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Cluster headache

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Abstract

Cluster headache is an excruciating, strictly one-sided pain syndrome with attacks that last between 15 minutes and 180 minutes and that are accompanied by marked ipsilateral cranial autonomic symptoms, such as lacrimation and conjunctival injection. The pain is so severe that female patients describe each attack as worse than childbirth. The past decade has seen remarkable progress in the understanding of the pathophysiological background of cluster headache and has implicated the brain, particularly the hypothalamus, as the generator of both the pain and the autonomic symptoms. Anatomical connections between the hypothalamus and the trigeminovascular system, as well as the parasympathetic nervous system, have also been implicated in cluster headache pathophysiology. The diagnosis of cluster headache involves excluding other primary headaches and secondary headaches and is based primarily on the patient's symptoms. Remarkable progress has been achieved in developing effective treatment options for single cluster attacks and in developing preventive measures, which include pharmacological therapies and neuromodulation.

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Figure 1: Schematic pathway representation summarizing the trigeminal-parasympathetic reflex.
Figure 2: Schematic peripheral and central pathway representation summarizing the pathogenesis of cluster headache.
Figure 3: Neuromodulation therapies for cluster headache.

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References

  1. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia 38, 1–211 (2018). This is the brand new edition of the International Classification of Headache Disorders. Next to describing >200 headache disorders, it contains up-to-date references and commentaries on all headache types, including cluster headache.

    Google Scholar 

  2. Sandrini, G. et al. Neurophysiological tests and neuroimaging procedures in non-acute headache (2nd edition). Eur. J. Neurol. 18, 373–381 (2011).

    CAS  PubMed  Google Scholar 

  3. Sjaastad, O. Cluster Headache Syndrome (W B Saunders Company Ltd, 1992).

    Google Scholar 

  4. Russell, M. B. Epidemiology and genetics of cluster headache. Lancet Neurol. 3, 279–283 (2004).

    PubMed  Google Scholar 

  5. Lin, K.-H. et al. Cluster headache in the Taiwanese — a clinic-based study. Cephalalgia 24, 631–638 (2004).

    PubMed  Google Scholar 

  6. Imai, N. et al. Clinical profile of cluster headaches in Japan: low prevalence of chronic cluster headache, and uncoupling of sense and behaviour of restlessness. Cephalalgia 31, 628–633 (2011).

    PubMed  Google Scholar 

  7. Rozen, T. D. & Fishman, R. S. Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden. Headache 52, 99–113 (2012).

    PubMed  Google Scholar 

  8. Manzoni, G. C. Gender ratio of cluster headache over the years: a possible role of changes in lifestyle. Cephalalgia 18, 138–142 (1998).

    CAS  PubMed  Google Scholar 

  9. May, A. Cluster headache: pathogenesis, diagnosis, and management. Lancet 366, 843–855 (2005).

    PubMed  Google Scholar 

  10. Ekbom, K. & Hardebo, J. E. Cluster headache: aetiology, diagnosis and management. Drugs 62, 61–69 (2002).

    CAS  PubMed  Google Scholar 

  11. Taga, A., Russo, M., Manzoni, G. C. & Torelli, P. Cluster headache with accompanying migraine-like features: a possible clinical phenotype. Headache 57, 290–297 (2017).

    PubMed  Google Scholar 

  12. Ekbom, K., Svensson, D. A., Traff, H. & Waldenlind, E. Age at onset and sex ratio in cluster headache: observations over three decades. Cephalalgia 22, 94–100 (2002).

    CAS  PubMed  Google Scholar 

  13. Kudrow, L. Cluster Headache: Mechanism & Management Oxford Univ. Press, 1980).

    Google Scholar 

  14. Manzoni, G. C. et al. Cluster headache — clinical findings in 180 patients. Cephalalgia 3, 21–30 (1983).

    CAS  PubMed  Google Scholar 

  15. Manzoni, G. C., 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 17, 44 (2016).

    PubMed  PubMed Central  Google Scholar 

  16. Lee, Y.-J. et al. Temperature variation and the incidence of cluster headache periods: a nationwide population study. Cephalalgia 34, 656–663 (2014).

    PubMed  Google Scholar 

  17. Italian Cooperative Study Group on the Epidemiology of Cluster Headache (ICECH). Case-control study on the epidemiology of cluster headache. I: Etiological factors and associated conditions. Neuroepidemiology 14, 123–127 (1995).

    Google Scholar 

  18. Sjaastad, O., Shen, J. M., Stovner, L. J. & Elsas, T. Cluster headache in identical twins. Headache 33, 214–217 (1993).

    CAS  PubMed  Google Scholar 

  19. Leone, M. et al. Increased familial risk of cluster headache. Neurology 56, 1233–1236 (2001).

    CAS  PubMed  Google Scholar 

  20. Russell, M. B., Andersson, P. G. & Thomsen, L. L. Familial occurrence of cluster headache. J. Neurol. Neurosurg. Psychiatry 58, 341–343 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Russell, M. B., Andersson, P. G., Thomsen, L. L. & Iselius, L. Cluster headache is an autosomal dominantly inherited disorder in some families: a complex segregation analysis. J. Med. Genet. 32, 954–956 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Baumber, L. et al. A genome-wide scan and HCRTR2 candidate gene analysis in a European cluster headache cohort. Neurology 66, 1888–1893 (2006).

    CAS  PubMed  Google Scholar 

  23. Rainero, I. et al. Association between the G1246A polymorphism of the hypocretin receptor 2 gene and cluster headache: a meta-analysis. J. Headache Pain 8, 152–156 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Bartsch, T., Levy, M. J., Knight, Y. E. & Goadsby, P. J. Differential modulation of nociceptive dural input to [hypocretin] orexin A and B receptor activation in the posterior hypothalamic area. Pain 109, 367–378 (2004).

    CAS  PubMed  Google Scholar 

  25. Weller, C. M. et al. Cluster headache and the hypocretin receptor 2 reconsidered: a genetic association study and meta-analysis. Cephalalgia 35, 741–747 (2015).

    PubMed  Google Scholar 

  26. Rainero, I. et al. A polymorphism of the hypocretin receptor 2 gene is associated with cluster headache. Neurology 63, 1286–1288 (2004).

    CAS  PubMed  Google Scholar 

  27. Schürks, M. et al. Cluster headache is associated with the G1246A polymorphism in the hypocretin receptor 2 gene. Neurology 66, 1917–1919 (2006).

    PubMed  Google Scholar 

  28. Barloese, M. et al. Sleep and chronobiology in cluster headache. Cephalalgia 35, 969–978 (2015).

    CAS  PubMed  Google Scholar 

  29. Cortelli, P. et al. Lack of association between mitochondrial tRNALeu(UUR) point mutation and cluster headache. Lancet 345, 1120–1121 (1995).

    CAS  PubMed  Google Scholar 

  30. Sjöstrand, C. et al. Analysis of nitric oxide synthase genes in cluster headache. Cephalalgia 22, 758–764 (2002).

    PubMed  Google Scholar 

  31. Sjöstrand, C., Giedratis, V., Ekbom, K., Waldenlind, E. & Hillert, J. CACNA1A gene polymorphisms in cluster headache. Cephalalgia 21, 953–958 (2001).

    PubMed  Google Scholar 

  32. Ofte, H. K., Tronvik, E. & Alstadhaug, K. B. Lack of association between cluster headache and PER3 clock gene polymorphism. J. Headache Pain 17, 18 (2016).

    PubMed Central  Google Scholar 

  33. Cevoli, S. et al. Investigation of the T3111C CLOCK gene polymorphism in cluster headache. J. Neurol. 255, 299–300 (2008).

    CAS  PubMed  Google Scholar 

  34. Rainero, I. et al. Lack of association between the 3092 T-->C Clock gene polymorphism and cluster headache. Cephalalgia 25, 1078–1081 (2005).

    CAS  PubMed  Google Scholar 

  35. Rainero, I. et al. Cluster headache is associated with the alcohol dehydrogenase 4 (ADH4) gene. Headache 50, 92–98 (2010).

    PubMed  Google Scholar 

  36. Zarrilli, F. et al. Molecular analysis of cluster headache. Clin. J. Pain 31, 52–57 (2015).

    PubMed  Google Scholar 

  37. Fourier, C. et al. Screening of two ADH4 variations in a Swedish cluster headache case-control material. Headache 56, 835–840 (2016).

    PubMed  PubMed Central  Google Scholar 

  38. Bacchelli, E. et al. A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants. J. Headache Pain 17, 114 (2016).

    PubMed  PubMed Central  Google Scholar 

  39. Ran, C. et al. Screening of genetic variants in ADCYAP1R1, MME and 14q21 in a Swedish cluster headache cohort. J. Headache Pain 18, 88 (2017).

    PubMed  PubMed Central  Google Scholar 

  40. Goadsby, P. J. Pathophysiology of cluster headache: a trigeminal autonomic cephalgia. Lancet Neurol. 1, 251–257 (2002).

    PubMed  Google Scholar 

  41. Moskowitz, M. A. Cluster headache: evidence for a pathophysiologic focus in the superior pericarotid cavernous sinus plexus. Headache 28, 584–586 (1988).

    CAS  PubMed  Google Scholar 

  42. Remahl, I. N., Waldenlind, E., Bratt, J. & Ekbom, K. Cluster headache is not associated with signs of a systemic inflammation. Headache 40, 276–281 (2000).

    CAS  PubMed  Google Scholar 

  43. Bovim, G., Jenssen, G. & Ericson, K. Orbital phlebography: a comparison between cluster headache and other headaches. Headache 32, 408–412 (1992).

    CAS  PubMed  Google Scholar 

  44. Nelson, R. F. et al. Cerebral blood flow studies in patients with cluster headache. Headache 20, 184–189 (1980).

    CAS  PubMed  Google Scholar 

  45. Markowitz, S., Saito, K. & Moskowitz, M. A. Neurogenically mediated plasma extravasation in dura mater: effect of ergot alkaloids. A possible mechanism of action in vascular headache. Cephalalgia 8, 83–91 (1988).

    CAS  PubMed  Google Scholar 

  46. Sakai, F., Meyer, J. S., Ishihara, N., Naritomi, H. & Deshmukh, V. D. Noninvasive 133XE inhalation measurements of regional cerebral blood flow in migraine and related headaches. Acta Neurol. Scand. Suppl. 64, 196–197 (1977).

    CAS  PubMed  Google Scholar 

  47. Henry, P. Y., Vernhiet, J., Orgogozo, J. M. & Caille, J. M. Cerebral blood flow in migraine and cluster headache. Compartmental analysis and reactivity to anaesthetic depression. Res. Clin. Studies Headache 6, 81–88 (1978).

    CAS  Google Scholar 

  48. Norris, J. W., Hachinski, V. C. & Cooper, P. W. Cerebral blood flow changes in cluster headache. Acta Neurol. Scand. 54, 371–374 (1976).

    CAS  PubMed  Google Scholar 

  49. Krabbe, A.A., Henriksen, L. & Olesen, J. Tomographic determination of cerebral blood flow during attacks of cluster headache. Cephalalgia 4, 17–23 (1984).

    CAS  PubMed  Google Scholar 

  50. May, A., Büchel, C., Turner, R. & Goadsby, P. J. Magnetic resonance angiography in facial and other pain: neurovascular mechanisms of trigeminal sensation. J. Cereb. Blood Flow Metab. 21, 1171–1176 (2001).

    CAS  PubMed  Google Scholar 

  51. Weaver-Agostoni, J. Cluster headache. Am. Family Physician 88, 122–128 (2013).

    Google Scholar 

  52. Leone, M. et al. The m-chlorophenylpiperazine test in cluster headache: A study on central serotoninergic activity. Cephalalgia 17, 666–672 (1997).

    CAS  PubMed  Google Scholar 

  53. Goadsby, P. J. & Edvinsson, L. Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain 117, 427–434 (1994).

    PubMed  Google Scholar 

  54. Plosker, G. L. & McTavish, D. Sumatriptan: a reappraisal of its pharmacology and therapeutic efficacy in the acute treatment of migraine and cluster headache. Drugs 47, 622–651 (1994).

    CAS  PubMed  Google Scholar 

  55. Edvinsson, L. & Tfelt-Hansen, P. The blood-brain barrier in migraine treatment. Cephalalgia 28, 1245–1258 (2008).

    CAS  PubMed  Google Scholar 

  56. Dodick, D. W. & Martin, V. Triptans and CNS side-effects: pharmacokinetic and metabolic mechanisms. Cephalalgia 24, 417–424 (2004).

    CAS  PubMed  Google Scholar 

  57. Jarrar, R. G., Black, D. F., Dodick, D. W. & Davis, D. H. Outcome of trigeminal nerve section in the treatment of chronic cluster headache. Neurology 60, 1360–1362 (2003).

    CAS  PubMed  Google Scholar 

  58. Bartsch, T., Knight, Y. E. & Goadsby, P. J. Activation of 5-HT1B/1D receptor in the periaqueductal gray inhibits nociception. Ann. Neurol. 56, 371–381 (2004).

    CAS  PubMed  Google Scholar 

  59. Tfelt-Hansen, P. C. Does sumatriptan cross the blood-brain barrier in animals and man? J. Headache Pain 11, 5–12 (2010).

    CAS  PubMed  Google Scholar 

  60. Goadsby, P. J. & Lipton, R. B. A review of paroxysmal hemicranias, SUNCT syndrome and other short-lasting headaches with autonomic feature, including new cases. Brain 120, 193–209 (1997). This is a comprehensive review that lays the foundations of the current concept of trigeminal-autonomic headaches by meticulously defining a class of headaches based solely on their clinical features.

    PubMed  Google Scholar 

  61. Fanciullacci, M., Alessandri, M., Sicuteri, R. & Marabini, S. Responsiveness of the trigeminovascular system to nitroglycerine in cluster headache patients. Brain 120, 283–288 (1997).

    PubMed  Google Scholar 

  62. 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 60, 119–123 (1995).

    CAS  PubMed  Google Scholar 

  63. Neeb, L. et al. Corticosteroids alter CGRP and melatonin release in cluster headache episodes. Cephalalgia 35, 317–326 (2015).

    PubMed  Google Scholar 

  64. Neeb, L., Hellen, P., Hoffmann, J., Dirnagl, U. & Reuter, U. Methylprednisolone blocks interleukin 1 beta induced calcitonin gene related peptide release in trigeminal ganglia cells. J. Headache Pain 17, 19 (2016).

    PubMed  PubMed Central  Google Scholar 

  65. Goadsby, P. J., Edvinsson, L. & Ekman, R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann. Neurol. 28, 183–187 (1990).

    CAS  PubMed  Google Scholar 

  66. Goadsby, P. J., Edvinsson, L. & Ekman, R. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann. Neurol. 23, 193–196 (1988).

    CAS  PubMed  Google Scholar 

  67. Tajti, J., Tuka, B., Botz, B., Helyes, Z. & Vecsei, L. Role of pituitary adenylate cyclase-activating polypeptide in nociception and migraine. CNS Neurol. Disord. Drug Targets 14, 540–553 (2015).

    CAS  PubMed  Google Scholar 

  68. Amin, F. M. et al. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain 137, 779–794 (2014).

    PubMed  Google Scholar 

  69. Tuka, B. et al. Release of PACAP-38 in episodic cluster headache patients — an exploratory study. J. Headache Pain 17, 69 (2016).

    PubMed  PubMed Central  Google Scholar 

  70. Sághy, É . et al. Stimulatory effect of pituitary adenylate cyclase-activating polypeptide 6–38, M65 and vasoactive intestinal polypeptide 6–28 on trigeminal sensory neurons. Neuroscience 308, 144–156 (2015).

    PubMed  Google Scholar 

  71. Akerman, S., Holland, P. R., Lasalandra, M. P. & Goadsby, P. J. Oxygen inhibits neuronal activation in the trigeminocervical complex after stimulation of trigeminal autonomic reflex, but not during direct dural activation of trigeminal afferents. Headache 49, 1131–1143 (2009). This is the best model hitherto that describes how oxygen inhalation may be effective in cluster headache.

    PubMed  Google Scholar 

  72. Akerman, S., Holland, P. R., Summ, O., Lasalandra, M. P. & Goadsby, P. J. A translational in vivo model of trigeminal autonomic cephalalgias: therapeutic characterization. Brain 135, 3664–3675 (2012).

    PubMed  Google Scholar 

  73. Robert, C. et al. Paraventricular hypothalamic regulation of trigeminovascular mechanisms involved in headaches. J. Neurosci. 33, 8827–8840 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. May, A. & Goadsby, P. The enigma of the interconnection of trigeminal pain and cranial autonomic symptoms. Cephalalgia 36, 727–729 (2015).

    PubMed  Google Scholar 

  75. May, A. & Goadsby, P. J. The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J. Cereb. Blood Flow Metab. 19, 115–127 (1999).

    CAS  PubMed  Google Scholar 

  76. Pietzsch, J. B., Garner, A., Gaul, C. & May, A. Cost-effectiveness of stimulation of the sphenopalatine ganglion (SPG) for the treatment of chronic cluster headache: a model-based analysis based on the Pathway CH-1 study. J. Headache Pain 16, 530 (2015).

    PubMed  Google Scholar 

  77. Ansarinia, M. et al. Electrical stimulation of sphenopalatine ganglion for acute treatment of cluster headaches: Views and perspectives. Headache 50, 1164–1174 (2010).

    PubMed  Google Scholar 

  78. Schoenen, J. et al. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia: Int. J. Headache 33, 816–830 (2013).

    Google Scholar 

  79. Jürgens, T. P. et al. Long-term effectiveness of sphenopalatine ganglion stimulation for cluster headache. Cephalalgia 37, 423–434 (2017). Together with Ref. 78, these studies show the effectiveness of modulating the parasympathetic SPG in patients with cluster headache, which has spurred interest in this structure as part of the pathophysiology of cluster headache.

    PubMed  Google Scholar 

  80. Guo, S. et al. Cranial parasympathetic activation induces autonomic symptoms but no cluster headache attacks. Cephalalgia https://doi.org/10.1177/0333102417738250 (2017).

    Google Scholar 

  81. Möller, M., Haji, A. A., Hoffmann, J. & May, A. Peripheral provocation of cranial autonomic symptoms is not sufficient to trigger cluster headache attacks. Cephalalgia https://doi.org/10.1177/0333102417738248 (2017).

    Google Scholar 

  82. Goadsby, P. J. Cluster headache and the trigeminal-autonomic reflex: driving or being driven? Cephalalgia https://doi.org/10.1177/0333102417738252 (2017).

    Google Scholar 

  83. Derbyshire, S. W. Exploring the pain ‘neuromatrix’. Curr. Rev. Pain 4, 467–477 (2000).

    CAS  PubMed  Google Scholar 

  84. Sandrini, G. et al. Asymmetrical reduction of the nociceptive flexion reflex threshold in cluster headache. Cephalalgia 20, 647–652 (2000).

    CAS  PubMed  Google Scholar 

  85. Sandrini, G. et al. Impairment of corneal pain perception in cluster headache. Pain 47, 299–304 (1991).

    PubMed  Google Scholar 

  86. Nappi, G. et al. Impaired circadian rhythmicity of nociceptive reflex threshold in cluster headache. Headache 42, 125–131 (2002).

    CAS  PubMed  Google Scholar 

  87. Ellrich, J., Ristic, D. & Yekta, S. S. Impaired thermal perception in cluster headache. J. Neurol. 253, 1292–1299 (2006).

    PubMed  Google Scholar 

  88. Perrotta, A. et al. Facilitated temporal processing of pain and defective supraspinal control of pain in cluster headache. Pain 154, 1325–1332 (2013).

    PubMed  Google Scholar 

  89. Wang, R. et al. Cognitive processing of cluster headache patients: evidence from event-related potentials. J. Headache Pain 15, 66 (2014).

    PubMed  PubMed Central  Google Scholar 

  90. Holland, P. R. Modulation of trigeminovascular processing: novel insights into primary headache disorders. Cephalalgia 29 (Suppl. 3), 1–6 (2009).

    PubMed  Google Scholar 

  91. Sprenger, T. et al. Altered metabolism in frontal brain circuits in cluster headache. Cephalalgia 27, 1033–1042 (2007).

    CAS  PubMed  Google Scholar 

  92. Sprenger, T. et al. Opioidergic changes in the pineal gland and hypothalamus in cluster headache: A ligand PET study. Neurology 66, 1108–1110 (2006).

    CAS  PubMed  Google Scholar 

  93. Yang, F. C. et al. Altered gray matter volume in the frontal pain modulation network in patients with cluster headache. Pain 154, 801–807 (2013).

    PubMed  Google Scholar 

  94. Absinta, M. et al. Selective decreased grey matter volume of the pain-matrix network in cluster headache. Cephalalgia 32, 109–115 (2012).

    PubMed  Google Scholar 

  95. Teepker, M. et al. Diffusion tensor imaging in episodic cluster headache. Headache 52, 274–282 (2012).

    PubMed  Google Scholar 

  96. Szabó, N. et al. White matter disintegration in cluster headache. J. Headache Pain 14, 64 (2013).

    PubMed  PubMed Central  Google Scholar 

  97. Chou, K.-H. et al. Altered white matter microstructural connectivity in cluster headaches: A longitudinal diffusion tensor imaging study. Cephalalgia 34, 1040–1052 (2014).

    PubMed  Google Scholar 

  98. Pringsheim, T. Cluster headache: evidence for a disorder of circadian rhythm and hypothalamic function. Can. J. Neurol. Sci. 29, 33–40 (2002).

    PubMed  Google Scholar 

  99. Strittmatter, M. et al. Altered activity of the sympathetic nervous system and changes in the balance of hypophyseal, pituitary and adrenal hormones in patients with cluster headache. Neuroreport 7, 1229–1234 (1996).

    CAS  PubMed  Google Scholar 

  100. Leone, M. & Bussone, G. A review of hormonal findings in cluster headache. Evidence for hypothalamic involvement. Cephalalgia 13, 309–317 (1993). This is one of the first studies pointing towards the hypothalamus as a crucial player in the pathophysiology of cluster headache.

    CAS  PubMed  Google Scholar 

  101. Schulte, L. H. & May, A. Functional neuroimaging in migraine: chances and challenges. Headache 56, 1474–1481 (2016).

    PubMed  Google Scholar 

  102. Schulte, L. H. & May, A. The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain 139, 1987–1993 (2016).

    PubMed  Google Scholar 

  103. Malick, A. et al. Trigeminohypothalamic and reticulohypothalamic tract neurons in the upper cervical spinal cord and caudal medulla of the rat. J. Neurophysiol. 84, 2078–2112 (2000).

    CAS  PubMed  Google Scholar 

  104. Holland, P. & Goadsby, P. J. The hypothalamic orexinergic system: Pain and primary headaches. Headache 47, 951–962 (2007).

    PubMed  Google Scholar 

  105. Barloese, M. et al. Reduced CSF hypocretin-1 levels are associated with cluster headache. Cephalalgia 35, 869–876 (2015).

    PubMed  Google Scholar 

  106. May, A. et al. Correlation between structural and functional changes in brain in an idiopathic headache syndrome. Nat. Med. 5, 836–838 (1999).

    CAS  PubMed  Google Scholar 

  107. May, A., Bahra, A., Büchel, C., Frackowiak, R. S. J. & Goadsby, P. J. Hypothalamic activation in cluster headache attacks. Lancet 352, 275–278 (1998). This is the first imaging study to visualize the hypothalamus as an initiator of acute attacks.

    CAS  PubMed  Google Scholar 

  108. Sprenger, T. et al. Specific hypothalamic activation during a spontaneous cluster headache attack. Neurology 62, 516–517 (2004).

    CAS  PubMed  Google Scholar 

  109. May, A., Bahra, A., Büchel, C., Frackowiak, R. S. J. & Goadsby, P. J. PET and MRA findings in cluster headache and MRA in experimental pain. Neurology 55, 1328–1335 (2000).

    CAS  PubMed  Google Scholar 

  110. Arkink, E. B. et al. The anterior hypothalamus in cluster headache. Cephalalgia 37, 1039–1050 (2017).

    PubMed  Google Scholar 

  111. Yang, F.-C. et al. The pathophysiology of episodic cluster headache: Insights from recent neuroimaging research. Cephalalgia https://doi.org/10.1177/0333102417716932 (2017).

    Google Scholar 

  112. Lodi, R. et al. Study of hypothalamic metabolism in cluster headache by proton MR spectroscopy. Neurology 66, 1264–1266 (2006).

    CAS  PubMed  Google Scholar 

  113. Wang, S.-J., Lirng, J.-F., Fuh, J.-L. & Chen, J.-J. Reduction in hypothalamic H-MRS metabolite ratios in patients with cluster headache. J. Neurol. Neurosurg. Psychiatry 77, 622–625 (2006).

    PubMed  PubMed Central  Google Scholar 

  114. Akram, H. et al. Ventral tegmental area deep brain stimulation for refractory chronic cluster headache. Neurology 86, 1676–1682 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Leone, M., Franzini, A., Broggi, G. & Bussone, G. Hypothalamic stimulation for intractable cluster headache: long-term experience. Neurology 67, 150–152 (2006).

    PubMed  Google Scholar 

  116. Leone, M., Franzini, A. & Bussone, G. Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable cluster headache. N. Engl. J. Med. 345, 1428–1429 (2001). This is the very first report of a successful treatment of cluster headache by hypothalamic DBS and is also the first study to translate basic science, that is, functional imaging results, into a treatment option.

    CAS  PubMed  Google Scholar 

  117. Fontaine, D. et al. Safety and efficacy of deep brain stimulation in refractory cluster headache: a randomized placebo-controlled double-blind trial followed by a 1-year open extension. J. Headache Pain 11, 23–31 (2010).

    CAS  PubMed  Google Scholar 

  118. Leone, M., Franzini, A., Proietti Cecchini, A. & Bussone, G. Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster headache. Pain 154, 89–94 (2013).

    PubMed  Google Scholar 

  119. Hodge, C. J., Apkarian, A. V., Stevens, R., Vogelsang, G. & Wisnicki, H. J. Locus coeruleus modulation of dorsal horn unit responses to cutaneous stimulation. Brain Res. 204, 415–420 (1981).

    PubMed  Google Scholar 

  120. Bussone, G. et al. Brainstem auditory evoked potential (BAEPs) in cluster headache (CH): new aspects for a central theory. Headache 26, 67–69 (1986).

    CAS  PubMed  Google Scholar 

  121. Bussone, G. Cluster headache: from treatment to pathophysiology. Neurol. Sci. 29 (Suppl. 1), S1–S6 (2008).

    PubMed  Google Scholar 

  122. Rocca, M. A. et al. Central nervous system dysregulation extends beyondthe pain-matrix network in cluster headache. Cephalalgia 30, 1383–1391 (2010).

    PubMed  Google Scholar 

  123. Yang, F.-C. et al. Altered hypothalamic functional connectivity in cluster headache: a longitudinal resting-state functional MRI study. J. Neurol. Neurosurg. Psychiatry 86, 437–445 (2014).

    PubMed  Google Scholar 

  124. Qiu, E., Tian, L., Wang, Y., Ma, L. & Yu, S. Abnormal coactivation of the hypothalamus and salience network in patients with cluster headache. Neurology 84, 1402–1408 (2015).

    PubMed  Google Scholar 

  125. Chou, K.-H. et al. Bout-associated intrinsic functional network changes in cluster headache: a longitudinal resting-state functional MRI study. Cephalalgia 37, 1152–1163 (2016). This study describes dynamic changes in functional connectivity in specific brain networks between cluster-bout periods, suggesting that these networks play an important part in the seasonal bout-like occurrence of episodic cluster headache.

    PubMed  Google Scholar 

  126. Montagna, P., Pierangeli, G. & Cortelli, P. The primary headaches as a reflection of genetic darwinian adaptive behavioral responses: views and perspectives. Headache 50, 273–289 (2010).

    PubMed  Google Scholar 

  127. Torelli, P. & Manzoni, G. Behavior during cluster headache. Curr. Pain Headache Rep. 9, 113–119 (2005).

    PubMed  Google Scholar 

  128. Schmahmann, J. D. & Sherman, J. C. The cerebellar cognitive affective syndrome. Brain 121, 561–579 (1998).

    PubMed  Google Scholar 

  129. Schmahmann, J. D., Weilburg, J. B. & Sherman, J. C. The neuropsychiatry of the cerebellum — insights from the clinic. Cerebellum 6, 254–267 (2007).

    PubMed  Google Scholar 

  130. Mehnert, J., Schulte, L., Timmann, D. & May, A. Activity and connectivity of the cerebellum in trigeminal nociception. NeuroImage 150, 112–118 (2017).

    PubMed  Google Scholar 

  131. Morelli, N. et al. Brainstem activation in cluster headache: an adaptive behavioural response? Cephalalgia 33, 416–420 (2013).

    PubMed  Google Scholar 

  132. Lund, N., Barloese, M., Petersen, A., Haddock, B. & Jensen, R. Chronobiology differs between men and women with cluster headache, clinical phenotype does not. Neurology 88, 1069–1076 (2017). This is an important study depicting sex differences in cluster headache symptoms.

    PubMed  Google Scholar 

  133. Bahra, A., May, A. & Goadsby, P. J. Cluster headache: a prospective clinical study with diagnostic implications. Neurology 58, 354–361 (2002).

    PubMed  Google Scholar 

  134. Gaul, C. et al. Differences in clinical characteristics and frequency of accompanying migraine features in episodic and chronic cluster headache. Cephalalgia 32, 571–577 (2012).

    CAS  PubMed  Google Scholar 

  135. Snoer, A., Lund, N., Beske, R., Jensen, R. & Barloese, M. Pre-attack signs and symptoms in cluster headache: characteristics and time profile. Cephalalgia https://doi.org/10.1177/0333102417726498 (2017). This study describes frequent symptoms that may precede attacks. Identification and recognition of pre-attack symptoms will help delineate cluster headache pathophysiology and may enable earlier abortive treatment.

    Google Scholar 

  136. Jurgens, T. P., Koch, H. J. & May, A. Ten years of chronic cluster — attacks still cluster. Cephalalgia 30, 1123–1126 (2010).

    PubMed  Google Scholar 

  137. Evans, R. W. & Schürks, M. Alcohol and cluster headaches. Headache 49, 126–129 (2009).

    PubMed  Google Scholar 

  138. Headache Classification Committee of the International Headache Society (IHS) . The International Classification of Headache Disorders 3rd edn (beta version). Cephalalgia 33, 629–808 (2013).

    Google Scholar 

  139. [No authors listed.] ICHD / Guidelines. International Headache Society http://www.ihs-headache.org/ichd-guidelines (2013). This is the website of the International Headache Society with the complete text of the current classification system in different languages.

  140. Cittadini, E. & Matharu, M. S. Symptomatic trigeminal autonomic cephalalgias. Neurologist 15, 305–312 (2009).

    PubMed  Google Scholar 

  141. De Pue, A., Lutin, B. & Paemeleire, K. Chronic cluster headache and the pituitary gland. J. Headache Pain 17, 23 (2016).

    PubMed  PubMed Central  Google Scholar 

  142. Martins, I. P. Cyclic nocturnal awakening: a warning sign of a cluster bout. Cephalalgia 35, 363–365 (2015).

    PubMed  Google Scholar 

  143. Lai, T.-H., Fuh, J.-L. & Wang, S.-J. Cranial autonomic symptoms in migraine: characteristics and comparison with cluster headache. J. Neurol. Neurosurg. Psychiatry 80, 1116–1119 (2009).

    PubMed  Google Scholar 

  144. Bahra, A. & Goadsby, P. J. Diagnostic delays and mis-management in cluster headache. Acta Neurol. Scand. 109, 175–179 (2004).

    CAS  PubMed  Google Scholar 

  145. Joshi, S., Rizzoli, P. & Loder, E. The comorbidity burden of patients with cluster headache: a population-based study. J. Headache Pain 18, 76 (2017).

    PubMed  PubMed Central  Google Scholar 

  146. Jensen, R. M., Lyngberg, A. & Jensen, R. H. Burden of cluster headache. Cephalalgia 27, 535–541 (2007).

    CAS  PubMed  Google Scholar 

  147. Sánchez Del Rio, M. et al. Errors in recognition and management are still frequent in patients with cluster headache. Eur. Neurol. 72, 209–212 (2014).

    PubMed  Google Scholar 

  148. Voiticovschi-Iosob, C. et al. Diagnostic and therapeutic errors in cluster headache: a hospital-based study. J. Headache Pain 15, 56 (2014).

    PubMed  PubMed Central  Google Scholar 

  149. Rozen, T. D. Cluster headache with aura. Curr. Pain Headache Rep. 15, 98–100 (2011).

    PubMed  Google Scholar 

  150. Ferrari, A. et al. Impact of continuing or quitting smoking on episodic cluster headache: a pilot survey. J. Headache Pain 14, 48 (2013).

    PubMed  PubMed Central  Google Scholar 

  151. Manzoni, G. C. Cluster headache and lifestyle: remarks on a population of 374 male patients. Cephalalgia 19, 88–94 (1999).

    CAS  PubMed  Google Scholar 

  152. Schurks, M., Kurth, T., Knorn, P., Pageler, L. & Diener, H. C. Predictors of hazardous alcohol consumption among patients with cluster headache. Cephalalgia 26, 623–627 (2006).

    CAS  PubMed  Google Scholar 

  153. May, A. Illicit drugs and cluster headache: an inevitable discussion. Cephalalgia 32, 1021–1022 (2012).

    PubMed  Google Scholar 

  154. Govare, A. & Leroux, E. Licit and illicit drug use in cluster headache. Curr. Pain Headache Rep. 18, 413 (2014).

    PubMed  Google Scholar 

  155. Rossi, P. et al. Illicit drug use in cluster headache patients and in the general population: a comparative cross-sectional survey. Cephalalgia 32, 1031–1040 (2012).

    PubMed  Google Scholar 

  156. Di Lorenzo, C. et al. The use of illicit drugs as self-medication in the treatment of cluster headache: results from an Italian online survey. Cephalalgia 36, 194–198 (2016).

    CAS  PubMed  Google Scholar 

  157. Louter, M. A. et al. Cluster headache and depression. Neurology 87, 1899–1906 (2016).

    PubMed  Google Scholar 

  158. Liang, J.-F. et al. Cluster headache is associated with an increased risk of depression: a nationwide population-based cohort study. Cephalalgia 33, 182–189 (2013).

    PubMed  Google Scholar 

  159. Levi, R., Edman, G. V., Ekbom, K. & Waldenlind, E. Episodic cluster headache. I: Personality and some neuropsychological characteristics in male patients. Headache 32, 119–125 (1992).

    CAS  PubMed  Google Scholar 

  160. Italian Cooperative Study Group on the Epidemiology of Cluster Headache (ICECH). Case-control study on the epidemiology of cluster headache. II: Anthropometric data and personality profile. Funct. Neurol. 15, 215–223 (2000).

    Google Scholar 

  161. Muñoz, I. et al. Personality traits in patients with cluster headache: a comparison with migraine patients. J. Headache Pain 17, 25 (2016).

    PubMed  PubMed Central  Google Scholar 

  162. Piacentini, S. H. M. J., Draghi, L., Cecchini, A. P. & Leone, M. Personality disorders in cluster headache: a study using the Millon Clinical Multiaxial Inventory-III. Neurol. Sci. 38, 181–184 (2017).

    PubMed  Google Scholar 

  163. Chervin, R. D. et al. Sleep disordered breathing in patients with cluster headache. Neurology 54, 2302–2306 (2000).

    CAS  PubMed  Google Scholar 

  164. Barloese, M. C. J., Jennum, P. J., Lund, N. T. & Jensen, R. H. Sleep in cluster headache — beyond a temporal rapid eye movement relationship? Eur. J. Neurol. 22, 656–e640 (2015).

    CAS  PubMed  Google Scholar 

  165. Evers, S., Barth, B., Frese, A., Husstedt, I.-W. & Happe, S. Sleep apnea in patients with cluster headache: a case-control study. Cephalalgia 34, 828–832 (2014).

    PubMed  Google Scholar 

  166. Nilsson Remahl, A. I., Laudon Meyer, E., Cordonnier, C. & Goadsby, P. J. Placebo response in cluster headache trials: a review. Cephalalgia 23, 504–510 (2003).

    CAS  PubMed  Google Scholar 

  167. May, A. et al. EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. Eur. J. Neurol. 13, 1066–1077 (2006).

    CAS  PubMed  Google Scholar 

  168. Robbins, M. S., Starling, A. J., Pringsheim, T. M., Becker, W. J. & Schwedt, T. J. Treatment of cluster headache: the American Headache Society evidence-based guidelines. Headache 56, 1093–1106 (2016). This is a very thorough and evidence-based treatment guideline for cluster headache.

    PubMed  Google Scholar 

  169. Lademann, V., Jansen, J.-P., Evers, S. & Frese, A. Evaluation of guideline-adherent treatment in cluster headache. Cephalalgia 36, 760–764 (2016).

    PubMed  Google Scholar 

  170. Cohen, A. S., Burns, B. & Goadsby, P. J. High-flow oxygen for treatment of cluster headache: a randomized trial. JAMA 302, 2451–2457 (2009). This is the first evidence-based study demonstrating the efficacy of oxygen inhalation in aborting acute cluster headache attacks.

    CAS  PubMed  Google Scholar 

  171. Petersen, A. S., Barloese, M. C., Lund, N. L. & Jensen, R. H. Oxygen therapy for cluster headache. A mask comparison trial. A single-blinded, placebo-controlled, crossover study. Cephalalgia 37, 214–224 (2017).

    PubMed  Google Scholar 

  172. Ekbom, K. et al. Subcutaneous sumatriptan in the acute treatment of cluster headache: a dose comparison study. The Sumatriptan Cluster Headache Study Group. Acta Neurol. Scand. 88, 63–69 (1993).

    CAS  PubMed  Google Scholar 

  173. The Sumatriptan Cluster Headache Study Group. Treatment of acute cluster headache with sumatriptan. N. Engl. J. Med. 325, 322–326 (1991).

    Google Scholar 

  174. Leone, M. & Proietti Cecchini, A. Long-term use of daily sumatriptan injections in severe drug-resistant chronic cluster headache. Neurology 86, 194–195 (2016).

    PubMed  PubMed Central  Google Scholar 

  175. Rapoport, A. M. et al. Zolmitriptan nasal spray in the acute treatment of cluster headache: a double-blind study. Neurology 69, 821–826 (2007).

    CAS  PubMed  Google Scholar 

  176. Cittadini, E. et al. Effectiveness of intranasal zolmitriptan in acute cluster headache: a randomized, placebo-controlled, double-blind crossover study. Arch. Neurol. 63, 1537–1542 (2006).

    PubMed  Google Scholar 

  177. Schuh-Hofer, S., Reuter, U., Kinze, S., Einhaupl, K. M. & Arnold, G. Treatment of acute cluster headache with 20 mg sumatriptan nasal spray — an open pilot study. J. Neurol. 249, 94–99 (2002).

    CAS  PubMed  Google Scholar 

  178. Van Vliet, J. A. et al. Intranasal sumatriptan in cluster headache: randomized placebo-controlled double-blind study. Neurology 60, 630–633 (2003).

    CAS  PubMed  Google Scholar 

  179. Bahra, A. et al. Oral zolmitriptan is effective in the acute treatment of cluster headache. Neurology 54, 1832–1839 (2000).

    CAS  PubMed  Google Scholar 

  180. Andersson, P. G. & Jespersen, L. T. Dihydroergotamine nasal spray in the treatment of attacks of cluster headache. A double-blind trial versus placebo. Cephalalgia 6, 51–54 (1986).

    CAS  PubMed  Google Scholar 

  181. Magnoux, E. & Zlotnik, G. Outpatient intravenous dihydroergotamine for refractory cluster headache. Headache 44, 249–255 (2004).

    CAS  PubMed  Google Scholar 

  182. Nagy, A. J., Gandhi, S., Bhola, R. & Goadsby, P. J. Intravenous dihydroergotamine for inpatient management of refractory primary headaches. Neurology 77, 1827–1832 (2011).

    CAS  PubMed  Google Scholar 

  183. Mills, T. M. & Scoggin, J. A. Intranasal lidocaine for migraine and cluster headaches. Ann. Pharmacother. 31, 914–915 (1997).

    CAS  PubMed  Google Scholar 

  184. Robbins, L. Intranasal lidocaine for cluster headache. Headache 35, 83–84 (1995).

    CAS  PubMed  Google Scholar 

  185. Costa, A. et al. The effect of intranasal cocaine and lidocaine on nitroglycerin-induced attacks in cluster headache. Cephalalgia 20, 85–91 (2000).

    CAS  PubMed  Google Scholar 

  186. Matharu, M. S., Levy, M. J., Meeran, K. & Goadsby, P. J. Subcutaneous octreotide in cluster headache: randomized placebo-controlled double-blind crossover study. Ann. Neurol. 56, 488–494 (2004).

    CAS  PubMed  Google Scholar 

  187. Bussone, G. et al. Double blind comparison of lithium and verapamil in cluster headache prophylaxis. Headache 30, 411–417 (1990).

    CAS  PubMed  Google Scholar 

  188. Leone, M. et al. Verapamil in the prophylaxis of episodic cluster headache: a double-blind study versus placebo. Neurology 54, 1382–1385 (2000).

    CAS  PubMed  Google Scholar 

  189. Koppen, H. et al. Cardiac monitoring of high-dose verapamil in cluster headache: an international Delphi study. Cephalalgia 36, 1385–1388 (2016).

    CAS  PubMed  Google Scholar 

  190. Olesen, J., Tfelt-Hansen, P. & Welch, K. The Headaches. (Lippincott Williams & Wilkins, 2006).

    Google Scholar 

  191. Ambrosini, A. et al. Suboccipital injection with a mixture of rapid- and long-acting steroids in cluster headache: a double-blind placebo-controlled study. Pain 118, 92–96 (2005).

    CAS  PubMed  Google Scholar 

  192. Leroux, E. et al. Suboccipital steroid injections for transitional treatment of patients with more than two cluster headache attacks per day: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 10, 891–897 (2011).

    CAS  PubMed  Google Scholar 

  193. Lambru, G., Shanahan, P., Watkins, L. & Matharu, M. S. Occipital nerve stimulation in the treatment of medically intractable SUNCT and SUNA. Pain Physician 17, 29–41 (2014).

    PubMed  Google Scholar 

  194. Ekbom, K. Lithium for cluster headache: review of the literature and preliminary results of long-term treatment. Headache 21, 132–139 (1981).

    CAS  PubMed  Google Scholar 

  195. Steiner, T. J., Hering, R., Couturier, E. G. M., Davies, P. T. G. & Whitmarsh, T. E. Double-blind placebo-controlled trial of lithium in episodic cluster headache. Cephalalgia 17, 673–675 (1997).

    CAS  PubMed  Google Scholar 

  196. Gallagher, R. M., Mueller, L. L. & Freitag, F. G. Divalproex sodium in the treatment of migraine and cluster headaches. J. Am. Osteopath Assoc. 102, 92–94 (2002).

    PubMed  Google Scholar 

  197. Hering, R. & Kuritzky, A. Sodium valproate in the treatment of cluster headache: an open clinical trial. Cephalalgia 9, 195–198 (1989).

    CAS  PubMed  Google Scholar 

  198. El Amrani, M., Massiou, H. & Bousser, M. G. A negative trial of sodium valproate in cluster headache: methodological issues. Cephalalgia 22, 205–208 (2002).

    CAS  PubMed  Google Scholar 

  199. Forderreuther, S., Mayer, M. & Straube, A. Treatment of cluster headache with topiramate: effects and side-effects in five patients. Cephalalgia 22, 186–189 (2002).

    CAS  PubMed  Google Scholar 

  200. Huang, W. Y., Lo, M. C., Wang, S. J., Tsai, J. J. & Wu, H. M. Topiramate in prevention of cluster headache in the Taiwanese. Neurol. India 58, 284–287 (2010).

    CAS  PubMed  Google Scholar 

  201. Schuh-Hofer, S., Israel, H., Neeb, L., Reuter, U. & Arnold, G. The use of gabapentin in chronic cluster headache patients refractory to first-line therapy. Eur. J. Neurol. 14, 694–696 (2007).

    CAS  PubMed  Google Scholar 

  202. Vukovic, V., Lovrencic-Huzjan, A., Budisic, M. & Demarin, V. Gabapentin in the prophylaxis of cluster headache: an observational open label study. Acta Clin. Croat. 48, 311–314 (2009).

    PubMed  Google Scholar 

  203. Monstad, I. et al. Preemptive oral treatment with sumatriptan during a cluster period. Headache 35, 607–613 (1995).

    CAS  PubMed  Google Scholar 

  204. Zebenholzer, K., Wober, C., Vigl, M. & Wessely, P. Eletriptan for the short-term prophylaxis of cluster headache. Headache 44, 361–364 (2004).

    PubMed  Google Scholar 

  205. Mulder, L. J. & Spierings, E. L. Naratriptan in the preventive treatment of cluster headache. Cephalalgia 22, 815–817 (2002).

    CAS  PubMed  Google Scholar 

  206. Sicuteri, F. et al. Beneficial effect of capsaicin application to the nasal mucosa in cluster headache. Clin. J. Pain 5, 49–53 (1989).

    CAS  PubMed  Google Scholar 

  207. Fusco, B. M., Marabini, S., Maggi, C. A., Fiore, G. & Geppetti, P. Preventative effect of repeated nasal applications of capsaicin in cluster headache. Pain 59, 321–325 (1994).

    PubMed  Google Scholar 

  208. Marks, D. R. et al. A double-blind placebo-controlled trial of intranasal capsaicin for cluster headache. Cephalalgia 13, 114–116 (1993).

    CAS  PubMed  Google Scholar 

  209. Saper, J. R. et al. Intranasal civamide for the treatment of episodic cluster headaches. Arch. Neurol. 59, 990–994 (2002).

    PubMed  Google Scholar 

  210. 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 16, 494–496 (1996).

    CAS  PubMed  Google Scholar 

  211. Pringsheim, T., Magnoux, E., Dobson, C. F., Hamel, E. & Aube, M. Melatonin as adjunctive therapy in the prophylaxis of cluster headache: a pilot study. Headache 42, 787–792 (2002).

    PubMed  Google Scholar 

  212. Kowacs, P. A. et al. Warfarin as a therapeutic option in the control of chronic cluster headache: a report of three cases. J. Headache Pain 6, 417–419 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Hakim, S. M. Warfarin for refractory chronic cluster headache: a randomized pilot study. Headache 51, 713–725 (2011).

    PubMed  Google Scholar 

  214. Hering-Hanit, R. & Gadoth, N. Baclofen in cluster headache. Headache 40, 48–51 (2000).

    CAS  PubMed  Google Scholar 

  215. Leone, M. et al. Transdermal clonidine in the prophylaxis of episodic cluster headache: an open study. Headache 37, 559–560 (1997).

    CAS  PubMed  Google Scholar 

  216. Tronvik, E. et al. Randomised trial on episodic cluster headache with an angiotensin II receptor blocker. Cephalalgia 33, 1026–1034 (2013).

    PubMed  Google Scholar 

  217. Evers, S. Botulinum toxin and the management of chronic headaches. Curr. Opin. Otolaryngol. Head Neck Surg. 12, 197–203 (2004).

    PubMed  Google Scholar 

  218. Sostak, P., Krause, P., Förderreuther, S., Reinisch, V. & Straube, A. Botulinum toxin type-A therapy in cluster headache: an open study. J. Headache Pain 8, 236–241 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Bratbak, D. F. et al. Pilot study of sphenopalatine injection of onabotulinumtoxinA for the treatment of intractable chronic cluster headache. Cephalalgia 36, 503–509 (2016).

    PubMed  Google Scholar 

  220. Nilsson Remahl, A. I., Ansjon, R., Lind, F. & Waldenlind, E. Hyperbaric oxygen treatment of active cluster headache: a double-blind placebo-controlled cross-over study. Cephalalgia 22, 730–739 (2002).

    CAS  PubMed  Google Scholar 

  221. Martelletti, P. et al. Neuromodulation of chronic headaches: position statement from the European Headache Federation. J. Headache Pain 14, 86 (2013).

    PubMed  PubMed Central  Google Scholar 

  222. Jürgens, T. P. et al. Stimulation of the sphenopalatine ganglion in intractable cluster headache: Expert consensus on patient selection and standards of care. Cephalalgia 34, 1100–1110 (2014).

    PubMed  Google Scholar 

  223. Barloese, M. C. J. et al. Cluster headache attack remission with sphenopalatine ganglion stimulation: experiences in chronic cluster headache patients through 24 months. J. Headache Pain 17, 67 (2016).

    PubMed  PubMed Central  Google Scholar 

  224. Burns, B., Watkins, L. & Goadsby, P. J. Treatment of intractable chronic cluster headache by occipital nerve stimulation in 14 patients. Neurology 72, 341–345 (2009).

    CAS  PubMed  Google Scholar 

  225. Fontaine, D. et al. Treatment of refractory chronic cluster headache by chronic occipital nerve stimulation. Cephalalgia 31, 1101–1105 (2011).

    PubMed  Google Scholar 

  226. Fontaine, D. et al. Occipital nerve stimulation improves the quality of life in medically-intractable chronic cluster headache: results of an observational prospective study. Cephalalgia 37, 1173–1179 (2017).

    PubMed  Google Scholar 

  227. Miller, S., Watkins, L. & Matharu, M. Treatment of intractable chronic cluster headache by occipital nerve stimulation: a cohort of 51 patients. Eur. J. Neurol. 24, 381–390 (2017).

    CAS  PubMed  Google Scholar 

  228. Leone, M., Proietti Cecchini, A., Messina, G. & Franzini, A. Long-term occipital nerve stimulation for drug-resistant chronic cluster headache. Cephalalgia 37, 756–763 (2017).

    PubMed  Google Scholar 

  229. Schoenen, J., Roberta, B., Magis, D. & Coppola, G. Noninvasive neurostimulation methods for migraine therapy: the available evidence. Cephalalgia 36, 1170–1180 (2016).

    PubMed  Google Scholar 

  230. Magis, D. & Schoenen, J. Advances and challenges in neurostimulation for headaches. Lancet Neurol. 11, 708–719 (2012). This is an excellent review on the indications for and efficacy of all current neuromodulation techniques in headache.

    PubMed  Google Scholar 

  231. Magis, D., Gérard, P. & Schoenen, J. Invasive occipital nerve stimulation for refractory chronic cluster headache: what evolution at long-term? Strengths and weaknesses of the method. J. Headache Pain 17, 8 (2016).

    PubMed  PubMed Central  Google Scholar 

  232. Magis, D. et al. Central modulation in cluster headache patients treated with occipital nerve stimulation: an FDG-PET study. BMC Neurol. 11, 25 (2011).

    PubMed  PubMed Central  Google Scholar 

  233. Wilbrink, L. A. et al. Occipital nerve stimulation in medically intractable, chronic cluster headache. The ICON study: rationale and protocol of a randomised trial. Cephalalgia 33, 1238–1247 (2013).

    PubMed  Google Scholar 

  234. Leone, M. Deep brain stimulation in headache. Lancet Neurol. 5, 873–877 (2006).

    PubMed  Google Scholar 

  235. Schoenen, J. et al. Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and mode of action. Brain 128, 940–947 (2005).

    CAS  PubMed  Google Scholar 

  236. Matharu, M. S. & Zrinzo, L. Deep brain stimulation in cluster headache: hypothalamus or midbrain tegmentum? Curr. Pain Headache Rep. 14, 151–159 (2010).

    PubMed  Google Scholar 

  237. Clelland, C. D., Zheng, Z., Kim, W., Bari, A. & Pouratian, N. Common cerebral networks associated with distinct deep brain stimulation targets for cluster headache. Cephalalgia 34, 224–230 (2014).

    PubMed  Google Scholar 

  238. Fontaine, D. et al. Anatomical location of effective deep brain stimulation electrodes in chronic cluster headache. Brain 133, 1214–1223 (2010).

    PubMed  Google Scholar 

  239. Seijo, F. et al. Neuromodulation of the posterolateral hypothalamus for the treatment of chronic refractory cluster headache: experience in five patients with a modified anatomical target. Cephalalgia 31, 1634–1641 (2011).

    CAS  PubMed  Google Scholar 

  240. Chabardès, S. et al. Endoventricular deep brain stimulation of the third ventricle: proof of concept and application to cluster headache. Neurosurgery 79, 806–815 (2016).

    PubMed  Google Scholar 

  241. Silberstein, S. D. et al. Non-invasive vagus nerve stimulation for the acute treatment of cluster headache: findings from the randomized, double-blind, sham-controlled ACT1 study. Headache 56, 1317–1332 (2016).

    PubMed  PubMed Central  Google Scholar 

  242. Goadsby, P. J. et al. Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: a randomized, double-blind, sham-controlled ACT2 study. Cephalalgia https://doi.org/10.1177/0333102417744362 (2017).

    Google Scholar 

  243. Gaul, C. et al. Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): a randomised controlled study. Cephalalgia 36, 534–546 (2015).

    PubMed  PubMed Central  Google Scholar 

  244. Torkamani, M. et al. The neuropsychology of cluster headache: cognition, mood, disability, and quality of life of patients with chronic and episodic cluster headache. Headache 55, 287–300 (2015).

    PubMed  PubMed Central  Google Scholar 

  245. D'Amico, D. et al. Health-related quality of life in patients with cluster headache during active periods. Cephalalgia 22, 818–821 (2002).

    CAS  PubMed  Google Scholar 

  246. Saunders, K., Merikangas, K., Low, N. C. P., Von Korff, M. & Kessler, R. C. Impact of comorbidity on headache-related disability. Neurology 70, 538–547 (2008).

    CAS  PubMed  Google Scholar 

  247. Jürgens, T. P. et al. Impairment in episodic and chronic cluster headache. Cephalalgia 31, 671–682 (2011).

    PubMed  Google Scholar 

  248. Abu Bakar, N. et al. The development and validation of the Cluster Headache Quality of life scale (CHQ). J. Headache Pain 17, 79 (2016).

    PubMed  PubMed Central  Google Scholar 

  249. Donnet, A. et al. Chronic cluster headache: a French clinical descriptive study. J. Neurol. Neurosurg. Psychiatr. 78, 1354–1358 (2007).

    CAS  Google Scholar 

  250. Palacios-Ceña, D. et al. Living with cluster headache: a qualitative study of patients’ perspectives. Headache 56, 1171–1182 (2016).

    PubMed  Google Scholar 

  251. Luerding, R. et al. Aggressiveness in different presentations of cluster headache: results from a controlled multicentric study. Cephalalgia 32, 528–536 (2012).

    PubMed  Google Scholar 

  252. Romero-Reyes, M., Pardi, V. & Akerman, S. A potent and selective calcitonin gene-related peptide (CGRP) receptor antagonist, MK-8825, inhibits responses to nociceptive trigeminal activation: Role of CGRP in orofacial pain. Exp. Neurol. 271, 95–103 (2015).

    CAS  PubMed  Google Scholar 

  253. Crowley, B. M. et al. Novel oxazolidinone calcitonin gene-related peptide (CGRP) receptor antagonists for the acute treatment of migraine. Bioorg. Med. Chem. Lett. 25, 4777–4781 (2015).

    CAS  PubMed  Google Scholar 

  254. Ho, T. W. et al. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology 83, 958–966 (2014).

    CAS  PubMed  Google Scholar 

  255. Bigal, M. E. et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: A multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol. 14, 1081–1090 (2015).

    CAS  PubMed  Google Scholar 

  256. Sun, H. et al. Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 15, 382–390 (2016).

    CAS  PubMed  Google Scholar 

  257. Goadsby, P. J. & Bartsch, T. On the functional neuroanatomy of neck pain. Cephalalgia 28 (Suppl. 1), 1–7 (2008).

    PubMed  Google Scholar 

  258. Lambru, G. & Matharu, M. S. Peripheral neurostimulation in primary headaches. Neurol. Sci. 35 (Suppl. 1), 77–81 (2014).

    PubMed  Google Scholar 

  259. Schuster, N. M. & Rapoport, A. M. New strategies for the treatment and prevention of primary headache disorders. Nat. Rev. Neurol. 12, 635–650 (2016).

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

Authors

Contributions

Introduction (A.M.); Epidemiology (P.P.-R. and D.M.); Mechanisms/pathophysiology (A.M. and S.-J.W.); Diagnosis, screening and prevention (T.J.S.); Management (S.E. and D.M.); Quality of life (P.P.-R.); Outlook (S.-J.W. and A.M.); Overview of the Primer (all authors).

Corresponding author

Correspondence to Arne May.

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Competing interests

A.M. has been a consultant or speaker for Allergan, Autonomic Technologies, Desitin, Electrocore and Teva and is the Editor in Chief for Cephalalgia. T.J.S. has acted as a consultant or has served on the advisory boards of Allergan, Amgen, Autonomic Technologies, Avanir, Dr. Reddy's, Nocira, Novartis and Teva; has stock options in Nocira and Second Opinion; and has received royalties from UpToDate. D.M. has received research and travel grants from ElectroCore LLC. P.P.-R. has received honoraria as a consultant or speaker from Allergan, Almirall, Chiesi, Eli Lilly, Novartis and Teva. S.E. has received honoraria as a speaker from or is a member of an advisory board for Allergan, Johnson & Johnson, Novartis, Reckitt Benckiser and TAD Pharma. S.-J.W. has served on the advisory boards of Daiichi-Sankyo, Eli Lilly and Taiwan Pfizer and has received honoraria as a moderator from the Taiwan branches of Bayer, Eisai, Eli Lilly and Pfizer.

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May, A., Schwedt, T., Magis, D. et al. Cluster headache. Nat Rev Dis Primers 4, 18006 (2018). https://doi.org/10.1038/nrdp.2018.6

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