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Neurotherapeutics logoLink to Neurotherapeutics
. 2010 Apr;7(2):220–228. doi: 10.1016/j.nurt.2010.02.001

Deep brain stimulation in trigeminal autonomic cephalalgias

Massimo Leone 1,, Angelo Franzini 2, Alberto Proietti Cecchini 1, Eliana Mea 1, Giovanni Broggi 2, Gennaro Bussone 1
PMCID: PMC5084104  PMID: 20430322

Summary

Cluster headache (CH), paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT syndrome) are primary headaches grouped together as trigeminal autonomic cephalalgias (TACs). All are characterized by short-lived unilateral head pain attacks associated with oculofacial autonomic phenomena. Neuroimaging studies have demonstrated that the posterior hypothalamus is activated during attacks, implicating hypothalamic hyperactivity in TAC pathophysiology and suggesting stimulation of the ipsilateral posterior hypothalamus as a means of preventing intractable CH. After almost 10 years of experience, hypothalamic stimulation has proved successful in preventing pain attacks in approximately 60% of the 58 documented chronic drug-resistant CH patients implanted at various centers. Positive results have also been reported in drug-resistant SUNCT and PH. Microrecording studies on hypothalamic neurons are increasingly being performed and promise to make it possible to more precisely identify the target site. The implantation procedure has generally proved safe, although it carries a small risk of brain hemorrhage. Long-term stimulation is proving to be safe: studies on patients under continuous hypothalamic stimulation have identified nonsymptomatic impairment of orthostatic adaptation as the only noteworthy change. Studies on pain threshold in chronically stimulated patients show increased threshold for cold pain in the distribution of the first trigeminal branch ipsilateral to stimulation. When the stimulator is switched off, changes in sensory and pain thresholds do not occur immediately, indicating that long-term hypothalamic stimulation is necessary to produce sensory and nociceptive changes, as also indicated by clinical experience that CH attacks are brought under control only after weeks of stimulation. Infection, transient loss of consciousness, and micturition syncope have been reported, but treatment interruption usually is not required.

Key Words: Cluster headache, paroxysmal hemicrania, SUNCT syndrome, trigeminal autonomic cephalgias, hypothalamus, deep brain stimulation

References

  • 1.Gildenberg PL. The history of stereotactic and functional neurosurgery. In: Gildenberg PL, Tasker RR, editors. Textbook of stereotactic and functional neurosurgery. 1st ed. New York: McGraw Hill; 1998. pp. 5–20. [Google Scholar]
  • 2.Bittar RG, Kar-Purkayastha I, Owen SL, Bear RE, Green A, Wang S, et al. Deep brain stimulation for pain relief: a meta-analysis. J Clin Neurosci. 2005;12:515–519. doi: 10.1016/j.jocn.2004.10.005. [DOI] [PubMed] [Google Scholar]
  • 3.Veloso F, Kumar K, Toth C. Headache secondary to deep brain implantation. Headache. 1998;38:507–515. doi: 10.1046/j.1526-4610.1998.3807507.x. [DOI] [PubMed] [Google Scholar]
  • 4.Young RF, Chambi VI. Pain relief by electrical stimulation of the periaqueductal and periventricular gray matter: evidence for a non-opioid mechanism. J Neurosurg. 1987;66:364–371. doi: 10.3171/jns.1987.66.3.0364. [DOI] [PubMed] [Google Scholar]
  • 5.Sano K, Sekino H, Hashimoto I, Amano K, Sugiyama H. Postero-medial hypothalamotomy in the treatment of tractable pain. Confin Neurol. 1975;37:285–290. doi: 10.1159/000102762. [DOI] [PubMed] [Google Scholar]
  • 6.Raskin NH, Hosobuchi Y, Lamb S. Headache may arise from perturbation of brain. Headache. 1987;27:416–420. doi: 10.1111/j.1526-4610.1987.hed2708416.x. [DOI] [PubMed] [Google Scholar]
  • 7.Bittar RG, Nandi D, Carter H, Aziz TZ. Somatotopic organization of the human periventricular gray matter. J Clin Neurosci. 2005;12:240–241. doi: 10.1016/j.jocn.2004.05.012. [DOI] [PubMed] [Google Scholar]
  • 8.Kumar K, Toth C, Nath R. Deep brain stimulation for intractable pain: a 15-year experience. Neurosurgery. 1997;40:736–746. doi: 10.1097/00006123-199704000-00015. [DOI] [PubMed] [Google Scholar]
  • 9.May A. New insights into headache: an update on functional and structural imaging findings. Nat Rev Neurol. 2009;5:199–209. doi: 10.1038/nrneurol.2009.28. [DOI] [PubMed] [Google Scholar]
  • 10.Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 2nd edition. Cephalalgia 2004;24(Suppl 1):8–160. [DOI] [PubMed]
  • 11.May A, Bahra A, Büchel C, Frackowiak RS, Goadsby PJ. Hypothalamic activation in cluster headache attacks. Lancet. 1998;352:275–278. doi: 10.1016/S0140-6736(98)02470-2. [DOI] [PubMed] [Google Scholar]
  • 12.May A, Bahra A, Büchel C, Turner R, Goadsby PJ. Functional MRI in spontaneous attacks of SUNCT: short-lasting neuralgiform headache with conjunctival injection and tearing. Ann Neurol. 1999;46:791–794. doi: 10.1002/1531-8249(199911)46:5<791::AID-ANA18>3.0.CO;2-8. [DOI] [PubMed] [Google Scholar]
  • 13.Matharu MS, Cohen AS, Frackowiak RSJ, Goadsby PJ. Posterior hypothalamic activation in paroxysmal hemicrania. Ann Neurol. 2006;59:535–545. doi: 10.1002/ana.20763. [DOI] [PubMed] [Google Scholar]
  • 14.Matharu MS, Cohen AS, McGonigle DJ, Ward N, Frackowiak RS, Goadsby PJ. Posterior hypothalamic and brainstem activation in hemicrania continua. Headache. 2004;44:747–761. doi: 10.1111/j.1526-4610.2004.04141.x. [DOI] [PubMed] [Google Scholar]
  • 15.May A, Ashbumer J, Büchel C, McGonigle DJ, Fristen KJ, Frackowiak RS, et al. Correlation between structural and functional changes in brain in an idiopathic headache syndrome. Nat Med. 1999;5:836–838. doi: 10.1038/10561. [DOI] [PubMed] [Google Scholar]
  • 16.Leone M, Franzini A, Bussone G. Stereotactic stimulation of posterior hypothalamic gray matter for intractable cluster headache. N Engl J Med. 2001;345:1428–1429. doi: 10.1056/NEJM200111083451915. [DOI] [PubMed] [Google Scholar]
  • 17.Kudrow L. Cluster headache, mechanism and management. New York: Oxford University Press; 1980. [Google Scholar]
  • 18.Sjaastad O. Cluster headache syndrome. Major Problems in Neurology 23. London, Philadelphia, Toronto: WB Saunders; 1992. [Google Scholar]
  • 19.Jarrar RG, Black DF, Dodick DW, Davis DH. Outcome of trigeminal nerve section in the treatment of chronic cluster headache. Neurology. 2003;60:1360–1362. doi: 10.1001/archneur.60.10.1360. [DOI] [PubMed] [Google Scholar]
  • 20.O’Brien MD, Kirkpatrick PJ, McCabe JJ. Trigeminal nerve section for chronic migrainous neuralgia. In: Olesen J, Goadsby PJ, editors. Cluster headache and related conditions. Frontiers in Headache Research 9. Oxford: Oxford University Press; 1999. pp. 291–295. [Google Scholar]
  • 21.Donnet A, Valade D, Regis J. Gamma knife treatment for refractory cluster headache: prospective open trial. J Neurol Neurosurg Psychiatry. 2005;76:218–221. doi: 10.1136/jnnp.2004.041202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Matharu MS, Goadsby PJ. Persistence of attacks of cluster headache after trigeminal nerve root section. Brain. 2002;125:976–984. doi: 10.1093/brain/awf118. [DOI] [PubMed] [Google Scholar]
  • 23.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;6:314–321. doi: 10.1016/S1474-4422(07)70058-3. [DOI] [PubMed] [Google Scholar]
  • 24.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;24:934–937. doi: 10.1111/j.1468-2982.2004.00742.x. [DOI] [PubMed] [Google Scholar]
  • 25.Goadsby PJ, Schoenen J, Ferrari MD, Silberstein SD, Dodick D. Towards a definition of intractable headache for use in clinical practice and trials. Cephalalgia. 2006;26:1168–1170. doi: 10.1111/j.1468-2982.2006.01173.x. [DOI] [PubMed] [Google Scholar]
  • 26.Leone M, Proietti Cecchini A, Mea E, D’Amico D, Tullo V, Grazzi L, et al. Therapeutic neurostimulation in chronic headaches: problems of patient selection. Neurol Sci. 2008;29:S59–S61. doi: 10.1007/s10072-008-0889-2. [DOI] [PubMed] [Google Scholar]
  • 27.Sumaptriptan Cluster Headache Study Group Treatment of acute cluster headache with sumatriptan. N Engl J Med. 1991;325:322–326. doi: 10.1056/NEJM199108013250505. [DOI] [PubMed] [Google Scholar]
  • 28.Turhal NS. Sumatriptan overdose in episodic cluster headache: a case report of overuse without event. Cephalalgia. 2001;21:700–700. doi: 10.1046/j.1468-2982.2001.00225.x. [DOI] [PubMed] [Google Scholar]
  • 29.May A, Leone M, Áfra J, Linde M, Sándor PS, Evers S, et al. EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. Eur J Neurol. 2006;13:1066–1077. doi: 10.1111/j.1468-1331.2006.01566.x. [DOI] [PubMed] [Google Scholar]
  • 30.Lipton RB, Micieli G, Russell D, Solomon S, Tfelt-Hansen P, Waldenlind E. Guidelines for controlled clinical trials of drugs in cluster headache. Cephalalgia. 1995;15:452–462. doi: 10.1046/j.1468-2982.1995.1506452.x. [DOI] [PubMed] [Google Scholar]
  • 31.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;369:1099–1106. doi: 10.1016/S0140-6736(07)60328-6. [DOI] [PubMed] [Google Scholar]
  • 32.Leone M, Franzini A, Cecchini AP, Broggi G, Bussone G. Stimulation of occipital nerve for drug-resistant chronic cluster headache. Lancet Neurol. 2007;6:289–291. doi: 10.1016/S1474-4422(07)70061-3. [DOI] [PubMed] [Google Scholar]
  • 33.Leone M, Franzini A, Broggi G, Mea E, Cecchini AP, Bussone G. Acute hypothalamic stimulation and ongoing cluster headache attacks. Neurology. 2006;67:1844–1845. doi: 10.1212/01.wnl.0000247273.93084.49. [DOI] [PubMed] [Google Scholar]
  • 34.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;52:1095–1099. doi: 10.1227/01.NEU.0000057698.29634.D6. [DOI] [PubMed] [Google Scholar]
  • 35.Franzini A, Ferroli P, Leone M, Bussone G, Broggi G. Hypothalamic deep brain stimulation for the treatment of chronic cluster headaches: a series report. Neuromodulation. 2004;7:1–8. doi: 10.1111/j.1525-1403.2004.04001.x. [DOI] [PubMed] [Google Scholar]
  • 36.Leone M, Franzini A, Broggi G, May A, Bussone G. Long-term follow up of bilateral hypothalamic stimulation for intractable cluster headache. Brain. 2004;127:2259–2264. doi: 10.1093/brain/awh245. [DOI] [PubMed] [Google Scholar]
  • 37.Schoenen J, Di Clemente L, Vandenheede M, Fumal A, De Pasqua V, Mouchamps M, et al. Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and mode of action. Brain. 2005;128:940–947. doi: 10.1093/brain/awh411. [DOI] [PubMed] [Google Scholar]
  • 38.Leone M, Franzini A, Broggi G, Bussone G. Hypothalamic stimulation for intractable cluster headache: long-term experience. Neurology. 2006;67:150–152. doi: 10.1212/01.wnl.0000223319.56699.8a. [DOI] [PubMed] [Google Scholar]
  • 39.Owen SLF, 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;14:955–960. doi: 10.1016/j.jocn.2006.07.012. [DOI] [PubMed] [Google Scholar]
  • 40.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;106:999–1005. doi: 10.3171/jns.2007.106.6.999. [DOI] [PubMed] [Google Scholar]
  • 41.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;28:285–295. doi: 10.1111/j.1468-2982.2007.01531.x. [DOI] [PubMed] [Google Scholar]
  • 42.D’Andrea G, Nordera GP, Piacentino M. Effectiveness of hypothalamic stimulation in two patients affected by intractable chronic cluster headache. Neurology. 2006;66(Suppl 2):A140–A140. [Google Scholar]
  • 43.Benabid AL, Chabardés S, Scigneuret E, Torres N. Intraventricular stimulation for targets close to the midline: periaqueductal gray, posterior hypothalamus, anterior hypothalamus, subcommissural structures. Acta Neurochir (Wien) 2006;148:i–lxiv. [Google Scholar]
  • 44.Mateos V, Scijo F, Lozano B, Álvarez Vega M, Fernández González F. Deep brain stimulation in refractory chronic cluster headache: first national cases [Estimulacion cerebral profunda en cefalea en racimos crónica refractaria primeros casos nationales] [In Spanish] Neurologia. 2007;22:96–96. [Google Scholar]
  • 45.Fontaine D, Lazorthes Y, Mertens P, Blond S, Géraud 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;11:23–31. doi: 10.1007/s10194-009-0169-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Sillay KA, Sani S, Starr PA. Deep brain stimulation for medically intractable cluster headache. Neurobiol Dis 2009 Jun 6 [Epub ahead of print]. [DOI] [PubMed]
  • 47.Brittain J-S, Green AL, Jenkinson N, Ray NJ, Holland P, Stein JF, et al. Local field potentials reveal a distinctive neural signature of cluster headache in the hypothalamus. Cephalalgia. 2009;29:1165–1173. doi: 10.1111/j.1468-2982.2009.01846.x. [DOI] [PubMed] [Google Scholar]
  • 48.Black D, Bartleson JD, Torgrimson SM, Davis DH. Two cases of chronic cluster headache treated successfully with hypothalamic deep brain stimulation. Neurology 2007:P07.065 (abstract).
  • 49.Swaab DF. Handbook of clinical neurology. Handbook of Clinical Neurology 80. Amsterdam: Elsevier; 2003. The human hypothalamus: basic and clinical aspects; Part II: Neuropathology of the human hypothalamus and adjacent structures. [Google Scholar]
  • 50.Sherrington CS. The integrative action of the nervous system. 2nd ed. New Haven, CT: Yale University Press; 1947. pp. 1–1. [Google Scholar]
  • 51.Loewy AD. Forebrain nuclei involved in autonomic control. Prog Brain Res. 1991;87:253–268. doi: 10.1016/S0079-6123(08)63055-1. [DOI] [PubMed] [Google Scholar]
  • 52.Cortelli P, Guaraldi P, Leone M, Pierangeli G, Barletta G, Grimaldi D, et al. Effect of deep brain stimulation of the posterior hypothalamic area on the cardiovascular system in chronic cluster headache patients. Eur J Neurol. 2007;14:1008–1015. doi: 10.1111/j.1468-1331.2007.01850.x. [DOI] [PubMed] [Google Scholar]
  • 53.Benarroch EE. Central autonomic network: functional organization and clinical correlations. Armonk, NY: Futura Publishing; 1997. Homeostasis, immunomodulation and antinociception; pp. 405–443. [Google Scholar]
  • 54.Abrahamson EE, Moore RY. The posterior hypothalamic area: chemoarchitecture and afferent connections. Brain Res. 2001;889:1–22. doi: 10.1016/S0006-8993(00)03015-8. [DOI] [PubMed] [Google Scholar]
  • 55.Vetrugno R, Pierangeli G, Leone M, Bussone G, Franzini A, Brogli G, et al. Effect on sleep of posterior hypothalamus stimulation in cluster headache. Headache. 2007;47:1085–1090. doi: 10.1111/j.1526-4610.2007.00864.x. [DOI] [PubMed] [Google Scholar]
  • 56.Talairach J, Tournoux P. Co-planar stereotaxic atlas of the human brain: 3-dimensional proportional system: an approach to cerebral imaging. Stuttgart: G. Thieme Verlag; 1988. [Google Scholar]
  • 57.Cordella R, Carella F, Leone M, Franzini A, Broggi G, Bussone G, et al. Spontaneous neuronal activity of the posterior hypothalamus in trigeminal autonomic cephalalgias. Neurol Sci. 2007;28:93–95. doi: 10.1007/s10072-007-0793-1. [DOI] [PubMed] [Google Scholar]
  • 58.Sani S, Shimamoto S, Turner RS, Levesque N, Starr PA. Micro-electrode recording in the posterior hypothalamic region in humans. Neurosurgery. 2009;64:161–167. doi: 10.1227/01.NEU.0000334051.91501.E3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Malick A, Strassman AM, Burstein R. Trigeminohypothalamic and reticulohypothalamic tract neurons in the upper cervical spinal cord and caudal medulla of the rat. J Neurophysiol. 2000;84:2078–2112. doi: 10.1152/jn.2000.84.4.2078. [DOI] [PubMed] [Google Scholar]
  • 60.Bartsch T, Levy MJ, Knight YE, Goadsby PJ. Differential modulation of nociceptive dural input to [hypocretin] orexin A and B receptor activation in the posterior hypothalamic area. Pain. 2004;109:367–378. doi: 10.1016/j.pain.2004.02.005. [DOI] [PubMed] [Google Scholar]
  • 61.Jürgens T, Leone M, Proietti-Cecchini A, Busch V, Mea E, Bussone G, et al. Hypothalamic deep-brain stimulation modulates thermal sensitivity and pain thresholds in cluster headache. Pain. 2009;146:84–90. doi: 10.1016/j.pain.2009.07.006. [DOI] [PubMed] [Google Scholar]
  • 62.Cohen AS, Matharu MS, Goadsby PJ. Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or cranial autonomic features (SUNA): a prospective clinical study of SUNCT and SUNA. Brain. 2006;129:2746–2760. doi: 10.1093/brain/awl202. [DOI] [PubMed] [Google Scholar]
  • 63.Black DF, Dodick DW. Two cases of medically and surgically intractable SUNCT: a reason for caution and an argument for a central mechanism. Cephalalgia. 2002;22:201–214. doi: 10.1046/j.1468-2982.2002.00348.x. [DOI] [PubMed] [Google Scholar]
  • 64.Leone M, Franzini A, D’Andrea G, Broggi G, Casucci G, Bussone G. Deep brain stimulation to relieve severe drug-resistant SUNCT. Ann Neurol. 2005;57:924–927. doi: 10.1002/ana.20507. [DOI] [PubMed] [Google Scholar]
  • 65.Lyons MK, Dodick DW, Evidente VG. Responsiveness of short-lasting unilateral neuralgiform headache with conjunctival injection and tearing to hypothalamic deep brain stimulation. J Neurosurg. 2009;110:279–281. doi: 10.3171/2008.4.17493. [DOI] [PubMed] [Google Scholar]
  • 66.Walcott BP, Bamber NI, Anderson DE. Successful treatment of chronic paroxysmal hemicrania with posterior hypothalamic stimulation: technical case report. Neurosurgery. 2009;65:E997–E997. doi: 10.1227/01.NEU.0000345937.05186.73. [DOI] [PubMed] [Google Scholar]
  • 67.May A, Leone M, Boecker H, Sprenger T, Juergens T, Bussone G, et al. Hypothalamic deep brain stimulation in positron emission tomography. J Neurosci. 2006;26:3589–3593. doi: 10.1523/JNEUROSCI.4609-05.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Leone M, Bussone G. Pathophysiology of trigeminal autonomic cephalalgias. Lancet Neurol. 2009;8:755–764. doi: 10.1016/S1474-4422(09)70133-4. [DOI] [PubMed] [Google Scholar]

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