Journal of Neurology

, Volume 266, Issue 5, pp 1059–1066 | Cite as

Cluster headache: pathophysiology, diagnosis and treatment

  • Srdjan LjubisavljevicEmail author
  • Jasna Zidverc Trajkovic


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


Cluster headache Pathophysiology Diagnosis Therapy 


Author contributions

Conception and design: SL. Acquisition of data: SL. Analysis and Interpretation of data: SL, JZT. Drafting the manuscript: SL. Revising it for intellectual content: SL, JZT. Final approval of the completed manuscript: SL, JZT.

Compliance with ethical standards

Conflicts of interest

No conflict of interest exists for any of the authors listed in the article.


  1. 1.
    Headache Classification Committee of the International Headache Society (IHS) (2018) The international classification of headache disorders. Cephalalgia 38(1):1–211 (3rd edn) CrossRefGoogle Scholar
  2. 2.
    Fischera M, Marziniak M, Gralow I et al (2008) The incidence and prevalence of cluster headache: a meta-analysis of population-based studies. Cephalalgia 28:614–618CrossRefGoogle Scholar
  3. 3.
    Schurks M, Kurth T, de Jesus J et al (2006) Cluster headache: clinical presentation, lifestyle features, and medical treatment. Headache 46:1246–1254CrossRefGoogle Scholar
  4. 4.
    Lund N, Barloese M, Petersen A et al (2017) Chronobiology differs between men and women with cluster headache, clinical phenotype does not. Neurology 88(11):1069–1076CrossRefGoogle Scholar
  5. 5.
    Zidverc-Trajkovic J, Markovic K, Radojicic A et al (2014) Cluster headache: is age of onset important for clinical presentation? Cephalalgia 34(9):664–670CrossRefGoogle Scholar
  6. 6.
    Ford JH, Nero D, Kim G et al (2018) Societal burden of cluster headache in the United States: a descriptive economic analysis. J Med Econ 21(1):107–111CrossRefGoogle Scholar
  7. 7.
    Steinberg A, Fourier C, Ran C et al (2018) Cluster headache—clinical pattern and a new severity scale in a Swedish cohort. Cephalalgia 38(7):1286–1295CrossRefGoogle Scholar
  8. 8.
    Lund N, Petersen A, Snoer A et al (2018) Cluster headache is associated with unhealthy lifestyle and lifestyle-related comorbid diseases: results from the Danish cluster headache survey. Cephalalgia Google Scholar
  9. 9.
    Russell MB (2004) Epidemiology and genetics of cluster headache. Lancet Neurol 3:279–283CrossRefGoogle Scholar
  10. 10.
    Rozen TD (2018) Cluster headache clinical phenotypes: tobacco nonexposed (never smoker and no parental secondary smoke exposure as a child) versus tobacco-exposed: results from the United States Cluster headache survey. Headache 58(5):688–699CrossRefGoogle Scholar
  11. 11.
    Robbins MS, Lipton RB (2010) The epidemiology of primary headache disorders. Semin Neurol 30(2):107–119CrossRefGoogle Scholar
  12. 12.
    Goadsby PJ (2002) Pathophysiology of cluster headache: a trigeminal autonomic cephalgia. Lancet Neurol 1:251–257CrossRefGoogle Scholar
  13. 13.
    May A (2005) Cluster headache: pathogenesis, diagnosis, and management. Lancet 366:843–855CrossRefGoogle Scholar
  14. 14.
    Ashina H, Newman L, Ashina S (2017) Calcitonin gene-related peptide antagonism and cluster headache: an emerging new treatment. Neurol Sci 38(12):2089–2093CrossRefGoogle Scholar
  15. 15.
    Frese A, Evers S, May A (2003) Autonomic activation in experimental trigeminal pain. Cephalalgia 23:67–68CrossRefGoogle Scholar
  16. 16.
    Barloese M, Petersen AS, Guo S et al (2017) Sphenopalatine ganglion stimulation induces changes in cardiac autonomic regulation in clusterheadache. Clin Physiol Funct Imaging. Google Scholar
  17. 17.
    Martins I, Gouveia R, Antunes J (2005) Double dissociation between autonomic symptoms and pain in cluster headache. Cephalalgia 25:398–400CrossRefGoogle Scholar
  18. 18.
    Goadsby PJ, Edvinsson L (1994) Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain 117:427–434CrossRefGoogle Scholar
  19. 19.
    Hardebo JE (1991) Activation of pain fibers to the internal carotid artery intracranially may cause the pain and local signs of reduced sympathetic and enhanced parasympathetic activity in cluster headache. Headache 31:314–320CrossRefGoogle Scholar
  20. 20.
    Strittmatter M, Hamann GF, Grauer M et al (1996) Altered activity of the sympathetic nervous system and changes in the balance of hypophyseal, pituitary and adrenal hormones in patients with cluster headache. Neuroreport 7:1229–1234CrossRefGoogle Scholar
  21. 21.
    Hofman MA, Zhou JN, Swaab DF (1996) Suprachiasmatic nucleus of the human brain: an immunocytochemical and morphometric analysis. J Comp Neurol 305:552–556Google Scholar
  22. 22.
    Cevoli S, Pizza F, Grimaldi D et al (2011) Cerebrospinal fluid hypocretin-1 levels during the active period of cluster headache. Cephalalgia 31(8):973–976CrossRefGoogle Scholar
  23. 23.
    Barloese M, Jennum P, Lund N et al (2015) Reduced CSF hypocretin-1 levels are associated with cluster headache. Cephalalgia 35(10):869–876CrossRefGoogle Scholar
  24. 24.
    May A, Bahra A, Buchel C et al (1998) Hypothalamic activation in cluster headache attacks. Lancet 352:275–278CrossRefGoogle Scholar
  25. 25.
    May A, Ashburner J, Buchel C et al (1999) Correlation between structural and functional changes in brain in an idiopathic headache syndrome. Nat Med 5:836–838CrossRefGoogle Scholar
  26. 26.
    Lodi R, Pierangeli G, Tonon C et al (2006) Study of hypothalamic metabolism in cluster headache by proton MR spectroscopy. Neurology 66:1264–1266CrossRefGoogle Scholar
  27. 27.
    Morelli N, Pesaresi I, Cafforio G et al (2009) Functional magnetic resonance imaging in episodic cluster headache. J Headache Pain 10:11–14CrossRefGoogle Scholar
  28. 28.
    Yang FC, Chou KH, Kuo CY et al (2018) The pathophysiology of episodic cluster headache: insights from recent neuroimaging research. Cephalalgia 38(5):970–983CrossRefGoogle Scholar
  29. 29.
    Arkink EB, Schmitz N, Schoonman GG et al (2017) The anterior hypothalamus in cluster headache. Cephalalgia 37(11):1039–1050CrossRefGoogle Scholar
  30. 30.
    Snoer A, Lund N, Beske R et al (2018) Pre-attack signs and symptoms in cluster headache: characteristics and time profile. Cephalalgia 38(6):1128–1137CrossRefGoogle Scholar
  31. 31.
    Bahra A, May A, Goadsby PJ (2002) Cluster headache: a prospective clinical study in 230 patients with diagnostic implications. Neurology 58:354–361CrossRefGoogle Scholar
  32. 32.
    Nesbitt AD, Goadsby PJ (2012) Cluster headache. BMJ 344:e2407CrossRefGoogle Scholar
  33. 33.
    Ekbom K (1968) Nitroglycerin as a provocative agent in cluster headache. Arch Neurol 19:487–493CrossRefGoogle Scholar
  34. 34.
    Drummond PD (2006) Mechanisms of autonomic disturbance in the face during and between attacks of cluster headache. Cephalalgia 26:633–641CrossRefGoogle Scholar
  35. 35.
    Marmura MJ, Pello SJ, Young WB (2010) Interictal pain in cluster headache. Cephalalgia 30:1531–1534CrossRefGoogle Scholar
  36. 36.
    Irimia P, Cittadini E, Paemeleire K et al (2008) Unilateral photophobia or phonophobia in migraine compared with trigeminal autonomic cephalalgias. Cephalalgia 28:626–630CrossRefGoogle Scholar
  37. 37.
    Zidverc-Trajkovic J, Podgorac A, Radojicic A et al (2013) Migraine-like accompanying features in patients with cluster headache. How important are they? Headache 53:1464–1469Google Scholar
  38. 38.
    Zidverc-Trajkovic J, Pavlovic AM, Mijajlovic M et al (2005) Cluster headache and paroxysmal hemicrania: differential diagnosis. Cephalalgia 25:244–248CrossRefGoogle Scholar
  39. 39.
    Wilbrink LA, Ferrari MD, Kruit MC et al (2009) Neuroimaging in trigeminal autonomic cephalgias: when, how, and of what? Curr Opin Neurol 22:247–253CrossRefGoogle Scholar
  40. 40.
    Mitsikostas DD, Ashina M, Craven A et al (2015) European Headache Federation consensus on technical investigation for primary headache disorders. J Headache Pain 17(1):5CrossRefGoogle Scholar
  41. 41.
    Ljubisavljevic S, Prazic A, Lazarevic M et al (2017) The rare painful phenomena—chronic paroxysmal hemicrania-tic syndrome as a clinically isolated syndrome of the central nervous system. Pain Physician 20(2):315–322Google Scholar
  42. 42.
    Voiticovschi-Iosob C, Allena M, De Cillis I et al (2014) Diagnostic and therapeutic errors in cluster headache: a hospital-based study. J Headache Pain 15:56CrossRefGoogle Scholar
  43. 43.
    Klapper JA, Klapper A, Voss T (2000) The misdiagnosis of cluster headache: a nonclinic, population-based, Internet survey. Headache 40:730–735CrossRefGoogle Scholar
  44. 44.
    Robbins MS (2013) The psychiatric comorbidities of cluster headache. Curr Pain Headache Rep 17:313CrossRefGoogle Scholar
  45. 45.
    Torelli P, Manzoni GC (2005) Behavior during cluster headache. Curr Pain Headache Rep 9:113–119CrossRefGoogle Scholar
  46. 46.
    Iacovelli E, Coppola G, Tinelli E et al (2012) Neuroimaging in cluster headache and other trigeminal autonomic cephalalgias. J Headache Pain 13:11–20CrossRefGoogle Scholar
  47. 47.
    Luerding R, Henkel K, Gaul C et al (2012) Aggressiveness in different presentations of cluster headache: results from a controlled multicentric study. Cephalalgia 32:528–536CrossRefGoogle Scholar
  48. 48.
    Rozen TD, Fishman RS (2012) Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden. Headache 52(1):99–113CrossRefGoogle Scholar
  49. 49.
    Barloese M, Jennum P, Knudsen S et al (2012) Cluster headache and sleep, is there a connection? A review. Cephalalgia 32(6):481–491CrossRefGoogle Scholar
  50. 50.
    Barloese MC, Jennum PJ, Lund NT et al (2015) Sleep in cluster headache beyond a temporal rapid eye movement relationship? Eur J Neurol 22(4):656CrossRefGoogle Scholar
  51. 51.
    Chervin RD, Zellek N, Lin X et al (2000) Sleep disordered breathing in patients with cluster headache. Neurology 54:2302–2306CrossRefGoogle Scholar
  52. 52.
    Zidverc-Trajkovic JJ, Pekmezovic TD, Sundic AL et al (2011) Comorbidities in cluster headache and migraine. Acta Neurol Belg 111(1):50–55Google Scholar
  53. 53.
    Matharu M et al (2010) Cluster headache. Clin Evid 02:1212Google Scholar
  54. 54.
    Cohen AS, Burns B, Goadsby PJ (2009) High flow oxygen for treatment of cluster headache. A randomized trial. JAMA 302:2451–2457CrossRefGoogle Scholar
  55. 55.
    Petersen AS, Barloese MC, Lund NL et al (2017) Oxygen therapy for cluster headache. A mask comparison trial. A single-blinded, placebo-controlled, crossover study. Cephalalgia 37(3):214–224CrossRefGoogle Scholar
  56. 56.
    Van Vliet JA, Bahra A, Martin V et al (2003) Intranasal sumatriptan in cluster headache—randomized placebo-controlled double-blind study. Neurology 60:630–633CrossRefGoogle Scholar
  57. 57.
    Cittadini E, May A, Straube A et al (2006) Effectiveness of intranasal zolmitriptan in acute cluster headache. A randomized, placebo-controlled, double-blind crossover study. Arch Neurol 63:1537–1542CrossRefGoogle Scholar
  58. 58.
    Jammes JL (1975) The treatment of cluster headaches with prednisone. Dis Nerv Syst 36:375–376Google Scholar
  59. 59.
    May A, Leone M, Afra J et al (2006) EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. Eur J Neurol 13:1066–1077CrossRefGoogle Scholar
  60. 60.
    Robbins MS, Starling AJ, Pringsheim TM et al (2016) Treatment of cluster headache: The American Headache Society evidence-based guidelines. Headache 56(7):1093–1106CrossRefGoogle Scholar
  61. 61.
    Lampl C, Rudolph M, Bräutigam E (2018) OnabotulinumtoxinA in the treatment of refractory chronic cluster headache. J Headache Pain 19(1):45CrossRefGoogle Scholar
  62. 62.
    Barloese M, Petersen A, Stude P et al (2018) Sphenopalatine ganglion stimulation for cluster headache, results from a large, open-label European registry. J Headache Pain 19(1):6CrossRefGoogle Scholar
  63. 63.
    Gaul C, Roguski J, Dresler T et al (2017) Efficacy and safety of a single occipital nerve blockade in episodic and chronic cluster headache: a prospective observational study. Cephalalgia 37(9):873–880CrossRefGoogle Scholar
  64. 64.
    Viswanath O, Rasekhi R, Suthar R et al (2018) Novel interventional nonopioid therapies in headache management. Curr Pain Headache Rep 22(4):29CrossRefGoogle Scholar
  65. 65.
    Loomba V, Upadhyay A, Kaveeshvar H (2016) Radiofrequency ablation of the sphenopalatine ganglion using cone beam computed tomography for intractable cluster headache. Pain Physician 19(7):E1093–E1096Google Scholar
  66. 66.
    Pedersen JL, Barloese M, Jensen RH (2013) Neurostimulation in cluster headache: a review of current progress. Cephalalgia 33(14):1179–1193CrossRefGoogle Scholar
  67. 67.
    Barbanti P, Aurilia C, Fofi L et al (2017) The role of anti-CGRP antibodies in the pathophysiology of primary headaches. Neurol Sci 38(Suppl 1):31–35CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Srdjan Ljubisavljevic
    • 1
    • 2
    Email author
  • Jasna Zidverc Trajkovic
    • 3
    • 4
  1. 1.Faculty of MedicineUniversity of NisNisSerbia
  2. 2.Clinic for Neurology, Clinical Center NisNisSerbia
  3. 3.Faculty of MedicineUniversity of BelgradeBelgradeSerbia
  4. 4.Clinic for Neurology, Clinical Center SerbiaBelgradeSerbia

Personalised recommendations