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Hypothalamic involvement and activation in cluster headache

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Abstract

Cluster headache is an episodic form of primary neurovascular headache that is both severe and relatively rare. It is characterized by episodes of headache with cranial parasympathetic activation and sympathetic impairment that come in bouts, or clusters. Its pathophysiology can be divided into understanding the attack phenotype and the biotype of the periodicity. Acute attacks of cluster headache are marked by trigeminal nerve-mediated pain and with cranial autonomic activation, trigeminal-autonomic cephalalgia; an activation that characterizes the phenotype of a group of headaches. The signature feature of cluster headache is its periodicity, the daily cycle of attacks when the patient is in an active bout, or the circumannual, or other period, cycling that distinguishes the on period from the off period.

Functional brain imaging with positron emission tomography and structural imaging with voxel-based morphometry have identified an area in the posterior hypothalamic gray as key in understanding cluster headache. This area is subtly enlarged in its gray matter volume, active during an acute cluster headache but inactive when patients are challenged between bouts. Cluster headache is likely to be a form of primary neurovascular pain whose phenotypic expression relies on the trigeminal-autonomic reflex, with a biotype determined by the brain area, the posterior hypothalamus, in which the lesion seems to be located. Understanding both the phenotypic expression and the biotype will, respectively, enable better acute attack treatments and better preventative management of this horrible form of headache.

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References and Recommended Reading

  1. eadache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988, 8:1–96.

    Article  Google Scholar 

  2. Sjaastad O, ed: Major Problems in Neurology, vol 23. Cluster Headache Syndrome. London: W.B. Saunders Company; 1992.

    Google Scholar 

  3. D’Alessandro R, Gamberini G, Benassi G, et al.: Cluster headache in the Republic of San Marino. Cephalalgia 1986, 6:159–162.

    Article  PubMed  CAS  Google Scholar 

  4. Ekbom K, Ahlborg B, Schele R: Prevalence of migraine and cluster headache in Swedish men of 18. Headache 1978, 18:9–19.

    Article  PubMed  CAS  Google Scholar 

  5. Bahra A, May A, Goadsby P: Diagnostic Patterns in Cluster Headache. Edited by Olesen J, Goadsby P. New York: Oxford University Press; 1999:61–65.

    Google Scholar 

  6. Kunkle EC, Pfieffer J, Wilhoit WM, Hamrick J: Recurrent brief headache in cluster pattern. Trans Am Neurol Assoc 1952, 27:240–243.

    Google Scholar 

  7. Ekbom K: Nitroglycerin as a provocative agent in cluster headache. Arch Neurol 1968, 19:487–493.

    PubMed  CAS  Google Scholar 

  8. Chazot G, Claustrat B, Brun J, et al.: A chronobiological study of melatonin, cortisol, growth hormone and prolactin secretion in cluster headache. Cephalalgia 1984, 4:213–220.

    Article  PubMed  CAS  Google Scholar 

  9. Ferrari E, Canepari C, Bossolo PA, et al.: Changes of biological rhythms in primary headache syndromes. Cephalalgia 1983, 3:58–68.

    PubMed  Google Scholar 

  10. Strittmatter M, Hamann GF, Grauer 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 1996, 7:1229–1234.

    Article  PubMed  CAS  Google Scholar 

  11. Ekbom K: Patterns of cluster headache with a note on the relations to angina pectoris and peptide ulcer. Acta Neurol Scand 1970, 46:225–237.

    PubMed  CAS  Google Scholar 

  12. Isler H: Episodic cluster headache from a textbook of 1745: Van Swieten’s classic description. Cephalalgia 1993, 13:172–174.

    Article  PubMed  CAS  Google Scholar 

  13. Kudrow L: Cluster Headache, Mechanism and Management. New York: Oxford University Press; 1980.

    Google Scholar 

  14. Horton B: The use of histamine in the treatment of specific types of headaches. J Am Med Assoc 1941, 116:377–383.

    Google Scholar 

  15. Fanciullacci M, Alessandri M, Figini M, et al.: Increases in plasma calcitonin gene-related peptide from extracerebral circulation during nitroglycerin-induced cluster headache attack. Pain 1995, 60:119–123.

    Article  PubMed  CAS  Google Scholar 

  16. Goadsby PJ, Edvinsson L: Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain 1994, 117:427–434.

    Article  PubMed  Google Scholar 

  17. Ekbom K, Greitz T: Carotid angiography in cluster headache. Acta Radiol Diagn (Stockh) 1970, 10:177–186.

    CAS  Google Scholar 

  18. Waldenlind E, Ekbom K, Torhall J: MR-angiography during spontaneous attacks of cluster headache: a case report. Headache 1993, 33:291–295.

    Article  PubMed  CAS  Google Scholar 

  19. den BoerMO, Heiligers JP, Saxena PR: Carotid vascular effects of ergotamine and dihydroergotamine in the pig: no exclusive mediation via 5-HT1-like receptors. Br J Pharmacol 1991, 104:183–189.

    Google Scholar 

  20. Le GrandB, Vie B, John GW: Effects of sumatriptan on coronary flow and left ventricular function in the isolated perfused guinea pig heart. J Cardiovasc Pharmacol 1998, 32:435–442.

    Article  PubMed  Google Scholar 

  21. Goadsby PJ, Lance JW: Brainstem effects on intra- and extracerebral circulations. Relation to migraine and cluster headache. In Basic Mechanisms of Headache. Edited by Olesen J, Olesen EL. Amsterdam: Elsevier Science Publishers; 1988:413–427.

    Google Scholar 

  22. May A, Goadsby PJ: The trigeminovascular system in humans: pathophysiological implications for primary headache syndromes of the neural influences of the cerebral circulation. J Cereb Blood Flow Metab 1999, 19:115–127.

    Article  PubMed  CAS  Google Scholar 

  23. Kudrow L: The cyclic relationship of natural illumination to cluster period frequency. Cephalalgia 1987, 7:76–78.

    Article  PubMed  Google Scholar 

  24. Kudrow L: Changes of testosterone levels in the cluster headache syndrome. Preliminary study. Minerva Med 1976, 67:1850–1853.

    PubMed  CAS  Google Scholar 

  25. Leone M, Patruno G, Vescovi A, Bussone G: Neuroendocrine dysfunction in cluster headache. Cephalalgia 1990, 10:235–239.

    Article  PubMed  CAS  Google Scholar 

  26. Nelson RF: Testosterone levels in cluster and non-cluster migrainous patients. Headache 1978, 18:265–267.

    Article  PubMed  CAS  Google Scholar 

  27. Waldenlind E, Gustafsson SA, Ekbom K, Wetterberg L: Circadian secretion of cortisol and melatonin in cluster headache during active cluster periods and remission. J Neurol Neurosurg Psychiatry 1987, 50:207–213.

    PubMed  CAS  Google Scholar 

  28. Couturier EG, Hering R, Steiner TJ: The first report of cluster headache in identical twins. Neurology 1991, 41:761.

    PubMed  CAS  Google Scholar 

  29. Sorensen SA, Araki S: Genetics. In The Headaches. Edited by Olesen J et al. New York: Raven Press; 1993:21–27.

    Google Scholar 

  30. Sjaastad O, Shen JM, Stovner LJ, Elsas T: Cluster headache in identical twins. Headache 1993, 33:214–217.

    Article  PubMed  CAS  Google Scholar 

  31. D’Amico D, Leone M, Moschiano F, Bussone G: Familial cluster headache: report of three families. Headache 1996, 36:41–43.

    Article  PubMed  CAS  Google Scholar 

  32. Russell MB, Andersson PG, Thomsen LL, Iselius L: Cluster headache is an autosomal dominantly inherited disorder in some families: a complex segregation analysis. J Med Genet 1995, 32:954–956.

    PubMed  CAS  Google Scholar 

  33. D’Amico D, Centonze V, Grazzi L, et al.: Coexistence of migraine and cluster headache: report of 10 cases and possible pathogenetic implications. Headache 1997, 37:21–25.

    Article  PubMed  CAS  Google Scholar 

  34. Seibel P, Grunewald T, Gendolla A, et al.: Investigation on the mitochondrial transfer RNA(Leu)(UUR) in blood cells from patients with cluster headache. J Neurol 1996, 243:305–307.

    Article  PubMed  CAS  Google Scholar 

  35. Shimomura T, Kitano A, Marukawa H, et al.: Point mutation in platelet mitochondrial tRNA(Leu(UUR)) in patient with cluster headache. Lancet 1994, 344:625.

    Article  PubMed  CAS  Google Scholar 

  36. Henry PY, Vernhiet J, Orgogozo JM, Caille JM: Cerebral blood flow in migraine and cluster headache. Compartmental analysis and reactivity to anaesthetic depression. Res Clin Stud Headache 1978, 6:81–88.

    PubMed  CAS  Google Scholar 

  37. Krabbe AA, Henriksen L, Olesen J: Tomographic determination of cerebral blood flow during attacks of cluster headache. Cephalalgia 1984, 4:17–23.

    Article  PubMed  CAS  Google Scholar 

  38. Nelson RF, du BoulayGH, Marshall J, et al.: Cerebral blood flow studies in patients with cluster headache. Headache 1980, 20:184–189.

    Article  PubMed  CAS  Google Scholar 

  39. Norris JW, Hachinski VC, Cooper PW: Cerebral blood flow changes in cluster headache. Acta Neurol Scand 1976, 54:371–374.

    PubMed  CAS  Google Scholar 

  40. Sakai F, Meyer JS, Ishihara N, et al.: Noninvasive 133XE inhalation measurements of regional cerebral blood flow in migraine and related headaches. Acta Neurol Scand Suppl 1977, 64:196–197.

    PubMed  CAS  Google Scholar 

  41. Afra J, Ertsey C, Jelencsik H, et al.: SPECT and TCD studies in cluster headache patients. Funct Neurol 1995, 10:259–264.

    PubMed  CAS  Google Scholar 

  42. Dahl A, Russell D, Nyberg HR, Rootwelt K: Cluster headache: transcranial Doppler ultrasound and rCBF studies. Cephalalgia 1990, 10:87–94.

    Article  PubMed  CAS  Google Scholar 

  43. Hering R, Couturier EGM, Davies PTG, Steiner TJ: 99mTCHMPAO study during cluster headache period and in acute cluster attacks. In Migraine and Other Headaches. Edited by Olesen J. New York: Raven Press; 1991:297–299.

    Google Scholar 

  44. Kobari M, Meyer JS, Ichijo M, Kawamura J: Cortical and subcortical hyperperfusion during migraine and cluster headache measured by Xe CT-CBF. Neuroradiology 1990, 32:4–11.

    Article  PubMed  CAS  Google Scholar 

  45. McHenry PY, Vernhiet J, Orgogozo JM, Caille JM: Cerebral blood flow in migraine and cluster headache. Res Clin Stud Headache 1978, 6:81–88.

    Google Scholar 

  46. Sakai F, Meyer JS: Regional cerebral hemodynamics during migraine and cluster headaches measured by the 133Xe inhalation method. Headache 1978, 18:122–132.

    Article  PubMed  CAS  Google Scholar 

  47. Schlake HP, Bottger IG, Grotemeyer KH, et al.: Single photon emission computed tomography with technetium-99m hexamethyl propylenamino oxime in the pain-free interval of migraine and cluster headache. Eur Neurol 1990, 30:153–156.

    PubMed  CAS  Google Scholar 

  48. Wesseling P, Suess E, Koch G, et al.: SPECT (99M)TC-HMPAO findings in acute headache and during symptom free interval. Cephalalgia 1989, 9:62–63.

    Google Scholar 

  49. Di Piero V, Fiacco F, Tombari D, Pantano P: Tonic pain: a SPET study in normal subjects and cluster headache patients. Pain 1997, 70:185–191.

    Article  Google Scholar 

  50. Fox PT, Mintun MA: Noninvasive functional brain mapping by change-distribution analysis of averaged PET images of H215O tissue activity. J Nucl Med 1989, 30:141–149.

    PubMed  CAS  Google Scholar 

  51. Frackowiak RS, Friston KJ: Functional neuroanatomy of the human brain: positron emission tomography-a new neuroanatomical technique. J Anat 1994, 184:211–225.

    PubMed  Google Scholar 

  52. Hsieh JC, Hannerz J, Ingvar M: Right-lateralised central processing for pain of nitroglycerin-induced cluster headache. Pain 1996, 67:59–68.

    Article  PubMed  CAS  Google Scholar 

  53. Hsieh JC, Belfrage M, Stone ES, et al.: Central representation of chronic ongoing neuropathic pain studied by positron emission tomography. Pain 1995, 63:225–236.

    Article  PubMed  CAS  Google Scholar 

  54. May A, Kaube H, Büchel C, et al.: Experimental cranial pain elicited by capsaicin: a PET-study. Pain 1998, 74:61–66. Using a PET study, it was shown that in migraine without aura certain areas in the brain stem were activated during the headache state, but not in the headache-free interval. It was suggested that this brain stem activation is inherent to the migraine attack itself and represents the so-called "migraine generator." The results suggested that this structure is more likely to be involved in trigeminal-transmitted pain.

    Article  PubMed  CAS  Google Scholar 

  55. May A, Bahra A, Büchel C, et al.: PET and MRA findings in cluster headache and MRA in experimental pain. Neurology 2000, in press.

  56. Weiller C, May A, Limmroth V, et al.: Brain stem activation in spontaneous human migraine attacks. Nat Med 1995, 1:658–660.

    Article  PubMed  CAS  Google Scholar 

  57. Derbyshire SW, Jones AK, Devani P, et al.: Cerebral responses to pain in patients with atypical facial pain measured by positron emission tomography. J Neurol Neurosurg Psychiatry 1994, 57:1166–1172.

    Article  PubMed  CAS  Google Scholar 

  58. May A, Bahra A, Büchel C, et al.: Hypothalamic activation in cluster headache attacks. Lancet 1998, 352:275–278. These findings establish central nervous system dysfunction in the region of the hypothalamus as the primum movens in the pathophysiology of cluster headace. The authors suggest that a radical reappraisal of this type of headache is needed and that it should, in general terms, be regarded as a neurovascular headache, to give equal weight to the pathologic and physiologic mechanisms that are at work.

    Article  PubMed  CAS  Google Scholar 

  59. Andersson JL, Muhr C, Lilja A: Regional cerebral blood flow and oxygen metabolism during migraine with and without aura. Cephalalgia 1997, 17:570–579.

    Article  PubMed  CAS  Google Scholar 

  60. Chabriat H, Tehindrazanarivelo A, Vera P, et al.: 5HT2 receptors in cerebral cortex of migraineurs studied using PET and 18Ffluorosetoperone. Cephalalgia 1995, 15:104–108.

    Article  PubMed  CAS  Google Scholar 

  61. Sachs H, Wolf A, Russell JA, Christman DR: Effect of reserpine on regional cerebral glucose metabolism in control and migraine subjects. Arch Neurol 1986, 43:1117–1123.

    PubMed  CAS  Google Scholar 

  62. Casey KL, Minoshima S, Berger KL, et al.: Positron emission tomographic analysis of cerebral structures activated specifically by repetitive noxious heat stimuli. J Neurophysiol 1994, 71:802–807.

    PubMed  CAS  Google Scholar 

  63. Jones AK, Friston K, Frackowiak RS: Localization of responses to pain in human cerebral cortex. Science 1992, 255:215–216.

    Article  PubMed  CAS  Google Scholar 

  64. Rosen SD, Paulesu E, Frith CD, et al.: Central nervous pathways mediating angina pectoris. Lancet 1994, 344:147–150.

    Article  PubMed  CAS  Google Scholar 

  65. Coghill RC, Talbot JD, Evans AC, et al.: Distributed processing of pain and vibration by the human brain. J Neurosci 1994, 14:4095–4108.

    PubMed  CAS  Google Scholar 

  66. Minoshima S, Morrow TJ, Koeppe RA, Casey KL: Involvement of the insular cortex in central autonomic regulation during painful thermal stimulation. J Cereb Blood Flow Metabol 1995, 15:859.

    Google Scholar 

  67. Hsieh JC, Stahle BM, Hagermark O, et al.: Traumatic nociceptive pain activates the hypothalamus and the periaqueductal gray: a positron emission tomography study. Pain 1996, 64:303–314.

    Article  PubMed  CAS  Google Scholar 

  68. Burton H, Videen TO, Raichle ME: Tactile vibration activated foci in insular and parietal opercular cortex studied with positron emission tomography. Somatosens Mot Res 1993, 3:297–308.

    Article  Google Scholar 

  69. Mesulam MM, Mufson EF: The Insula of Reil in Man and Monkey. Architectonics, Connectivity and Function. In Cerebral Cortex. Edited by Peters A, Jones EG. New York: Plenum Press; 1985:179–226.

    Google Scholar 

  70. Goadsby PJ, Zagami AS, Lambert GA: Neural processing of craniovascular pain: a synthesis of the central structures involved in migraine. Headache 1991, 31:365–371.

    Article  PubMed  CAS  Google Scholar 

  71. Goadsby PJ, Silberstein SD, eds: Headache. New York: Butterworth-Heinemann; 1997.

    Google Scholar 

  72. May A, Ashburner J, Büchel C, et al.: Correlation between structural and functional changes in brain in an idiopathic headache syndrome. Nat Med 1999, 5:836–838. The results indicate that the current view of the neurobiology of cluster headache requires a complete revision and that this periodic headache is associated with a previously unrecognized brain abnormality in the hypothalamic region. The authors believe that VBM has the potential to change in the most fundamental way our concept of primary headache disorders, requiring a radical reappraisal of the tenet of structural normality.

    Article  PubMed  CAS  Google Scholar 

  73. Evans, AC, Kamber M, Collins DL, Macdonald D: An MRIbased probabilistic atlas of neuroanatomy. In Magnetic Resonance Scanning and Epilepsy. Edited by Shorvon S et al. New York: Plenum Press; 1994:263–274.

    Google Scholar 

  74. Lance JW, Goadsby PJ: Mechanism and Management of Headache, edn 6. Oxford: Butterworth-Heinemann; 1998.

    Google Scholar 

  75. Moore RY: Circadian rhythms: basic neurobiology and clinical applications. Annu Rev Med 1997, 48:253–266.

    Article  PubMed  CAS  Google Scholar 

  76. Hardebo JE: How cluster headache is explained as an intracavernous inflammatory process lesioning sympathetic fibres. Headache 1994, 34:125–131.

    Article  PubMed  CAS  Google Scholar 

  77. Hannerz J, Ericson K, Bergstrand G: Orbital phlebography in patients with cluster headache. Cephalalgia 1987, 7:207–211.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  79. May A, Büchel C, Bahra A, et al.: Intra-cranial vessels in trigeminal transmitted pain: a PET study. Neuroimage 1999, 9:453–460.

    Article  PubMed  CAS  Google Scholar 

  80. Goadsby PJ, Duckworth JW: Effect of stimulation of trigeminal ganglion on regional cerebral blood flow in cats. Am J Physiol 1987, 253:270–274.

    Google Scholar 

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  1. Department of Neurology, University of Regensburg, Universitätsstrabe 84, 93053, Regensburg, Germany

    Arne May MD

  2. University Department of Clinical Neurology, Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, 1N 3BG, London, WC, UK

    Peter J. Goadsby MD, DSc

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May, A., Goadsby, P.J. Hypothalamic involvement and activation in cluster headache. Current Science Inc 5, 60–66 (2001). https://doi.org/10.1007/s11916-001-0011-4

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