Cluster Headache: Epidemiology, Pathophysiology, Clinical Features, and Diagnosis

Main Article Content

Helin Gosalia Diana Y. Wei Peter J. Goadsby

Abstract

Cluster headache is a primary headache disorder and is the most prevalent of the trigeminal autonomic cephalalgias. Cluster headache significantly impacts those affected, necessitating early diagnosis and management. Despite unique clinical features, such as patients experiencing attacks in a circannual pattern and often with a circadian rhythm within bouts, cluster headache patients often are misdiagnosed, mismanaged and have a delay in diagnosis. Preclinical, neuroimaging and clinical studies have advanced our understanding of cluster headache pathophysiology. The trigeminovascular system, the trigeminal autonomic reflex, and the hypothalamus are all involved in the pathophysiology of cluster headache. As our understanding of the pathophysiology of cluster headaches has evolved, new therapeutic options, such as calcitonin gene-related peptide monoclonal antibodies, non-invasive vagal nerve stimulation and sphenopalatine ganglion stimulation, have proved to have efficacy in the treatment of cluster headache. Herein, we aim to review developments to aid readers in their understanding of this debilitating disorder. 

Keywords: Cluster headache, pathophysiology, diagnosis, clinical, calcitonin-gene related peptide

Article Details

How to Cite
GOSALIA, Helin; WEI, Diana Y.; GOADSBY, Peter J.. Cluster Headache: Epidemiology, Pathophysiology, Clinical Features, and Diagnosis. Medical Research Archives, [S.l.], v. 10, n. 12, dec. 2022. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/3363>. Date accessed: 28 mar. 2024. doi: https://doi.org/10.18103/mra.v10i12.3363.
Section
Research Articles

References

1. Goadsby PJ, Lipton RB. A review of paroxysmal hemicranias, SUNCT syndrome and other short-lasting headaches with autonomic feature, including new cases. Brain. 1997;120 ( Pt 1):193-209. Doi: 10.1093/brain/120.1.193.
2. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211. Doi: 10.1177/0333102417738202.
3. Ekbom K. A clinical comparison of cluster headache and migraine. Acta Neurol Scand. 1970;46:Suppl 41:41-48.
4. Burish MJ, Pearson SM, Shapiro RE, Zhang W, Schor LI. Cluster headache is one of the most intensely painful human conditions: Results from the International Cluster Headache Questionnaire. Headache: The Journal of Head and Face Pain. 2021;61(1):117-124. Doi: 10.1111/head.14021.
5. Hoffmann J, May A. Diagnosis, pathophysiology, and management of cluster headache. Lancet Neurol. 2018;17(1):75-83. Doi: 10.1016/S1474-4422(17)30405-2.
6. Louter MA, Wilbrink LA, Haan J, et al. Cluster headache and depression. Neurology. 2016;87(18):1899-1906. Doi: 10.1212/WNL.0000000000003282.
7. Kim BS, Chung PW, Kim BK, et al. The impact of remission and coexisting migraine on anxiety and depression in cluster headache. J Headache Pain. 2020;21(1):58. Doi: 10.1186/s10194-020-01120-7.
8. Jorge RE, Leston JE, Arndt S, Robinson RG. Cluster headaches: association with anxiety disorders and memory deficits. Neurology. 1999;53(3):543-547. Doi: 10.1212/wnl.53.3.543.
9. Petersen AS, Lund N, Snoer A, Jensen RH, Barloese M. The economic and personal burden of cluster headache: a controlled cross-sectional study. J Headache Pain. 2022;23(1):58. Doi: 10.1186/s10194-022-01427-7.
10. Koehler PJ. Prevalence of headache in Tulp's Observationes Medicae (1641) with a description of cluster headache. Cephalalgia. 1993;13(5):318-320. Doi: 10.1046/j.1468-2982.1993.1305318.x.
11. Isler H. Episodic cluster headache from a textbook of 1745: van Swieten's classic description. Cephalalgia. 1993;13(3):172-174; discussion 149. Doi: 10.1046/j.1468-2982.1993.1303172.x.
12. Harris W. Neuritis and neuralgia. The Lancet. 1926;207(5356):885. Doi: 10.1016/S0140-6736(00)45254-2.
13. Boes CJ, Capobianco DJ, Matharu MS, Goadsby PJ. Wilfred Harris' early description of cluster headache. Cephalalgia. 2002;22(4):320-326. Doi: 10.1046/j.1468-2982.2002.00360.x.
14. Horton BT, MacLean AR, Craig WM. A new syndrome of vascular headache; results of treatment with histamine; a preliminary report. Mayo Clinic Proceedings. 1939;14:250-257.
15. Kunkle EC, Pfeiffer JB, Jr., Wilhoit WM, Hamrick LW, Jr. Recurrent brief headache in cluster pattern. Trans Am Neurol Assoc. 1952;56(77th Meeting):240-243.
16. Bahra A, Goadsby PJ. Diagnostic delays and mis-management in cluster headache. Acta Neurol Scand. 2004;109(3):175-179. Doi: 10.1046/j.1600-0404.2003.00237.x.
17. Frederiksen HH, Lund NL, Barloese MC, Petersen AS, Jensen RH. Diagnostic delay of cluster headache: A cohort study from the Danish Cluster Headache Survey. Cephalalgia. 2020;40(1):49-56. Doi: 10.1177/0333102419863030.
18. 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(6):614-618. Doi: 10.1111/j.1468-2982.2008.01592.x.
19. Sjaastad O, Bakketeig LS. Cluster headache prevalence. Vaga study of headache epidemiology. Cephalalgia. 2003;23(7):528-533. Doi: 10.1046/j.1468-2982.2003.00585.x.
20. Russell MB. Epidemiology and genetics of cluster headache. Lancet Neurol. 2004;3(5):279-283. Doi: 10.1016/S1474-4422(04)00735-5.
21. Bahra A, May A, Goadsby PJ. Cluster headache: a prospective clinical study with diagnostic implications. Neurology. 2002;58(3):354-361. Doi: 10.1212/wnl.58.3.354.
22. Crespi J, Gulati S, Salvesen Ø, et al. Epidemiology of diagnosed cluster headache in Norway. Cephalalgia Reports. 2022;5. Doi: 10.1177/25158163221075569.
23. Couturier EG, Hering R, Steiner TJ. The first report of cluster headache in identical twins. Neurology. 1991;41(5):761. Doi: 10.1212/wnl.41.5.761.
24. Kudrow L, Kudrow DB. Inheritance of cluster headache and its possible link to migraine. Headache. 1994;34(7):400-407. Doi: 10.1111/j.1526-4610.1994.hed3407400.x.
25. Bordini CA, Arruda MA, Ciciarelli M, Daripa M, Martins Coelho J, Speciali JG. Cluster headache: report of seven cases in three families. Funct Neurol. 1997;12(5):277-282.
26. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell. 1996;87(3):543-552. Doi: 10.1016/s0092-8674(00)81373-2.
27. Haan J, van Vliet JA, Kors EE, et al. No involvement of the calcium channel gene (CACNA1A) in a family with cluster headache. Cephalalgia. 2001;21(10):959-962. Doi: 10.1046/j.1468-2982.2001.00283.x.
28. Ofte HK, Tronvik E, Alstadhaug KB. Lack of association between cluster headache and PER3 clock gene polymorphism. J Headache Pain. 2015;17:18. Doi: 10.1186/s10194-016-0611-3.
29. Fan Z, Hou L, Wan D, Ao R, Zhao D, Yu S. Genetic association of HCRTR2, ADH4 and CLOCK genes with cluster headache: a Chinese population-based case-control study. J Headache Pain. 2018;19(1):1. Doi: 10.1186/s10194-017-0831-1.
30. Weller CM, Wilbrink LA, Houwing-Duistermaat JJ, et al. Cluster headache and the hypocretin receptor 2 reconsidered: a genetic association study and meta-analysis. Cephalalgia. 2015;35(9):741-747. Doi: 10.1177/0333102414557839.
31. Rainero I, Rivoiro C, Gallone S, et al. Lack of Association between the 3092 T°C Clock Gene Polymorphism and Cluster Headache. Cephalalgia. 2005;25(11):1078-1081. Doi: 10.1111/j.1468-2982.2005.00965.x.
32. Eising E, Pelzer N, Vijfhuizen LS, et al. Identifying a gene expression signature of cluster headache in blood. Sci Rep. 2017;7:40218. Doi: 10.1038/srep40218.
33. Harder AVE, Winsvold BS, Noordam R, et al. Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache. Ann Neurol. 2021;90(2):203-216. Doi: 10.1002/ana.26146.
34. Bacchelli E, Cainazzo MM, Cameli C, et al. A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants. J Headache Pain. 2016;17(1):114. Doi: 10.1186/s10194-016-0705-y.
35. Ran C, Fourier C, Michalska JM, et al. Screening of genetic variants in ADCYAP1R1, MME and 14q21 in a Swedish cluster headache cohort. J Headache Pain. 2017;18(1):88. Doi: 10.1186/s10194-017-0798-y.
36. O'Connor E, Fourier C, Ran C, et al. Genome-Wide Association Study Identifies Risk Loci for Cluster Headache. Ann Neurol. 2021;90(2):193-202. Doi: 10.1002/ana.26150.
37. Gormley P, Anttila V, Winsvold BS, et al. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet. 2016;48(8):856-866. Doi: 10.1038/ng.3598.
38. Stewart WF, Wood C, Reed ML, Roy J, Lipton RB, Group AA. Cumulative lifetime migraine incidence in women and men. Cephalalgia. 2008;28(11):1170-1178. Doi: 10.1111/j.1468-2982.2008.01666.x.
39. Peng KP, Takizawa T, Lee MJ. Cluster headache in Asian populations: Similarities, disparities, and a narrative review of the mechanisms of the chronic subtype. Cephalalgia. 2020;40(10):1104-1112. Doi: 10.1177/0333102420923646.
40. 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(5):613-617. Doi: 10.1136/jnnp.70.5.613.
41. Lund N, Barloese M, Petersen A, Haddock B, Jensen R. Chronobiology differs between men and women with cluster headache, clinical phenotype does not. Neurology. 2017;88(11):1069-1076. Doi: 10.1212/WNL.0000000000003715.
42. Taga A, Manzoni GC, Russo M, Paglia MV, Torelli P. Childhood-Onset Cluster Headache: Observations From a Personal Case-Series and Review of the Literature. Headache. 2018;58(3):443-454. Doi: 10.1111/head.13244.
43. van Vliet JA, Favier I, Helmerhorst FM, Haan J, Ferrari MD. Cluster headache in women: relation with menstruation, use of oral contraceptives, pregnancy, and menopause. J Neurol Neurosurg Psychiatry. 2006;77(5):690-692. Doi: 10.1136/jnnp.2005.081158.
44. Kudrow L. Response of cluster headache attacks to oxygen inhalation. Headache. 1981;21(1):1-4. Doi:
10.1111/j.1526-4610.1981.hed2101001.x.
45. Fogan L. Treatment of cluster headache. A double-blind comparison of oxygen v air inhalation. Arch Neurol. 1985;42(4):362-363. Doi: 10.1001/archneur.1985.04060040072015.
46. Jurgens TP, Schaefer C, May A. Treatment of cluster headache in pregnancy and lactation. Cephalalgia. 2009;29(4):391-400. Doi: 10.1111/j.1468-2982.2008.01764.x.
47. Giraud P, Chauvet S. Cluster headache during pregnancy: case report and literature review. Headache. 2009;49(1):136-139. Doi: 10.1111/j.1526-4610.2008.01289.x.
48. Schor LI, Pearson SM, Shapiro RE, Zhang W, Miao H, Burish MJ. Cluster headache epidemiology including pediatric onset, sex, and ICHD criteria: Results from the International Cluster Headache Questionnaire. Headache. 2021;61(10):1511-1520. Doi: 10.1111/head.14237.
49. Dodick D, Rozen T, Goadsby P, Silberstein S. Cluster headache. Cephalalgia. 2000;20(9):787-803. Doi: 10.1046/j.1468-2982.2000.00118.x.
50. Kudrow L. The cyclic relationship of natural illumination to cluster period frequency. Cephalalgia. 1987;7 Suppl 6:76-78. Doi: 10.1177/03331024870070S623.
51. May A. Cluster headache: pathogenesis, diagnosis, and management. The Lancet. 2005;366(9488):843-855. Doi: 10.1016/S0140-6736(05)67217-0.
52. Bussone G, Leone M, Peccarisi C, et al. Double blind comparison of lithium and verapamil in cluster headache prophylaxis. Headache. 1990;30(7):411-417. Doi: 10.1111/j.1526-4610.1990.hed3007411.x.
53. Steiner T, Hering R, Couturier E, Davies P, Whitmarsh T. Double-Blind Placebo-Controlled Trial of Lithium in Episodic Cluster Headache. Cephalalgia. 1997;17(6):673-675. Doi: 10.1046/j.1468-2982.1997.1706673.x.
54. Goadsby PJ, Dodick DW, Leone M, et al. Trial of Galcanezumab in Prevention of Episodic Cluster Headache. N Engl J Med. 2019;381(2):132-141. Doi: 10.1056/NEJMoa1813440.
55. Dodick DW, Goadsby PJ, Lucas C, et al. Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: Results from 3-month double-blind treatment. Cephalalgia. 2020;40(9):935-948. Doi: 10.1177/0333102420905321.
56. Vollesen ALH, Snoer A, Beske RP, et al. Effect of Infusion of Calcitonin Gene-Related Peptide on Cluster Headache Attacks: A Randomized Clinical Trial. JAMA Neurol. 2018. Doi: 10.1001/jamaneurol.2018.1675.
57. Barloese M, Haddock B, Lund NT, Petersen A, Jensen R. Chronorisk in cluster headache: A tool for individualised therapy? Cephalalgia. 2018;38(14):2058-2067. Doi: 10.1177/0333102418769955.
58. Giffin NJ, Ruggiero L, Lipton RB, et al. Premonitory symptoms in migraine: An electronic diary study. Neurology. 2003;60(6):935-940. Doi: 10.1212/01.wnl.0000052998.58526.a9.
59. Karsan N, Goadsby PJ. Migraine: beyond pain. Practical Neurology. 2021:practneurol-2020-002844. Doi: 10.1136/practneurol-2020-002844.
60. Snoer A, Lund N, Beske R, Hagedorn A, Jensen RH, Barloese M. Cluster headache beyond the pain phase: A prospective study of 500 attacks. Neurology. 2018;91(9):e822-e831. Doi: 10.1212/01.wnl.0000542491.92981.03.
61. Wei DY, Goadsby PJ. Comprehensive clinical phenotyping of nitroglycerin infusion induced cluster headache attacks. Cephalalgia. 2021;41(8):913-933. Doi: 10.1177/0333102421989617.
62. Cittadini E, Matharu MS, Goadsby PJ. Paroxysmal hemicrania: a prospective clinical study of 31 cases. Brain. 2008;131(Pt 4):1142-1155. Doi: 10.1093/brain/awn010.
63. Goadsby PJ. Pathophysiology of cluster headache: a trigeminal autonomic cephalgia. Lancet Neurol. 2002;1(4):251-257. Doi: 10.1016/s1474-4422(02)00104-7.
64. May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. Hypothalamic activation in cluster headache attacks. Lancet. 1998;352(9124):275-278. Doi: 10.1016/S0140-6736(98)02470-2.
65. Welsh DK, Takahashi JS, Kay SA. Suprachiasmatic nucleus: cell autonomy and network properties. Annu Rev Physiol. 2010;72:551-577. Doi: 10.1146/annurev-physiol-021909-135919.
66. Hannibal J, Moller M, Ottersen OP, Fahrenkrug J. PACAP and glutamate are co-stored in the retinohypothalamic tract. J Comp Neurol. 2000;418(2):147-155. Doi: 10.1002/(SICI)1096-9861(20000306)418:2<147::AID-CNE2>3.0.CO;2-.
67. Penev PD, Zee PC. Melatonin: a clinical perspective. Ann Neurol. 1997;42(4):545-553. Doi: 10.1002/ana.410420404.
68. Brzezinski A. Melatonin in humans. N Engl J Med. 1997;336(3):186-195. Doi: 10.1056/NEJM199701163360306.
69. Waldenlind E, Ekbom K, Wetterberg L, et al. Lowered circannual urinary melatonin concentrations in episodic cluster headache. Cephalalgia. 1994;14(3):199-204. Doi: 10.1046/j.1468-2982.1994.014003199.x.
70. Bruera O, Sances G, Leston J, et al. Plasma melatonin pattern in chronic and episodic headaches: evaluation during sleep and waking. Funct Neurol. 2008;23(2):77-81.
71. Chazot G, Claustrat B, Brun J, Jordan D, Sassolas G, Schott B. A chronobiological study of melatonin, cortisol growth hormone and prolactin secretion in cluster headache. Cephalalgia. 1984;4(4):213-220. Doi: 10.1046/j.1468-2982.1984.0404213.x.
72. 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(7):494-496. Doi: 10.1046/j.1468-2982.1996.1607494.x.
73. Pringsheim T, Magnoux E, Dobson CF, Hamel E, Aube M. Melatonin as adjunctive therapy in the prophylaxis of cluster headache: a pilot study. Headache. 2002;42(8):787-792. Doi: 10.1046/j.1526-4610.2002.02181.x.
74. Peres MF, Rozen TD. Melatonin in the preventive treatment of chronic cluster headache. Cephalalgia. 2001;21(10):993-995. Doi: 10.1046/j.1468-2982.2001.00307.x.
75. Galley HF, Lowes DA, Allen L, Cameron G, Aucott LS, Webster NR. Melatonin as a potential therapy for sepsis: a phase I dose escalation study and an ex vivo whole blood model under conditions of sepsis. J Pineal Res. 2014;56(4):427-438. Doi: 10.1111/jpi.12134.
76. Gelfand AA, Goadsby PJ. The Role of Melatonin in the Treatment of Primary Headache Disorders. Headache. 2016;56(8):1257-1266. Doi: 10.1111/head.12862.
77. Franzini A, Ferroli P, Leone M, Broggi G. Stimulation of the posterior hypothalamus for treatment of chronic intractable cluster headaches: first reported series. Neurosurgery. 2003;52(5):1095-1099; discussion 1099-1101. Doi: 10.1227/01.NEU.0000057698.29634.D6.
78. Bartsch T, Pinsker MO, Rasche D, et al. Hypothalamic deep brain stimulation for cluster headache: experience from a new multicase series. Cephalalgia. 2008;28(3):285-295. Doi: 10.1111/j.1468-2982.2007.01531.x.
79. Nowacki A, Schober M, Nader L, et al. Deep Brain Stimulation for Chronic Cluster Headache: Meta-Analysis of Individual Patient Data. Annals of Neurology. 2020;88(5):956-969. Doi: 10.1111/j.1468-2982.2007.01531.x.
80. Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev. 2017;97(2):553-622. Doi: 10.1152/physrev.00034.2015.
81. May A, Kaube H, Buchel C, et al. Experimental cranial pain elicited by capsaicin: a PET study. Pain. 1998;74(1):61-66. Doi: 10.1016/S0304-3959(97)00144-9.
82. May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. PET and MRA findings in cluster headache and MRA in experimental pain. Neurology. 2000;55(9):1328-1335. Doi: 10.1212/wnl.55.9.1328.
83. Schoenen J, Jensen RH, Lanteri-Minet M, et al. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia. 2013;33(10):816-830. Doi: 10.1177/0333102412473667.
84. Goadsby PJ, Sahai-Srivastava S, Kezirian EJ, et al. Safety and efficacy of sphenopalatine ganglion stimulation for chronic cluster headache: a double-blind, randomised controlled trial. Lancet Neurol. 2019;18(12):1081-1090. Doi: 10.1016/S1474-4422(19)30322-9.
85. Loomba V, Upadhyay A, Kaveeshvar H. Radiofrequency Ablation of the Sphenopalatine Ganglion Using Cone Beam Computed Tomography for Intractable Cluster Headache. Pain Physician. 2016;19(7):E1093-1096.
86. Amighi D, Majedi H, Tafakhori A, Orandi A. The Efficacy of Sphenopalatine Ganglion Block and Radiofrequency Denervation in the Treatment of Cluster Headache: A Case Series. Anesth Pain Med. 2020;10(6):e104466. Doi: 10.5812/aapm.104466.
87. Bratbak DF, Nordgard S, Stovner LJ, et al. Pilot study of sphenopalatine injection of onabotulinumtoxinA for the treatment of intractable chronic cluster headache. Cephalalgia. 2016;36(6):503-509. Doi: 10.1177/0333102415597891.
88. Guo S, Petersen AS, Schytz HW, et al. Cranial parasympathetic activation induces autonomic symptoms but no cluster headache attacks. Cephalalgia. 2018;38(8):1418-1428. Doi: 10.1177/0333102417738250.
89. Moller M, Haji AA, Hoffmann J, May A. Peripheral provocation of cranial autonomic symptoms is not sufficient to trigger cluster headache attacks. Cephalalgia. 2018;38(8):1498-1502. Doi: 10.1177/0333102417738248.
90. Wei DY, Goadsby PJ. Cluster headache pathophysiology - insights from current and emerging treatments. Nature reviews Neurology. 2021;17(5):308-324. Doi: 10.1038/s41582-021-00477-w.
91. Goadsby PJ, Hoskin KL. The distribution of trigeminovascular afferents in the nonhuman primate brain Macaca nemestrina: a c-fos immunocytochemical study. J Anat. 1997;190 ( Pt 3):367-375. Doi: 10.1046/j.1469-7580.1997.19030367.x.
92. 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):427-434. Doi: 10.1046/j.1469-7580.1997.19030367.x.
93. Tuka B, Szabo N, Toth E, et al. Release of PACAP-38 in episodic cluster headache patients - an exploratory study. J Headache Pain. 2016;17(1):69. Doi: 10.1186/s10194-016-0660-7.
94. 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(2):119-123. Doi: 10.1016/0304-3959(94)00097-X.
95. Snoer A, Vollesen ALH, Beske RP, et al. Calcitonin-gene related peptide and disease activity in cluster headache. Cephalalgia. 2019;39(5):575-584. Doi: 10.3390/brainsci10010030.