|Year : 2018 | Volume
| Issue : 5 | Page : 3-8
Cluster headache: Epidemiology, pathophysiology, clinical features, and diagnosis
Diana Yi-Ting Wei1, Jonathan Jia Yuan Ong2, Peter James Goadsby1
1 Department of Basic and Clinical Neuroscience, Headache Group, Institute of Psychiatry, Psychology and Neuroscience, King's College London; NIHR-Wellcome Trust King's Clinical Research Facility, King's College Hospital, London, UK
2 Department of Basic and Clinical Neuroscience, Headache Group, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Department of Medicine, Division of Neurology, National University Health System, University Medicine Cluster, Singapore
|Date of Web Publication||11-Apr-2018|
Dr. Peter James Goadsby
King's College London, Wellcome Foundation Building, Denmark Hill Campus West, London SE5 9PJ
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Cluster headache is a primary headache disorder affecting up to 0.1% of the population. Patients suffer from cluster headache attacks lasting from 15 to 180 min up to 8 times a day. The attacks are characterized by the severe unilateral pain mainly in the first division of the trigeminal nerve, with associated prominent unilateral cranial autonomic symptoms and a sense of agitation and restlessness during the attacks. The male-to-female ratio is approximately 2.5:1. Experimental, clinical, and neuroimaging studies have advanced our understanding of the pathogenesis of cluster headache. The pathophysiology involves activation of the trigeminovascular complex and the trigeminal-autonomic reflex and accounts for the unilateral severe headache, the prominent ipsilateral cranial autonomic symptoms. In addition, the circadian and circannual rhythmicity unique to this condition is postulated to involve the hypothalamus and suprachiasmatic nucleus. Although the clinical features are distinct, it may be misdiagnosed, with patients often presenting to the otolaryngologist or dentist with symptoms. The prognosis of cluster headache remains difficult to predict. Patients with episodic cluster headache can shift to chronic cluster headache and vice versa. Longitudinally, cluster headache tends to remit with age with less frequent bouts and more prolonged periods of remission in between bouts.
Keywords: Cluster headache, diagnosis, epidemiology, pathophysiology, trigeminal autonomic cephalalgias
|How to cite this article:|
Wei DY, Yuan Ong JJ, Goadsby PJ. Cluster headache: Epidemiology, pathophysiology, clinical features, and diagnosis. Ann Indian Acad Neurol 2018;21, Suppl S1:3-8
|How to cite this URL:|
Wei DY, Yuan Ong JJ, Goadsby PJ. Cluster headache: Epidemiology, pathophysiology, clinical features, and diagnosis. Ann Indian Acad Neurol [serial online] 2018 [cited 2020 Jan 19];21, Suppl S1:3-8. Available from: http://www.annalsofian.org/text.asp?2018/21/5/3/229736
| Introduction|| |
Cluster headache is a primary headache disorder, belonging to the trigeminal autonomic cephalalgias (TACs). Descriptions of the disorder in the literature dates as far back as 1641, where the Dutch physician Nicolaes Tulp, famous from Rembrandt's painting, “The anatomy lesson,” described a recurring severe unilateral headache lasting no longer than 2 h in the Observationes Medicae. However, cranial autonomic features were not described therein. Wilfred Harris (1869–1960), a Madras-born London neurologist, described cluster headache in his classic monograph Neuritis and Neuralgia in 1926; this was probably the earliest clear recognition of it as a separate entity from migraine and trigeminal neuralgia. In 1936, Harris named these headaches migrainous neuralgia or ciliary (migrainous) neuralgia, where he recorded the unilaterality of attacks, severity, associated autonomic features, and frequency of attacks. His description was the first recorded reports of cluster headache in the English medical literature. The same clinical features are detailed in the International Classification Headache Disorder-3 (ICHD-3). This review will cover the epidemiology, pathophysiology, clinical features, and diagnosis of the disorder.
| Epidemiology|| |
Given the low prevalence of cluster headache compared to migraine, it is difficult to assess accurately the prevalence of cluster headache in the community. Nonetheless, given the specific features of cluster headache, it is possible to identify possible cases in the community, using questionnaires based on the ICHD criteria. Community-based studies have been performed to ascertain the prevalence of cluster headache. They are generally modeled on a two-step process. The first step is to screen for possible cluster headache cases either through mailed questionnaires or structured interviews based on the ICHD criteria. Following this, interviews are performed by neurologists or trained interviewers to assess cases further. Fischera et al. reviewed 16 population-based studies published up to August 2007, specifically looking at cluster headache prevalence in a meta-analysis and found that the 1-year prevalence varied greatly between the studies and ranged from 3 to 150/100,000. Their pooled lifetime prevalence was 0.12%. The study with the highest prevalence found in this meta-analysis was the Vågå study in Norway where the principal investigator Sjaastad personally interviewed and examined 1828 inhabitants of Vågå. The study identified seven subjects with cluster headache, corresponding to a prevalence of 381 per 100,000 (95% confidence intervals: 153–783). Since August 2007, there have been two further population-based studies, one from the Republic of Georgia with a prevalence of 87 per 100,000 and in rural Ethiopia with a prevalence of 1.3%.
| Sex|| |
Cluster headache has been historically considered to have a male preponderance, with a high male-to-female ratio, and thought to be different between episodic cluster headache (ECH) and chronic cluster headache (CCH). In a study involving 545 patients with ECH and CCH examined between 1963 and 1997, it was observed that there was a downward trend in male preponderance over this period. Although there is still an overall male preponderance for cluster headache, this did not differ between ECH and CCH. Subanalysis of the gender ratio by the age of onset revealed that the male-to-female ratio was highest in patients where the age of onset was between 20 and 49 years old; in ECH, this was 7.2:1; and in CCH, this was 11.0:1. The male-to-female ratio was lowest when the age of onset was after 50, where the ratio was 2.3:1 in ECH and 0.6:1 in CCH. The authors postulated that this could be related to sex hormone regulation and environmental factors. Others have suggested that the decreasing male-to-female ratio reflects the change in women's lifestyle over the decades, possibly related to the increase in cigarette smoking and alcohol use. Bahra et al. found that the male-to-female ratio to be 2.5:1 and has been consistent through the decade.
The cluster headache attack clinical phenotype is similar between men and women.,, However, women with cluster headache tend to have more nausea and vomiting with their attacks., The mean age of onset of cluster headache in both genders is similar, with the mean age of onset being in the third decade. For CCH, there is a bimodal pattern in women with peaks in the second and sixth decade as compared with men.
Unlike in migraine, no clear relationship between cluster headache, and estrogen has been established, in particular with oral contraception, hormone replacement therapy, menses, pregnancy, and the menopause.,
| Genetics|| |
In the last two decades, genetic links have been explored the following reports of cluster headaches in monozygotic twin pairs,,, from twin registry survey, and genetic epidemiological surveys,,,, suggesting a higher risk for family members compared with the general population. It is thought that first-degree relatives have a 5–18 times higher risk, and in second degree relatives, 1–3 times increased risk as compared to the general population.
However, the inheritance and genetics of the disorder are complex, and thus far no confirmed gene has been found to be clearly associated with cluster headache. Initial studies suggest a possible relationship to the hypocretin receptor 2 gene.,, However, a large study from The Netherlands and their meta-analysis could not confirm findings from earlier studies. Similarly, the recent first genome-wide association study involving 99 Italian patients with cluster headache did not show a statistically significant association; however, a suggestive association with a variant of the pituitary adenylate cyclase activating peptide receptor gene  was reported. Much larger cohorts are clearly required to confirm these initial findings.
| Race|| |
The majority of the large-scale epidemiological studies have been performed in Caucasians. Consequently, less is known regarding the prevalence of cluster headache across the world. In the US, a retrospective study at an academic headache center found that African-American women seemed to develop cluster headache more often than African-American men (25% vs. 17.4%). There have been community-based headache studies in Malaysia where they did not identify any cases of cluster headache in a population size of 595. In rural Ethiopia, the prevalence of cluster headache between 1992 and 1993 was reported to be extremely rare at 0.03%, whereas in 2011, the prevalence of cluster headache was found to be 1.3%, reflecting the other prevalence from the meta-analysis mentioned above.
As compared to Caucasians, variations in clinical phenotype among eastern Asians have been reported. These studies were largely clinic based, and they reported that the sense of agitation during cluster headache attacks was less prominent. There was also a lower prevalence of CCH observed.,,,,
| Pathophysiology|| |
The pathophysiology of cluster headache is complex and the underlying mechanisms are not fully elucidated. Cluster headache is a neurovascular rather than a vascular headache, with vascular cerebral changes being driven by the effects of trigeminal-autonomic reflex activation., The trigeminal-autonomic reflex is a pathway which consists of a brainstem connection between the trigeminal nerve and facial cranial nerve parasympathetic outflow  and is activated with the stimulation of the trigeminovascular pathways [Figure 1].
|Figure 1: Cluster headache pathophysiology. Pain afferents from the trigeminovascular system traverse the ophthalmic division of the trigeminal nerve, taking signals from the cranial vessels and dura mater (shown by purple fibers). These inputs synapse in the TCC and project to higher brain structures such as the thalamus (T) and cortex resulting in pain perception (shown in blue fibers). Activation of the trigeminovascular system by stimulation of dural structures also causes neuronal activation in the SSN within the pons, which is the origin of cells for the cranial parasympathetic autonomic vasodilator pathway. There is subsequent activation of this parasympathetic reflex through the outflow from the SSN and is relayed through the SPG (shown by pink fibres), but also through the facial (VIIth cranial) nerve (not shown). Activation of both trigeminal and autonomic nerves defines the trigeminal autonomic reflex arc, which is integral to the pathophysiology of cluster headache and the other TACs. The HT is functionally connected to the ipsilateral trigeminal system and other brain areas of the pain matrix. Red dashed lines indicate the pathways by which the HT controls or triggers pain. A third-order sympathetic nerve lesion thought to be caused by vascular changes to the ICA in the cavernous sinus with subsequent irritation of the local plexus of nerve fibers, can give rise to sympathetic symptoms ( Incomplete Horner syndrome More Details) (shown by yellow fibers). IML = Intermediolateral tract of spinal cord, SCG = Superior cervical ganglion, SN = Suprachiasmatic nucleus, TCC = Trigeminocervical complex, SSN = Superior salivatory nucleus, SPG = Sphenopalatine ganglion, HT = Hypothalamus, ICA = Internal carotid artery|
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The trigeminovascular pathway consists of neurons innervating the cerebral vessels and dura mater through cell bodies in the trigeminal ganglion. The ganglion contains bipolar cells, with peripherally there are synaptic connection with the cerebral vessels and dura mater and centrally there are fibers synapsing in the trigeminocervical complex (TCC), which are the trigeminal nucleus caudalis in the caudal brainstem and high cervical cord in the dorsal horns of C1 and C2. There are projections from the TCC up to the thalamus, resulting in activation of cortical structures involved in pain processing, such as the frontal cortex, insulae, and cingulate cortex. The cell bodies of the trigeminal ganglion contain several vasodilator peptides that innervate the blood vessels. These include calcitonin gene-related peptide (CGRP), substance P, and neurokinin A. CGRP is elevated during both spontaneous  and nitroglycerin-triggered cluster headache attacks, providing evidence that the trigeminovascular pathway is activated during attacks.
The associated cranial autonomic symptoms characteristic of cluster headache arise from the reflex activation of the trigeminal-autonomic reflex pathway through parasympathetic outflow from the superior salivatory nucleus, the cranial facial nerve, through the sphenopalatine ganglion, resulting in vasodilatation and parasympathetic activation. Clinically, this presents as lacrimation, conjunctival injection, and nasal congestion. When the first division of the trigeminal nerve is activated by pain, such as by capsaicin injection, carotid vasodilation and parasympathetic activation have been observed.
These clinical features of cluster headache suggest a central mechanism, in particular, the hypothalamus. Kudrow observed that cluster headache bouts occur at the same time each year in a circannual pattern, particularly during the change in clocks to daylight savings in seasons. He postulated that this was linked with photoperiodism, otherwise known as length of daylight, and that this could be attributed centrally to the hypothalamus, suggesting an inability to synchronize the internal circannual pacemaker with the external environmental light cues. Melatonin is produced in the pineal gland, and its rate of secretion has a strong circadian rhythm regulated by the suprachiasmatic nucleus, which receives sympathetic innervation from the hypothalamus and autonomic centers of the thoracic spinal cord, the sympathetic cervical plexus, and the carotid plexus. The main environmental stimulus for the diurnal production of melatonin is light intensity, with this information reaching the suprachiasmatic nucleus of the hypothalamus through a direct pathway from the retina. During bouts in ECH patients, melatonin secretion has been found to be lower, with the characteristic nocturnal peak being blunted , with abnormal melatonin metabolite excretion., The usefulness of melatonin replacement in the management of cluster headache has been reported from case reports,, a small placebo-controlled study, and in a study looking at melatonin as an adjunctive therapy in cluster headache prevention. Further studies looking at the role of other neuroendocrine hormones such as cortisol,, testosterone,,,,, and orexin  have provided further evidence for the involvement of the hypothalamus in cluster headache.
From functional neuroimaging studies, the posterior hypothalamus has been observed to be activated during spontaneous cluster headache attacks , and cluster headache attacks triggered by intravenous nitroglycerin. The role of the hypothalamus in cluster headache was further supported by the therapeutic effect of targeting the posterior hypothalamic gray through deep brain stimulation in cluster headache patients.,,
| Clinical Features and Diagnosis|| |
As compared to other disorders within the TAC category, patients with cluster headache experience multiple attacks of relatively short-lasting severe headaches [Table 1]. The headaches are characteristically excruciating, unilateral, and commonly involves the first division of the trigeminal nerve, over the peri- and retro-orbital regions and in the temple. The pain can be perceived to have arisen from the sinuses or from the dentition, and patients often present to an otolaryngologist or dentist for this reason. The quality of the pain is severe, intense, sharp, and burning and it is commonly described to be worse than childbirth. It is aptly also known as “suicide headaches.” The attack generally builds up quickly in intensity resulting in a severe pain, which dissipates in a similar timeframe, with a clear onset and resolution to the attack. The attacks are strictly unilateral, however, on occasion attacks can switch sides within the same bout (14%), or a side-shift may occur from one bout to other (18%).
|Table 1: Cluster headache diagnostic criteria (adapted from International Classification of Headache Disorders, Third edition)|
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Without treatment, cluster headache attacks may last from 15 min to 3 h, with an average of 45–90 min in duration. During an attack, patients experience cranial autonomic symptoms, which include lacrimation, eye redness, eye discomfort such as grittiness, ptosis, nasal congestion, rhinorrhea, aural fullness, throat swelling, and flushing. These cranial autonomic symptoms are present on ipsilateral to the pain and is thought to be due to parasympathetic activation., In addition, sympathetic impairment  presenting as miosis and Partial Horner syndrome More Details may occur. Wilfred Harris was the first to recognize that Horner syndrome could occur in cluster headache.
One prominent feature during attacks is the sense of restlessness and agitation. This is a useful feature that can help in distinguishing cluster headache from migraine. During an episode, migraine patients prefer to lie still. In contradistinction, cluster headache patients pace or rock during attacks and attempt to lessen the intensity of the pain by applying pressure to the affected area., In general, once an attack terminates, patients are pain-free until their next attack. Patients may have attacks ranging once every other day up to 8 times a day. There is a tendency for the attacks to occur at night and patients report a sleep association. A remarkable observation is that attacks seem to occur at the same time each day and have a circadian pattern.
The duration, in which patients have cluster headache attacks, is called a bout, and this can range on average between 6 and 12 weeks. Patients with cluster headaches may experience bouts separated by months or even years of remission., Episodic and chronic cluster headache is defined by the remission duration between bouts. CCH patients have persistent attacks occurring for more than one year without remission, or a remission period lasting less than three months, without preventive medication. About 15%–20% of patients suffer from chronic cluster headache. It is important to distinguish episodic from CCH s as it can help guide decisions regarding management. ECH patients may notice a pattern to their bouts, typically occurring around spring and autumn, at the time of the equinoxes. Some CCH patients may notice an increase in attacks during these times of the year. This circannual phenomenon is not clearly understood but may implicate the hypothalamus in the pathogenesis.
Patients have noticed that their attacks may be triggered by various substances. These include alcohol, strong smells such as petroleum and nail varnish, and nitrate-containing foods such as cured meats. Triggers may bring on attacks for ECH patients who are in a bout or for CCH patients. In the research context, the administration of intravenous nitroglycerin can induce cluster headache attacks in a reproducible way.,
Cluster headache is still underdiagnosed and suboptimally managed, and patients often have a delay to their diagnosis. The US cluster headache survey found that cluster headache patients on average have more than 5 years delay in diagnosis with only 21% receiving a correct diagnosis at the time of initial presentation. Bahra and Goadsby found in their tertiary headache center that the mean time to diagnosis dropped from 22 years in the 1960s to 2.6 years in the 1990s in the UK although the mean number of general practitioners seen before a diagnosis was made remains at three.
| Prognosis|| |
The natural history of cluster headache is difficult to predict. In patients with initial ECH, 13% may subsequently develop CCH. On the contrary, 33% of patients with initial CCH may shift to the episodic pattern during the course of the disorder. Anecdotally, cluster headache tends to remit  with age with less frequent bouts and more prolonged periods of remission between bouts.
| Conclusion|| |
Cluster headache is a primary headache disorder with distinct features of unilateral intense pain of a relatively short duration, with prominent cranial autonomic symptoms, and a circadian and circannual rhythm. It is one of the most painful and disabling disorders known to humans. The pathogenesis involving the trigeminal-autonomic reflex, the trigeminovascular pathway, and hypothalamus provides an explanation for the clinical phenotype. The advances in our understanding of the pathophysiology have led to the development of various novel treatments, ranging from deep brain stimulation of the posterior hypothalamus to CGRP monoclonal antibodies targeted at neuropeptides involved in the trigeminovascular pathway. These topics will be covered elsewhere in this series. Further studies are required to unravel the exact role of the hypothalamus in cluster headache and to understand the natural history of this devastating condition.
Financial support and sponsorship
Conflicts of interest
Peter James Goadsby reports grants and personal fees from Allergan, Amgen, and Eli-Lilly and Company; personal fees from Akita Biomedical, Alder Biopharmaceuticals, Avanir Pharma, Cipla Ltd., Dr Reddy's Laboratories, eNeura, Electrocore LLC, Novartis, Pfizer Inc., Quest Diagnostics Scion, Teva Pharmaceuticals, Trigemina Inc., Scion; personal fees from MedicoLegal work, Journal Watch, Up-to-Date, Massachusetts Medical Society, Oxford University Press; and in addition, Dr. Goadsby has a patent Magnetic stimulation for headache assigned, without fee, to eNeura.
| References|| |
Koehler PJ. Prevalence of headache in Tulp's Observationes Medicae (1641) with a description of cluster headache. Cephalalgia 1993;13:318-20.
Harris W. Neuritis and Neuralgia. 1st
ed. London: Humphrey Milford, Oxford University Press; 1926.
Boes CJ, Capobianco DJ, Matharu MS, Goadsby PJ. Wilfred Harris' early description of cluster headache. Cephalalgia 2002;22:320-6.
Harris W. Ciliary neuralgia and its treatment. Br Med J 1936;1:457-60.
Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd
edition. Cephalalgia. 2018;38:1-211
Fischera M, Marziniak M, Gralow I, Evers S. The incidence and prevalence of cluster headache: A meta-analysis of population-based studies. Cephalalgia 2008;28:614-8.
Sjaastad O, Bakketeig LS. Cluster headache prevalence. Vågå study of headache epidemiology. Cephalalgia 2003;23:528-33.
Katsarava Z, Dzagnidze A, Kukava M, Mirvelashvili E, Djibuti M, Janelidze M, et al.
Prevalence of cluster headache in the Republic of Georgia: Results of a population-based study and methodological considerations. Cephalalgia 2009;29:949-52.
Mengistu G, Alemayehu S. Prevalence and burden of primary headache disorders among a local community in Addis Ababa, Ethiopia. J Headache Pain 2013;14:30.
Ekbom K, Svensson DA, Träff H, Waldenlind E. Age at onset and sex ratio in cluster headache: Observations over three decades. Cephalalgia 2002;22:94-100.
Manzoni GC. Gender ratio of cluster headache over the years: A possible role of changes in lifestyle. Cephalalgia 1998;18:138-42.
Bahra A, May A, Goadsby PJ. Cluster headache: A prospective clinical study with diagnostic implications. Neurology 2002;58:354-61.
Manzoni GC, Micieli G, Granella F, Martignoni E, Farina S, Nappi G, et al.
Cluster headache in women: Clinical findings and relationship with reproductive life. Cephalalgia 1988;8:37-44.
Rozen TD, Niknam RM, Shechter AL, Young WB, Silberstein SD. Cluster headache in women: Clinical characteristics and comparison with cluster headache in men. J Neurol Neurosurg Psychiatry 2001;70:613-7.
Manzoni GC, Taga A, Russo M, Torelli P. Age of onset of episodic and chronic cluster headache - A review of a large case series from a single headache centre. J Headache Pain 2016;17:44.
Granella F, Sances G, Zanferrari C, Costa A, Martignoni E, Manzoni GC, et al.
Migraine without aura and reproductive life events: A clinical epidemiological study in 1300 women. Headache 1993;33:385-9.
Sjaastad O, Shen JM, Stovner LJ, Elsås T. Cluster headache in identical twins. Headache 1993;33:214-7.
Roberge C, Bouchard JP, Simard D, Gagné R. Cluster headache in twins. Neurology 1992;42:1255-6.
Couturier EG, Hering R, Steiner TJ. The first report of cluster headache in identical twins. Neurology 1991;41:761.
Svensson D, Ekbom K, Pedersen NL, Träff H, Waldenlind E. A note on cluster headache in a population-based twin register. Cephalalgia 2003;23:376-80.
Russell MB, Andersson PG, Thomsen LL. Familial occurrence of cluster headache. J Neurol Neurosurg Psychiatry 1995;58:341-3.
Kudrow L, Kudrow DB. Inheritance of cluster headache and its possible link to migraine. Headache 1994;34:400-7.
Leone M, Russell MB, Rigamonti A, Attanasio A, Grazzi L, D'Amico D, et al.
Increased familial risk of cluster headache. Neurology 2001;56:1233-6.
El Amrani M, Ducros A, Boulan P, Aidi S, Crassard I, Visy JM, et al.
Familial cluster headache: A series of 186 index patients. Headache 2002;42:974-7.
Russell MB. Epidemiology and genetics of cluster headache. Lancet Neurol 2004;3:279-83.
Rainero I, Gallone S, Valfrè W, Ferrero M, Angilella G, Rivoiro C, et al.
A polymorphism of the hypocretin receptor 2 gene is associated with cluster headache. Neurology 2004;63:1286-8.
Baumber L, Sjöstrand C, Leone M, Harty H, Bussone G, Hillert J, et al.
A genome-wide scan and HCRTR2 candidate gene analysis in a European cluster headache cohort. Neurology 2006;66:1888-93.
Schürks M, Kurth T, Geissler I, Tessmann G, Diener HC, Rosskopf D, et al.
Cluster headache is associated with the G1246A polymorphism in the hypocretin receptor 2 gene. Neurology 2006;66:1917-9.
Weller CM, Wilbrink LA, Houwing-Duistermaat JJ, Koelewijn SC, Vijfhuizen LS, Haan J, et al.
Cluster headache and the hypocretin receptor 2 reconsidered: A genetic association study and meta-analysis. Cephalalgia 2015;35:741-7.
Bacchelli E, Cainazzo MM, Cameli C, Guerzoni S, Martinelli A, Zoli M, et al.
A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants. J Headache Pain 2016;17:114.
Alders EE, Hentzen A, Tan CT. A community-based prevalence study on headache in malaysia. Headache 1996;36:379-84.
Tekle Haimanot R, Seraw B, Forsgren L, Ekbom K, Ekstedt J. Migraine, chronic tension-type headache, and cluster headache in an Ethiopian rural community. Cephalalgia 1995;15:482-8.
Lin KH, Wang PJ, Fuh JL, Lu SR, Chung CT, Tsou HK, et al.
Cluster headache in the taiwanese - A clinic-based study. Cephalalgia 2004;24:631-8.
Xie Q, Huang Q, Wang J, Li N, Tan G, Zhou J, et al.
Clinical features of cluster headache: An outpatient clinic study from China. Pain Med 2013;14:802-7.
Moon HS, Park JW, Lee KS, Chung CS, Kim BK, Kim JM, et al.
Clinical features of cluster headache patients in Korea. J Korean Med Sci 2017;32:502-6.
Dong Z, Di H, Dai W, Pan M, Li Z, Liang J, et al.
Clinical profile of cluster headaches in china - A clinic-based study. J Headache Pain 2013;14:27.
Imai N, Yagi N, Kuroda R, Konishi T, Serizawa M, Kobari M, et al.
Clinical profile of cluster headaches in Japan: Low prevalence of chronic cluster headache, and uncoupling of sense and behaviour of restlessness. Cephalalgia 2011;31:628-33.
Goadsby PJ. Pathophysiology of cluster headache: A trigeminal autonomic cephalgia. Lancet Neurol 2002;1:251-7.
May A, Goadsby PJ. The trigeminovascular system in humans: Pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab 1999;19:115-27.
Goadsby PJ, Edvinsson L. Human in vivo
evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain 1994;117 (Pt 3):427-34.
Fanciullacci M, Alessandri M, Figini M, Geppetti P, Michelacci S. Increase in plasma calcitonin gene-related peptide from the extracerebral circulation during nitroglycerin-induced cluster headache attack. Pain 1995;60:119-23.
Knight YE, Classey JD, Lasalandra MP, Akerman S, Kowacs F, Hoskin KL, et al.
Patterns of fos expression in the rostral medulla and caudal pons evoked by noxious craniovascular stimulation and periaqueductal gray stimulation in the cat. Brain Res 2005;1045:1-1.
Spencer SE, Sawyer WB, Wada H, Platt KB, Loewy AD. CNS projections to the pterygopalatine parasympathetic preganglionic neurons in the rat: A retrograde transneuronal viral cell body labeling study. Brain Res 1990;534:149-69.
May A, Bahra A, Büchel C, Frackowiak RS, Goadsby PJ. PET and MRA findings in cluster headache and MRA in experimental pain. Neurology 2000;55:1328-35.
Kudrow L. The cyclic relationship of natural illumination to cluster period frequency. Cephalalgia 1987;7 Suppl 6:76-8.
Wurtman RJ, Axelrod J, Phillips LS. Melatonin synthesis in the pineal gland: Control by light. Science 1963;142:1071-3.
Waldenlind E, Gustafsson SA, Ekbom K, Wetterberg L. Circadian secretion of cortisol and melatonin in cluster headache during active cluster periods and remission. J Neurol Neurosurg Psychiatry 1987;50:207-13.
Waldenlind E, Ekbom K, Wetterberg L, Fanciullacci M, Marabini S, Sicuteri F, et al.
Lowered circannual urinary melatonin concentrations in episodic cluster headache. Cephalalgia 1994;14:199-204.
Leone M, Lucini V, D'Amico D, Grazzi L, Moschiano F, Fraschini F, et al.
Abnormal 24-hour urinary excretory pattern of 6-sulphatoxymelatonin in both phases of cluster headache. Cephalalgia 1998;18:664-7.
Nagtegaal JE, Smits MG, Swart AC, Kerkhof GA, van der Meer YG. Melatonin-responsive headache in delayed sleep phase syndrome: Preliminary observations. Headache 1998;38:303-7.
Peres MF, Rozen TD. Melatonin in the preventive treatment of chronic cluster headache. Cephalalgia 2001;21:993-5.
Leone M, D'Amico D, Moschiano F, Fraschini F, Bussone G. Melatonin versus placebo in the prophylaxis of cluster headache: A double-blind pilot study with parallel groups. Cephalalgia 1996;16:494-6.
Pringsheim T, Magnoux E, Dobson CF, Hamel E, Aubé M. Melatonin as adjunctive therapy in the prophylaxis of cluster headache: A pilot study. Headache 2002;42:787-92.
Facchinetti F, Nappi G, Cicoli C, Micieli G, Ruspa M, Bono G, et al.
Reduced testosterone levels in cluster headache: A stress-related phenomenon? Cephalalgia 1986;6:29-34.
Kudrow L. Plasma testosterone levels in cluster headache preliminary results. Headache 1976;16:28-31.
Nelson RF. Testosterone levels in cluster and non-cluster migrainous headache patients. Headache 1978;18:265-7.
Klimek A. Plasma testosterone levels in patients with cluster headache. Headache 1982;22:162-4.
Romiti A, Martelletti P, Gallo MF, Giacovazzo M. Low plasma testosterone levels in cluster headache. Cephalalgia 1983;3:41-4.
Holland PR, Goadsby PJ. Cluster headache, hypothalamus, and orexin. Curr Pain Headache Rep 2009;13:147-54.
Sprenger T, Boecker H, Tolle TR, Bussone G, May A, Leone M, et al.
Specific hypothalamic activation during a spontaneous cluster headache attack. Neurology 2004;62:516-7.
Morelli N, Pesaresi I, Cafforio G, Maluccio MR, Gori S, Di Salle F, et al.
Functional magnetic resonance imaging in episodic cluster headache. J Headache Pain 2009;10:11-4.
May A, Bahra A, Büchel C, Frackowiak RS, Goadsby PJ. Hypothalamic activation in cluster headache attacks. Lancet 1998;352:275-8.
Leone M, Franzini A, Bussone G. Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable cluster headache. N Engl J Med 2001;345:1428-9.
Leone M, Franzini A, Cecchini AP, Broggi G, Bussone G. Hypothalamic deep brain stimulation in the treatment of chronic cluster headache. Ther Adv Neurol Disord 2010;3:187-95.
Schoenen J, Di Clemente L, Vandenheede M, Fumal A, De Pasqua V, Mouchamps M, et al.
Hypothalamic stimulation in chronic cluster headache: A pilot study of efficacy and mode of action. Brain 2005;128:940-7.
Bahra A, Goadsby PJ. Diagnostic delays and mis-management in cluster headache. Acta Neurol Scand 2004;109:175-9.
Dodick DW, Rozen TD, Goadsby PJ, Silberstein SD. Cluster headache. Cephalalgia 2000;20:787-803.
Drummond PD. Autonomic disturbances in cluster headache. Brain 1988;111(Pt 5):1199-209.
Drummond PD. Mechanisms of autonomic disturbance in the face during and between attacks of cluster headache. Cephalalgia 2006;26:633-41.
May A. Cluster headache: Pathogenesis, diagnosis, and management. Lancet 2005;366:843-55.
May A. Diagnosis and clinical features of trigemino-autonomic headaches. Headache 2013;53:1470-8.
Nesbitt AD, Goadsby PJ. Cluster headache. BMJ 2012;344:e2407.
Tfelt-Hansen PC, Tfelt-Hansen J. Nitroglycerin headache and nitroglycerin-induced primary headaches from 1846 and onwards: A historical overview and an update. Headache 2009;49:445-56.
Sances G, Tassorelli C, Pucci E, Ghiotto N, Sandrini G, Nappi G, et al.
Reliability of the nitroglycerin provocative test in the diagnosis of neurovascular headaches. Cephalalgia 2004;24:110-9.
Rozen TD, Fishman RS. Cluster headache in the United States of America: Demographics, clinical characteristics, triggers, suicidality, and personal burden. Headache 2012;52:99-113.
Manzoni GC, Micieli G, Granella F, Tassorelli C, Zanferrari C, Cavallini A, et al.
Cluster headache – Course over ten years in 189 patients. Cephalalgia 1991;11:169-74.