Martelletti, Paolo

Mitsikostas, Dimos Dimitrios

Journal of Headache and Pain

English

PubMed

MARTELLETTI, Paolo

Archivio della ricerca- Università di Roma La Sapienza

Martelletti and Mitsikostas The Journal of Headacheand Pain  (2015) 16:59 DOI 10.1186/s10194-015-0545-1EDITORIAL Open AccessCluster headache: a quasi-rare disorderneeding a reappraisalPaolo Martelletti1 and Dimos-Dimitrios Mitsikostas2*Keywords: Cluster headache; Trigeminal autonomic cephalagias; Epidemiology; Burden; Pathophysiology;TreatmentThis Editorial introduces the 2015 Open Thematic Seriesdedicated to Cluster Headache (CH) and other RareHeadaches. For too long researchers have focused theirattention on other most popular, sometimes clumsy orfoggy forms of headache, overlooking this important andquasi-rare headache disorder [1].Apparently CH represents the most peculiar formamong the Trigeminal Autonomic Cephalalgias (TACs).The unbearable periorbital side-locked pain is coupledby ipsilateral cranial autonomic symptoms (conjunctivalinjection, lacrimation and rhinorrhea) and causes a vastdisability although the overall burden of this disease hasnot yet found a complete systematization.Especially its chronic form, characterized by more dayswith attacks than not in the year span, represents a strictminority (10 % of CH, 0,01 % overall) and hits 70.000 on asample of 100 millions of people. Even if these numbersare relatively small the impact of this disease is destruc-tive, thus CH represents a niche worth to be re-focused.Recently Chronic CH (CCH) refractory to whichevermedical therapy (rCCH) has been systematized from aclinical point of view [2].The personal burden caused by CH, meant as loss ofemployment, homebound days and disability is higher inwomen than in men [3].CH lifetime prevalence is 1/1000 and over the past de-cades a progressive reduction of the male/female ratiohas been reported, being now 2.1:1 [4]. Even if CH iseasy to diagnose on the basis of its peculiar features, thetiming over the day of the attacks (up to 8), a temporallydefined active cluster period (60–90 days) and its seasonal* Correspondence: dimosmitsikostas@me.com2Department of Neurology, Athens Naval Hospital, Athens, GreeceFull list of author information is available at the end of the article© 2015 Martelletti and Mitsikostas. This is an OAttribution License (http://creativecommons.orin any medium, provided the original work is precurrence, only 1/3 of these patients is rightly diagnosed,with an unacceptable delay of 5.3 years and consequentlymore than 2/3 of them never receive a correct treatment[1, 5, 6].Actually the current pathophysiological theory of CHis oriented towards a posterior hypothalamic dysfunction[7] but further pharmacological studies shall selectivelyfocus this area. Recently the allele G of the G1246AHCRTR2 polymorphism was been found to be associ-ated with CH, indicating that hypocretin/orexin system’speptides may be involved in the transmission of pain, inautonomic and neuroendocrine functions, and in thepathogenesis of CH [8, 9].For too many years sumatriptan, verapamil and corti-costeroids have been the cornerstones of CH treatment[1]; we hope that the starting era of monoclonal anti-bodies against Calcitonin Gene-Related Peptide mightinclude CH as therapeutic target. An ongoing phase 3RCT on the use of LY2951742 in episodic CH throughits preventative subcutaneous administration every 30 dayscould change the future management of CH [10].Other approaches to chronic cluster headache are thenew mini-invasive and non-invasive neuromodulation tech-niques. The European Headache Federation recommendscaution in using these techniques [11] because only fewcontrolled studies have been carried out yet.Among these new approaches, Vagal Nerve Stimuation(VNS) and sphenopalatine ganglion stimulation (SPG)seem promising but still classified at Class IV evidence[12, 13]; SPG shows contrasting evidence [14]. All theseapproaches need to be further confirmed and validatedby ad hoc RCTs.Lastly, patients’ education is another important topicto be re-considered: sleep pattern changes, alcoholicpen Access article distributed under the terms of the Creative Commonsg/licenses/by/4.0), which permits unrestricted use, distribution, and reproductionroperly credited.Martelletti and Mitsikostas The Journal of Headache and Pain  (2015) 16:59 Page 2 of 2beverages, NO-derived cardiovascular drugs and phospho-diesterase inhibitors widely self-prescribed for erectile dys-function trigger additional bouts during CH active phases[1]. Furthermore, a more diffuse physicians education onCH management should lead to an earlier diagnosis and amore adequate treatment of this headache disorder [15].Thus we trust that this Open Thematic Series dedicatedto Cluster Headache could thicken the attention on afamed and quasi-rare headache disorder.Author details1Department of Clinical and Molecular Medicine, Sapienza University, Rome,Italy. 2Department of Neurology, Athens Naval Hospital, Athens, Greece.Received: 15 June 2015 Accepted: 16 June 2015References1. Martelletti P. Pharmacotherapy of cluster headache and beyond. ExpertOpinion in Pharmacotherapy 2015; June 1:1–5 [Epub ahead of print]doi:10.1517/14656566.2015.10527412. Mitsikostas DD, Edvinsson L, Jensen RH et al (2014) Refractory chroniccluster headache: a consensus statement on clinical definition from theEuropean Headache Federation. J Headache Pain 15:793. Rozen TD, Fishman RS (2012) Female Cluster Headache in the United Statesof America: what are the gender differences? Results from the United StatesCluster Headache Survey. J Neurol Sci 317:17–284. Manzoni GC (1998) Gender ratio of cluster headache over the years: apossible role of changes in lifestyle. Cephalalgia 18(3):138–425. Voiticovschi-Iosob C, Allena M, De Cillis I et al (2014) Diagnostic andtherapeutic errors in cluster headache: a hospital-based study. J HeadachePain 15:56. doi:10.1186/1129-2377-15-566. Sánchez Del Rio M, Leira R, Pozo-Rosich P, Laínez JM, Alvarez R, Pascual J(2014) Errors in recognition and management are still frequent in patientswith cluster headache. Eur Neurol 72:209–127. Goadsby P (2012) Trigeminal autonomic cephalalgias. Continuum (MinneapMinn) 18:883–958. Rainero I, Rubino E, Valfrè W, Gallone S, De Martino P, Zampella E, Pinessi L(2007) Association between the G1246A polymorphism of the hypocretinreceptor 2 gene and cluster headache: a meta-analysis. J Headache Pain8:152–69. Rainero I, Gallone S, Valfrè W, Ferrero M, Angilella G, Rivoiro C, Rubino E, DeMartino P, Savi L, Ferrone M, Pinessi L (2004) A polymorphism of thehypocretin receptor 2 gene is associated with cluster headache. Neurology63:1286–810. ClinicalTrial.gov A study of LY2951742 in participants with episodic clusterheadache. Available at: https://clinicaltrial.gov/ct2/show/NCT02397473[Last accessed 15 June 2015].11. Martelletti P, Jensen RH, Antal A, Arcioni R, Brighina F, de Tommaso M,Franzini A, Fontaine D, Heiland M, Jürgens TP, Leone M, Magis D,Paemeleire K, Palmisani S, Paulus W, May A (2013) Neuromodulation ofchronic headaches: position statement from the European HeadacheFederation. J Headache Pain 14:8612. Nesbitt AD, Marin JC, Tompkins E et al (2015) Initial use of a novelnoninvasive vagus nerve stimulator for cluster headache treatment.Neurology 84:1249–5313. Pietzsch JB, Garner A, Gaul C, May A (2015) Cost-effectiveness of stimulationof the sphenopalatine ganglion (SPG) for the treatment of chronic clusterheadache: a model-based analysis based on the pathway CH-1 study.J Headache Pain 16:4814. Bendersky DC, Hem SM, Yampolsky CG (2015) Unsuccessful pulsedradiofrequency of the sphenopalatine ganglion in patients with chronic clusterheadache and subsequent successful thermocoagulation. Pain Pract 15:E40–515. Martelletti P, Mitsikostas DD, Lampl C, Katsarava Z, Osipova V, Paemeleire K,Edvinsson L, Siva A, Valade D, Steiner TJ, Jensen RH (2013) Framing educationon headache disorders into the Global Burden of Disease Study 2010. TheEuropean Headache Federation stands ready. 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Cluster headache: a quasi-rare disorder needing a reappraisal

Paolo Martelletti

Dimos-Dimitrios Mitsikostas

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Cluster headache: a quasi-rare disorder needing a reappraisal

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