to synthesize quantitative sensory testing results in cluster headache (CH) patients and to identify somatosensory differences from healthy subjects (HS), and 2) between symptomatic and asymptomatic sides in CH patients. Two independent reviewers conducted a literature search in MEDLINE, EMBASE, Web of Science, and CINAHL databases. Studies with observational designs were included. Methodological quality and risk of bias were assessed with the Newcastle Ottawa Scale. The selected studies underwent qualitative and quantitative analyses. The qualitative analysis showed inconsistent findings among multiple studies. Meta-analysis showed lower pressure pain thresholds (PPTs) on the symptomatic side of CH patients than HS in V 2 (standardized mean difference [SMD] -1.01 [95% confidence interval (CI) -1.79, -.23], P = .01, I 2 = 73%, n = 114), V 3 (SMD -1 [95% CI -1.54, .45], P < .01, I 2 = 82%, n = 354), and cervical region (SMD -1.25 [95% CI -2.07, -.44], P < .01, I 2 = 84%, n = 194). Furthermore, lower PPTs than those detected in HS were found on the asymptomatic side in V 3 (SMD -.77 [95% CI -1.27, -.27], P < .01, I 2 = 79%, n = 354) and in the cervical region (SMD -1.13 [95% CI -1.97, -.3], P < .01, I 2 = 85%, n = 194). However, no differences were found in V 1 or the extratrigeminal points between these groups. No significant changes were found between symptomatic and asymptomatic sides in trigeminal and extratrigeminal regions. Mechanical hyperalgesia in the trigemino-cervical region of patients with CH could suggest the presence of central pain mechanisms. These results are of clinical relevance because their presence could be associated with a poorer prognosis, chronification, and treatment response. PERSPECTIVE: This study provides consistent findings on the somatosensory profile characterizing patients with CH. Clinicians should assess PPTs and other quantitative sensory testing variables in the trigeminal and extratrigeminal (cervical) regions., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Pain thresholds and primary headaches, including cluster headache attacks, have circadian rhythmicity. Thus, they might share a common neuronal mechanism., Objective: This study aimed to elucidate how the modulation of nociceptive input in the brainstem changes from noon to midnight. Insights into the mechanism of these fluctuations could allow for new hypotheses about the pathophysiology of cluster headache., Methods: This repeated measure observational study was conducted at the University Hospital Zurich from December 2019 to November 2022. Healthy adults between 18 and 85 years of age were eligible. All participants were examined at noon and midnight. We tested the pain threshold on both sides of the foreheads with quantitative sensory testing, assessed tiredness levels, and obtained high-field (7 Tesla) and high-resolution functional magnetic resonance imaging (MRI) at each visit. Functional connectivity was assessed at the two visits by performing a region-of-interest analysis. We defined nuclei in the brainstem implicated in processing nociceptive input as well as the thalamus and suprachiasmatic nucleus as the region-of-interest., Results: Ten people were enrolled, and seven participants were included. First, we did not find statistically significant differences between noon and midnight of A-delta-mediated pain thresholds (median mechanical pain threshold at noon: left 9.2, right 9.2; at night: left 6.5, right 6.1). Second, after correction for a false discovery rate, we found changes in the mechanical pain sensitivity to have a statistically significant effect on changes in the functional connectivity between the left parabrachial nucleus and the suprachiasmatic nucleus (T = -40.79)., Conclusion: The MRI data analysis suggested that brain stem nuclei and the hypothalamus modulate A-delta-mediated pain perception; however, these changes in pain perception did not lead to statistically significantly differing pain thresholds between noon and midnight. Hence, our findings shed doubt on our hypothesis that the physiologic circadian rhythmicity of pain thresholds could drive the circadian rhythmicity of cluster headache attacks., (© 2024 The Author(s). Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Cluster headache, characterised by attacks of severe, recurrent, unilateral headache and ipsilateral cranial autonomic symptoms, remains a primary headache with an elusive pathophysiology. Recent advances have introduced effective treatments and broadened understanding of the clinical features of cluster headache. These features are similar in patients globally, but regional differences in prevalence and burden exist. International collaborations have led to identification of eight genetic loci associated with cluster headache. The pathophysiological mechanisms are still not fully understood but recent studies show that targeting the trigeminal autonomic reflex by neurostimulation, or targeting the neuropeptide calcitonin gene-related peptide (CGRP), might lessen the attack burden. The US Food and Drug Administration has approved galcanezumab, a monoclonal antibody targeting CGRP, as the first specific preventive treatment for episodic cluster headache. However, a preventive effect was not replicated in chronic cluster headache, and the European Medicines Agency did not approve galcanezumab, restricting its availability in Europe. Owing to the low prevalence of cluster headache, continued collaboration through multicentre clinical trials and data sharing will be imperative for further breakthroughs in understanding and management., Competing Interests: Declaration of interests ASP has received a restricted research grant (payment to their institution) and conference attendance from Lundbeck Pharma, and personal fees from Pfizer for teaching activities. NL has received a restricted research grant from Lundbeck Pharma (payment to their institution), a research grant from the Capital Region Research Foundation, support for conference attendance from Pfizer, and personal fees from teaching activities for general practitioners from Dagens Medicin and Pfizer (personal). PJG reports, over the past 36 months: grants from Celgene and Kallyope; personal fees from Aeon Biopharma, AbbVie, Amgen, eNeura, CoolTech, Dr Reddys, Eli Lilly, Epalex, Linpharma, Lundbeck, Novartis, Pfizer, Sanofi, Satsuma, Shiratronics, and Teva Pharmaceuticals; participation on a data and safety monitoring board for Aeon Biopharma and Man & Science; personal fees for advice through Gerson Lehrman Group, Guidepoint, SAI Med Partners, and Vector Metric; fees for educational materials from CME Outfitters; publishing royalties or fees from Massachusetts Medical Society, Oxford University Press, UptoDate, and Wolters Kluwer; and a patent for magnetic stimulation for headache (WO2016090333 A1) assigned to eNeura, without fee. PJG is a board member of the American Headache Society, Migraine Trust, and Organisation for Understanding Cluster Headache. ACB reports honoraria for presentations from Novartis, Teva, and Lundbeck; and research funding from the Swedish Brain Foundation and the Mellby Gård Foundation. S-JW has received honoraria as a moderator from AbbVie, Biogen, Eli Lilly, Hava Biopharma, and Pfizer; has received consulting fees from AbbVie, Eli Lilly Taiwan, Percept, and Pfizer Taiwan; and has received research grants from the Taiwan branches of Eli Lilly, Lundbeck, Novartis, and Orient Europharma. RF reports research grants from Bioprojet, Jazz Pharmaceuticals, Netherlands Brain Foundation, and ZonMW (fee for institution); educational honoraria from Novartis (fee for institution), Teva Pharmaceutical Industries, Bioprojet, and Lundbeck Pharma (personal fees); consultancy for AbbVie, Eli Lilly, and Takeda (fee for institution); and is a member of the cluster headache section of the Dutch Headache guidelines (unpaid). MB reports grant funding from the Will Erwin Headache Research Foundation; travel support for attending meetings from the American Headache Society; has served as a consultant for Lundbeck, Beckley Psytech, Praxis Precision Medicines, and PureTech Health; is a site investigator for a cluster headache clinical trial funded by Lundbeck; was a paid guest for a video podcast by the American Academy of Neurology, is a paid survey respondent for Doximetry, and is an unpaid member of the medical advisory board of Clusterbusters. S-JC was involved as a site investigator of a multicentre trial sponsored by Allergan, AbbVie, Hyundai Pharmaceutical, Ildong Pharmaceutical, Eli Lilly, Pfizer, and Lundbeck; and has received lecture fees or advisory honoraria from AbbVie Korea, Lundbeck, Eli Lilly Korea, SK Chemicals, Teva Pharmaceutical Industries, and Pfizer. MFPP reports consulting fees for AbbVie–Allergan, Ache, Eli Lilly, Eurofarma, Libbs, Lundbeck, Kenvue, Pfizer, Sanofi-Aventis, and Teva Pharmaceutical Industries; travel support from Teva; participation in advisory boards for AbbVie-Allergan, Eli Lilly, Pfizer, Kenvue, Eurofarma, and Sonofi-Aventis; and is president of the Brazilian Association for Cluster Headache and Migraine (unpaid). RHJ received a restricted research grant (for institution) for work on cluster headache from Lundbeck Pharma; received a research grant for treatment trial for idiopathic intracranial hypertension (for institution) from Novo Nordisk Foundation; is on an advisory board for Lundbeck Pharma and has received fees for participation on an advisory board (for institution); has received personal fees for educational and teaching activities from Pfizer, Teva Pharmaceutical Industries, Novartis, AbbVie, Lundbeck, and Eli Lilly; is chair of the Master of Headache Disorders at the University of Copenhagen, a director of the Danish Headache Center, and undertakes unpaid activities as a director of Lifting The Burden., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: To identify the most common locations of cluster headache pain from an international, non-clinic-based survey of participants with cluster headache, and to compare these locations to other cluster headache features as well as to somatotopic maps of peripheral, brainstem, thalamic, and cortical areas., Background: Official criteria for cluster headache state pain in the orbital, supraorbital, and/or temporal areas, yet studies have noted pain extending beyond these locations, and the occipital nerve appears relevant, given the effectiveness of suboccipital corticosteroid injections and occipital nerve stimulation. Furthermore, cranial autonomic features vary between patients, and it is not clear if the trigeminovascular reflex is dermatome specific (e.g., do patients with maxillary or V2 division pain have more rhinorrhea?). Finally, functional imaging studies show early activation of the posterior hypothalamus in a cluster headache attack. However, the first somatosensory area to be sensitized is unclear; the first area can be hypothesized based on the complete map of pain locations., Methods: The International Cluster Headache Questionnaire was an internet-based cross-sectional survey that included a clickable pain map of the face. These data were compared to several other datasets: (1) a meta-analysis of 22 previous publications of pain location in cluster headache (consisting of 6074 patients); (2) four cephalic dermatome maps; (3) participants' survey responses for demographics, autonomic features, and effective medications; and (4) previously published somatotopic maps of the brainstem, thalamus, primary somatosensory cortex, and higher order somatosensory cortex., Results: One thousand five hundred eighty-nine participants completed the pain map portion of the survey, and the primary locations of pain across all respondents was the orbital, periorbital, and temporal areas with a secondary location in the lower occiput; these primary and secondary locations were consistent with our meta-analysis of 22 previous publications. Of the four cephalic dermatomes (V1, V2, V3, and a combination of C2-3), our study found that most respondents had pain in two or more dermatomes (range 85.7% to 88.7%, or 1361-1410 of 1589 respondents, across the four dermatome maps). Dermatomes did not correlate with their respective autonomic features or with medication effectiveness. The first area to be sensitized in the canonical somatosensory pathway is either a subcortical (brainstem or thalamus) or higher order somatosensory area (parietal ventral or secondary somatosensory cortices) because the primary somatosensory cortex (area 3b) and somatosensory area 1 have discontinuous face and occipital regions., Conclusions: The primary pain locations in cluster headache are the orbital, supraorbital, and temporal areas, consistent with the official International Classification of Headache Disorders criteria. However, activation of the occiput in many participants suggests a role for the occipital nerve, and the pain locations suggest that somatosensory sensitization does not start in the primary somatosensory cortex., (© 2024 American Headache Society.)

Several lines of evidence suggest that cluster headache is related to chronobiology and sleep. Nevertheless, the nature of such a relationship is unclear. In this view, the objective evaluation of sleep in cluster headache has strong theoretical and clinical relevance. Here, we provide an in-depth narrative review of the literature on objective sleep assessment in cluster headache. We found that only a small number of studies (N = 12) focused on this topic. The key research aims were directed to assess: (a) the relationship between cluster headache and sleep breathing disorders; (b) the temporal relationship between sleep stages/events and cluster headache attacks; (c) sleep macrostructure in patients with cluster headache. No studies considered sleep microstructure. The reviewed studies are heterogeneous, conducted by a few research groups, and often characterised by relevant methodological flaws. Results are substantially inconclusive considering the main hypothesis. We outline several methodological points that should be considered for future research, and suggest that evaluating sleep microstructure, local sleep electrophysiology and actigraphic measures may strongly increase knowledge on the relationship between sleep and cluster headache., (© 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Cluster headache (CH) is the most frequent primary trigeminal autonomic cephalalgia (Goadsby, 2001). Clinical symptoms have been clearly identified and are described in the IHS classification. Cluster-like headache (CLH), or symptomatic cluster headache, is a rare syndrome in which CH is associated with or disclosed by another neurological disease. The relationship between the two diseases is debated on a spatial and temporal bases. Relief of CH symptoms on treatment of the associated disease is a further argument. However, the simultaneous occurrence of the two diseases may be coincidental. First, the characteristics and pathogenesis of CH are reviewed. Second, published examples of CLH are described, including the pathophysiology proposed by the authors in each particular situation. In the final part, criteria for the identification of CLH in clinical practice are developed. [ABSTRACT FROM AUTHOR]

Object: The characteristics of cluster headache (CH) patients in many countries and the diagnostic and therapeutic approach have been described in several publications, but so far no clinical data have been published from Turkey., Material Methods: This is a cross-sectional retrospective study that includes all patients who were diagnosed with CH and referred to our headache clinic, Dokuz Eylül University Faculty of Medicine, Neurology Department from 1991 to January 2018., Results: We included 114 patients (24 females and 90 males) in our study. The mean age at onset was 31.68 ± 12.72 (range 13-68). Eighty-six (78.18%) patients had episodic cluster headache (ECH) and 24 (21.82%) patients had chronic cluster headache (CCH). The age at onset was significantly higher in the patients with CCH than with ECH (p = 0.002). The most common location was orbitotemporal for both genders. The most common accompanying symptoms were lacrimation (80.73%). The male:female ratio in all patients was 3:7, 3.8:1 in those with CCH and 4:1 in those with ECH. Eighty-nine (87.25%) patients had prophylactic treatment and 60 of them received verapamil., Conclusion: In our study, some clinical features of our patients were similar to those of Europe and America or the Asian countries and some of them not. There are regional differences in cluster headache patients. With more awareness of cluster headache and research from many countries, clinical differences can be revealed more objectively in the future.

Background: People with cluster headache (CH) are frequently burdened by misdiagnosis or diagnostic delay. The peculiar somatic and behavioral changes characterizing patients with CH are not useful to improve diagnostic accuracy. In our clinical experience, we noticed a typical voice quality with low and croaking tone in patients with CH. In this cross-sectional study, we evaluated, by digital voice analysis, whether it is possible to identify typical voice quality characterizing patients with CH compared with healthy controls (HCs). Furthermore, to investigate whether putative differences in voice characteristics could be underpinned by constitutional aspects or pathological processes of vocal cords, subjects underwent a videolaryngostroboscopy. Smoking habits and alcohol consumption were specifically investigated., Methods: After conducting digital recording of the voices from both patients with CH and HCs in a soundproof insulated cabin in the laboratory of the Audiology Department, a set of voice parameters was analyzed. We included the measures of fundamental frequency, calculations of jitter and shimmer, and noise-to-harmonics ratios as well as quantities related to the spectral tilt (i.e., H1-H2, H1-A1, H1-A2, and H1-A3) in 20 patients with CH and in 13 HCs. A videolaryngostroboscopy was performed in all subjects., Results: Patients with CH, explored during the cluster bout period, showed significantly lower second harmonic (H1-H2) values compared with HCs (-6.9 ± 7.6 vs. 2.1 ± 6.7, p = 0.002), usually characterizing the so-called creaky voice. By using a laryngoscopy investigation, a significantly higher prevalence of mild to moderate vocal cord edema and laryngopharyngeal reflux signs were found in patients with CH (100% of patients with CH vs. 15% of HC, p < 0.001)., Conclusion: Creaky phonation is a "physiological mode of laryngeal operation" usually underpinned by shortened and thickened vocal folds. Creaky voice phonation can be due to a vocal fold's reduced capability to become slack or flaccid secondary to vocal cord edema underpinned by laryngopharyngeal reflux affecting the phonatory mechanisms in patients with CH. The laryngopharyngeal reflux may represent a dysautonomic sign related to the increased parasympathetic tone during in-bout period, reinforcing the hypothesis of an extracranial autonomic dysfunction as part of CH clinical picture., (© 2021 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Aim: To describe the clinical characteristics and therapeutic options available to paediatric patients with cluster headache., Method: Based on a literature search of the medical databases PubMed, LILACS, and Web of Science and using selected descriptors, we carried out a systematic review of case reports on cluster headache in paediatric patients published from 1990 to 2020., Results: Fifty-one patients (29 males, 22 females) with a mean (SD) age of 9 years 7 months (3y 10mo; range 2-16y) were diagnosed with cluster headache. The mean (SD) diagnosis was made 27.8 months (26.2mo) after the onset of cluster headache. Pain occurred at night or on waking up (76.5%) and consisted of 1 to 3 attacks per day (62.7%) lasting 30 to 120 minutes (68.6%). Headaches were unilateral (90.2%), had a pulsatile character (64.7%), and severe intensity (100%). There were autonomic manifestations (90.2%) predominantly ipsilateral to pain, in this order: lacrimation; conjunctival injection; nasal congestion; ptosis; eyelid oedema; and rhinorrhoea. Sumatriptan and oxygen inhalation were the most effective treatments for acute manifestation. Prophylaxis, corticosteroids, verapamil, and gabapentin were the most effective drugs., Interpretation: Due to the small number of published studies, this review could not provide reliable data; however, it appears that cluster headache in children and adolescents is similar to adults, both in clinical characteristics and treatment. What this paper adds Cluster headache in children and adolescents is poorly studied. Cluster headache is uncommon before 10 years of age and diagnosis is difficult in the first few years of life. Treatment of cluster headache in children and adolescents is similar to that used in adults. The notion of the effectiveness of prophylactic treatment is based only on authors' experience., (© 2021 Mac Keith Press.)

Cluster headache (CH) is the most common form of trigeminal autonomic cephalalgia. Current treatments have several limitations, and new drugs are required. This article first briefly reviews present acute and preventive treatments in CH, their mechanism of action and limitations, then describes the state of the art in recent clinical drug trials since 2015, and ends with a critique of trials in the CH field. Research is limited by lack of knowledge of pathophysiology and lack of animal models. In the past 5 years, no brand-new treatment has emerged, but promising drugs, such as CGRP(R) antibodies, are under study. According to the literature and guidelines, clinicians and researchers should be aware of many limitations in study protocols: concomitant medication, patient sample size, patients' protocol compliance, and study designs that tend to restrict patient recruitment., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Cluster headache is a debilitating primary headache disorder that affects approximately 0.1% of the population worldwide. Cluster headache attacks involve severe unilateral pain in the trigeminal distribution together with ipsilateral cranial autonomic features and a sense of agitation. Acute treatments are available and are effective in just over half of the patients. Until recently, preventive medications were borrowed from non-headache indications, so management of cluster headache is challenging. However, as our understanding of cluster headache pathophysiology has evolved on the basis of key bench and neuroimaging studies, crucial neuropeptides and brain structures have been identified as emerging treatment targets. In this Review, we provide an overview of what is known about the pathophysiology of cluster headache and discuss the existing treatment options and their mechanisms of action. Existing acute treatments include triptans and high-flow oxygen, interim treatment options include corticosteroids in oral form or for greater occipital nerve block, and preventive treatments include verapamil, lithium, melatonin and topiramate. We also consider emerging treatment options, including calcitonin gene-related peptide antibodies, non-invasive vagus nerve stimulation, sphenopalatine ganglion stimulation and somatostatin receptor agonists, discuss how evidence from trials of these emerging treatments provides insights into the pathophysiology of cluster headache and highlight areas for future research.

Although cranial autonomic symptoms (CAS) are typical in cluster headache (CH), some individuals with CH show no CAS during their headache attacks. Probable cluster headache (PCH) is a subtype of CH that fulfils all but one criterion of CH. This study aimed to investigate the frequency and clinical features of CH and PCH without CAS in comparison to those with CAS. We analysed data from the Korea Cluster Headache Registry, a prospective multicentre registry involving data from 16 hospitals. Of the 216 participants with CH and 26 with PCH, 19 (8.8%) and 7 (26.9%), respectively, did not have CAS. Participants with CH without CAS exhibited less severe anxiety (General Anxiety Disorder-7 score, median [interquartile range], 2.0 [1.0-6.0] vs 8.0 [3.0-12.0], p = 0.001) and depression (Patient Health Questionnaire-9 score, 3.0 [1.0-7.0] vs 7.0 [3.0-11.0], p = 0.042) than those with CAS. Among participants with PCH, headache intensity was less severe in participants without CAS than in those with CAS (numeric rating scale, 8.0 [7.0-8.0] vs 9.5 [8.0-10.0], p = 0.015). In conclusion, a significant proportion of participants with CH and PCH did not have CAS. Some clinical features of CH and PCH differed based on the presence of CAS.

Background: Previous studies have shown worse cognitive performance in cluster headache (CH) patients compared to healthy controls; however, little is known about cognitive performance in episodic CH (ECH) patients outside and inside the active cluster (AC)., Objective: Our aim is to compare cognitive function in ECH patients outside and inside the AC., Methods: In this cross-sectional, observational study, four neuropsychological tests (Trail Making Test [TMT], Stroop Test [ST], verbal fluency [VF], and Symbol Digit Modalities Test [SDT]) were completed by 21 ECH patients at two different points in time: outside and inside the AC. We also assessed self-reported sleep quality and the presence of anxiety or depressive symptoms. Scores were compared., Results: There was not any difference between the scores of the neuropsychological tests performed outside and inside the AC (TMT-A: 23 vs. 23.5; p = 0.984; TMT-B: 96.5 vs. 85.9; p = 0.104; ST word reading: 101.0 vs. 101.2; p = 0.938; ST color naming: 73.0 vs. 73.4; p = 0.858; ST color word: 44.0 vs. 46.0; p = 0.498; SDMT: 44.0 vs. 44.6; p = 0.961; VF phonemic: 29.5 vs. 30.2; p = 0.714; VF semantic: 20 vs. 21; p = 0.489). We found a worsening in the sleep quality component of the Pittsburgh Sleep Quality Index median scores in patients outside the AC (2 vs. 1; p = 0.046)., Conclusions: Our findings suggest that patients with ECH have a similar cognitive performance outside and during the AC., (© 2021 American Headache Society.)

Objective: To determine the pain intensity of cluster headache through a large survey by comparing it to other painful disorders. Furthermore, to investigate the relationship between maximal pain, autonomic, and other clinical symptoms, as well as demographic attributes of cluster headache., Background: The pain of cluster headache is anecdotally considered to be one of the worst pains in existence. The link between pain and autonomic features of cluster headache is understood mechanistically through the trigeminovascular reflex, though it is not clear if this is a graded response. Links between pain and other features of cluster headache are less well understood., Methods: This Internet-based cross-sectional survey included questions on cluster headache diagnostic criteria, which were used as part of the inclusion/exclusion criteria for the study. Respondents were asked to rate a cluster headache attack on the 0-10 numerical rating scale. Additionally, they were asked if they had experienced a list of other painful conditions such as labor pain or nephrolithiasis; if so they were asked to rate that pain as well. The survey also included demographics, mood scores, and treatment responses., Results: A total of 1604 cluster headache respondents were included in the analysis. Respondents rated cluster headache as significantly (p < 0.001) more intense than every other pain condition examined. Cluster headache attacks were rated as 9.7 ± 0.6 (mean ± standard deviation) on the numerical rating scale, followed by labor pain (7.2 ± 2.0), pancreatitis (7.0 ± 1.5), and nephrolithiasis (6.9 ± 1.9). The majority of cluster headache respondents rated a cluster headache attack at maximal or 10.0 pain (72.1%, 1157/1604). Respondents with maximal pain were statistically significantly more likely to have cranial autonomic features compared to respondents with less pain: conjunctival injection or lacrimation 91% (1057/1157) versus 85% (381/447), eyelid edema 77% (887/1157) versus 66% (293/447), forehead/facial sweating 60% (693/1157) versus 49% (217/447), fullness in the ear 47% (541/1157) versus 35% (155/447), and miosis/ptosis 85% (1124/1157) versus 75% (426/447) (all p values <0.001). Respondents with maximal pain also had other statistically significant findings: more frequent attacks (4.0 ± 2.0 attacks per day vs. 3.5 ± 2.0 attacks per day), higher Hopelessness Depression Symptom Questionnaire scores (24.5 ± 16.9 vs. 21.1 ± 15.2), decreased overall effectiveness from calcium channel blockers (on a 5-point Likert scale), and more likely female: 34% (389/1157) versus 24% (108/447) (all p values <0.001). Pain intensity was not associated with restlessness, headache duration, age of onset, episodic/chronic status, or the effectiveness of any acute or preventive medication other than calcium channel blockers., Conclusions: Cluster headache is an intensely painful disorder, even in the context of other disorders considered intensely painful. Maximal pain intensity is associated with more cranial autonomic features, suggesting a graded response between pain and autonomic features. Maximal pain intensity is also associated with headache frequency but not duration, suggesting a relationship between pain intensity and mechanisms controlling headache onset, but not between pain intensity and mechanisms controlling headache offset., (© 2020 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

We investigated if dynamic pressure pain sensitivity in the symptomatic area is associated with pressure sensitivity in local and distant pain-free areas in cluster headache (CH). A pressure algometry set consisting of 8 rollers with fixed pressure levels ranging from 500 to 5300 g was used to assess dynamic pressure pain sensitivity in men with episodic CH. Each roller was moved from an anterior-to-posterior direction over the temporalis muscle. The load level of the first painful roller was considered the dynamic pain threshold (DPT). Further, pain elicited during DPT (roller evoked pain) was also assessed. We used a pressure algometer to determine pressure pain thresholds (PPTs) over the temporalis muscle, C5/C6 joint, second metacarpal, and tibialis anterior. Patients were assessed in an asymptomatic (remission) phase, at least 6 months after their last cluster period and without taking pharmacological treatment. Forty men with episodic CH (mean age 42 years) were included. Both outcomes, DPTs (r = 0.781, P < 0.001) and roller-evoked pain (r = 0.586; P < 0.001) were bilaterally correlated. Further, DPT, but not roller-evoked pain, was moderately associated with PPTs measured at the symptomatic (temporalis: r = 0.665, P < 0.001) and distant pain-free (C5-C6 joint: r = 0.389, P = 0.013; second metacarpal: r = 0.551, P < 0.001; and, tibialis anterior: r = 0.308, P = 0.035) points. Dynamic pressure sensitivity in the trigeminal area was correlated to pressure pain sensitivity at both symptomatic and distant pain-free areas in men with CH supporting the use of roller pressure algometry. Dynamic pressure algometry may be a new tool for assessing the status of sensitization in primary headaches.

Purpose of Review: This review provides an update on chronic cluster headache (CH) focusing on clinical features, pathophysiology, and management as well as comparisons between Eastern and Western populations., Recent Findings: Chronic CH in Eastern populations was relatively rare, compared to that in Western populations. Lacrimation and/or conjunctival injection is the most frequently reported cranial autonomic symptom, and visual aura is predominant in chronic CH patients. Neuroimaging evidence in both ethnic groups suggests that CH pathophysiology involves the hypothalamus and pain-modulatory areas, with dynamic alternations between CH episodes. Recent evidence indicates that midbrain dopaminergic systems may participate in CH chronicity. Noteworthy advances have emerged in neuromodulatory therapies for chronic CH, but treatment with calcitonin gene-related peptide (CGRP) monoclonal antibodies has been unsuccessful. Recent evidence shows divergence of chronic CH between Eastern and Western populations. Neuromodulatory therapies but not CGRP inhibition is effective in this intractable patient group.

Background: Cluster headache is a highly disabling neurological disorder., Purpose: The purpose of this review is to highlight recent therapeutic advances in the treatment of cluster headache such as monoclonal antibodies as well as non-invasive vagus nerve stimulation, and examine future potential therapeutic targets., Discussion: Several therapeutic agents currently in use may have underlying mechanisms important to cluster headache pathophysiology and have yet to be completely elucidated. The psychobiological aspects of cluster headache have a significant impact on patients, as well as pose limitations for treatment. Neuropeptides may play a role in underlying mechanisms in why cluster headache patients are frequent tobacco smokers. Alterations in the hypothalamic-pituitary-adrenal axis and neuroinflammation may play a role in suicidality. The circadian nature of cluster headache may generate the development of future treatment options. New understanding of mechanisms underlying post-traumatic headache may also provide insights into cluster headache pathophysiology., Conclusion: Molecular targets and neuromodulation advances have paved the way for a new generation of therapeutic agents in cluster headache. There are several other potential targets., (© 2020 American Headache Society.)

Introduction: Cluster headache (CH) is the most common trigeminal autonomic cephalalgia with a significant need for novel treatment options. While the use of most of the acute CH medications is supported by clinical trials and based on a pathophysiological concept for the generation of pain, the scientific evidence for preventive CH medications is very limited., Areas Covered: This article reviews acute and preventive substances for the pharmacological treatment of CH with a focus on the mode of action of these drugs. We also summarized the clinical trial evidence and discuss future research directions., Expert Opinion: Recommendations for current pharmacological CH therapies, in particular for CH prevention, are often based on small open label studies with inconclusive results. Larger trials are missing. A shared pathophysiological mechanism of action of these preventatives does not exist. Future studies with CGRP(R) antibodies and novel substances with specific actions are needed and will thereby help to understanding the pathophysiology of CH.

Cluster headache (CH) shows a more severe clinical picture than migraine (Mig). We tested whether brain changes can explain such difference. Multimodal MRI was acquired in attack-free patients with CH (n = 12), Mig (n = 13) and in normal controls (NC, n = 13). We used FSL for MRI data analysis and nonparametric permutation testing for voxelwise analyses (p < 0.01, corrected). CH showed lower grey matter (GM) volume, compared to Mig and NC, in frontal cortex regions (inferior frontal gyrus and frontal pole [FP], respectively) and, only compared to Mig, in lateral occipital cortex (LOC). Functional connectivity (FC) of CH was higher than Mig and NC within working memory and executive control networks and, only compared to Mig, between cerebellar and auditory language comprehension networks. In the attack-free state, the CH brain seems to be characterized by: (i) GM volume decrease, compared to both Mig and NC, in pain modulation regions (FP) and, only with respect to Mig, in a region of visual processing modulation during pain and working memory (LOC); (ii) increased FC at short range compared to both Mig and NC and at long range only with respect to Mig, in key cognitive networks, likely due to maladaptation towards more severe pain experience.

Background: Task-free imaging approaches using PET have shown the posterior hypothalamus to be specifically activated during but not outside cluster headache attacks. Evidence from task related functional imaging approaches however is scarce., Methods: Twenty-one inactive cluster headache patients (episodic cluster headache out of bout), 16 active cluster headache patients (10 episodic cluster headache in bout, 6 chronic cluster headache) and 18 control participants underwent high resolution brainstem functional magnetic resonance imaging of trigeminal nociception using gaseous ammonia as a painful stimulus., Results: Following trigeminonociceptive stimulation with ammonia there was a significantly stronger activation within the posterior hypothalamus in episodic cluster headache patients out of bout when compared to controls. When contrasting estimates of the pain contrast, active cluster headache patients where in between the two other groups but did not differ significantly from either., Conclusion: The posterior hypothalamus might thus be hyperexcitable in cluster headache patients outside the bout while excitability to external nociceptive stimuli decreases during in bout periods, probably due to frequent hypothalamic activation and possible neurotransmitter exhaustion during cluster attacks.

Objective: To investigate the temporal changes of circadian rhythmicity in relation to the disease course in patients with cluster headache., Methods: In this multicenter study, patients with cluster headache were recruited between September 2016 and July 2018. We evaluated the patients for circadian rhythmicity and time of cluster headache attacks in the current bout and any experience of bout-to-bout change in circadian rhythmicity. We analyzed the patterns of circadian rhythmicity in relation to the disease progression (the number of total lifetime bouts, grouped into deciles)., Results: Of the 175 patients in their active, within-bout period, 86 (49.1%) had circadian rhythmicity in the current bout. The prevalence of circadian rhythmicity in the active period was overall similar regardless of disease progression. Sixty-three (46.3%) out of 136 patients with ≥2 bouts reported bout-to-bout changes in circadian rhythmicity. The most frequent time of cluster headache attacks was distributed evenly throughout the day earlier in the disease course and dichotomized into hypnic and midday as the number of lifetime bouts increased ( p  = 0.037 for the homogeneity of variance). When grouped into nighttime and daytime, nighttime attacks were predominant early in the disease course, while daytime attacks increased with disease progression (up to 7th deciles of total lifetime bouts, p  = 0.001) and decreased in patients with the most advanced disease course ( p  = 0.013 for the non-linear association)., Conclusions: Circadian rhythmicity is not a fixed factor, and changes according to the disease course. Our findings will be valuable in providing a new insight into the stability of functional involvement of the suprachiasmatic nucleus in the pathophysiology of cluster headache.

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., (© 2019 American Headache Society.)

Objective: The aim of this study was to measure the interictal burden (IIB) associated with cluster headache (CH)., Background: CH is characterized by an alternation of excruciatingly painful attacks and pain-free periods. Absence of pain does not necessarily imply absence of symptoms, though. Some may persist or improve more slowly than pain; others may arise in between attacks., Methods: Participants filled out an online survey based on the EUROLIGHT questionnaire. Inclusion criteria were a reported diagnosis of CH and residency in a European country; exclusion criteria were refusal to give informed consent and to complete the questionnaire., Results: Most of the burden was related to higher headache frequencies: ongoing symptoms despite pain freedom, impaired autonomy due to avoidance of triggers, reluctance to tell others about the disease, and the feeling of not being understood by family and friends, employers and colleagues. Irreversible, potentially accumulating burden may occur if headache frequency is high; examples are impairment of career options, relationships, and family planning issues. Worrying about future attacks and avoiding potential triggers occur independently from attack frequency and disease duration. There were no differences between the in-bout and the out-bout period among participants with episodic CH. Participants with chronic CH reported greater IIB., Conclusions: Even between attacks CH can have a huge and potentially irreversible impact on life. Different types of IIB were identified, all of which may contribute to the total burden of disease. As cumulative burden might be irreversible, prevention strategies need to be developed., (© 2019 American Headache Society.)

Background: Chronic cluster headache is the most disabling form of cluster headache. The mainstay of treatment is attack prevention, but the available management options have little efficacy and are associated with substantial side-effects. In this study, we aimed to assess the safety and efficacy of sphenopalatine ganglion stimulation for treatment of chronic cluster headache., Methods: We did a randomised, sham-controlled, parallel group, double-blind, safety and efficacy study at 21 headache centres in the USA. We recruited patients aged 22 years or older with chronic cluster headache, who reported a minimum of four cluster headache attacks per week that were unsuccessfully controlled by preventive treatments. Participants were randomly assigned (1:1) via an online adaptive randomisation procedure to either stimulation of the sphenopalatine ganglion or a sham control that delivered a cutaneous electrical stimulation. Patients and the clinical evaluator and surgeon were masked to group assignment. The primary efficacy endpoint, which was analysed with weighted generalised estimated equation logistic regression models, was the difference between groups in the proportion of stimulation-treated ipsilateral cluster attacks for which relief from pain was achieved 15 min after the start of stimulation without the use of acute drugs before that timepoint. Efficacy analyses were done in all patients who were implanted with a device and provided data for at least one treated attack during the 4-week experimental phase. Safety was assessed in all patients undergoing an implantation procedure up to the end of the open-label phase of the study, which followed the experimental phase. This trial is registered with ClinicalTrials.gov, number NCT02168764., Findings: Between July 9, 2014, and Feb 14, 2017, 93 patients were enrolled and randomly assigned, 45 to the sphenopalatine ganglion stimulation group and 48 to the control group. 36 patients in the sphenopalatine ganglion stimulation group and 40 in the control group had at least one attack during the experimental phase and were included in efficacy analyses. The proportion of attacks for which pain relief was experienced at 15 min was 62·46% (95% CI 49·15-74·12) in the sphenopalatine ganglion stimulation group versus 38·87% (28·60-50·25) in the control group (odds ratio 2·62 [95% CI 1·28-5·34]; p=0·008). Nine serious adverse events were reported by the end of the open-label phase. Three of these serious adverse events were related to the implantation procedure (aspiration during intubation, nausea and vomiting, and venous injury or compromise). A fourth serious adverse event was an infection that was attributed to both the stimulation device and the implantation procedure. The other five serious adverse events were unrelated. There were no unanticipated serious adverse events., Interpretation: Sphenopalatine ganglion stimulation seems efficacious and is well tolerated, and potentially offers an alternative approach to the treatment of chronic cluster headache. Further research is need to clarify its place in clinical practice., Funding: Autonomic Technologies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To investigate central sensitization (CS) in cluster headache (CH) and to evaluate its relationship with disease characteristics and psychological comorbidities., Design: Cross-sectional study., Settings: Whether CS occurs in CH, as it does in other primary headaches, is a subject of debate. Few studies have evaluated the presence of CS and its relationship with psychological comorbidities in patients with CH., Subjects: Twenty patients with episodic or chronic CH and 16 healthy controls were recruited., Methods: The variables evaluated included frequency, intensity and duration of headache attacks, pressure pain thresholds (PPTs) and wind-up (WU) ratios of pain bilaterally measured over trigeminal and extratrigeminal areas, and results of questionnaires regarding anxiety and depression (Hospital Anxiety and Depression Scale [HADS], Beck Depression Inventory [BDI], State-Trait Anxiety Inventory [STAI]), quality of life (Short Form-36 [SF-36]), headache impact (Headache Impact Test [HIT-6]), and allodynia (Allodynia Symptom Checklist [ASC])., Results: PPT levels were significantly lower in the CH group compared with the healthy participants (all tested points, P < 0.001). No differences were found in WU ratios between groups. However, differences in HADS (P < 0.01), BDI (P < 0.01), STAI (P < 0.01), SF-36 (P < 0.01), HIT-6 (P < 0.001), and ASC (P < 0.01) were observed between groups. The healthy group showed a moderate negative correlation between SF-36 and BDI (rho = -0.59, P = 0.03). Likewise, the CH group showed a moderate negative correlation between frequency and BDI (rho = -0.52, P = 0.03), a strong positive correlation between duration and HADS (rho = 0.86, P < 0.01), and a moderate negative correlation between intensity and PPT over symptomatic V1 (rho = -0.66, P < 0.01) and over asymptomatic V1 (rho = -0.65, P < 0.01). The CH group also showed a moderate negative correlation between SF-36 and anxiety and depression variables., Conclusions: Our findings show that patients with CH have lower PPT levels at cranial and extracranial points, suggesting, as in other primary headaches, the presence of CS. We have also found a high prevalence of psychiatric comorbidities that correlate with the length and frequency of attacks. These findings highlight the importance of a multidisciplinary approach to the treatment of patients with CH., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To review and discuss the putative role of light, sleep, and the biological clock in cluster headache., Discussion: Cluster headache attacks are believed to be modulated in the hypothalamus; moreover, the severe pain and typical autonomic cranial features associated with cluster headache are caused by abnormal activity of the trigeminal-autonomic reflex. The temporal pattern of cluster headache attacks suggests involvement of the biological clock, and the seasonal pattern is influenced by the number of daylight hours. Although sleep is often reported as a trigger for cluster headache attacks, to date no clear correlation has been established between these attacks and sleep stage., Conclusions: We hypothesize that light, sleep, and the biological clock can change the brain's state, thereby lowering the threshold for activating the trigeminal-autonomic reflex, resulting in a cluster headache attack. Understanding the mechanisms that contribute to the daily and seasonal fluctuations in cluster headache attacks may provide new therapeutic targets.

(1) Background: Spatial changes in pressure sensitivity have been described in migraine and tension-type headaches. Our aim was to determine differences in the spatial distribution of pressure pain sensitivity of the temporalis muscle between cluster headache (CH) patients and headache-free controls; (2) Methods: Pressure pain thresholds (PPTs) were determined over nine points covering the temporalis muscle in 40 men with episodic CH and 40 matched headache-free controls in a blinded fashion. Topographical pressure pain sensitivity maps were constructed based on interpolation of the PPTs. Patients were evaluated in a pain-free period (remission phase), at least 3 months from the last attack and without medication; (3) Results: The analysis of covariance (ANCOVA) found significant difference between points (F = 21.887; P < 0.001) and groups (F = 24.416; P = 0.602), but not between sides (F = 0.440; P = 0.508). No effect of depression (F = 0.014; P = 0.907) or anxiety (F = 0.696; F = 0.407) was observed. A post-hoc analysis revealed: 1) lower PPTs at all points in patients than in controls, 2) an anterior-to-posterior gradient in patients but not in controls, with lower PPTs located in the anterior column. Large between-groups effects were shown in all points (standardized mean difference, SMD > 0.8); (4) Conclusions: Bilateral pressure pain hypersensitivity to pressure pain in the temporalis muscle and an anterior-to-posterior gradient to pressure pain was observed in men with episodic CH.

Objective: To review and discuss the literature relevant to the role of brainstem structure and function in headache., Background: Primary headache disorders, such as migraine and cluster headache, are considered disorders of the brain. As well as head-related pain, these headache disorders are also associated with other neurological symptoms, such as those related to sensory, homeostatic, autonomic, cognitive and affective processing that can all occur before, during or even after headache has ceased. Many imaging studies demonstrate activation in brainstem areas that appear specifically associated with headache disorders, especially migraine, which may be related to the mechanisms of many of these symptoms. This is further supported by preclinical studies, which demonstrate that modulation of specific brainstem nuclei alters sensory processing relevant to these symptoms, including headache, cranial autonomic responses and homeostatic mechanisms., Review Focus: This review will specifically focus on the role of brainstem structures relevant to primary headaches, including medullary, pontine, and midbrain, and describe their functional role and how they relate to mechanisms of primary headaches, especially migraine.

Background: Anger is involved in the emotional experience of pain. Individuals with migraine are more likely to hold their anger-in than controls. However, only one study evaluated anger in cluster headache (CH). The objective is to compare anger between migraine and CH patients., Methods: One hundred thirty-five migraine and 108 CH patients completed the State Trait Anger Expression Inventory (STAXI-2), composed of 7 subscales. State Anger measures the intensity of the individual's angry feelings at the time of testing. Trait Anger evaluates general predisposition to become angry. Anger Expression Out and Anger Expression In measure the extent to which anger could be overtly expressed or suppressed. Anger Control Out and Anger Control In evaluate how individual try to control the outward or inward expression of anger. Anger Expression Index is a general index., Results: CH patients have higher median scores than migraine patients in State Anger (46 vs 44, p = 0.012). CH patients have lower scores in Anger Control Out (44 vs 50, p = 0.016). In subgroup analysis, CH patients during the cluster period have higher scores than chronic migraine patients in State Anger (47 vs 44, p = 0.035), while CH patients in headache-free period did not differ from migraine patients., Conclusions: Migraine and CH patients differ in state anger, indicating that CH patients experienced higher intensity of anger during the time of testing. These data add new information about emotional regulation in headache patients and could support the hypothesis of different emotional and behavioral responses to pain in migraine and CH patients.

Objective: To describe the role of biochemical anomalies of tyrosine (TYR), tryptophan (TRP), and arginine (ARG) metabolism in patients suffering from episodic and chronic cluster headache (CCH)., Background: The pathogenesis of cluster headache (CH) and the process that transforms the episodic into the chronic form are unknown. However, the accompanying symptoms suggest a dysfunction of the sympathetic system and hypothalamus along with anomalies of metabolism of catecholamines, elusive amines, and nitric oxide (NO) metabolism., Methods: We describe the results obtained from the last papers published on this issue. The level of metabolites were analyzed by different high-performance liquid chromatography methods., Results: In both episodic and CH patients, the levels of dopamine and elusive amines are very elevated. The only biochemical difference found in studies between episodic and chronic cluster was that norepinephrine levels were significantly lower in episodic cluster in comparison to control and chronic subjects. In addition, the levels of ARG, homoarginine, and citrulline, precursors of synthesis of NO, were significantly lower in chronic cluster., Conclusions: All these results suggest that TYR, TRP, and ARG metabolism is abnormal and may constitute a biochemical fingerprint of CH patients. The increased levels of norepinephrine in chronic cluster constitute a possible cause of chronicity of this primary headache. The high levels of tryptamine and its activity on the central serotoninergic system may explain why the length of CH is brief in comparison to migraine and tension-type headache. The low levels of ARG, homoarginine, and citrulline may be the consequence of high circulating levels of α 1 -agonists, such as epinephrine and norepinephrine, and their biochemical interaction with endothelial trace amine-associated receptor 1 that induces activation of NO synthase, resulting in NO synthesis in the circulation, NO release, intense vasodilation, and as a result, the cluster attack., (© 2019 American Headache Society.)

The criterion for the remission period of chronic cluster headache (CCH) was recently revised from < 1 month to < 3 months in the third edition of the International Classification of Headache Disorders (ICHD-3). However, information on the clinical features of CCH based on the ICHD-3 criteria is currently limited. The present study aimed to investigate the clinical features of CCH based on ICHD-3 using data from the Korean Cluster Headache Registry (KCHR). The KCHR is a multicentre prospective registry of patients with cluster headache (CH) from 15 hospitals. Among the 250 participants with CH, 12 and 176 participants were classified as having CCH and episodic cluster headache (ECH), respectively. Among 12 participants with CCH, 6 (50%) had remission periods of < 1 month, and the remaining 6 (50%) had a remission period of 1-3 months. Six participants had CCH from the time of onset of CH, and in the other 6 participants, CCH evolved from ECH. CCH subjects had later age of onset of CH, developed the condition after a longer interval after CH onset, and had more migraine and less nasal congestion and/or rhinorrhoea than ECH subjects. Clinical features of CCH with remission periods < 1 month were not significantly different from those of CCH with remission periods of 1-3 months, except for the total number of bouts. More current smoking and less diurnal rhythmicity were observed in participants with CCH evolved from ECH compared to those with ECH. In conclusion, the number of subjects with CCH doubled when the revised ICHD-3 criteria were used. Most of clinical characteristics of CCH did not differ when the previous and current version of ICHD was applied and compared. Some clinical features of CCH were different from those of ECH, and smoking may have a role in CH chronification., Competing Interests: SJ Cho was involved as a site investigator of a multicentre trial sponsored by Otsuka Korea, Eli Lilly and Company, and Novartis, worked as an advisory member for Teva, and received research support from Hallym University Research Fund 2016 and a grant from the Korean Neurological Association (KNA-16-MI-09). MK Chu was a site investigator for a multi-centre trial sponsored by Otsuka Korea, Novartis International AG, and Eli Lilly and Company. He worked as an advisory member for Teva, and received lecture honoraria from Allergan Korea, Handok-Teva, and Yuyu Pharmaceutical Company in the past 24 months. The other authors, except for SJ Cho and MK Chu, declare no potential conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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.

Background: Cluster headache attacks follow a striking circadian rhythm with an intriguing influence of sleep. We aim to investigate differences in sleep quality, chronotype, and the ability to alter individual sleep rhythms in episodic and chronic cluster headache patients vs controls., Methods: Cluster headache patients and non-headache controls from the Dutch Leiden University Cluster headache neuro-Analysis program aged 18 and above completed web-based questionnaires in a cross-sectional study., Results: A total of 478 episodic, 147 chronic cluster headache patients and 367 controls participated. Chronic cluster headache patients had more often early chronotypes than controls, as measured by mid-sleep phase (P = .021 adjusted B -15.85 minutes CI -29.30; -2.40). Compared to controls, chronic cluster headache participants were less able to alter their sleep rhythms (P < .001 adjusted B -1.65 CI -2.55; 0.74), while episodic cluster headache participants reported more difficulty in coping with reduced sleep (P = .025 adjusted B 0.75 CI 0.09; 1.40). Sleep quality was reduced in both types of cluster headache compared to controls ("poor sleepers": 71.4% (105/147) in chronic and 48.3% (235/367) in episodic cluster headache vs 25.6% (94/367) in controls; both P < .001; episodic adjusted B -1.71 CI 0.10; 0.32; chronic adjusted B -0.93 CI 0.24; 0.65)., Conclusion: Sleep quality is decreased in both episodic and chronic cluster headache, most likely caused by cluster headache attacks that strike during the night. Episodic cluster headache patients report more difficulty in coping with reduced sleep, while chronic patients are less able to alter their sleep rhythm. Although not directly proven, cluster headache patients will likely benefit from a structured, regular daily schedule., (© 2019 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals, Inc. on behalf of American Headache Society.)

Objectives: Cluster headaches are a set of episodic and chronic pain syndromes that are sources of significant morbidity for patients. The standard of care for cluster headaches remains medication therapy, however a minority of patients will remain refractory to treatment despite changes to dosage and therapeutic combinations. In these patients, functional neuromodulation using Deep Brain Stimulation (DBS) presents the opportunity to alleviate the significant pain that is experienced by targeting the neurophysiological substrates that mediate pain., Material and Methods: We review the literature on chronic cluster headache, including the growing number of DBS case reports and series that describe the alleviation of pain in a majority of patients through conventional or endoventricular targeting of the posterior hypothalamus and ventral tegmental area, with a minimal side effect profile., Results: In this review, the history and outcomes of DBS use for medication-refractory cluster headaches are examined, with discussion on future directions for improving this novel treatment modality and providing efficacious, longer-lasting pain relief in headache patients., Conclusion: In patients with chronic cluster headache, functional neuromodulation using DBS presents the opportunity to alleviate the significant pain that is experienced by targeting the neurophysiological substrates that mediate pain., (© 2018 International Neuromodulation Society.)

Cluster headache (CH) has always been considered a type of primary headache affecting predominantly male subjects in early and medium adulthood. However, recent studies carried out in large case series of patients with CH show that not infrequently it may set in also after age 50; by contrast, onset before adolescence is very rare. Additionally, when onset occurs before age 14 or from the sixth decade of life onward, male predominance decreases to the point that in chronic forms CH predominantly affects the female sex. This particular pattern of the gender ratio in relation to onset in different age groups suggests that hormonal factors may actually play a role in the genesis of CH. In particular, future studies should be aimed at investigating the possible protective role of estrogen.

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).

The comprehension of cluster headache (CH) has greatly benefited from the tremendous progress of the neuroimaging techniques over the last 20 years. Since the pioneering study of May et al. (1998), the neuroimaging results have indeed revolutionized the conception of this disease, now considered as a dysfunction of the central nervous system. Clinical, neuroendocrinological, and neuroimaging studies strongly suggested the involvement of the hypothalamus as the generator of cluster headache attacks. However, the latency of the improvement and the inefficacy of the hypothalamic deep brain stimulation (DBS) in the acute phase suggested that the hypothalamus might play a modulating role, pointing to the presence of some dysfunctional brain networks, normalized or modulated by the DBS. Despite the great importance of possible dysfunctional hypothalamic networks in cluster headache pathophysiology, only quite recently the scientific community has begun to explore the functional connectivity of these circuits using resting-state functional magnetic resonance imaging. This is a neuroimaging technique extensively employed to investigate the functional connectivity among separated regions of the brain at rest in the low-frequency domain (< 0.1 Hz). Here, we present a review of the few resting-state functional magnetic resonance imaging studies investigating the hypothalamic network contributing to a deeper comprehension of this neurological disorder. These studies seem to demonstrate that both the hypothalamus and the diencephalic-mesencephalic junction regions might play an important role in the pathophysiology of CH. However, future studies are needed to confirm the results and to clarify if the observed dysfunctional networks are a specific neural fingerprint of the CH pathophysiology or an effect of the severe acute pain. It will be also crucial to clarify the neural pathways of the chronicization of this disorder.

Cluster headache (CH) is characterized by attacks of severe, strictly unilateral pain that is orbital, supraorbital, temporal, or any combination of these, lasts 15-180 min, and occurs from once every other day to eight times a day. The pain is associated with ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial sweating, miosis, ptosis and/or eyelid edema, and/or with restlessness or agitation. The understanding of the pathophysiological mechanisms behind CH is far from complete, but CH is considered to be a neurovascular and chronobiologic headache disorder, with a pivotal role played by the central brain mechanisms. The diagnosis of CH is based on a careful history that elicits the clinical features of attacks, ipsilateral autonomic phenomena, and the cyclical nature of the bouts in which the attacks occur. Additional diagnostic interventions are needed to rule out secondary causes of CH. The main focus of therapy is to abort attacks once they have begun and to prevent future attacks. Alternative interventions in patients with CH who have not experienced any meaningful benefit from preventive drugs are well defined. Although there have been advances in the diagnosis and therapy of CH, a significant number of CH patients experience misdiagnoses and diagnostic delay, which stalls the possibility of the timely application of adequate abortive and preventive therapy.

Migraine is a common, severe disease, affecting the brain and blood vessels, causing much pain, time missed from work and family, and severe disability. It affects approximately 12% of most Western populations studied and affects women three times more than men. Cluster headache is a much less common dysfunction of the hypothalamus, involving the sphenopalatine ganglion and other areas; it causes more frequent, shorter, and even more intense pain than migraine. The pain usually comes in cycles and is associated with ipsilateral autonomic features and associated with irritability and inability to stay still. It affects less than 0.1% of the population and is slightly more prevalent in men than women. Although we have some acute care and preventive medications for both types of headache, no treatment is optimal for each patient and some will not respond well or have significant adverse events to existing therapies.

Cutaneous allodynia (CA) is an abnormal pain in response to non-painful stimuli. In the present study, we sought to investigate the presence of CA, its associated factors, and its clinical implications in patients with cluster headache (CH). In this cross-sectional study, we analysed data from a prospective multicentre registry enrolling consecutive patients with CH. We identified CA during and between headache attacks using the 12-item Allodynia Symptom Checklist (ASC) administered during the CH bout period. Comorbid depression and anxiety were ascertained using the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorder (GAD-7) scales. Headache impact was evaluated using the Headache Impact Test-6 (HIT-6). Of 119 eligible patients, 48 and two (40.3% and 1.7%) had CA during and between headache attacks, respectively. In univariable analyses, total CH duration, major depressive disorder (MDD), and generalized anxiety disorder (GAD) were associated with CA during headache attack. They remained significantly associated with CA during headache attack in multivariable analyses. Patients with CA during headache attack had higher headache impact (P = 0.002). A "50% responder" analysis showed no difference in outcome of acute and preventive treatment between patients with and without CA during headache attack. Patients with CH commonly experienced CA during headache attack, but not between headache attacks. CA during headache attack was associated with disease duration, depression, and anxiety.

Objective: Primary headache and obesity are highly prevalent disorders in the general population. Although many studies have reported an association between the two, there is still no overall comprehension about this relationship. To gain a more accurate understanding in this regard, we analyzed data from a 2011 cross-sectional study in Chongqing, China., Methods: Patients with a chief complaint of headache were administered a headache questionnaire and diagnosed by neurology doctors in accordance with the International Classification of Headache Disorders 2nd Edition (ICHD-II) criteria. Patients aged < 18 years or diagnosed with secondary headache were excluded., Results: Of 1327 patients who cited headache as the chief complaint, 16 were excluded for missing data, while 396 were diagnosed with chronic headache (177 chronic migraine [CM], 186 chronic tension-type headache [CTTH], and 33 other chronic headache) and 915 with episodic headache (369 episodic migraine [EM], 319 episodic tension-type headache [ETTH], and 227 other episodic headache). Chronic headache patients had a higher number of headache days per month, longer duration of headache history, and greater tendency to overuse analgesics than episodic headache patients. The CM and ETTH patients were more apt to be overweight and had a significantly greater body mass index (BMI; p < 0.05) than the EM and CTTH patients. Overweight (odds ratio [OR] = 3.64; 95% confidence interval (CI), 1.19-8.81) and obesity (OR = 28.63; 95% CI, 2.96-276.6) were independently associated with CM but not with other headaches, and this association was not influenced by other factors such as medication overuse., Conclusions: The relationship between headache and overweight/obesity varies depending on the type of primary headache. CM patients are more likely to have a higher body mass index than EM patients, while ETTH patients are more likely to be overweight/obese than CTTH patients.

Primary headaches are one of the most prevalent neurological disorders and can occur during a wide range of lifespan. Primary headaches, especially migraine, are cyclic disorders with a complex sequence of symptoms within every headache attack. There is no systematic review of whether these symptoms changes during lifespan. Indeed, the clinical presentation of migraine shows an age-dependent change with a significantly shorter duration of the attacks and occurrence of different paroxysmal symptoms, such as vomiting, abdominal pain or vertigo, in childhood and, in contrast, largely an absence of autonomic signs and a more often bilateral headache in the elderly. The age-dependent differences in the clinical presentation are less distinct in cluster headache and, especially, in tension-type headache. The differences in the clinical presentation are in agreement with the idea that the connectivity of hypothalamic areas with different brainstem areas, especially the central parasympathetic areas, is important for the clinical manifestation of migraine, as well as, the change during lifespan.