Abstract
The hallmark of primary headaches belonging to the group known as the trigeminal autonomic cephalalgias is unilateral headache accompanied by cranial autonomic symptoms. Being relatively rare and poorly understood, they represent a clinical challenge, leading to underdiagnosis and undertreatment. While the headache is the most obvious and disabling symptom, it is only part of a complex symptomatology which hints at the involved pathophysiological mechanisms. Activation of the trigeminal-autonomic reflex results in the aforementioned cranial autonomic symptoms, which are well understood; however, it is obvious that this brainstem reflex is regulated by higher centers that seemingly play a pivotal role in the attacks and the wide range of other symptoms indicating a homeostatic disturbance. These symptoms, as well as a number of well-validated findings, implicate the hypothalamus in the pathophysiology. over the course of the past 2–3 decades, novel therapies and technological advances have helped increase our knowledge of these clinical syndromes, and will likely continue to do so in the coming years as we witness the arrival of new drugs and neurostimulation options. In this review, the clinical presentation for cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing, and hemicrania continua is covered, along with our current understanding of the common pathophysiology and clinical manifestations.
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References
Headache Classification Committee of the International Headache Society (IHS) (2013) The international classification of headache disorders, 3rd edition (beta version). Cephalalgia 33:629–808. doi:10.1177/0333102413485658
Jensen RM, Lyngberg A, Jensen RH (2007) Burden of cluster headache. Cephalalgia 27:535–541. doi:10.1111/j.1468-2982.2007.01330.x
Fischera M, Marziniak M, Gralow I, Evers S (2008) The incidence and prevalence of cluster headache: a meta-analysis of population-based studies. Cephalalgia 28:614–618. doi:10.1111/j.1468-2982.2008.01592.x
Lund N, Barloese M, Petersen A et al (2017) Chronobiology differs between men and women with cluster headache, clinical phenotype does not. Neurology. doi:10.1212/WNL.0000000000003715
Rozen TD, Fishman RS (2011) Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden*. Headache 52:99–113. doi:10.1111/j.1526-4610.2011.02028.x
Irimia P, Cittadini E, Paemeleire K et al (2008) Unilateral photophobia or phonophobia in migraine compared with trigeminal autonomic cephalalgias. Cephalalgia 28:626–630. doi:10.1111/j.1468-2982.2008.01565.x
Kudrow L (1987) The cyclic relationship of natural illumination to cluster period frequency. Cephalalgia 7(Suppl 6):76–78
Barloese M, Lund N, Petersen A et al (2015) Sleep and chronobiology in cluster headache. Cephalalgia 35:969–978. doi:10.1177/0333102414564892
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 13:1066–1077. doi:10.1111/j.1468-1331.2006.01566.x
Jürgens TP, Schulte LH, May A (2013) Oxygen treatment is effective in migraine with autonomic symptoms. Cephalalgia 33:65–67. doi:10.1177/0333102412465206
Cipriani A, Saunders K, Attenburrow M-J et al (2016) A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development. Mol Psychiatry 21:1324–1332. doi:10.1038/mp.2016.86
Maihöfner C, Speck V, Sperling W, Giede-Jeppe A (2013) Complete remission of SUNCT syndrome by intravenous glucocorticoid treatment. Neurol Sci 34:1811–1812. doi:10.1007/s10072-012-1282-8
Jarrar RG, Black DF, Dodick DW, Davis DH (2003) Outcome of trigeminal nerve section in the treatment of chronic cluster headache. Neurology 60:1360–1362
Láinez MJ, Guillamón E (2017) Cluster headache and other TACs: pathophysiology and neurostimulation options. Headache 57:327–335. doi:10.1111/head.12874
Antonaci F, Sjaastad O (1989) Chronic paroxysmal hemicrania (CPH): a review of the clinical manifestations. Headache 29:648–656
Summ O, Evers S (2013) Mechanism of action of indomethacin in indomethacin-responsive headaches. Curr Pain Headache Rep 17:327. doi:10.1007/s11916-013-0327-x
Cittadini E, Matharu MS, Goadsby PJ (2008) Paroxysmal hemicrania: a prospective clinical study of 31 cases. Brain 131:1142–1155. doi:10.1093/brain/awn010
Goadsby PJ (2005) Trigeminal autonomic cephalalgias: fancy term or constructive change to the IHS classification? J Neurol Neurosurg Psychiatry 76:301–305. doi:10.1136/jnnp.2004.036012
Afridi SK, Shields KG, Bhola R, Goadsby PJ (2006) Greater occipital nerve injection in primary headache syndromes—prolonged effects from a single injection. Pain 122:126–129. doi:10.1016/j.pain.2006.01.016
Williams MH, Broadley SA (2008) SUNCT and SUNA: clinical features and medical treatment. J Clin Neurosci 15:526–534. doi:10.1016/j.jocn.2006.09.006
Cohen AS, Matharu MS, Goadsby PJ (2006) 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 129:2746–2760. doi:10.1093/brain/awl202
Matharu MS, Cohen AS, Boes CJ, Goadsby PJ (2003) Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing syndrome: a review. Curr Pain Headache Rep 7:308–318
Favoni V, Grimaldi D, Pierangeli G et al (2013) SUNCT/SUNA and neurovascular compression: new cases and critical literature review. Cephalalgia 33:1337–1348. doi:10.1177/0333102413494273
Benoliel R, Sharav Y (1998) Trigeminal neuralgia with lacrimation or SUNCT syndrome? Cephalalgia 18:85–90. doi:10.1046/j.1468-2982.1998.1802085.x
Simms HN, Honey CR (2011) The importance of autonomic symptoms in trigeminal neuralgia. Clinical article. J Neurosurg 115:210–216. doi:10.3171/2011.4.JNS101843
Spierings ELH (2013) Hemicrania Continua should not be classified as a trigeminal autonomic cephalalgia. Headache J Head Face Pain 53:869–870. doi:10.1111/head.12093
Tepper D (2015) Hemicrania continua. Headache J Head Face Pain 55:919–920. doi:10.1111/head.12598
Bovim G, Jenssen G, Ericson K (1992) Orbital phlebography: a comparison between cluster headache and other headaches. Headache 32:408–412
May A, Büchel C, Turner R, Goadsby PJ (2001) Magnetic resonance angiography in facial and other pain: neurovascular mechanisms of trigeminal sensation. J Cereb Blood Flow Metab 21:1171–1176. doi:10.1097/00004647-200110000-00005
Torelli P, Cologno D, Cademartiri C, Manzoni GC (2001) Application of the International Headache Society classification criteria in 652 cluster headache patients. Cephalalgia 21:145–150. doi:10.1046/j.1468-2982.2001.00185.x
Leone M, Bussone G (2009) Pathophysiology of trigeminal autonomic cephalalgias. Lancet Neurol 8:755–764. doi:10.1016/S1474-4422(09)70133-4
May A, Bahra A, Büchel C et al (1998) Hypothalamic activation in cluster headache attacks. Lancet 352:275–278. doi:10.1016/S0140-6736(98)02470-2
Frese A, Evers S, May A (2003) Autonomic activation in experimental trigeminal pain. Cephalalgia 23:67–68. doi:10.1046/j.1468-2982.2003.00462.x
Obermann M, Yoon M-S, Dommes P et al (2007) Prevalence of trigeminal autonomic symptoms in migraine: a population-based study. Cephalalgia 27:504–509. doi:10.1111/j.1468-2982.2007.01316.x
May A, Goadsby PJ (1999) The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab 19:115–127. doi:10.1097/00004647-199902000-00001
Goadsby PJ, Edvinsson L (1996) Neuropeptide changes in a case of chronic paroxysmal hemicrania—evidence for trigemino-parasympathetic activation. Cephalalgia 16:448–450
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(Pt 3):427–434
Akerman S, Holland PR, Lasalandra MP, Goadsby PJ (2009) Oxygen inhibits neuronal activation in the trigeminocervical complex after stimulation of trigeminal autonomic reflex, but not during direct dural activation of trigeminal afferents. Headache 49:1131–1143. doi:10.1111/j.1526-4610.2009.01501.x
Bartsch T, Knight YE, Goadsby PJ (2004) Activation of 5-HT(1B/1D) receptor in the periaqueductal gray inhibits nociception. Ann Neurol 56:371–381. doi:10.1002/ana.20193
Edvinsson L, Uddman R (2005) Neurobiology in primary headaches. Brain Res Brain Res Rev 48:438–456. doi:10.1016/j.brainresrev.2004.09.007
Bratbak DF, Nordgård S, Stovner LJ et al (2016) Pilot study of sphenopalatine injection of onabotulinumtoxinA for the treatment of intractable chronic cluster headache. Cephalalgia 36:503–509. doi:10.1177/0333102415597891
Jürgens TP, Barloese M, May A et al (2017) Long-term effectiveness of sphenopalatine ganglion stimulation for cluster headache. Cephalalgia 37:423–434. doi:10.1177/0333102416649092
Edvinsson L (2015) CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment. Br J Clin Pharmacol 80:193–199. doi:10.1111/bcp.12618
Barbanti P, Aurilia C, Egeo G et al (2017) Serotonin receptor targeted therapy for migraine treatment: an overview of drugs in phase I and II clinical development. Expert Opin Investig Drugs 26:269–277. doi:10.1080/13543784.2017.1283404
Sun H, Dodick DW, Silberstein S et al (2016) Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 15:382–390. doi:10.1016/S1474-4422(16)00019-3
Vollesen ALH, Ashina M (2017) PACAP38: emerging drug target in migraine and cluster headache. Headache J Head Face Pain 57:56–63. doi:10.1111/head.13076
Leone M, Rigamonti A, Bussone G (2002) Cluster headache sine headache: two new cases in one family. Cephalalgia 22:12–14
Pareja JA (1995) Chronic paroxysmal hemicrania: dissociation of the pain and autonomic features. Headache 35:111–113
Lodi R, Pierangeli G, Tonon C et al (2006) Study of hypothalamic metabolism in cluster headache by proton MR spectroscopy. Neurology 66:1264–1266. doi:10.1212/01.wnl.0000208442.07548.71
Wang S-J, Lirng J-F, Fuh J-L, Chen J-J (2006) Reduction in hypothalamic 1H-MRS metabolite ratios in patients with cluster headache. J Neurol Neurosurg Psychiatry 77:622–625. doi:10.1136/jnnp.2005.081836
May A, Ashburner J, Büchel C et al (1999) Correlation between structural and functional changes in brain in an idiopathic headache syndrome. Nat Med 5:836–838. doi:10.1038/10561
Sprenger T, Willoch F, Miederer M et al (2006) Opioidergic changes in the pineal gland and hypothalamus in cluster headache: a ligand PET study. Neurology 66:1108–1110. doi:10.1212/01.wnl.0000204225.15947.f8
Matharu MS, Cohen AS, Frackowiak RSJ, Goadsby PJ (2006) Posterior hypothalamic activation in paroxysmal hemicrania. Ann Neurol 59:535–545. doi:10.1002/ana.20763
May A, Bahra A, Büchel C et al (1999) Functional magnetic resonance imaging in spontaneous attacks of SUNCT: short-lasting neuralgiform headache with conjunctival injection and tearing. Ann Neurol 46:791–794
Sprenger T, Valet M, Platzer S et al (2005) SUNCT: bilateral hypothalamic activation during headache attacks and resolving of symptoms after trigeminal decompression. Pain 113:422–426. doi:10.1016/j.pain.2004.09.021
Matharu MS, Cohen AS, McGonigle DJ et al (2004) Posterior hypothalamic and brainstem activation in hemicrania continua. Headache 44:747–761. doi:10.1111/j.1526-4610.2004.04141.x
Holland P, Goadsby PJ (2007) The hypothalamic orexinergic system: pain and primary headaches. Headache 47:951–962. doi:10.1111/j.1526-4610.2007.00842.x
Bartsch T, Levy MJ, Knight YE, Goadsby PJ (2004) Differential modulation of nociceptive dural input to [hypocretin] orexin A and B receptor activation in the posterior hypothalamic area. Pain 109:367–378. doi:10.1016/j.pain.2004.02.005
Barloese M, Jennum P, Lund N et al (2014) Reduced CSF hypocretin-1 levels are associated with cluster headache. Cephalalgia. doi:10.1177/0333102414562971
Weller CM, Wilbrink LA, Houwing-Duistermaat JJ et al (2014) Cluster headache and the hypocretin receptor 2 reconsidered: a genetic association study and meta-analysis. Cephalalgia. doi:10.1177/0333102414557839
Sakurai T (2007) The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 8:171–181. doi:10.1038/nrn2092
Barloese MCJ (2015) Neurobiology and sleep disorders in cluster headache. J Headache Pain 16:562. doi:10.1186/s10194-015-0562-0
Chabi A, Zhang Y, Jackson S et al (2015) Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis. Cephalalgia 35:379–388. doi:10.1177/0333102414544979
Leone M, Franzini A, Cecchini AP et al (2010) Deep brain stimulation in trigeminal autonomic cephalalgias. Neurotherapeutics 7:220–228. doi:10.1016/j.nurt.2010.02.001
May A, Leone M, Boecker H et al (2006) Hypothalamic deep brain stimulation in positron emission tomography. J Neurosci Off J Soc Neurosci 26:3589–3593. doi:10.1523/JNEUROSCI.4609-05.2006
Stillman M, Spears R (2008) Endocrinology of cluster headache: potential for therapeutic manipulation. Curr Pain Headache Rep 12:138–144
Leone M, Lucini V, D’Amico D et al (1995) Twenty-four-hour melatonin and cortisol plasma levels in relation to timing of cluster headache. Cephalalgia 15:224–229
Barloese M, Jennum PJ, Lund NT, Jensen RH (2015) Sleep in cluster headache—beyond a temporal rapid eye movement relationship? Eur J Neurol 22:656-e40. doi:10.1111/ene.12623
Romiti A, Martelletti P, Gallo MF, Giacovazzo M (1983) Low plasma testosterone levels in cluster headache. Cephalalgia 3:41–44
Barloese M, Jennum P, Knudsen S, Jensen R (2012) Cluster headache and sleep, is there a connection? A review. Cephalalgia 32:481–491. doi:10.1177/0333102412441090
Dexter JD, Weitzman ED (1970) The relationship of nocturnal headaches to sleep stage patterns. Neurology 20:513–518
Terzaghi M, Ghiotto N, Sances G et al (2010) Episodic cluster headache: nREM prevalence of nocturnal attacks. Time to look beyond macrostructural analysis? Headache 50:1050–1054. doi:10.1111/j.1526-4610.2010.01658.x
Evers S, Barth B, Frese A et al (2014) Sleep apnea in patients with cluster headache: a case–control study. Cephalalgia 34:828–832. doi:10.1177/0333102414544038
Kayed K, Godtlibsen OB, Sjaastad O (1978) Chronic paroxysmal hemicrania IV: “REM sleep locked” nocturnal headache attacks. Sleep 1:91–95
Eulenburg A (1878) Lehrbuch der Nervenkrankheiten. Hirschwald, Berlin
Bruyn GW, Bootsma BK, Klawans HL (1976) Cluster headache and bradycardia. Headache 16:11–15
Erdinler I, Afsar N, Sanli A, Okmen E (2004) Asystole associated with cluster headache. Can J Cardiol 20:1369–1370
Ekbom K (1970) Heart rate, blood pressure, and electrocardiographic changes during provoked attacks of cluster headache. Acta Neurol Scand 46:215–224
Manzoni GC, Terzano MG, Moretti G, Cocchi M (1981) Clinical observations on 76 cluster headache cases. Eur Neurol 20:88–94
Russell D, Storstein L (1983) Cluster headache: a computerized analysis of 24 h Holter ECG recordings and description of ECG rhythm disturbances. Cephalalgia 3:83–107
Attanasio A, Capria A, Quatrana M et al (1990) Sinus bradycardia, junctional rhythm and blood pressure increase during repeated cluster headache attacks. Headache 30:509–510
Micieli G, Cavallini A, Bosone D et al (1993) Imbalance of heart rate regulation in cluster headache as based on continuous 24-h recordings. Clin Auton Res 3:291–298
Sacquegna T, Cortelli P, Amici R et al (1985) Cardiovascular changes in cluster headache. Headache 25:75–78
Boiardi A, Munari L, Milanesi I et al (1988) Impaired cardiovascular reflexes in cluster headache and migraine patients: evidence for an autonomic dysfunction. Headache 28:417–422
Boiardi A, Paggetta C, Milanesi I et al (1987) Cardiovascular reflex responses in cluster headache patients: basal autonomic alterations. Funct Neurol 2:569–574
Kruszewski P (1993) Respiratory sinus arrhythmia in cluster headache syndrome. Headache 33:98–104
Kruszewski P, Bordini C, Brubakk AO, Sjaastad O (1992) Cluster headache: alterations in heart rate, blood pressure and orthostatic responses during spontaneous attacks. Cephalalgia 12:172–177
Kruszewski P, Bordini C, Brubakk AO, Sjaastad O (1995) Cluster headache: cardiovascular responses to head-up tilt. Headache 35:465–469
De Marinis M, Strano S, Granata M et al (1995) Sympathetic-parasympathetic activation during spontaneous attacks of cluster headache: evaluation by spectral analysis of heart-rate fluctuations. Cephalalgia 15:504–510
Cortelli P, Guaraldi P, Leone M et al (2007) Effect of deep brain stimulation of the posterior hypothalamic area on the cardiovascular system in chronic cluster headache patients. Eur J Neurol 14:1008–1015. doi:10.1111/j.1468-1331.2007.01850.x
Barloese MCJ, Brinth L, Mehlsen J et al (2015) Blunted autonomic response in cluster headache patients. Cephalalgia. doi:10.1177/0333102415576724
Barloese MCJ, Mehlsen J, Brinth L et al (2015) Reduced baroreflex sensitivity in cluster headache patients. Headache J Head Face Pain 55:815–824. doi:10.1111/head.12586
Vetrugno R, Pierangeli G, Leone M et al (2007) Effect on sleep of posterior hypothalamus stimulation in cluster headache. Headache 47:1085–1090. doi:10.1111/j.1526-4610.2007.00864.x
Waldrop TG, Mullins DC, Henderson MC (1986) Effects of hypothalamic lesions on the cardiorespiratory responses to muscular contraction. Respir Physiol 66:215–224
Dun NJ, Le Dun S, Chen CT et al (2000) Orexins: a role in medullary sympathetic outflow. Regul Pept 96:65–70
Donadio V, Liguori R, Vandi S et al (2014) Lower wake resting sympathetic and cardiovascular activities in narcolepsy with cataplexy. Neurology 83:1080–1086. doi:10.1212/WNL.0000000000000793
Meyer EL, Waldenlind E, Marcus C (2003) Diminished nocturnal lipolysis in cluster headache: a sign of central sympathetic dysregulation? Neurology 61:1250–1254
Akerman S, Simon B, Romero-Reyes M (2017) Vagus nerve stimulation suppresses acute noxious activation of trigeminocervical neurons in animal models of primary headache. Neurobiol Dis 102:96–104. doi:10.1016/j.nbd.2017.03.004
Charleston L (2015) Do trigeminal autonomic cephalalgias represent primary diagnoses or points on a continuum? Curr Pain Headache Rep 19:22. doi:10.1007/s11916-015-0493-0
Newman LC (2015) Trigeminal autonomic cephalalgias. Contin Lifelong Learn Neurol 21:1041–1057. doi:10.1212/CON.0000000000000190
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The author has been a speaker and consultant for Autonomic Technologies, Inc. (ATI), for which he has received honoraria.
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Barloese, M.C.J. The pathophysiology of the trigeminal autonomic cephalalgias, with clinical implications. Clin Auton Res 28, 315–324 (2018). https://doi.org/10.1007/s10286-017-0468-9
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DOI: https://doi.org/10.1007/s10286-017-0468-9