Occipital nerve stimulation for intractable chronic cluster headache or migraine: A critical analysis of direct treatment costs and complications

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1 Original Article Occipital nerve stimulation for intractable chronic cluster headache or migraine: A critical analysis of direct treatment costs and complications Cephalalgia 33(16) ! International Headache Society 2013 Reprints and permissions: sagepub.co.uk/journalspermissions.nav DOI: / cep.sagepub.com Oliver Mueller 1, Hans-Christoph Diener 2, Philipp Dammann 1, Kasja Rabe 2, Vincent Hagel 1, Ulrich Sure 1 and Charly Gaul 2,3 Abstract Background: Occipital nerve stimulation (ONS) has been shown to be effective for selected patients with intractable headache disorders. We performed a prospective critical evaluation of complications and direct treatment costs. Methods: Twenty-seven patients with chronic cluster headache (CCH, n ¼ 24) or chronic migraine (CM, n ¼ 3) underwent a trial phase with bilateral ONS and subsequent implantation of a permanent generator (IPG), if responsive to treatment according to predefined criteria. Procedural and long-term complications as well as direct treatment costs of neuromodulation therapy of ONS were recorded over a mean follow-up period of 20 months (range 5 47 months). Results: Twenty-five of 27 patients (93%) responded to treatment. Twenty-one complications in 14 patients were identified, necessitating reoperation in 13 cases. Overall treatment costs were E761,043, including hardware-related costs of E506,019, costs for primary hospital care of E210,496, and complications related to hospitalization costs of E44,528. This results in a per case-based cost of E9445 for hospitalization and E18,741 for hardware costs, totaling E28,186. Conclusion: ONS for treatment of refractory CCH and CM is a cost-intensive treatment option with a significant complication rate. Nevertheless, patients with refractory primary headache disorders may experience substantial relief of pain attacks, and headache days, respectively. Keywords Chronic cluster headache, chronic migraine, occipital nerve stimulation (ONS), treatment costs, complications, outcome Date received: 7 April 2013; revised: 17 April 2013; 13 May 2013; accepted: 17 May 2013 Introduction Migraine and cluster headache are the most common disabling primary headache disorders (1). Chronic cluster headache (CCH) and chronic migraine (CM) have a substantial impact on health-related quality of life (HRQOL), as well as on social and economic costs (SEC) (2,3). Patients with CCH or CM report social deprivation in family relations and friendships, and of career drawbacks due to their inability to take part in social activities or work during attacks (4 6). Guidelines for the treatment of CM are based on multimodal therapeutic approaches including behavioral therapy, psychological support, physical therapy, and medical treatment for attack abortion (e.g. nonsteroidal antiinflammatory drugs (NSAIDs) or triptans), and prophylaxis (e.g. topiramate or botulinum toxin) (7 10). Therapy for CCH is based on permanent prophylactic medication (verapamil, topiramate or lithium), and on acute medication aborting the attacks (nasally or percutaneously administered triptans), and oxygen (11). Cost burden of the illness is mainly caused by subcutaneous or endonasal triptans and consumption of oxygen. In CCH monthly expenses for medical 1 Department of Neurosurgery, University Hospital Essen, Germany 2 Department of Neurology, University Hospital Essen, Germany 3 Migraine and Headache Clinic, Königstein, Germany Corresponding author: Oliver Mueller, Department of Neurosurgery, University Hospital Essen, Hufelandstr. 55, D Essen, Germany. oliver.mueller@uk-essen.de

2 1284 Cephalalgia 33(16) treatment will reach or even exceed E1500 per patient (2). For CM costs are estimated to be tenfold lower. However, socioeconomic burden of CM is approximately three times higher than for episodic migraine (12). Beside expenses for medical treatment, the socioeconomic costs caused in the wake of unemployability cumulate (13). Despite multimodal approaches and prophylactic and acute medical therapy, there will be 5% 15% of patients with CCH and CM who will continue to suffer attacks and headache days refractory to treatment (11,14). For those patients neuromodulative surgical approaches were developed over the last decade. Deep brain stimulation (DBS) was effective but resulted in major complications in some patients. Therefore, less invasive procedures were introduced to treat refractory headache disorders (15,16). Among them, occipital nerve stimulation (ONS) has been favored for an assumed low rate of major complications, and substantial effectiveness in the response to treatment (17 21). Yet, data focusing on procedure-related complications are sparse, and literature dealing with direct treatment costs concerning procedure-related hardware as well as hospital costs for the health insurance system (based on the German Diagnosis Related Groups system (G- DRG)) are lacking (22). This prospective observational study reports treatment results of a single-center experience with 27 patients undergoing ONS for CCH or CM. Special attention was given to long-term complication rates and costs directly related to therapy. Study purposes and the treatment protocol were approved by the local ethics committee of the Essen Medical School ( ). Material and methods Patient selection and evaluation Between December 2008 and September 2012, a total of 27 patients with refractory CCH (24) or CM (three) underwent ONS. Patient selection was performed at the Headache Outpatient Clinic of the Department of Neurology by experienced headache specialists. Headache refractory to treatment was diagnosed for CCH if the patient continued to suffer daily attacks without attack-free periods for more than four weeks per year despite prophylactic medication either alone or in combination (verapamil > 450 mg/day (d), topiramate >150 mg/d, lithium according to blood serum levels), or if side effects of the prophylactic or acute medication impeded sufficient control of attacks. CM was diagnosed according to International Headache Society (IHS) 2004 criteria in patients suffering 15 or more headache days per months with at least eight attacks fulfilling IHS criteria for migraine (23). CM was defined as refractory according to the recommendations of the German Migraine and Headache Society in patients who suffered persistent attacks despite adequate prophylactic medication and a multimodal treatment concept for more than 12 months (24). All patients were asked to keep a headache diary for at least three months to define an individual baseline of headache days and/or daily attacks. Patients were informed about the observational study and consent was given for participation. Prior to operation patients were assessed with a custom-made, nonstandardized questionnaire. A magnetic resonance imaging scan (MRI) of the neurocranium including contrastenhanced series was performed to rule out secondary headache disorders. Implantation All patients underwent a preliminary implantation of bilateral electrodes, under general anesthesia with the patient in the prone position in a standardized fashion described previously, that were externalized at the flank (21,25). In all patients ONS was performed bilaterally for CCH and CM via a midline incision 3 cm beneath the external occipital protuberance. For stimulation either eight-pole (e.g. Octrode Õ, St. Jude Medical, St. Paul, MN, USA), or four-pole (e.g. Pisces Quad Plus Õ, Medtronic Inc., Minneapolis, MN, USA) electrodes were employed. Electrodes were placed strictly subcutaneously, targeting from the midline to the mastoid. Placement of the leads parallel to the atlas was intraoperatively ensured by fluoroscopy. A restrained loop was placed in a subcutaneous pocket suprascapular before the leads were connected to extension wires at the midthoracic level. Extension leads were externalized at the flank and secured with atraumatic suture (e.g. Prolene 2.0 Õ, Johnson & Johnson GmbH, Neuss, Germany) to the skin. Intraoperatively, only adequate resistances were verified ( Ohm), as from our experience this operation technique warrants a highly reproducible stimulation of the main trunk of the greater occipital nerve. Therefore, the intraoperative testing of the achieved paresthesia appears to be superfluous. Stimulation settings Leads were programmed in a way that paresthesia covered the occipital and nuchal region in the course of the greater occipital nerve. Stimulation parameters were only partially prefixed (impulse width of 390 us, at 40 Hz), which was convenient for all patients. All patients underwent a test stimulation period of 30 days (CCH) and 45 days (CM), respectively. During the test phase patients continued the headache diary.

3 Mueller et al Success of stimulation was determined by a 50% reduction of headache days or attacks, and/or relief of pain intensity during the attacks as rated on a numeric rating scale (NRS) from zero (pain free) to ten (maximum pain intensity). Evaluation of the diaries was performed interdisciplinarily by a neurologist and a neurosurgeon. Patients responding to treatment received an implantable permanent generator (IPG; e.g. Synergy Õ, Medtronic Inc; EonC Õ, EonMini Õ, St. Jude Medical). Implantation site of the IPG was to the patient s preference: either abdominal or gluteal. Complications and costs During the follow-up (FU) period, all complications were recorded and classified as procedure related or coincidental. To evaluate treatment costs directly linked to the procedure, we prospectively assessed all expenses for hardware on the basis of each current proposal for electrodes and IPGs at that time. Additionally, costs for hospitalization were included based on the G-DRG for CCH (G44.0) and complex migraine (G43.8), respectively. International Classification of Diseases 10 German Modification (ICD-10-GM) and the Operation- and Procedure- Classification (OPS) for 2012 were used to calculate G-DRG reimbursement including cost weight, base rate and adjustment factors. The OPS for peripheral nerve stimulation (PNS) were and c1, respectively, triggering DRG B17B with a reimbursement of E4,084 per hospitalization. In case of readmission of the patient for arbitrary reasons within 30 days, cases were conflated according to current regulation of the German health care system. Procedure surcharges were calculated only on the basis of cost of the hardware, leaving individual hospital negotiations with health insurance companies out of consideration. Results Twenty-seven patients (nine females, 18 males; mean age 30 years) were treated with ONS in this prospective study. Among this population 24 patients suffering from CCH, and three patients with CM were operated on. Mean FU was 20 months. Two patients were lost to FU after eight and 12 months, respectively. For patient characteristics, see Table 1. Clinical FU Two patients did not respond to treatment, both suffering from CCH. One CCH patient did not respond with a reduction of the cluster attacks, but felt substantial relief of the accompanying migraine. Overall response rate in this single-center series was 89% at Table 1. Diagnosis, gender, length of follow-up (months) and response to treatment for each patient. Subject n Diagnosis Gender Follow-up (m) Treatment responder 1 CCH F 47 R 2 CCH M 46 R 3 CCH M 45 R 4 CCH M 24 (NR) a 5 CCH M 37 R 6 CCH M 43 R 7 CCH M 32 R 8 CCH M 27 R 9 CCH M 24 R 10 CCH F 12 R 11 CCH M 30 R 12 CCH M 16 NR 13 CCH M 17 R 14 CCH M 20 R 15 CCH M 24 R 16 CCH M 20 R 17 CCH F 8 R 18 CCH F 4 NR 19 CCH F 9 R 20 CCH F 12 R 21 CCH M 4 R 22 CCH M 4 R 23 CCH F 6 R 24 CCH M 5 R 25 CM F 5 R 26 CM F 12 R 27 CM M 5 R CCH: chronic cluster headache; CM: chronic migraine. a No reduction in cluster attacks, but reduction of intensity of accompanying tension headache. three months short-term FU. At last FU, 21 of 27 patients remained responders to ONS therapy (78%). All patients followed for more than six months reported intercurrent episodes with a significant increase of cluster attacks or headache days with aggravated migraine at latest FU, requiring medical intervention by increased doses of prophylactic drugs or acute medication. CM patients suffered on average 27 headache days (20 30 days) preoperatively. At last FU mean headache days dropped down to mean 20 days (10 30 days). Two of three patients needed fewer triptans during migraine attacks. All CM patients stated that the duration of migraine attacks was reduced by 50%. Patients with refractory CCH experienced five attacks per day on average (one to 14 attacks/day)

4 1286 Cephalalgia 33(16) with a mean pain score of 8 on the NRS preoperatively. When seen for latest FU, the number of attacks declined on average to three (zero to eight attacks/ day). Additionally, the NRS score was lower at an average of 5 (0 9 NRS). Patients consumed 1.5 triptans (range zero to six doses) per day before stimulation. At latest FU a mean of 0.9 doses/day was used. Six patients were able to terminate the use of triptans for acute medication during the attacks. Thirteen patients repeatedly experienced pain-free days without CCH attacks for at least five days in a row. Accordingly, 21 of 27 patients reported satisfaction with the operative result compared to their preoperative status in our questionnaire, but furthermore 22 of 27 patients would recommend the procedure to other patients. Nonhardware-related complications Five nonhardware-related complications were observed in 27 patients (19%). Two patients reported worsening of the cluster attacks by the stimulation after six months of initially successful trials. Therefore, one patient discontinued stimulation for four months before another trial was initiated. Afterward, the stimulation did not provoke cluster attacks anymore, but the initially good response returned to a level at which the stimulation only supported acute medication to interrupt the attacks more quickly. The other patient declined another trial and was lost to FU after eight months. One patient lost effectiveness of the stimulation after six months, despite every conceivable reprogramming of the stimulation with regards to pulse width, amplitude, frequency, and continuous and discontinuous stimulation. The patient finally received intravenous dihydroergotamine (DHE; 10 mg total dose) as an offlabel medication (DHE is not approved for CM and CH in Germany), which controlled CCH for an FU period of eight months, so far (26). ONS provoked uncontrollable nausea in one patient. Nausea was directly related to the stimulation and was refractory to antiemetic medication. When the stimulation was turned off, nausea disappeared immediately. Even sub-threshold stimulation provoked this phenomenon. With all antiemetic medication failing, we even tried transcutaneous stimulation of the vagal nerve, ipsi- and contralaterally to control nausea (27). However, it did not show any influence on the complaints. The problem remains unsolved to date. So far, we have not found this complication reported in recent literature. A pressure ulcer formed in one patient at the scar of the IPG that was located under the belt. It was conservatively treated with dry dressings and mended without further consequences. Details are given in Table 2. Table 2. List of hardware-related or non-hardware-related complications and the subsequent necessity of re-operation. Hardware-related complications Local pain/discomfort 4 3 Cable breaks 3 3 Lead dislocation 1 a IPG discharge 2 2 Non hardware-related complications Infections 6 5 Pressure ulcers at operation site 1 Nausea, refractory 1 Conversion of stimulation effect 2 Loss of stimulation effect 1 Intercurrent cluster episodes 21/21 b a Iatrogenic; maintained stimulation by second lead. b Referring to chronic cluster headache (CCH) patients only. Hardware-related complications In 14 of 27 (52%) patients, therapy-associated complications were noted. The majority of complications were local infections, leading to explantation of the hardware in four patients (15%). Of these patients, two experienced recurrent infections requiring several surgical interventions. In two patients the gluteal IPGs had to be replaced for sciatic irritations. In one of these patients the extension lead presumably broke during the procedure and had to be exchanged in another operation. Two patients complained of local pain at the connector site; one of them had to be revised (21). Two generators had to be replaced because the battery ran down (after 46 and 48 months, respectively). One stimulation electrode developed malfunction after 46 months and had to be revised. Another lead wire broke after four months, but stimulation could be performed for both sides with the contralateral electrode. Thus, the broken lead did not have to be replaced. This might be explained by the fact that in the same patient an iatrogenic lead displacement of an electrode occurred. When the extension wires were exchanged during IPG implantation, the stimulation lead was presumably pulled for too long, displacing it for about 3 cm compared to preoperative X-rays. Still, the lead was in place to establish a sufficient stimulation over the occiput in the patient, even more covering the contralateral site with the broken lead. One extension lead had to be exchanged four weeks after implantation. Technical investigation of the electrode suggested a damage of the isolation, suggesting n Required re-operation

5 Mueller et al Table 3. Breakdown of in-hospital costs for the test period, secondary and subsequent operations. Hospitalization costs (E) calculated for DRG B17B a Trial period 109,296 Final implantation 101,200 Subsequent interventions (incl. complications) 44,528 a Interventions at the peripheral nerve system. Table 4. Hardware materials employed in all patients are listed. Direct hardware-related costs n Total (E) Leads 62 67,182 Extensions ,590 IPGs ,907 Patient programmer 30 20,340 IPGs: implantable permanent generators. an iatrogenic complication. Yet, peri- and postoperative testing of the system in this patient showed normal resistances. The extension lead had to be replaced, and the system has worked ever since. Hospitalization costs On the basis of the G-DRG B17B (procedures affecting peripheral or cranial nerves; flat rate payment E4048 per case), overall costs for hospitalization totaled E255,024. Hospitalization costs were calculated as follows: For the testing period costs for 27 cases were calculated to E109,296. In 25 cases IPGs were implanted afterward, which incurred costs of another E. Re-operations for complications (e.g. removal of infected hardware) or run out IPGs were taken into account only if the initial procedure for the patient affected was 30 or more days ago. Otherwise, cases (n ¼ 2) were subsequently summarized in a single DRG, triggering reimbursement only once. Consecutive costs for re-hospitalizations were calculated to be E44,528 (see also Table 3). Overall per case costs were calculated at E9445, or E7796, respectively, without consecutive hospitalization costs as listed before. Hardware costs Standardized implantation procedures included bilateral stimulation leads (Octrode, St. Jude Medical; Pisces Quad (Plus), Medtronic Inc) and extension leads that were at first externalized, and after successful trial phase exchanged for another pair of wires. Individual treatment costs ranged between E2345 for the trial phase only, and E18,200 for successful stimulation including IPG implantation. A total of 62 stimulation leads were implanted, amounting to E67,182. Expenses for extension kits totaled E39,590. Thirty IPGs were implanted, which came to a total volume of E378,907 (overview in Table 4). Finally, patient programmers amounted to E20,340. Thus, E506,019 was calculated for total treatment costs overall. Prices for electrodes, leads and IPGs were calculated from firm offers for bilateral ONS. Overall treatment costs amounted to E761,043 for 27 patients in a 47-month period. Thus, mean treatment costs were calculated at E28,186 per case. This calculation neglects the continuing visits at the headache center, neurosurgical outpatient department or neurologist, as we deemed the effect of the consecutive costs of minor importance for overall treatment costs. Discussion Neuromodulative procedures have been shown to be effective as an additional treatment option for refractory headaches for more than a decade. For CCH, randomized trials with sham stimulation were not yet performed. Weiner and Reed were the first to report on ONS for intractable occipital neuralgia (18). Subsequently, ONS was adopted for other primary headache disorders in refractory conditions (19,28). Case series with short- up to long-term FUs were reported that showed good to excellent response of CCH and CM to ONS (19,20,29). Effectiveness of the stimulation was comparable to published data of DBS procedures but harbored a lower morbidity (15,30). Yet, multicenter studies conducted to analyze the value of ONS for the treatment of refractory CM lacked evidence of significant impact on CM (31,32). Nevertheless, CM and CCH patients seem to respond to treatment in about 80% of the cases with a reduction of headache days, headache attacks and/or reduction of pain intensity between 30% and 100% (20,21,29,32 34). Individual reduction of attacks and headache days vary significantly between studies (17,20,29,31 33,35,36). Predictive factors for response to ONS could neither be established from the current literature nor from our own experience (37). Assuming a success rate of 80%, it is debatable whether lead electrodes and IPGs should be implanted all-in-one or whether a trial phase is justified to selected responders and nonresponders. From our personal experience, we suggest performing a test phase rather than implanting an all-in-one procedure (21). One may assume that one or two out of ten IPGs will be wasted in patients who do not benefit

6 1288 Cephalalgia 33(16) from ONS. This will spare treatment costs for IPGs of at least of E9939 before taxes per case (calculated for Synergy Õ, Medtronic Inc, cheapest multichannel IPG required with use of bilateral electrodes). Still, costs of the second operations rise and cumulate for all cases. Complications have been reported in nearly every study, but morbidity rates can be taken only from systematic reviews (22,33). In the beginning of ONS, lead dislocation was a major issue (19,35). Using paddle electrodes reduced the rate of dislocated electrodes almost to zero. Paddles require a more invasive surgical approach, but may be associated with less scar formation around the leads (33). With improvement of implantation techniques, it became clear that creation of stress loops leads to stable placement of electrodes (38). Interestingly, the use of externalized extension leads did not cause more dislocations, nor is the location of the IPG (abdominal or gluteal) associated with increased lead migration in our series. Strict standard operation procedures (SOP) may help implanters to further reduce the rate of lead dislocations as well as to reduce the infection rate. Infection is a hazardous complication for any implanted device as it necessitates explantation of the whole system in most cases (33). Perioperative administration of intravenous antibiotics (preferably thirdgeneration cephalosporines) have lowered infection rate to a minimum (39). Even though we externalized the extension leads for 30 and more days, we did not find an increase of infections at the exit site or in conjunction with the leads themselves. Of the four patients suffering this specific complication in our series, infection site was distant to the extension leads. In two cases infections developed at the IPG site, far from the externalization and after removal of the extension leads. One of these patients suffered a localized infection around the connector of the stimulation lead prior to the IPG infection, due to a fistula that was caused by the laced thread securing the connector. In the remaining two patients repetitive generalized infections occurred despite extremely careful handling, strict aseptic proceedings and, after first relapse, performing an all-in-one implantation afterward. Both patients suffered from defilement of the skin and acne with history of recurrent pustules. After suffering infections for the second time implantation was abandoned in both patients. Even though we consider the complication rate high in the present series, the rate of re-operations is similar or even lower comparatively to previously published studies (20,31). CCH and CM both carry a severe burden for the patients in regards to social isolation, but also economic distress. Direct treatment cost in CCH patients were calculated up to E9073 for a six-month period in a tertiary headache center (2). Stokes et al. calculated health care costs in CM patients to be substantially lower, amounting to approximately E1535 (United States (US)), and E588 (Canada) within one year, respectively (12). In a recent analysis, annual treatment costs for CM in Germany were estimated to be E1495 (13). In our series, individual average treatment costs for ONS were calculated to be E28, over a 48-month period (mean individual FU 20 months). So far, two generators had to be exchanged because of battery discharge. From our data, we suppose that nonrechargeable IPGs in ONS will have a durability of about four to six years. Lifespan for rechargeable IPGs is indicated for about 10 years (e.g. Eon Mini TM IPG, St. Jude Medical, technical information), producing even higher individual therapy costs. Treatment costs of ONS have to be balanced against conservative pain treatment costs. Unfortunately, to date there is virtually no report on savings in therapy costs based on the calculation of ONS-related costs and the reduction of medical treatment costs. A major drawback of the present study is that we can offer only sparse information on the reduction of conservative treatment costs. Assuming that a daily intake of 1.5 triptan doses preoperatively costs E49,31 (calculated for Imigran Õ -Inject, GlaxoSmithKline GmbH & Co KG, Munich, Germany; single-dose equivalent E36.98), conservative medical treatment costs were reduced at latest FU to an average of E33,28 (0.9 doses/day) for CCH patients. However, a part of the patients used triptans nasal spray, which reduced the costs and most migraine patients are treated with oral triptans. CM patients rather use oral triptans or nasally administered triptans in severe attacks. This dilutes the economic aspect for ONS in CM further. Furthermore, it is important to compare ONS treatment costs with treatment expenses managing other chronic neurological diseases. For this, we gathered data on therapy costs of Parkinson s disease (PD) treatment with DBS and disease-modifying therapy for relapsing remitting multiple sclerosis (MS). Managing PD with DBS is a widely accepted treatment option and numerous reports on long-term FUs have been published thus far. With respect to analysis of treatment costs, it is of great importance to outweigh procedureand hardware-related costs against substantial decrease in medical costs. In a recent analysis patients receiving DBS versus best medical treatment (BMT) were followed prospectively for six months, identifying a decrease in levodopa equivalents (LEDD) by 13% in the treatment group. Still, medical costs did not decrease significantly in this study as a raised consumption for dopamine agonists and catechol-o-methyltransferase (COMT) inhibitors was found (40). However, in another study a substantial reduction in medical treatment costs for patients undergoing DBS

7 Mueller et al for stimulation of subthalamic nuclei was found after one year. Hardware- and procedure-related costs for the initial implantation (E18,456) were comparable to our data (41). The study period, again, is too short to analyze subsequent costs of battery replacement. Cost-of-illness studies in MS revealed that diseasemodifying therapies account for 69% of the total annual treatment costs. Estimated mean annual MSrelated health care costs in the US amount to $23,434 (42). A recent prospective study of annual treatment cost in Germany for a patient with relapsing remitting MS totaled E25,270 (indirect costs: E4457, direct costs: E17,792); costs of secondary progressive MS are 1.7-fold higher (43). MS has an estimated prevalence comparable to CCH, therefore treatment costs for disease-modifying therapies can be balanced against treatment costs of ONS in CCH. Bearing this in mind, one might conclude from our data that ONS is an expensive treatment option initially, but concerning direct subsequent costs of ONS, therapy expenses may further decrease with length of observation period and ongoing success of therapy. In our series we did not find a single patient who remained completely pain free after ONS, even though patients reported attack-free intervals during three months. Thus, remaining conservative medical treatment costs have to be taken into account when counting costs for ONS at all. Nevertheless, for the clinical results in our series more than 80% of the patients were responders to ONS and gained substantial relief of frequency of attacks, intensity of attacks, and duration of attacks, respectively. This is in accordance with previously reported data (18,20,29,35). It is also reflected in the questionnaires, in which 78% reported that they were satisfied with their physical and psychological conditions compared to preoperative status. Furthermore, 81.5% would recommend ONS to other patients with refractory headaches. Success of treatment equally accounted for CCH and CM. Yet, mid- and longterm FU data for CM in our series cannot be provided. A longer FU for our CM patients has to be awaited. Additionally, it has to be kept in mind that any study on ONS is subjected to a negative selection bias as so far only the most refractory patients are subjected to ONS. This in turn justifies using even an expensive treatment as every other therapy failed in these patients. Conclusion ONS is an expensive procedure that should be reserved for patients with refractory headaches. The method carries a substantial risk of complications; among them infection seems to be of critical importance. In patients who respond to treatment attack-free periods of several weeks can be accomplished. The majority of patients will still suffer attacks, but they decrease in frequency and intensity as compared to an individually ascertained baseline. In comparison to other progressive neurological disorders, ONS for CCH and CM has a relatively high initial cost factor that may favorably decrease over a long observation period concerning annual individual treatment costs. Clinical implications. ONS is a valuable but still cost-intensive therapy for treating refractory headache disorders.. ONS harbors a significant complication rate even in experienced hands.. Patients who are responsive to treatment may experience a substantial decrease of frequency of cluster attacks and/or intensity of their headaches days. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Conflicts of interest O. Mueller has received honoraria from St. Jude Medical, Autonomic Technologies, and a restricted grant from Medtronic. C. Gaul has received honoraria for contributing to advisory boards or oral presentations from St. Jude Medical, Electrocore, Autonomic Technologies, and a restricted grant from Medtronic. H. Diener has received honoraria for contributing to advisory boards from St. Jude Medical and Medtronic. P. Dammann, K. Rabe, V. Hagel and U. Sure have nothing to declare. References 1. Robbins MS and Lipton RB. The epidemiology of primary headache disorders. Semin Neurol 2010; 30: Gaul C, Finken J, Biermann J, et al. Treatment costs and indirect costs of cluster headache: A health economics analysis. Cephalalgia 2011; 31: Wang SJ, Wang PJ, Fuh JL, et al. Comparisons of disability, quality of life, and resource use between chronic and episodic migraineurs: A clinic-based study in Taiwan. Cephalalgia 2013; 33:

8 1290 Cephalalgia 33(16) 4. Bigal ME, Serrano D, Reed M, et al. Chronic migraine in the population: Burden, diagnosis, and satisfaction with treatment. Neurology 2008; 71: Munakata J, Hazard E, Serrano D, et al. Economic burden of transformed migraine: Results from the American Migraine Prevalence and Prevention (AMPP) Study. Headache 2009; 49: Bussone G, Usai S, Grazzi L, et al. Disability and quality of life in different primary headaches: Results from Italian studies. Neurol Sci 2004; 25(Suppl 3): S105 S Diener HC, Holle D and Dodick D. Treatment of chronic migraine. Curr Pain Headache Rep 2010; 15: Diener HC, Dodick DW, Goadsby PJ, et al. Utility of topiramate for the treatment of patients with chronic migraine in the presence or absence of acute medication overuse. Cephalalgia 2009; 29: Diener HC, Dodick DW, Aurora SK, et al. OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia 2010; 30: Diener HC, Bussone G, de Liano H, et al. Placebo-controlled comparison of effervescent acetylsalicylic acid, sumatriptan and ibuprofen in the treatment of migraine attacks. Cephalalgia 2004; 24: Gaul C, Diener HC and Mu ller OM. Cluster headache: Clinical features and therapeutic options. Dtsch Arztebl Int 2011; 108: Stokes M, Becker WJ, Lipton RB, et al. Cost of health care among patients with chronic and episodic migraine in Canada and the USA: Results from the International Burden of Migraine Study (IBMS). Headache 2011; 51: Bloudek LM, Stokes M, Buse DC, et al. Cost of healthcare for patients with migraine in five European countries: Results from the International Burden of Migraine Study (IBMS). J Headache Pain 2012; 13: Irimia P, Palma JA, Fernandez-Torron R, et al. Refractory migraine in a headache clinic population. BMC Neurol 2011; 11: Leone M, Franzini A, Cecchini AP, et al. Hypothalamic deep brain stimulation in the treatment of chronic cluster headache. Ther Adv Neurol Disord 2010; 3: Leone M, Franzini A, Proietti Cecchini A, et al. Deep brain stimulation in trigeminal autonomic cephalalgias. Neurotherapeutics 2010; 7: Magis D, Gerardy PY, Remacle JM, et al. Sustained effectiveness of occipital nerve stimulation in drug-resistant chronic cluster headache. Headache 2011; 51: Weiner RL and Reed KL. Peripheral neuromodulation for control of intractable occipital neuralgia. Neuromodulation 1999; 2: Popeney CA and Alo KM. Peripheral neurostimulation for the treatment of chronic, disabling transformed migraine. Headache 2003; 43: Burns B, Watkins L and Goadsby PJ. Treatment of medically intractable cluster headache by occipital nerve stimulation: Long-term follow-up of eight patients. Lancet 2007; 369: Mueller OM, Gaul C, Katsarava Z, et al. Occipital nerve stimulation for the treatment of chronic cluster headache lessons learned from 18 months experience. Cen Eur Neurosurg 2011; 72: Magis D and Schoenen J. Advances and challenges in neurostimulation for headaches. Lancet Neurol 2012; 11: The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004; 24 (Suppl 1): May A and Ju rgens TP. Diagnosis and therapy of chronic headaches [in German]. Nervenarzt 2010; 81: ; quiz Mu ller OM, Gaul C, Katsarava Z, et al. Bilateral occipital nerve stimulation for the treatment of chronic cluster headache: Case series and initiation of a prospective study [in German]. Fortschr Neurol Psychiatr 2010; 78: Nagy AJ, Gandhi S, Bhola R, et al. Intravenous dihydroergotamine for inpatient management of refractory primary headaches. Neurology 2011; 77: Sallam H, McNearney TA, Doshi D, et al. Transcutaneous electrical nerve stimulation (TENS) improves upper GI symptoms and balances the sympathovagal activity in scleroderma patients. Dig Dis Sci 2007; 52: Matharu MS, Bartsch T, Ward N, et al. Central neuromodulation in chronic migraine patients with suboccipital stimulators: A PET study. Brain 2004; 127: Magis D, Allena M, Bolla M, et al. Occipital nerve stimulation for drug-resistant chronic cluster headache: A prospective pilot study. Lancet Neurol 2007; 6: Leone M, Proietti Cecchini A, Franzini A, et al. Lessons from 8 years experience of hypothalamic stimulation in cluster headache. Cephalalgia 2008; 28: ; discussion Silberstein SD, Dodick DW, Saper J, et al. Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine: Results from a randomized, multicenter, double-blinded, controlled study. Cephalalgia 2012; 32: Saper JR, Dodick DW, Silberstein SD, et al. Occipital nerve stimulation for the treatment of intractable chronic migraine headache: ONSTIM feasibility study. Cephalalgia 2011; 31: Jasper JF and Hayek SM. Implanted occipital nerve stimulators. Pain Physician 2008; 11: Burns B, Watkins L and Goadsby PJ. Treatment of intractable chronic cluster headache by occipital nerve stimulation in 14 patients. Neurology 2009; 72: Schwedt TJ, Dodick DW, Hentz J, et al. Occipital nerve stimulation for chronic headache long-term safety and efficacy. Cephalalgia 2007; 27: Leone M, Franzini A, Cecchini AP, et al. Stimulation of occipital nerve for drug-resistant chronic cluster headache. Lancet Neurol 2007; 6: Paemeleire K and Bartsch T. Occipital nerve stimulation for headache disorders. Neurotherapeutics 2010; 7:

9 Mueller et al Falowski S, Wang D, Sabesan A, et al. Occipital nerve stimulator systems: Review of complications and surgical techniques. Neuromodulation 2010; 13: Forbes SS and McLean RF. Review article: The anesthesiologist s role in the prevention of surgical site infections. Can J Anaesth 2013; 60: Weaver FM, Stroupe KT, Cao L, et al. Parkinson s disease medication use and costs following deep brain stimulation. Mov Disord 2012; 27: Valldeoriola F, Morsi O, Tolosa E, et al. Prospective comparative study on cost-effectiveness of subthalamic stimulation and best medical treatment in advanced Parkinson s disease. Mov Disord 2007; 22: Owens GM, Olvey EL, Skrepnek GH, et al. Perspectives for managed care organizations on the burden of multiple sclerosis and the cost-benefits of disease-modifying therapies. J Manag Care Pharm 2013; 19: S41 S Karampampa K, Gustavsson A, Miltenburger C, et al. Treatment experience, burden and unmet needs (TRI- BUNE) in MS study: Results from Germany. Mult Scler 2012; 18: