Neuromodulation in Cluster Headache

  • Linda D’Antona
  • Alberto Proietti Cecchini
  • Massimo Leone
  • Manjit MatharuEmail author
Part of the Headache book series (HEAD)


Cluster headache (CH) is a trigeminal autonomic cephalalgias (TAC) characterized by strictly unilateral, excruciating painful headaches that occur in association with ipsilateral cranial autonomic features. Neuromodulation for the treatment of CH can involve both peripheral and central targets. Peripheral targets include stimulation of the sphenopalatine ganglion, vagus nerve and the greater occipital nerve. Central targeting includes deep brain stimulation of the posterior hypothalamus/ventral tegmental area as well as high cervical spinal cord stimulation. This chapter explores the mechanisms, operative techniques and clinical evidence supporting each method.


Trigeminal autonomic cephalalgia Cluster headache Deep brain stimulation Spinal cord stimulation Occipital nerve stimulation Sphenopalatine ganglion stimulation Vagal nerve stimulation 


  1. 1.
    Headache Classification Subcommittee of The International Headache Society. The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38:1–211.Google Scholar
  2. 2.
    Leone M, Proietti Cecchini A. Advances in the understanding of cluster headache. Expert Rev Neurother. 2017;17(2):165–72.PubMedCrossRefGoogle Scholar
  3. 3.
    Russell MB. Epidemiology and genetics of cluster headache. Lancet Neurol. 2004;3(5):279–83.PubMedCrossRefGoogle Scholar
  4. 4.
    Gaul C, Diener HC, Muller OM. Cluster headache: clinical features and therapeutic options. Dtsch Arztebl Int. 2011;108(33):543–9.PubMedPubMedCentralGoogle Scholar
  5. 5.
    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(2):115–27.PubMedCrossRefGoogle Scholar
  6. 6.
    Miller S, Sinclair AJ, Davies B, Matharu M. Neurostimulation in the treatment of primary headaches. Pract Neurol. 2016;16(5):362–75.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Schoenen J, Jensen RH, Lanteri-Minet M, Lainez MJ, Gaul C, Goodman AM, et al. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia. 2013;33(10):816–30.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Barloese MC, Jurgens TP, May A, Lainez JM, Schoenen J, Gaul C, et al. Cluster headache attack remission with sphenopalatine ganglion stimulation: experiences in chronic cluster headache patients through 24 months. J Headache Pain. 2016;17(1):67.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Jurgens TP, Schoenen J, Rostgaard J, Hillerup S, Lainez MJ, Assaf AT, et al. Stimulation of the sphenopalatine ganglion in intractable cluster headache: expert consensus on patient selection and standards of care. Cephalalgia. 2014;34(13):1100–10.PubMedCrossRefGoogle Scholar
  10. 10.
    Burns B, Watkins L, Goadsby PJ. Treatment of medically intractable cluster headache by occipital nerve stimulation: long-term follow-up of eight patients. Lancet. 2007;369(9567):1099–106.PubMedCrossRefGoogle Scholar
  11. 11.
    Magis D, Allena M, Bolla M, De Pasqua V, Remacle JM, Schoenen J. Occipital nerve stimulation for drug-resistant chronic cluster headache: a prospective pilot study. Lancet Neurol. 2007;6(4):314–21.PubMedCrossRefGoogle Scholar
  12. 12.
    Miller S, Watkins L, Matharu M. Treatment of intractable chronic cluster headache by occipital nerve stimulation: a cohort of 51 patients. Eur J Neurol. 2017;24(2):381–90.CrossRefGoogle Scholar
  13. 13.
    Leone M, Proietti Cecchini A, Messina G, Franzini A. Long-term occipital nerve stimulation for drug-resistant chronic cluster headache. Cephalalgia. 2017;37(8):756–63.CrossRefGoogle Scholar
  14. 14.
    Afridi SK, Shields KG, Bhola R, Goadsby PJ. Greater occipital nerve injection in primary headache syndromes—prolonged effects from a single injection. Pain. 2006;122(1–2):126–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Ambrosini A, Vandenheede M, Rossi P, Aloj F, Sauli E, Pierelli F, et al. Suboccipital injection with a mixture of rapid- and long-acting steroids in cluster headache: a double-blind placebo-controlled study. Pain. 2005;118(1–2):92–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Anthony M. Headache and the greater occipital nerve. Clin Neurol Neurosurg. 1992;94(4):297–301.PubMedCrossRefGoogle Scholar
  17. 17.
    Bartsch T, Goadsby PJ. Stimulation of the greater occipital nerve induces increased central excitability of dural afferent input. Brain. 2002;125(Pt 7):1496–509.CrossRefGoogle Scholar
  18. 18.
    Bartsch T, Goadsby PJ. Increased responses in trigeminocervical nociceptive neurons to cervical input after stimulation of the dura mater. Brain. 2003;126(Pt 8):1801–13.CrossRefGoogle Scholar
  19. 19.
    Magis D, Bruno MA, Fumal A, Gerardy PY, Hustinx R, Laureys S, et al. Central modulation in cluster headache patients treated with occipital nerve stimulation: an FDG-PET study. BMC Neurol. 2011;11:25.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    de Quintana-Schmidt C, Casajuana-Garreta E, Molet-Teixido J, Garcia-Bach M, Roig C, Clavel-Laria P, et al. Stimulation of the occipital nerve in the treatment of drug-resistant cluster headache. Rev Neurol. 2010;51(1):19–26.PubMedGoogle Scholar
  21. 21.
    Fontaine D, Christophe Sol J, Raoul S, Fabre N, Geraud G, Magne C, et al. Treatment of refractory chronic cluster headache by chronic occipital nerve stimulation. Cephalalgia. 2011;31(10):1101–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Fontaine D, Blond S, Lucas C, Regis J, Donnet A, Derrey S, et al. Occipital nerve stimulation improves the quality of life in medically-intractable chronic cluster headache: results of an observational prospective study. Cephalalgia. 2017;37(12):1173–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Mueller O, Diener HC, Dammann P, Rabe K, Hagel V, Sure U, et al. Occipital nerve stimulation for intractable chronic cluster headache or migraine: a critical analysis of direct treatment costs and complications. Cephalalgia. 2013;33(16):1283–91.PubMedCrossRefGoogle Scholar
  24. 24.
    Burns B, Watkins L, Goadsby PJ. Treatment of intractable chronic cluster headache by occipital nerve stimulation in 14 patients. Neurology. 2009;72(4):341–5.CrossRefGoogle Scholar
  25. 25.
    Magis D, Gerardy PY, Remacle JM, Schoenen J. Sustained effectiveness of occipital nerve stimulation in drug-resistant chronic cluster headache. Headache. 2011;51(8):1191–201.PubMedCrossRefGoogle Scholar
  26. 26.
    Bossut DF, Maixner W. Effects of cardiac vagal afferent electrostimulation on the responses of trigeminal and trigeminothalamic neurons to noxious orofacial stimulation. Pain. 1996;65(1):101–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Miller S, Matharu M. Non-invasive neuromodulation in primary headaches. Curr Pain Headache Rep. 2017;21(3):14.PubMedCrossRefGoogle Scholar
  28. 28.
    Oshinsky ML, Murphy AL, Hekierski H Jr, Cooper M, Simon BJ. Noninvasive vagus nerve stimulation as treatment for trigeminal allodynia. Pain. 2014;155(5):1037–42.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Kraus T, Kiess O, Hosl K, Terekhin P, Kornhuber J, Forster C. CNS BOLD fMRI effects of sham-controlled transcutaneous electrical nerve stimulation in the left outer auditory canal—a pilot study. Brain Stimul. 2013;6(5):798–804.PubMedCrossRefGoogle Scholar
  30. 30.
    Beekwilder JP, Beems T. Overview of the clinical applications of vagus nerve stimulation. J Clin Neurophysiol. 2010;27(2):130–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Gaul C, Diener HC, Silver N, Magis D, Reuter U, Andersson A, et al. Non-invasive vagus nerve stimulation for PREVention and acute treatment of chronic cluster headache (PREVA): a randomised controlled study. Cephalalgia. 2016;36(6):534–46.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Leone M, D’Amico D, Frediani F, Moschiano F, Grazzi L, Attanasio A, et al. Verapamil in the prophylaxis of episodic cluster headache: a double-blind study versus placebo. Neurology. 2000;54(6):1382–5.PubMedCrossRefGoogle Scholar
  33. 33.
    Silberstein SD, Mechtler LL, Kudrow DB, Calhoun AH, McClure C, Saper JR, 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. 2016;56(8):1317–32.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Goadsby PJ, de Coo IF, Silver N, Tyagi A, Ahmed F, Gaul C, 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. 2018;38(5):959–69.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Van Buyten JP, Al-Kaisy A, Smet I, Palmisani S, Smith T. High-frequency spinal cord stimulation for the treatment of chronic back pain patients: results of a prospective multicenter European clinical study. Neuromodulation. 2013;16(1):59–65.PubMedCrossRefGoogle Scholar
  36. 36.
    Al-Kaisy A, Van Buyten JP, Smet I, Palmisani S, Pang D, Smith T. Sustained effectiveness of 10 kHz high-frequency spinal cord stimulation for patients with chronic, low back pain: 24-month results of a prospective multicenter study. Pain Med. 2014;15(3):347–54.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Wolter T, Kiemen A, Kaube H. High cervical spinal cord stimulation for chronic cluster headache. Cephalalgia. 2011;31(11):1170–80.CrossRefGoogle Scholar
  38. 38.
    Lambru G, Trimboli M, Palmisani S, Smith T, Al-Kaisy A. Safety and efficacy of cervical 10 kHz spinal cord stimulation in chronic refractory primary headaches: a retrospective case series. J Headache Pain. 2016;17(1):66.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Matharu MS, Zrinzo L. Deep brain stimulation in cluster headache: hypothalamus or midbrain tegmentum? Curr Pain Headache Rep. 2010;14(2):151–9.CrossRefGoogle Scholar
  40. 40.
    May A, Ashburner J, Buchel C, McGonigle DJ, Friston KJ, Frackowiak RS, et al. Correlation between structural and functional changes in brain in an idiopathic headache syndrome [see comments]. Nat Med. 1999;5(7):836–8.CrossRefGoogle Scholar
  41. 41.
    Matharu MS. Functional and structural neuroimaging in primary headache disorders. PhD Thesis. Institute of Neurology, University of London, London. 2006.Google Scholar
  42. 42.
    Zrinzo L, Foltynie T, Limousin P, Hariz MI. Reducing hemorrhagic complications in functional neurosurgery: a large case series and systematic literature review. J Neurosurg. 2012;116(1):84–94.PubMedCrossRefGoogle Scholar
  43. 43.
    Chen T, Mirzadeh Z, Chapple K, Lambert M, Ponce FA. Complication rates, lengths of stay, and readmission rates in “awake” and “asleep” deep brain simulation. J Neurosurg. 2017;127(2):360–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Fenoy AJ, Simpson RK Jr. Risks of common complications in deep brain stimulation surgery: management and avoidance. J Neurosurg. 2014;120(1):132–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Patel DM, Walker HC, Brooks R, Omar N, Ditty B, Guthrie BL. Adverse events associated with deep brain stimulation for movement disorders: analysis of 510 consecutive cases. Neurosurgery. 2015;11(Suppl 2):190–9.PubMedGoogle Scholar
  46. 46.
    Akram H, Miller S, Lagrata S, Hyam J, Jahanshahi M, Hariz M, et al. Ventral tegmental area deep brain stimulation for refractory chronic cluster headache. Neurology. 2016;86(18):1676–82.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Leone M, Franzini A, Cecchini AP, Bussone G. Efficacy of hypothalamic stimulation for chronic drug-resistant cluster headache. Cephalalgia. 2012;32(4):267–8.PubMedCrossRefGoogle Scholar
  48. 48.
    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(19):1428–9.CrossRefGoogle Scholar
  49. 49.
    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):1095–9.Google Scholar
  50. 50.
    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(Pt 4):940–7.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Leone M, Franzini A, Broggi G, Bussone G. Hypothalamic stimulation for intractable cluster headache: long-term experience. Neurology. 2006;67(1):150–2.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Starr PA, Barbaro NM, Raskin NH, Ostrem JL. Chronic stimulation of the posterior hypothalamic region for cluster headache: technique and 1-year results in four patients. J Neurosurg. 2007;106(6):999–1005.CrossRefGoogle Scholar
  53. 53.
    Owen SL, Green AL, Davies P, Stein JF, Aziz TZ, Behrens T, et al. Connectivity of an effective hypothalamic surgical target for cluster headache. J Clin Neurosci. 2007;14(10):955–60.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Bartsch T, Pinsker MO, Rasche D, Kinfe T, Hertel F, Diener HC, et al. Hypothalamic deep brain stimulation for cluster headache: experience from a new multicase series. Cephalalgia. 2008;28(3):285–95.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Bartsch T, Paemeleire K, Goadsby PJ. Neurostimulation approaches to primary headache disorders. Curr Opin Neurol. 2009;22(3):262–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Fontaine D, Lazorthes Y, Mertens P, Blond S, Geraud G, Fabre N, 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. 2010;11(1):23–31.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Seijo F, Saiz A, Lozano B, Santamarta E, Alvarez-Vega M, Seijo E, 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. 2011;31(16):1634–41.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Holl EM, Petersen EA, Foltynie T, Martinez-Torres I, Limousin P, Hariz MI, et al. Improving targeting in image-guided frame-based deep brain stimulation. Neurosurgery. 2010;67(2 Suppl Operative):437–47.PubMedGoogle Scholar
  59. 59.
    Foltynie T, Zrinzo L, Martinez-Torres I, Tripoliti E, Petersen E, Holl E, et al. MRI-guided STN DBS in Parkinson’s disease without microelectrode recording: efficacy and safety. J Neurol Neurosurg Psychiatry. 2011;82(4):358–63.PubMedCrossRefGoogle Scholar
  60. 60.
    Leone M, Franzini A, Proietti Cecchini A, Bussone G. Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster headache. Pain. 2013;154(1):89–94.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Leone M, Franzini A, Broggi G, May A, Bussone G. Long-term follow-up of bilateral hypothalamic stimulation for intractable cluster headache. Brain. 2004;127(Pt 10):2259–64.PubMedCrossRefGoogle Scholar
  62. 62.
    D’Andrea G, Nordera GP, Piacentino M. Effectiveness of hypothalamic stimulation in two patients affected by intractable chronic cluster headache. Neurology. 2006;5(Suppl 2):140.Google Scholar
  63. 63.
    Hidding U, May A. Mere surgery will not cure cluster headache—implications for neurostimulation. Cephalalgia. 2011;31(1):112–5.PubMedCrossRefGoogle Scholar
  64. 64.
    Seijo-Fernandez F, Saiz A, Santamarta E, Nader L, Alvarez-Vega MA, Lozano B, et al. Long-term results of deep brain stimulation of the mamillotegmental fasciculus in chronic cluster headache. Stereotact Funct Neurosurg. 2018;96:1–8.CrossRefGoogle Scholar
  65. 65.
    Chabardes S, Carron R, Seigneuret E, Torres N, Goetz L, Krainik A, et al. Endoventricular deep brain stimulation of the third ventricle: proof of concept and application to cluster headache. Neurosurgery. 2016;79(6):806–15.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Leone M, Bussone G. Pathophysiology of trigeminal autonomic cephalalgias. Lancet Neurol. 2009;8(8):755–64.PubMedCrossRefGoogle Scholar
  67. 67.
    Leone M, May A, Franzini A, Broggi G, Dodick D, Rapoport A, et al. Deep brain stimulation for intractable chronic cluster headache: proposals for patient selection. Cephalalgia. 2004;24(11):934–7.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Martelletti P, Jensen RH, Antal A, Arcioni R, Brighina F, de Tommaso M, et al. Neuromodulation of chronic headaches: position statement from the European Headache Federation. J Headache Pain. 2013;14:86.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Kudrow L. Cluster headache: mechanisms and management. Oxford: Oxford University Press; 1980.Google Scholar
  70. 70.
    Leone M, Bussone G. A review of hormonal findings in cluster headache. Evidence for hypothalamic involvement. Cephalalgia. 1993;13(5):309–17.PubMedCrossRefGoogle Scholar
  71. 71.
    May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. Hypothalamic activation in cluster headache attacks. Lancet. 1998;352(9124):275–8.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    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(1):11–4.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Linda D’Antona
    • 1
  • Alberto Proietti Cecchini
    • 2
  • Massimo Leone
    • 2
  • Manjit Matharu
    • 1
    • 3
    Email author
  1. 1.Headache and Facial Pain Centre, UCL Queen Square Institute of Neurology and National Hospital of Neurology and NeurosurgeryLondonUK
  2. 2.Neuroalgology DepartmentThe Foundation of the Carlo Besta Neurological Institute, IRCCSMilanItaly
  3. 3.Headache GroupInstitute of Neurology and The National Hospital for Neurology and NeurosurgeryLondonUK

Personalised recommendations