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Efficacy and safety of surgical treatment of cluster headache
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Original article
Efficacy and safety of surgical treatment of cluster headache夽 Robert Belvis a,∗ , Rodrigo Rodríguez b , Marina Guasch a , María Jesús Álvarez b , Joan Molet b , Carles Roig a a b
Unidad de Cefaleas y Neuralgias, Servicio de Neurología, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Unidad de Neurocirugía Funcional, Servicio de Neurocirugía, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
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Article history: Received 21 January 2019 Accepted 7 March 2019 Available online xxx Keywords: Headache Cluster Radiofrequency Stimulation
a b s t r a c t Background and objectives: Cluster headache (CR) is the most severe human headache and is chronic in 10%–20% of patients, and 10% can become refractory to all effective drugs. In this scenario, surgical procedures are indicated: radiofrequencies of the sphenopalatine ganglion ipsilateral to pain (RF-SPG), bilateral stimulation of the occipital nerves (NOM-S) and deep brain stimulation (DBS) of the ipsilateral posterior hypothalamus. The efficacy and safety of each of these procedures has been specifically analyzed, but the progress of a series of patients following this surgical route in order of aggressiveness has not been described. Patients: Patients with chronic and refractory CR according to the criteria of the European Headache Federation. The patients underwent RF-SPG, NOM-S sequentially if the previous procedure had been ineffective, and DBS if the previous procedure had been ineffective. Results: We prospectively included 44 patients between November 2003 and June 2018 with an average age of 38.3 years; 70% were men. The mean follow-up was 87.4 months. Nineteen patients responded to 74 procedures of RF-SPG (33.3%). Of the remaining 25 patients, a NOM-S device was implanted in 22, showing an efficacy of 50%. Finally, 9 patients underwent ECP of the ipsilateral lower-posterior hypothalamus with an efficacy of 88.8%. No serious complications were found following any of these three procedures. Conclusions: The sequential application of these three surgical procedures succeeded in reversing the serious situation of chronic CR refractory to an episodic CR in 93% of patients with acceptable surgical morbidity. ˜ S.L.U. All rights reserved. © 2019 Elsevier Espana,
Eficacia y seguridad del tratamiento quirúrgico en la cefalea en racimos r e s u m e n Palabras clave: Cefalea Clúster Radiofrecuencia Estimulación
Antecedentes y objetivo: La cefalea en racimos (CR) es la cefalea humana más grave y se cronifica en un 10-20% de pacientes, pudiendo llegar a ser refractaria a todos los fármacos eficaces en un 10% de ellos. En este escenario se indican procedimientos quirúrgicos: radiofrecuencias del ganglio esfenopalatino ipsilateral al dolor (RF-GEFP), estimulación bilateral de los nervios occipitales (E-NOM) y estimulación cerebral profunda (ECP) del hipotálamo postero-inferior ipsilateral. Se ha analizado específicamente la eficacia y seguridad de cada uno de ellas, pero no se ha descrito la evolución de una serie de pacientes siguiendo este itinerario quirúrgico por orden de agresividad. Pacientes: Pacientes con CR crónica y refractaria según los criterios de la European Headache Federation. Fueron sometidos secuencialmente a RF-GEFP, E-NOM si ineficacia del anterior y ECP si ineficacia del anterior. Resultados: Incluimos prospectivamente 44 pacientes entre Noviembre de 2003 y Junio de 2018 con una ˜ siendo el 70% hombres. El seguimiento medio fue de 87.4 meses. Respondieron edad media de 38,3 anos a 74 procedimientos de RF-GEFP 19 pacientes (33.3%). De los 25 restantes, se implantó un dispositivo de E-NOM en 22 de ellos, mostrando una eficacia del 50%. Finalmente, se sometieron a ECP del hipotálamo postero-inferior ipsilateral 9 pacientes con una eficacia del 88.8%. No se constataron complicaciones graves en ninguno de los tres procedimientos.
夽 Please cite this article as: Belvis R, Rodríguez R, Guasch M, Álvarez MJ, Molet J, Roig C. Eficacia y seguridad del tratamiento quirúrgico en la cefalea en racimos. Med Clin (Barc). 2019. https://doi.org/10.1016/j.medcli.2019.03.023 ∗ Corresponding author. E-mail address: [email protected] (R. Belvis). ˜ S.L.U. All rights reserved. 2387-0206/© 2019 Elsevier Espana,
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Conclusiones: La aplicación secuencial de los tres procedimientos quirúrgicos logró revertir la grave situación de CR crónica y refractaria a CR episódica en el 93% de los pacientes con una morbilidad quirúrgica aceptable. ˜ S.L.U. Todos los derechos reservados. © 2019 Elsevier Espana,
Introduction Cluster headache (CH), is the most severe headache that humans can experience. It affects one in every thousand people,1 predominantly men 3–7: 12 and starts around the age of 20–30.3,4 CH is a primary headache in the group of trigeminal-autonomic headaches distinguished by the occurrence of autonomic signs in the territory of the first branch of the trigeminal nerve in 97% of patients.4–6 Its pathophysiology is unknown but the trigeminovascular system and the peripheral autonomic nervous system are clearly involved; and the central hypothalamus.5 The pain affects the eye, orbit and temporal area and is of severe/very severe intensity, so the patient shows significant restlessness and/or agitation. It usually lasts between 15 min and 3 h and the most common autonomic signs, all ipsilateral to pain, are: myosis, conjunctival injection, blepharoptosis, rhinorrhoea and tearing.4,6 However, although cases of CH have been known since the XVII7 century and that its clinical symptomatology is extraordinary, its diagnostic delay is excessively high (from 3 to 11 years) because it is often diagnosed as migraine, sinusitis, dental, ophthalmological, psychiatric pathology.8 It is accompanied by depression in 60% of cases9 and suicidal ideation occurs in 55%, reaching the attempt stage in 2%.10 Smoking has also been associated in 70–90% of patients11 and 31% use addictive drugs.12 CH occurs episodically in 80–90% of cases and may be seasonal, usually evening/night. However, 10–20% of cases are chronic,4,6,13 understanding as such those in which there are no remissions in a year, or a remission of less than one month.6 Of these, 10% will be refractory (rCCH) to preventive drugs13,14 : verapamil, corticosteroids, lithium, topiramate and valproic acid; as well as botulinum toxin A or anaesthetic occipital nerve blocks. Surgical procedures are indicated in patients with rCCH. Traditionally, radiofrequencies (RF), chemical neurolysis, cryosurgery, microvascular decompression, neurectomy, stereotactic radiosurgery have been performed, using the trigeminal nerve, the petrosal nerves, the Gasser ganglion or the sphenopalatine ganglion (SPG) as targets.15 Nowadays, only ipsilateral-to-pain RF on SPG (RF-SPG) remains. This is due to the fact that non-invasive surgical neurostimulation techniques began to be used at the beginning of the millennium, with bilateral greater occipital nerve stimulation (GONS) and hypothalamus stimulation as treatment options through deep brain stimulation (DBS). Usually, ipsilateral-to-pain RF-SPG is the procedure of choice due to its minimally invasive nature, followed by bilateral GONS with hypothalamic DBS. We report our experience of 15 years of surgical procedures performed in consecutive patients with rCCH.
Patients and methods Functional neurosurgery was implemented in our center in the year 1998 in Parkinson’s disease, currently having treated more than 250 patients with this disease.16 With this experience, the CH functional neurosurgery program began in 2003. All procedures to be performed are previously discussed once a month in the Craniofacial Pain Committee (code C30; CA D.CRANIOF), hospital committee made up of neurologists, neurosurgeons, anaesthetists and psychiatrists.
Figure 1. RF-SPG. Fluoroscopic image showing the location of a 21G RF electrode in the pterygopalatine fossa inserted by subzygomatic approach under locoregional anaesthesia and sedation in a rCCH patient.
Participating patients met the rCCH criteria according to the International Headache Society (ICHD-3)6 and the European Headache Federation (EHF).14 All of them were undergoing selfadministered subcutaneous sumatriptan and 100% oxygen therapy with 15 l/min flow through a mask with a reservoir as symptomatic pain home treatment. As preventive therapy, all of them had received without efficacy: verapamil, corticosteroids, lithium, valproic acid and topiramate at high doses. Brain MRI with intracranial angio-MRI and orbital study was normal in all patients. The RF-SPG ipsilateral-to-pain in rCCH was developed in 1997.17 It is an outpatient procedure15 which is performed with the patient in decubitus position with the head fixed and under locoregional anaesthesia and sedation. Through a sub-zygomatic approach, a 21G needle provided with an RF electrode is inserted up to about 4 cm deep where the pterygopalatine fossa that contains the SPG is located. The needle insertion is assisted by radioscopy (Fig. 1) and, once placed, it is replaced by the RF electrode connected to a generator inducing currents of 45 V and 2 Hz in pulsed RF. Thermal RF, currently in disuse, used temperatures of up to 80 ◦ C during the 60 s.15 Regarding Bilateral GONS, this began to be used in 2006 in Rcch.18 It may seem paradoxical to use occipital nerve stimulation, whose nuclei are located in the cervical cord at level C2, for rCCH, which is a trigeminovascular headache. However, the sensitive nucleus of the trigeminal nerve descends to the C2 level. In this way, occipital stimulation can modulate the trigeminovascular system and vice versa, so there is a clear convergence of inputs between both nerve pathways, although an anatomical connection in C2 between the nucleus of the trigeminal nerve and that of the occipital nerves has not been clearly established. GONS stimulator requires general anaesthesia and a minimum admission of 24 h and consists of the bilateral implantation of electrodes fixed to the occipital bone by means of horizontal screw-
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Figure 2. Bilateral GONS. Skull X-ray showing the location of bilateral occipital stimulation electrodes (with radiopaque markings) of a patient with RF-SPG-refractory rCCH. Both electrodes are fixed to the occipital bone by means of screw-plate devices. The wiring is tunnelled subcutaneously to a generator located in the lower back.
plate devices on the occipital nerves 15 (Fig. 2). The leads descend by subcutaneous tunnelling through the dorsocervical midline and is directed to the generator that is placed above the gluteal area. The stimulation parameters are individually adjusted with a wireless control in periodic outpatient visits according to pain control and the occurrence of paraesthesia/dysesthesia. For its part, DBS began in the sixties in epileptic and psychiatric patients and was first applied in rCCH in 2001.19 DBS consists in the introduction of a stimulation electrode through a frontal trephination opening in the posterior inferior hypothalamus using a stereotactic guide.15 Before surgery, a frame-based stereotaxy and a cranial CT scan is performed, where stereotaxy marks are placed to locate the hypothalamus. CT images are superimposed on brain MRI images previously obtained through neuronavigation to obtain the best entry point and path. After the electrode insertion into the hypothalamus (Fig. 3), the leads are tunnelled subcutaneously from the trephination opening to the paraumbilical area, where the generator is placed. It is a procedure similar to that performed on other surgical interventions with brain targets such Parkinson’s disease, epilepsy or in some psychiatric diseases. The stimulation parameters are individually adjusted with wireless control in periodic visits in a manner similar to that of GONS.15 In this study we have analysed demographic aspects (age and gender) of the patients and disease progression (age of onset of episodic CH, chronic CH and rCCH), as well as the treatments received prior to the surgical intervention. The primary efficacy endpoint in the treatment of rCCH is not agreed upon and the daily number of CH attacks is normally used, with the understanding that a treatment is effective when it reduces the number of daily CH attacks by more than 50% after 3 months of having received such treatment (the surgical procedure in our study) compared to the baseline month before starting it. We also analysed the conversion rate of chronic to episodic CH as an efficacy variable. In addition, we analysed the consumption of subcutaneous sumatriptan and the numerical pain scale (NPS) score from 0-no pain to 10-maximum pain, as secondary efficacy
Figure 3. DBS. Cranial CT showing the location of a stimulation electrode (marked with an arrow) in the left posteroinferior hypothalamus, ipsilateral-to-pain, in a rCCH patient refractory to RF-SPG and bilateral GONS. The electrode is inserted through a frontal trephination and guided to the hypothalamus by stereotaxy. The leads are tunnelled subcutaneously to the generator located in the paraumbilical area.
variables. Finally, we recorded intraoperative and postoperative complications as safety variables. Results We prospectively include 44 patients with rCCH meeting the ICHD-36 and EHF14 criteria between November 2003 and June 2018 with an average follow-up of 87.4 months. The average age of CH onset was 28.5 years as an episodic form and it became chronic CH in a period of 7 years on average (35.5 average age), and in rCCH 3 years later (38.3 average age) with 70.4% of the patients being males. The average of ineffective oral preventive drugs taken by the patients was 5.3. 25% of the patients had received botulinum toxin A and 40% had received ipsilateral major occipital nerve blocks with anaesthetic and corticosteroids, being equally ineffective or transiently effective. 105 surgical procedures were performed in the 44 patients included. Specifically, 74 ipsilateral-to-pain RF-SPG procedures, 22 implants of bilateral GONS devices were performed and, finally, 10 patients underwent DBS (Fig. 4). RF-SPG 74 RF-SPG procedures (83% pulsed RF and 16% thermal RF) were performed in 44 rCCH patients with a mean age of 39.1 years (Fig. 4). The average of daily CH attacks decreased from 4.4 to 2.95 at 3 months of post-surgery follow-up with a decrease in subcutaneous sumatriptan consumption from 3.4 to 2.7 (50%) and in the NPS scale of 10 points to 7. Fifteen patients (33.3%) achieved the goal of moving from chronic to episodic CH. Most of these patients (95.5%) only received one RF-SPG. Successive RF-SPG procedures were per-
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follow-up, there was the breakage of another electrode, so both cases had to undergo surgery for a second time in order to correct these defects.
n=44 RF-SPGRF -SPG Non-effective: 25
Effective: 19
Discussion GONS
Refractory: 1
Effective: 14
2
Non-effective: 8
DBS
Refractory: 1
Effective: 8
Non-effective: 1
Figure 4. Flow chart of the 44 patients with rCCH showing their surgical itinerary between 2003 and 2018.
formed 3 months after the previous one (pulsed or thermal) in 25 patients, but these managed to increase the response percentage in only 4 more patients (4.5%). One patient experienced a vasovagal syncope as the only intraoperative complication. As for postoperative complications, one patient experienced buccal paraesthesia up to 3 months and another patient suffered palatal hypoesthesia. GONS 22 GONS devices were implanted bilaterally in the 25 patients refractory to RF-SPEG (Fig. 4). Of the 3 remaining patients, one declined the GONS and 2 patients had an DBS directly because there was no GONS at the time they were assessed. The mean age of patients undergoing surgery was 41.2 years, with 63.6% being men. The average daily CH attacks decreased from 5.7 to 3.2 (43.8%) at 3 months post-surgery. Likewise, daily consumption of subcutaneous sumatriptan was reduced from 4.4 to 2.2 (50%) and the NPS scale score was reduced from 10 points to 6.4. Eleven patients (50%) managed to move from a chronic CH to an episodic form and 3 of them (13.6%) managed to disconnect the stimulator while the rest remain connected. Regarding safety, 4 patients had system infections that forced their replacement. Also, one electrode broke and another disconnected during follow-up. No surgical electrode reimplantation was necessary in any of these 2 cases, as stimulation continued with the contralateral electrode. DBS Finally, 9 patients underwent ipsilateral posterior hypothalamus stimulation (Fig. 4) with a mean age of 44.6 years, with 87.7% being men. Of these, 7 experienced GONS ineffectiveness, but the other 2 did not try GONS because their cases were prior to the implementation of this stimulation technique in our center, as already mentioned. In order to understand the severity of these patients, it should be noted that 4 of them (44.4%) were jointly undergoing follow-up by the Suicide Unit of our center due to high-risk suicidal ideation. The average daily CH attacks decreased from 6.5 to 1.9 (70.7%) at 3 months post-surgery, daily consumption of subcutaneous sumatriptan was reduced from 5.7 to 1.4 (75.4%) and the average score on the NPS scale was reduced from 10 points to 4.5. Eight patients (88.8%) managed to move from chronic to episodic CH and one of them was able to discontinue the treatment. No intraoperative complications were recorded. In the postoperative cranial CT control, the poor positioning of one electrode was observed, and in the
We report the first series of patients with rCCH in the medical literature in which the evolution of patients is analysed after undergoing the different surgical techniques indicated in a refractory therapy setting: RF-SPG, GONS and DBS. Several studies have specifically analysed the efficacy and safety of each of these techniques in patients with rCCH, but not their progressive sequential application. In our series, 93% of patients with rCCH substantially improved their quality of life at 3 months post-intervention, and in a sustained manner over time (mean of 8 years), after sequentially applying the surgical algorithm: RF-GEP – GONS – DBS (Fig. 4). The efficacy sustainability of these surgeries over time invalidates a potential placebo effect. On the other hand, we did not record significant surgical or neurological complications. Regarding RF-SPG, only 2 prospective uncontrolled series have been published20,21 including a total of 53 patients, of which 37 are patients included in the present study,21 plus 105 additional patients in retrospective series and clinical cases.15,22 The efficacy of RF-SPG in rCCH shown by these studies is 46%, similar to that of our series, but the follow-up found in the literature studies does not go beyond 2 years, while we have carried out a medium follow-up of 7 years and efficacy is reduced to 33%. Reported complications are scarce and usually completely reversible in less than 3 months: epistaxis, buccal hematoma, reflex bradycardia, transient hypoesthesia of the palate, jaw and posterior pharyngeal wall. The case of a patient with maxillary anaesthesia as a permanent sequel has been reported. However, the future of RF-SPG is bleak because a SPG microstimulator which is implanted in the pterygopalatine fossa has just been validated in Europe through a minimally invasive transoral approach. It only requires pterygopalatine fossa CT imaging planning and antibiotic prophylaxis. The patient regulates the stimulation with a remote wireless controller. It was designed as a symptomatic treatment of CH attacks, showing an efficacy close to 68% but, surprisingly, it has also demonstrated a preventive efficacy of 55%, superior to RF-SPG and sustained in follow-ups above 2 years.15,23,24 Currently, 172 rCCH patients treated with GONS devices have been reported in the medical literature,15,25–27 of which 4 are from our present series,25 showing an efficacy of 65–78% in pain reduction, managing to go from chronic to episodic CH in up to 40% of patients (50% in our series). Paraesthesia in the scalp is the most common adverse effect, close to 100%, but only in 25% of these cases it is necessary to modify the stimulation parameters. A postoperative complication is infection (5% in the literature and 13% in our series), but we must bear in mind that these patients are usually corticodependent, so there is a special risk of infection in them. Another complication is electrode displacement, described in up to 0–20% of cases and their malfunction in 3%. Finally, it should be noted that all patients must inexorably undergo new battery replacement surgeries, when they are non-rechargeable, occurring in 65% of patients in an average of 6 years, depending on the frequency and intensity of the stimulation required to control pain.15 Regarding DBS, 82 patients with rCCH undergoing this treatment have been reported in the literature,28–31 mostly from open label series (the largest of 19 patients30 ) and only 11 patients28 have undergone DBS, analysing the stimulator when turned on compared to off. The efficacy reported in the literature is close to 70% during follow-ups over 8 years (87% in our series). However,
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despite being the most effective surgical procedure, it is not without risks, with one operative death (1.2%) being reported due to cerebral haemorrhage. Isolated cases of infection, non-fatal cerebral haemorrhage, epileptic seizure, diplopia, transient ischemic attack, tremor, dystonia, thirst and appetite changes, and syncope have also been described.31 Fortunately, we have not recorded any adverse effects of this type. Given the serious impact on the quality of life in patients with rCCH, the application of surgical procedures should not be delayed. Given the lack of efficacy or intolerance of verapamil, topiramate and lithium at optimal doses, a maximum of 2 oral corticosteroid regimens in one year and botulinum toxin A and at least 2 ipsilateral anaesthetic GON blocks, surgical procedures are recommended, and their indication should be established through multidisciplinary committee consensus. As only a few patients are affected, it is very difficult for a surgical team to overcome a pathology-specific learning curve that achieves optimal morbidity and mortality. However, experience can be drawn from the teams that are dedicated to functional neurosurgery in other pathologies such as Parkinson’s disease, epilepsy or psychiatric diseases, as they are similar surgeries. Conflict of interests The authors declare no conflict of interest. References 1. Hagen K, Åsberg AN, Uhlig BL, Tronvik E, Brenner E, Stjern M, et al. The epidemiology of headache disorders: a face-to-face interview of participants in HUNT4. J Headache Pain. 2018;19:25. 2. Manzoni GC. Gender ratio of cluster headache over the years: a possible role of changes in lifestyle. Cephalalgia. 1998;18:138–42. 3. Ekbom K, Svensson DA, Traff H, Waldenlind E. Age at onset and sex ratio in cluster headache: observations over three decades. Cephalalgia. 2002;22:94–100. 4. Bahra A, May A, Goadsby PJ. Cluster headache: a prospective clinical study with diagnostic implications. Neurology. 2002;58:354–61. 5. May A, Schwedt TJ, Magis D, Pozo-Rosich P, Evers S, Wang SJ. Cluster headache. Nat Rev Dis Primers. 2018;4:18006. 6. Headache Classification Committee of the International Headache Society (IHS). The international classification of headache disorders, 3rd edition. Cephalalgia. 2018;38:1–211. 7. Koehler PJ. Prevalence of headache in Tulp’s observationes medicae (1641) with a description of cluster headache. Cephalalgia. 1993;13:318–20. 8. Sánchez Del Rio M, Leira R, Pozo-Rosich P, Laínez JM, Alvarez R, Pascual J. Errors in recognition and management are still frequent in patients with cluster headache. Eur Neurol. 2014;72:209–12. 9. Louter MA, Wilbrink LA, Haan J, van Zwet EW, van Oosterhout WP, Zitman FG, et al. Cluster headache and depression. Neurology. 2016;87:1899–906. 10. Rozen TD, Fishman RS. Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden. Headache. 2012;52:99–113. 11. Ferrari A, Zappaterra M, Righi F, Ciccarese M, Tiraferri I, Pini LA, et al. Impact of continuing or quitting smoking on episodic cluster headache: a pilot survey. J Headache Pain. 2013;14:48.
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12. De Coo IF, Naber WC, Wilbrink LA, Haan J, Ferrari MD, Fronczek R. Increased use of illicit drugs in a Dutch cluster headache population. Cephalalgia. 2019;39:626–34. 13. Robbins MS, Starling AJ, Pringsheim TM, Becker WJ, Schwedt TJ. Treatment of cluster headache: The American Headache Society Evidence-Based Guidelines. Headache. 2016;56:1093–106. 14. Mitsikostas DD, Edvinsson L, Jensen RH, Katsarava Z, Lampl C, Negro A, et al. Refractory chronic cluster headache: a consensus statement on clinical definition from the European Headache Federation. J Headache Pain. 2014;15:79. 15. Belvís R. Manual práctico de procedimientos invasivos y quirúrgicos en cefaleas y neuralgias. Madrid: IMC (International Marketing & Communication); 2018. 16. De Quintana-Schmidt C, Pascual-Sedano B, Alvarez-Holzapfel MJ, Gironell A, Leidinger A, Benito N, et al. Complications related with implanted devices in patients with Parkinson’s disease treated with deep brain stimulation. A study of a series of 124 patients over a period of 16 years. Rev Neurol. 2014;59:49–56. 17. Sanders M, Zuurmond WW. Efficacy of sphenopalatine ganglion blockade in 66 patients suffering from cluster headache: a 12- to 70-month follow-up evaluation. J Neurosurg. 1997;87:876–80. 18. Schwedt TJ, Dodick DW, Trentman TL, Zimmerman RS. Occipital nerve stimulation for chronic cluster headache and hemicrània continua: pain relief and persistence of autonomic features. Cephalalgia. 2006;26:1025–7. 19. 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;345:1428–9. 20. Fang L, Jingjing L, Ying S, Lan M, Tao W, Nan J. Computerized tomographyguided sphenopalatine ganglion pulsed radiofrequency treatment in 16 patients with refractory cluster headaches: twelve- to 30-month follow-up evaluations. Cephalalgia. 2016;36:106–12. 21. Salgado-López L, de Quintana-Schmidt C, Belvis Nieto R, Roig Arnall C, Rodríguez Rodriguez R, Álvarez Holzapfel MJ, et al. Efficacy of sphenopalatine ganglion radiofrequency in refractory chronic cluster headache. World Neurosurg. 2018;122:262–9. 22. Sanders M, Zuurmond WW. Efficacy of sphenopalatine ganglion blockade in 66 patients suffering from cluster headache: a 12- to 70-month followup evaluation. J Neurosurg. 1997;87:876–80. 23. Jurgens TP, Barloese M, May A, Lainez JM, Schoenen J, Gaul C, et al. Longterm effectiveness of sphenopalatine ganglion stimulation fo cluster headache. Cephalalgia. 2017;37:423–34. 24. Barloese M, Petersen A, Stude P, Jurgens T, Jensen RH, May A. Sphenopalatine ganglion stimulation for cluster headache, results from alarge, open-label European registry. J Headache Pain. 2018;19:6. 25. de Quintana-Schmidt C, Casajuana-Garreta E, Molet-Teixidó J, García-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;51:19–26. 26. 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;24:381–90. 27. Leone M, Proietti Cecchini A, Messina G, Franzini A. Long-term occipital nerve stimulation for drug-resistant chronic cluster headache. Cephalalgia. 2017;37:756–63. 28. 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 doubleblind trial followed by a one-year open extension. J Headache Pain. 2010;11:23–31. 29. 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;31:1634–41. 30. Akram H, Miller S, Lagrata S, Hariz M, Ashburner J, Behrens T, et al. Ventral tegmental area deep brain stimulation for refractory chronic cluster headache. Neurology. 2016;86:1676–82. 31. Vyas DB, Ho AL, Dadey DY, Pendharkar AV, Sussman ES, Cowan R, et al. Deep brain stimulation for chronic cluster headache: a review. Neuromodulation. 2018.
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Original article
Efficacy and safety of surgical treatment of cluster headache夽 Robert Belvis a,∗ , Rodrigo Rodríguez b , Marina Guasch a , María Jesús Álvarez b , Joan Molet b , Carles Roig a a b
Unidad de Cefaleas y Neuralgias, Servicio de Neurología, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Unidad de Neurocirugía Funcional, Servicio de Neurocirugía, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
a r t i c l e
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Article history: Received 21 January 2019 Accepted 7 March 2019 Available online xxx Keywords: Headache Cluster Radiofrequency Stimulation
a b s t r a c t Background and objectives: Cluster headache (CR) is the most severe human headache and is chronic in 10%–20% of patients, and 10% can become refractory to all effective drugs. In this scenario, surgical procedures are indicated: radiofrequencies of the sphenopalatine ganglion ipsilateral to pain (RF-SPG), bilateral stimulation of the occipital nerves (NOM-S) and deep brain stimulation (DBS) of the ipsilateral posterior hypothalamus. The efficacy and safety of each of these procedures has been specifically analyzed, but the progress of a series of patients following this surgical route in order of aggressiveness has not been described. Patients: Patients with chronic and refractory CR according to the criteria of the European Headache Federation. The patients underwent RF-SPG, NOM-S sequentially if the previous procedure had been ineffective, and DBS if the previous procedure had been ineffective. Results: We prospectively included 44 patients between November 2003 and June 2018 with an average age of 38.3 years; 70% were men. The mean follow-up was 87.4 months. Nineteen patients responded to 74 procedures of RF-SPG (33.3%). Of the remaining 25 patients, a NOM-S device was implanted in 22, showing an efficacy of 50%. Finally, 9 patients underwent ECP of the ipsilateral lower-posterior hypothalamus with an efficacy of 88.8%. No serious complications were found following any of these three procedures. Conclusions: The sequential application of these three surgical procedures succeeded in reversing the serious situation of chronic CR refractory to an episodic CR in 93% of patients with acceptable surgical morbidity. ˜ S.L.U. All rights reserved. © 2019 Elsevier Espana,
Eficacia y seguridad del tratamiento quirúrgico en la cefalea en racimos r e s u m e n Palabras clave: Cefalea Clúster Radiofrecuencia Estimulación
Antecedentes y objetivo: La cefalea en racimos (CR) es la cefalea humana más grave y se cronifica en un 10-20% de pacientes, pudiendo llegar a ser refractaria a todos los fármacos eficaces en un 10% de ellos. En este escenario se indican procedimientos quirúrgicos: radiofrecuencias del ganglio esfenopalatino ipsilateral al dolor (RF-GEFP), estimulación bilateral de los nervios occipitales (E-NOM) y estimulación cerebral profunda (ECP) del hipotálamo postero-inferior ipsilateral. Se ha analizado específicamente la eficacia y seguridad de cada uno de ellas, pero no se ha descrito la evolución de una serie de pacientes siguiendo este itinerario quirúrgico por orden de agresividad. Pacientes: Pacientes con CR crónica y refractaria según los criterios de la European Headache Federation. Fueron sometidos secuencialmente a RF-GEFP, E-NOM si ineficacia del anterior y ECP si ineficacia del anterior. Resultados: Incluimos prospectivamente 44 pacientes entre Noviembre de 2003 y Junio de 2018 con una ˜ siendo el 70% hombres. El seguimiento medio fue de 87.4 meses. Respondieron edad media de 38,3 anos a 74 procedimientos de RF-GEFP 19 pacientes (33.3%). De los 25 restantes, se implantó un dispositivo de E-NOM en 22 de ellos, mostrando una eficacia del 50%. Finalmente, se sometieron a ECP del hipotálamo postero-inferior ipsilateral 9 pacientes con una eficacia del 88.8%. No se constataron complicaciones graves en ninguno de los tres procedimientos.
夽 Please cite this article as: Belvis R, Rodríguez R, Guasch M, Álvarez MJ, Molet J, Roig C. Eficacia y seguridad del tratamiento quirúrgico en la cefalea en racimos. Med Clin (Barc). 2019. https://doi.org/10.1016/j.medcli.2019.03.023 ∗ Corresponding author. E-mail address: [email protected] (R. Belvis). ˜ S.L.U. All rights reserved. 2387-0206/© 2019 Elsevier Espana,
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Conclusiones: La aplicación secuencial de los tres procedimientos quirúrgicos logró revertir la grave situación de CR crónica y refractaria a CR episódica en el 93% de los pacientes con una morbilidad quirúrgica aceptable. ˜ S.L.U. Todos los derechos reservados. © 2019 Elsevier Espana,
Introduction Cluster headache (CH), is the most severe headache that humans can experience. It affects one in every thousand people,1 predominantly men 3–7: 12 and starts around the age of 20–30.3,4 CH is a primary headache in the group of trigeminal-autonomic headaches distinguished by the occurrence of autonomic signs in the territory of the first branch of the trigeminal nerve in 97% of patients.4–6 Its pathophysiology is unknown but the trigeminovascular system and the peripheral autonomic nervous system are clearly involved; and the central hypothalamus.5 The pain affects the eye, orbit and temporal area and is of severe/very severe intensity, so the patient shows significant restlessness and/or agitation. It usually lasts between 15 min and 3 h and the most common autonomic signs, all ipsilateral to pain, are: myosis, conjunctival injection, blepharoptosis, rhinorrhoea and tearing.4,6 However, although cases of CH have been known since the XVII7 century and that its clinical symptomatology is extraordinary, its diagnostic delay is excessively high (from 3 to 11 years) because it is often diagnosed as migraine, sinusitis, dental, ophthalmological, psychiatric pathology.8 It is accompanied by depression in 60% of cases9 and suicidal ideation occurs in 55%, reaching the attempt stage in 2%.10 Smoking has also been associated in 70–90% of patients11 and 31% use addictive drugs.12 CH occurs episodically in 80–90% of cases and may be seasonal, usually evening/night. However, 10–20% of cases are chronic,4,6,13 understanding as such those in which there are no remissions in a year, or a remission of less than one month.6 Of these, 10% will be refractory (rCCH) to preventive drugs13,14 : verapamil, corticosteroids, lithium, topiramate and valproic acid; as well as botulinum toxin A or anaesthetic occipital nerve blocks. Surgical procedures are indicated in patients with rCCH. Traditionally, radiofrequencies (RF), chemical neurolysis, cryosurgery, microvascular decompression, neurectomy, stereotactic radiosurgery have been performed, using the trigeminal nerve, the petrosal nerves, the Gasser ganglion or the sphenopalatine ganglion (SPG) as targets.15 Nowadays, only ipsilateral-to-pain RF on SPG (RF-SPG) remains. This is due to the fact that non-invasive surgical neurostimulation techniques began to be used at the beginning of the millennium, with bilateral greater occipital nerve stimulation (GONS) and hypothalamus stimulation as treatment options through deep brain stimulation (DBS). Usually, ipsilateral-to-pain RF-SPG is the procedure of choice due to its minimally invasive nature, followed by bilateral GONS with hypothalamic DBS. We report our experience of 15 years of surgical procedures performed in consecutive patients with rCCH.
Patients and methods Functional neurosurgery was implemented in our center in the year 1998 in Parkinson’s disease, currently having treated more than 250 patients with this disease.16 With this experience, the CH functional neurosurgery program began in 2003. All procedures to be performed are previously discussed once a month in the Craniofacial Pain Committee (code C30; CA D.CRANIOF), hospital committee made up of neurologists, neurosurgeons, anaesthetists and psychiatrists.
Figure 1. RF-SPG. Fluoroscopic image showing the location of a 21G RF electrode in the pterygopalatine fossa inserted by subzygomatic approach under locoregional anaesthesia and sedation in a rCCH patient.
Participating patients met the rCCH criteria according to the International Headache Society (ICHD-3)6 and the European Headache Federation (EHF).14 All of them were undergoing selfadministered subcutaneous sumatriptan and 100% oxygen therapy with 15 l/min flow through a mask with a reservoir as symptomatic pain home treatment. As preventive therapy, all of them had received without efficacy: verapamil, corticosteroids, lithium, valproic acid and topiramate at high doses. Brain MRI with intracranial angio-MRI and orbital study was normal in all patients. The RF-SPG ipsilateral-to-pain in rCCH was developed in 1997.17 It is an outpatient procedure15 which is performed with the patient in decubitus position with the head fixed and under locoregional anaesthesia and sedation. Through a sub-zygomatic approach, a 21G needle provided with an RF electrode is inserted up to about 4 cm deep where the pterygopalatine fossa that contains the SPG is located. The needle insertion is assisted by radioscopy (Fig. 1) and, once placed, it is replaced by the RF electrode connected to a generator inducing currents of 45 V and 2 Hz in pulsed RF. Thermal RF, currently in disuse, used temperatures of up to 80 ◦ C during the 60 s.15 Regarding Bilateral GONS, this began to be used in 2006 in Rcch.18 It may seem paradoxical to use occipital nerve stimulation, whose nuclei are located in the cervical cord at level C2, for rCCH, which is a trigeminovascular headache. However, the sensitive nucleus of the trigeminal nerve descends to the C2 level. In this way, occipital stimulation can modulate the trigeminovascular system and vice versa, so there is a clear convergence of inputs between both nerve pathways, although an anatomical connection in C2 between the nucleus of the trigeminal nerve and that of the occipital nerves has not been clearly established. GONS stimulator requires general anaesthesia and a minimum admission of 24 h and consists of the bilateral implantation of electrodes fixed to the occipital bone by means of horizontal screw-
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Figure 2. Bilateral GONS. Skull X-ray showing the location of bilateral occipital stimulation electrodes (with radiopaque markings) of a patient with RF-SPG-refractory rCCH. Both electrodes are fixed to the occipital bone by means of screw-plate devices. The wiring is tunnelled subcutaneously to a generator located in the lower back.
plate devices on the occipital nerves 15 (Fig. 2). The leads descend by subcutaneous tunnelling through the dorsocervical midline and is directed to the generator that is placed above the gluteal area. The stimulation parameters are individually adjusted with a wireless control in periodic outpatient visits according to pain control and the occurrence of paraesthesia/dysesthesia. For its part, DBS began in the sixties in epileptic and psychiatric patients and was first applied in rCCH in 2001.19 DBS consists in the introduction of a stimulation electrode through a frontal trephination opening in the posterior inferior hypothalamus using a stereotactic guide.15 Before surgery, a frame-based stereotaxy and a cranial CT scan is performed, where stereotaxy marks are placed to locate the hypothalamus. CT images are superimposed on brain MRI images previously obtained through neuronavigation to obtain the best entry point and path. After the electrode insertion into the hypothalamus (Fig. 3), the leads are tunnelled subcutaneously from the trephination opening to the paraumbilical area, where the generator is placed. It is a procedure similar to that performed on other surgical interventions with brain targets such Parkinson’s disease, epilepsy or in some psychiatric diseases. The stimulation parameters are individually adjusted with wireless control in periodic visits in a manner similar to that of GONS.15 In this study we have analysed demographic aspects (age and gender) of the patients and disease progression (age of onset of episodic CH, chronic CH and rCCH), as well as the treatments received prior to the surgical intervention. The primary efficacy endpoint in the treatment of rCCH is not agreed upon and the daily number of CH attacks is normally used, with the understanding that a treatment is effective when it reduces the number of daily CH attacks by more than 50% after 3 months of having received such treatment (the surgical procedure in our study) compared to the baseline month before starting it. We also analysed the conversion rate of chronic to episodic CH as an efficacy variable. In addition, we analysed the consumption of subcutaneous sumatriptan and the numerical pain scale (NPS) score from 0-no pain to 10-maximum pain, as secondary efficacy
Figure 3. DBS. Cranial CT showing the location of a stimulation electrode (marked with an arrow) in the left posteroinferior hypothalamus, ipsilateral-to-pain, in a rCCH patient refractory to RF-SPG and bilateral GONS. The electrode is inserted through a frontal trephination and guided to the hypothalamus by stereotaxy. The leads are tunnelled subcutaneously to the generator located in the paraumbilical area.
variables. Finally, we recorded intraoperative and postoperative complications as safety variables. Results We prospectively include 44 patients with rCCH meeting the ICHD-36 and EHF14 criteria between November 2003 and June 2018 with an average follow-up of 87.4 months. The average age of CH onset was 28.5 years as an episodic form and it became chronic CH in a period of 7 years on average (35.5 average age), and in rCCH 3 years later (38.3 average age) with 70.4% of the patients being males. The average of ineffective oral preventive drugs taken by the patients was 5.3. 25% of the patients had received botulinum toxin A and 40% had received ipsilateral major occipital nerve blocks with anaesthetic and corticosteroids, being equally ineffective or transiently effective. 105 surgical procedures were performed in the 44 patients included. Specifically, 74 ipsilateral-to-pain RF-SPG procedures, 22 implants of bilateral GONS devices were performed and, finally, 10 patients underwent DBS (Fig. 4). RF-SPG 74 RF-SPG procedures (83% pulsed RF and 16% thermal RF) were performed in 44 rCCH patients with a mean age of 39.1 years (Fig. 4). The average of daily CH attacks decreased from 4.4 to 2.95 at 3 months of post-surgery follow-up with a decrease in subcutaneous sumatriptan consumption from 3.4 to 2.7 (50%) and in the NPS scale of 10 points to 7. Fifteen patients (33.3%) achieved the goal of moving from chronic to episodic CH. Most of these patients (95.5%) only received one RF-SPG. Successive RF-SPG procedures were per-
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follow-up, there was the breakage of another electrode, so both cases had to undergo surgery for a second time in order to correct these defects.
n=44 RF-SPGRF -SPG Non-effective: 25
Effective: 19
Discussion GONS
Refractory: 1
Effective: 14
2
Non-effective: 8
DBS
Refractory: 1
Effective: 8
Non-effective: 1
Figure 4. Flow chart of the 44 patients with rCCH showing their surgical itinerary between 2003 and 2018.
formed 3 months after the previous one (pulsed or thermal) in 25 patients, but these managed to increase the response percentage in only 4 more patients (4.5%). One patient experienced a vasovagal syncope as the only intraoperative complication. As for postoperative complications, one patient experienced buccal paraesthesia up to 3 months and another patient suffered palatal hypoesthesia. GONS 22 GONS devices were implanted bilaterally in the 25 patients refractory to RF-SPEG (Fig. 4). Of the 3 remaining patients, one declined the GONS and 2 patients had an DBS directly because there was no GONS at the time they were assessed. The mean age of patients undergoing surgery was 41.2 years, with 63.6% being men. The average daily CH attacks decreased from 5.7 to 3.2 (43.8%) at 3 months post-surgery. Likewise, daily consumption of subcutaneous sumatriptan was reduced from 4.4 to 2.2 (50%) and the NPS scale score was reduced from 10 points to 6.4. Eleven patients (50%) managed to move from a chronic CH to an episodic form and 3 of them (13.6%) managed to disconnect the stimulator while the rest remain connected. Regarding safety, 4 patients had system infections that forced their replacement. Also, one electrode broke and another disconnected during follow-up. No surgical electrode reimplantation was necessary in any of these 2 cases, as stimulation continued with the contralateral electrode. DBS Finally, 9 patients underwent ipsilateral posterior hypothalamus stimulation (Fig. 4) with a mean age of 44.6 years, with 87.7% being men. Of these, 7 experienced GONS ineffectiveness, but the other 2 did not try GONS because their cases were prior to the implementation of this stimulation technique in our center, as already mentioned. In order to understand the severity of these patients, it should be noted that 4 of them (44.4%) were jointly undergoing follow-up by the Suicide Unit of our center due to high-risk suicidal ideation. The average daily CH attacks decreased from 6.5 to 1.9 (70.7%) at 3 months post-surgery, daily consumption of subcutaneous sumatriptan was reduced from 5.7 to 1.4 (75.4%) and the average score on the NPS scale was reduced from 10 points to 4.5. Eight patients (88.8%) managed to move from chronic to episodic CH and one of them was able to discontinue the treatment. No intraoperative complications were recorded. In the postoperative cranial CT control, the poor positioning of one electrode was observed, and in the
We report the first series of patients with rCCH in the medical literature in which the evolution of patients is analysed after undergoing the different surgical techniques indicated in a refractory therapy setting: RF-SPG, GONS and DBS. Several studies have specifically analysed the efficacy and safety of each of these techniques in patients with rCCH, but not their progressive sequential application. In our series, 93% of patients with rCCH substantially improved their quality of life at 3 months post-intervention, and in a sustained manner over time (mean of 8 years), after sequentially applying the surgical algorithm: RF-GEP – GONS – DBS (Fig. 4). The efficacy sustainability of these surgeries over time invalidates a potential placebo effect. On the other hand, we did not record significant surgical or neurological complications. Regarding RF-SPG, only 2 prospective uncontrolled series have been published20,21 including a total of 53 patients, of which 37 are patients included in the present study,21 plus 105 additional patients in retrospective series and clinical cases.15,22 The efficacy of RF-SPG in rCCH shown by these studies is 46%, similar to that of our series, but the follow-up found in the literature studies does not go beyond 2 years, while we have carried out a medium follow-up of 7 years and efficacy is reduced to 33%. Reported complications are scarce and usually completely reversible in less than 3 months: epistaxis, buccal hematoma, reflex bradycardia, transient hypoesthesia of the palate, jaw and posterior pharyngeal wall. The case of a patient with maxillary anaesthesia as a permanent sequel has been reported. However, the future of RF-SPG is bleak because a SPG microstimulator which is implanted in the pterygopalatine fossa has just been validated in Europe through a minimally invasive transoral approach. It only requires pterygopalatine fossa CT imaging planning and antibiotic prophylaxis. The patient regulates the stimulation with a remote wireless controller. It was designed as a symptomatic treatment of CH attacks, showing an efficacy close to 68% but, surprisingly, it has also demonstrated a preventive efficacy of 55%, superior to RF-SPG and sustained in follow-ups above 2 years.15,23,24 Currently, 172 rCCH patients treated with GONS devices have been reported in the medical literature,15,25–27 of which 4 are from our present series,25 showing an efficacy of 65–78% in pain reduction, managing to go from chronic to episodic CH in up to 40% of patients (50% in our series). Paraesthesia in the scalp is the most common adverse effect, close to 100%, but only in 25% of these cases it is necessary to modify the stimulation parameters. A postoperative complication is infection (5% in the literature and 13% in our series), but we must bear in mind that these patients are usually corticodependent, so there is a special risk of infection in them. Another complication is electrode displacement, described in up to 0–20% of cases and their malfunction in 3%. Finally, it should be noted that all patients must inexorably undergo new battery replacement surgeries, when they are non-rechargeable, occurring in 65% of patients in an average of 6 years, depending on the frequency and intensity of the stimulation required to control pain.15 Regarding DBS, 82 patients with rCCH undergoing this treatment have been reported in the literature,28–31 mostly from open label series (the largest of 19 patients30 ) and only 11 patients28 have undergone DBS, analysing the stimulator when turned on compared to off. The efficacy reported in the literature is close to 70% during follow-ups over 8 years (87% in our series). However,
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despite being the most effective surgical procedure, it is not without risks, with one operative death (1.2%) being reported due to cerebral haemorrhage. Isolated cases of infection, non-fatal cerebral haemorrhage, epileptic seizure, diplopia, transient ischemic attack, tremor, dystonia, thirst and appetite changes, and syncope have also been described.31 Fortunately, we have not recorded any adverse effects of this type. Given the serious impact on the quality of life in patients with rCCH, the application of surgical procedures should not be delayed. Given the lack of efficacy or intolerance of verapamil, topiramate and lithium at optimal doses, a maximum of 2 oral corticosteroid regimens in one year and botulinum toxin A and at least 2 ipsilateral anaesthetic GON blocks, surgical procedures are recommended, and their indication should be established through multidisciplinary committee consensus. As only a few patients are affected, it is very difficult for a surgical team to overcome a pathology-specific learning curve that achieves optimal morbidity and mortality. However, experience can be drawn from the teams that are dedicated to functional neurosurgery in other pathologies such as Parkinson’s disease, epilepsy or psychiatric diseases, as they are similar surgeries. Conflict of interests The authors declare no conflict of interest. References 1. Hagen K, Åsberg AN, Uhlig BL, Tronvik E, Brenner E, Stjern M, et al. The epidemiology of headache disorders: a face-to-face interview of participants in HUNT4. J Headache Pain. 2018;19:25. 2. Manzoni GC. Gender ratio of cluster headache over the years: a possible role of changes in lifestyle. Cephalalgia. 1998;18:138–42. 3. Ekbom K, Svensson DA, Traff H, Waldenlind E. Age at onset and sex ratio in cluster headache: observations over three decades. Cephalalgia. 2002;22:94–100. 4. Bahra A, May A, Goadsby PJ. Cluster headache: a prospective clinical study with diagnostic implications. Neurology. 2002;58:354–61. 5. May A, Schwedt TJ, Magis D, Pozo-Rosich P, Evers S, Wang SJ. Cluster headache. Nat Rev Dis Primers. 2018;4:18006. 6. Headache Classification Committee of the International Headache Society (IHS). The international classification of headache disorders, 3rd edition. Cephalalgia. 2018;38:1–211. 7. Koehler PJ. Prevalence of headache in Tulp’s observationes medicae (1641) with a description of cluster headache. Cephalalgia. 1993;13:318–20. 8. Sánchez Del Rio M, Leira R, Pozo-Rosich P, Laínez JM, Alvarez R, Pascual J. Errors in recognition and management are still frequent in patients with cluster headache. Eur Neurol. 2014;72:209–12. 9. Louter MA, Wilbrink LA, Haan J, van Zwet EW, van Oosterhout WP, Zitman FG, et al. Cluster headache and depression. Neurology. 2016;87:1899–906. 10. Rozen TD, Fishman RS. Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden. Headache. 2012;52:99–113. 11. Ferrari A, Zappaterra M, Righi F, Ciccarese M, Tiraferri I, Pini LA, et al. Impact of continuing or quitting smoking on episodic cluster headache: a pilot survey. J Headache Pain. 2013;14:48.
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12. De Coo IF, Naber WC, Wilbrink LA, Haan J, Ferrari MD, Fronczek R. Increased use of illicit drugs in a Dutch cluster headache population. Cephalalgia. 2019;39:626–34. 13. Robbins MS, Starling AJ, Pringsheim TM, Becker WJ, Schwedt TJ. Treatment of cluster headache: The American Headache Society Evidence-Based Guidelines. Headache. 2016;56:1093–106. 14. Mitsikostas DD, Edvinsson L, Jensen RH, Katsarava Z, Lampl C, Negro A, et al. Refractory chronic cluster headache: a consensus statement on clinical definition from the European Headache Federation. J Headache Pain. 2014;15:79. 15. Belvís R. Manual práctico de procedimientos invasivos y quirúrgicos en cefaleas y neuralgias. Madrid: IMC (International Marketing & Communication); 2018. 16. De Quintana-Schmidt C, Pascual-Sedano B, Alvarez-Holzapfel MJ, Gironell A, Leidinger A, Benito N, et al. Complications related with implanted devices in patients with Parkinson’s disease treated with deep brain stimulation. A study of a series of 124 patients over a period of 16 years. Rev Neurol. 2014;59:49–56. 17. Sanders M, Zuurmond WW. Efficacy of sphenopalatine ganglion blockade in 66 patients suffering from cluster headache: a 12- to 70-month follow-up evaluation. J Neurosurg. 1997;87:876–80. 18. Schwedt TJ, Dodick DW, Trentman TL, Zimmerman RS. Occipital nerve stimulation for chronic cluster headache and hemicrània continua: pain relief and persistence of autonomic features. Cephalalgia. 2006;26:1025–7. 19. 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;345:1428–9. 20. Fang L, Jingjing L, Ying S, Lan M, Tao W, Nan J. Computerized tomographyguided sphenopalatine ganglion pulsed radiofrequency treatment in 16 patients with refractory cluster headaches: twelve- to 30-month follow-up evaluations. Cephalalgia. 2016;36:106–12. 21. Salgado-López L, de Quintana-Schmidt C, Belvis Nieto R, Roig Arnall C, Rodríguez Rodriguez R, Álvarez Holzapfel MJ, et al. Efficacy of sphenopalatine ganglion radiofrequency in refractory chronic cluster headache. World Neurosurg. 2018;122:262–9. 22. Sanders M, Zuurmond WW. Efficacy of sphenopalatine ganglion blockade in 66 patients suffering from cluster headache: a 12- to 70-month followup evaluation. J Neurosurg. 1997;87:876–80. 23. Jurgens TP, Barloese M, May A, Lainez JM, Schoenen J, Gaul C, et al. Longterm effectiveness of sphenopalatine ganglion stimulation fo cluster headache. Cephalalgia. 2017;37:423–34. 24. Barloese M, Petersen A, Stude P, Jurgens T, Jensen RH, May A. Sphenopalatine ganglion stimulation for cluster headache, results from alarge, open-label European registry. J Headache Pain. 2018;19:6. 25. de Quintana-Schmidt C, Casajuana-Garreta E, Molet-Teixidó J, García-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;51:19–26. 26. 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;24:381–90. 27. Leone M, Proietti Cecchini A, Messina G, Franzini A. Long-term occipital nerve stimulation for drug-resistant chronic cluster headache. Cephalalgia. 2017;37:756–63. 28. 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 doubleblind trial followed by a one-year open extension. J Headache Pain. 2010;11:23–31. 29. 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;31:1634–41. 30. Akram H, Miller S, Lagrata S, Hariz M, Ashburner J, Behrens T, et al. Ventral tegmental area deep brain stimulation for refractory chronic cluster headache. Neurology. 2016;86:1676–82. 31. Vyas DB, Ho AL, Dadey DY, Pendharkar AV, Sussman ES, Cowan R, et al. Deep brain stimulation for chronic cluster headache: a review. Neuromodulation. 2018.