Sacral Neuromodulation for Refractory Lower Urinary Tract Dysfunction: Results of a Nationwide Registry in Switzerland

european urology 51 (2007) 1357 1363 available at www.sciencedirect.com journal homepage: www.europeanurology.com Neuro-urology Sacral Neuromodulation for Refractory Lower Urinary Tract Dysfunction: Results of a Nationwide Registry in Switzerland Thomas M. Kessler a, *, Eric Buchser b, Sylvain Meyer c, Daniel S. Engeler d, Abdul-Wahab Al-Khodairy e, Ulf Bersch f, Christophe E. Iselin g, Bruno Roche h, Daniel M. Schmid i, Brigitte Schurch j, Stephane Zrehen k, Fiona C. Burkhard a on behalf of the Swiss Sacral Neuromodulation Working Group a Department of Urology, University of Bern, Bern, Switzerland b Division of Anesthesiology, Regional Hospital Morges, Morges, Switzerland c Division of Obstetrics and Gynecology, Regional Hospital Morges, Morges, Switzerland d Department of Urology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland e Spinal Cord Unit, Rehabilitation Clinic SuvaCare, Sion, Switzerland f Swiss Paraplegic Center, Nottwil, Switzerland g Department of Urology, University of Geneva, Switzerland h Proctology Unit, Department of Visceral Surgery, University of Geneva, Switzerland i Department of Urology, University of Zürich, Zürich, Switzerland j Spinal Cord Injury Center, University of Zürich, Zürich, Switzerland k Medtronic Europe, Tolochenaz, Switzerland Article info Article history: Accepted November 3, 2006 Published online ahead of print on November 13, 2006 Keywords: Sacral neuromodulation Lower urinary tract dysfunction Swiss Registry Abstract Objective: To assess the efficacy and safety of sacral neuromodulation (SNM) in patients with refractory lower urinary tract dysfunction in Switzerland based on a nationwide registry. Patients and methods: A total of 209 patients (181 females, 28 males) underwent SNM testing between July 2000 and December 2005 in Switzerland. Subjective symptom improvement, bladder/pain diary variables, adverse events, and their management were prospectively registered. Results: SNM testing was successful (defined as improvement of more than 50% in bladder/pain diary variables) in 102 of 209 patients (49%). An implantable pulse generator (IPG) was placed in 91 patients (89% of all successfully tested and 44% of all tested patients). Of the IPG-implanted patients, 71 had urge incontinence, 13 nonobstructive chronic urinary retention, and 7 chronic pelvic pain syndrome. After a median follow-up of 24 mo, SNM was successful in 64 of the 91 IPG-implanted patients (70%) but failed in 27 patients. SNM was continued in 15 of the 27 patients considered failures, because following troubleshooting SNM response improved subjectively and the patients were satisfied. However, improvement in bladder/pain diary variables remained less than 50%. In the other 12 patients both the leads and the IPG were explanted. During the test phase and during/following IPG implantation, 6% (12 of 209) and 11% (10 of 91) adverse event rates and 1% (3 of 209) and 7% (6 of 91) surgical revision rates were reported, respectively. Conclusions: SNM is an effective and safe treatment for refractory lower urinary tract dysfunction. Adverse events are usually transient and can be treated effectively. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, University of Bern, 3010 Bern, Switzerland. Tel. +41 31 632 20 45; Fax: +41 31 632 21 81. E-mail address: tkessler@gmx.ch (T.M. Kessler). 0302-2838/$ see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2006.11.011

1358 european urology 51 (2007) 1357 1363 1. Introduction Sacral neuromodulation (SNM) with InterStim 1 Therapy (Medtronic, Minneapolis, Minnesota, USA) is becoming an accepted treatment for patients with refractory lower urinary tract dysfunction, such as urgency-frequency syndrome, urge incontinence, nonobstructive chronic urinary retention, and chronic pelvic pain syndrome. In Europe, SNM has been performed since 1994 after receiving European conformity approval, the CE mark. In the United States, SNM was approved by the Food and Drug Administration in 1997. In Switzerland, according to the legislative regulations of the Swiss Federal Office of Social Insurances (SFOSI), efficacy and safety data of all patients treated with SNM (both tested and permanently implanted) have been prospectively entered into a database, the Swiss Registry, since July 2000. The results from the Swiss Registry are the main factor on which the decision is based whether in future SNM will be covered by the Swiss health care system. Here we report the results of SNM derived from this systematic, prospective, and nationwide database. 2. Patients and methods 2.1. Patients Data from a consecutive series of 209 patients (181 females, 28 males) who underwent SNM testing between 1 July 2000 and 31 December 2005 were prospectively registered. Indications for SNM included urge incontinence, nonobstructive chronic urinary retention, and chronic pelvic pain syndrome. All patients were refractory to conventional therapies and underwent a complete urologic evaluation before SNM treatment, including medical history, physical examination, bladder and/ or pain diary, urine analysis, urine culture, and urodynamic studies. Informed consent was obtained from all patients. 2.2. Data collection The SFOSI approved reimbursement of SNM for the treatment of lower urinary tract dysfunction under the condition that the data from all tested and implanted patients would be registered in a database. Medtronic Switzerland was assigned to monitor and maintain the Swiss Registry. Data entered included previous treatments, testing/implantation techniques, testing/implantation characteristics, baseline and follow-up visits, as well as adverse events and their management. 2.3. Surgical and testing technique During the study period (Fig. 1), different techniques were used depending on the treating physician s preferences: (1) SNM testing using temporary (unipolar wire electrodes) leads (185 patients), which is the traditional percutaneous or peripheral nerve evaluation (PNE) [1]. In case of successful testing, (a) both the definitive lead and the implantable pulse generator (IPG) were implanted simultaneously (59 patients), or (b) another test phase using definitive leads was performed (11 patients). (2) SNM testing using definitive leads (24 patients) externalized by an extension (a) following open lead implantation through a median incision over the sacrum (13 patients) [2], or (b) after minimally invasive percutaneous tined lead placement Fig. 1 Most patients underwent sacral neuromodulation testing with temporary leads. Overall, the test phase was successful in 49% (102 of 209) of patients; 89% (91 of 102) of the successfully tested patients and 44% (91 of 209) of all tested patients underwent implantation of the implantable pulse generator.

european urology 51 (2007) 1357 1363 1359 (11 patients) [3]. In case of successful testing, the extension was removed and the IPG implanted. For placement of the electrode, a needle and lead were inserted into the third sacral foramen (occasionally S2 or S4 was used). The optimal position of the needle and the lead was determined by the motor and/or sensory response to temporary electrical stimulation of the sacral nerves. The classic response to S3 stimulation was a contraction of the anal sphincter (the bellows response), plantar flexion of the big toe, and a pulse-related sensation felt in the rectum, bladder, perineum, scrotum, or vagina. All patients completed a bladder and/or pain diary during the test phase. In accordance with the literature [4 8], an improvement of more than 50% in bladder/pain diary variables (number of leakages, pad use, number of voids, number of catheterizations, pain visual analogue scale of 0 to 10) was considered a positive test, an indication for implantation of the IPG, and success in follow-up. The IPG was placed subcutaneously in the anterior abdominal wall in the early study period and thereafter in the upper buttock. When IPG-implanted patients reported a loss of symptom improvement, a troubleshooting algorithm was followed: An antero-posterior and lateral X-ray of the sacrum was obtained. If the lead was in good position, the system was checked for malfunctioning and reprogrammed extensively before the unit was removed. When the lead had migrated, it was repositioned and reinforced whenever possible, otherwise the lead was removed and a new lead implanted. 2.4. Outcome measures Primary outcome measures were the assessment of subjective symptom improvement and changes in bladder/pain diary variables of all SNM tested and permanently implanted patients. Secondary outcome measures were the incidence and treatment of adverse events due to SNM. 2.5. Statistical analysis Data are presented as median and interquartile range (IQR). Comparing related samples, the Wilcoxon signed rank test was used or the Student s t-test when distribution parameters allowed. In unrelated samples, the Mann-Whitney U-test was applied for quantitative variables and the Fisher s exact test for categorical variables. A p value of <0.05 was considered significant. Statistical analyses were performed using SAS 9.1 (SAS Institute, Inc., Cary, North Carolina, USA). 3. Results 3.1. Test phase The median age of the 209 patients undergoing SNM testing was 58 yr (IQR: 47 70). A total of 153 suffered from urge incontinence (137 females, 16 males), 39 from nonobstructive chronic urinary retention (33 females, 6 males) and 17 from chronic pelvic pain syndrome (11 females, 6 males). The median duration of the initial test phase was significantly ( p < 0.0001) longer when definitive leads (median test phase: 23 days, IQR: 12 28) compared to temporary leads (median test phase: 7 days, IQR: 5 8) were used. Initial and overall (considering both initial testing with temporary leads as well as additional testing with definitive leads) SNM testing (Fig. 1) was successful in 96 (46%) and 102 (49%) of the 209 patients. There was a significantly ( p = 0.03) higher success rate of initial SNM testing when definitive (16 of 24, 67%) rather than temporary (80 of 185, 43%) leads were used. SNM testing with temporary and definitive leads was performed bilaterally in all patients and in 12 patients, respectively. In 1 patient with failed prior unilateral testing using a definitive lead, an additional bilateral test was performed that was successful. In addition, 6 patients in whom initial SNM testing with temporary leads failed had a successful testing result when definitive leads were subsequently used, so that these patients underwent IPG implantation. In all patients in whom SNM testing with definitive leads was considered a failure, the definitive leads were explanted. 3.2. IPG-implanted patients Ninety-one of the 102 successfully tested patients (89%; ie, 44% of all 209 tested patients) underwent implantation of the IPG (median age: 57 yr, IQR: 47 70; 85 females, 6 males). The remaining 11 patients refused IPG implantation for personal reasons despite positive testing. Of the IPG-implanted patients, 11 patients (4 with urge incontinence, 5 with nonobstructive chronic urinary retention, and 2 with chronic pelvic pain syndrome) were stimulated bilaterally with a two-channel device (Synergy 1 n = 3, Twin 1 n = 8) and 80 (67 with urge incontinence, 8 with nonobstructive chronic urinary retention, and 5 with chronic pelvic pain syndrome) unilaterally with a one-channel device (InterStim 1 ). The median follow-up of the IPG-implanted patients with urge incontinence, nonobstructive chronic urinary retention, and chronic pelvic pain syndrome was 24 mo (IQR: 8 37), 12 mo (IQR: 5 29), and 10 mo (IQR: 5 11), respectively. SNM resulted in significant improvement of bladder/pain diary variables, which was maintained over time regardless of the type of lower urinary tract dysfunction. There was a sustained subjective symptom improvement of more than 50% following IPG implantation in patients with urge incontinence (Table 1) and nonobstructive chronic urinary retention (Table 2). In those suffering from chronic pelvic

1360 european urology 51 (2007) 1357 1363 Table 1 Bladder diary variables and subjective symptom improvement of the 71 patients implanted with an implantable pulse generator suffering from urge incontinence at baseline, first follow-up, and last follow-up Baseline (A) First follow-up (B) Last follow-up (C) Median (IQR) Median (IQR) Median (IQR) Number of leakages per 24 h a 5 (2 10) 0 (0 2) 0 (0 2) Pad use per 24 h b 4 (2 5) 1 (0 2) 1 (0 3) Number of voids per 24 h c 10 (5 13) 6 (4 7) 6 (4 8) Subjective symptom improvement (%) 70 (20 90) 80 (40 99) a AvsBp < 0.0001, A vs C p < 0.0001. b AvsBp < 0.0001, A vs C p < 0.0001. c AvsBp < 0.0001, A vs C p = 0.0005. Table 2 Bladder diary variables and subjective symptom improvement of the 13 patients implanted with an implantable pulse generator suffering from nonobstructive chronic urinary retention at baseline, first follow-up, and last follow-up Baseline (A) First follow-up (B) Last follow-up (C) Median (IQR) Median (IQR) Median (IQR) Number of catheterizations per 24 h a 4 (2 4) 0 (0 0) 0 (0 0) Number of voids per 24 h b 3 (0 6) 6 (6 9) 5 (5 6) Subjective symptom improvement (%) 95 (59 100) 85 (51 100) a AvsBp = 0.0001, A vs C p = 0.001. b AvsBp = 0.25, A vs C p = 0.23. pain syndrome, subjective symptom improvement decreased slightly over time (Table 3). After a median follow-up of 24 mo (IQR: 8 37), SNM was successful in 64 of the 91 IPG-implanted patients (70%) but failed in 27 patients (21 of 71 with urge incontinence, 4 of 13 with nonobstructive chronic urinary retention, and 2 of 7 with chronic pelvic pain syndrome). SNM was continued in 15 (2 were stimulated bilaterally using a two-channel device; Synergy 1 n = 1, Twin 1 n = 1) of the 27 patients considered failures because, following troubleshooting, SNM response improved subjectively in more than 50% and the patients were satisfied with their situation. However, the improvement in bladder/pain diary variables remained less than 50%. In the other 12 patients (8 of 71 with urge incontinence, 3 of 13 with nonobstructive chronic urinary retention, and 1 of 7 with chronic pelvic pain syndrome) the leads and IPG were explanted due to refractory complete loss of the initial positive SNM effect. None of these 12 patients was stimulated bilaterally. 3.3. Adverse events During the test phase, adverse events were recorded in 12 of the 209 patients (6%). Lead migration was reported in 9 patients (all with temporary leads), wound infection in 2 patients (1 with temporary leads, 1 with tined leads), and refractory pain at the tined lead site in 1 patient. Surgical revision was required in 1% (3 of 209) because of wound infection (n = 2) and refractory pain at the tined lead site (n =1). During/following the IPG implantation (Table 4), adverse events were recorded in 10 of the 91 patients (11%). Surgical revision was required in 7% (6 of 91) due to wound infection at the IPG site (n = 1), lead migration (n = 2, 1 definitive lead without tines and Table 3 Pain visual analogue scale and subjective symptom improvement of the 7 patients implanted with an implantable pulse generator suffering from chronic pelvic pain syndrome at baseline, first follow-up, and last follow-up Baseline (A) First follow-up (B) Last follow-up (C) Median (IQR) Median (IQR) Median (IQR) Visual analogue scale a 8 (8 9) 0 (0 1) 2 (1 4) Subjective symptom improvement (%) 100 (100 100) 65 (45 90) a AvsBp = 0.03, A vs C p = 0.03.

european urology 51 (2007) 1357 1363 1361 Table 4 Adverse events during/following the IPG implantation in all implanted patients (n = 91) Adverse events Lead migration 2 Broken lead 1 Wound infection at the IPG site 2 Pain at the IPG site 3 IPG migration 1 IPG malfunction after magnetic resonance imaging 1 Total 10 (11%) IPG, implantable pulse generator. 1 tined lead), broken lead (n = 1), IPG migration (n = 1), and IPG malfunction after magnetic resonance imaging (n = 1). So far, only one IPG had to be replaced due to battery depletion 5.3 yr after implantation. 4. Discussion The SNM technique was developed in the early 1980s at the University of San Francisco, California, by Tanagho and Schmidt [9] and has since evolved into a widely applied therapy for patients with refractory lower urinary tract and faecal dysfunction with more than 25,000 implanted systems worldwide. After failed conservative therapy, SNM is considered a good alternative for urgency-frequency syndrome, urge incontinence, nonobstructive chronic urinary retention, chronic pelvic pain syndrome, constipation, and faecal incontinence before resorting to more invasive treatment options such as bladder augmentation, urinary diversion, bowel resection, sphincter repair procedures, or a permanent stoma. Reports concerning systematic national data collection are rare. Spinelli et al [10] reported the results from the Italian SNM Registry. However, only patients undergoing permanent implantation were enrolled, and data of the tested population was not available. To our knowledge the present study is the first to report prospective, systematic, nationwide SNM data both on tested and permanently implanted patients suffering from refractory lower urinary tract dysfunction. In the present study, SNM testing was successful in about 50% of our patients, which is in line with the 40 50% success rate of traditional PNE [4,11,12]. However, not all successfully tested patients underwent IPG implantation; about 10% refused it for personal reasons. Although scepticism from the patients and/or referring physicians viewpoint regarding SNM (despite successful testing) may be n assumed, the exact reason for this phenomenon remains unclear. Some patients undergoing traditional PNE have false negative testing results due to the suboptimal testing procedure with temporary leads [2,4,8]. To minimize technical failures, a two-stage implantation technique using a definitive lead for SNM testing was introduced by Janknegt et al [2]. The advantages of definitive lead placement versus traditional PNE are that the definitive lead is less prone to migration and allows for a longer test phase and, in the case of positive testing, the lead remains in the same position. Thus, an additional test phase with definitive leads was performed in some of our patients in whom initial SNM testing with temporary leads failed. Of these patients with prior negative PNE, 50% (6 of 12) were tested positive when using definitive leads, which is considerably lower than the 80% (8 of 10) reported by Janknegt et al [2]. In the present study, the initial test phase was significantly longer (median: 23 days vs 7 days) and more successful (67% vs 43%) when definitive rather than temporary leads were used. This is in line with other studies showing that the two-stage technique had a higher short- and long-term success rate [13] and that the eligibility for IPG implantation significantly increased from 50% after a traditional to 80% after a prolonged test phase using definitive leads [8]. With the traditional one-stage SNM technique (simultaneous implantation of both definitive lead and IPG) after positive PNE, there is a chance that the patient s beneficial response to the temporary lead is not reproduced because of the differences inherent in the temporary and definitive leads and the inability to place the lead in the exact same position in the sacral foramen [14]. Thus, additional SNM testing with definitive leads was done in some of our patients before IPG implantation, despite prior positive PNE. However, since the new self-blocking tined lead [3] has been introduced, the minimally invasive tined lead technique has been progressively used in Switzerland for the initial test procedure without prior PNE and has become the standard procedure in some centres. Considering that SNM testing using definitive leads is more reliable for accurate patient selection than the traditional PNE [2 4,8], additional testing with definitive leads may be necessary despite prior positive/negative PNE to minimize false positive/ negative testing responses. This might justify the (at least initially) markedly higher costs of SNM testing using tined leads. The role of bilateral SNM is unclear, and there is also no consensus regarding its use in Switzerland.

1362 european urology 51 (2007) 1357 1363 From our data we cannot conclude if unilateral or bilateral stimulation should be preferred. Considering the small number of bilaterally stimulated patients in each group of lower urinary tract dysfunction, we performed no subanalysis due to the lack of statistical power to detect significant differences. It may be argued that bilateral stimulation is an overtreatment and wastes resources, as in most patients one lead for successful SNM is sufficient. However, there is no predictive factor to identify patients who may benefit from bilateral stimulation. Moreover, while testing the lead during implantation and in the following initial test phase, it often remains unclear which side provides better results. Thus, bilateral SNM testing allows for a more complete evaluation and possibly offers the patient a higher chance of responding to SNM. At the time of the second stage, the side that is less efficacious can be removed or remain implanted for possible backup in case the other side fails. Recent reports have shown SNM to have a sustained efficacy and acceptable safety profile in the long term [15 17]. This is in line with the present study, in which a significant SNM effect was maintained over time, although our follow-up is limited (median: 24 mo) and the results, especially in the patients with chronic pelvic pain syndrome, tend to get worse with time. Considering an improvement of more than 50% in bladder/pain diary variables as success, SNM failed in 27 patients (30%) in the course of follow-up, despite initial positive results. Troubleshooting subjectively improved SNM response in more than 50% (15 of 27) of patients, and SNM was continued, even though the improvement in bladder/pain diary variables remained less than 50%. This mirrors the divergent concerns and priorities of patients and physicians, which may lead to a widely varying subjective and objective outcome assessment [18]. In the remaining 12 patients, the leads and IPG were explanted due to refractory (subjective and objective) complete loss of the initial positive SNM effect. Our adverse event and surgical revision rates for IPG-implanted patients are comparable with the Italian Registry [10] and lower than initially reported by the Sacral Nerve Stimulation Study Group [11,19,20]. This may be explained by technical improvements achieved during the last few years and the experience gained after the pioneering era [17]. It should be taken into account, however, that we did not consider lead explantation after uneventful SNM testing or for SNM failure during follow-up without lead migration/dysfunction as an adverse event, as it is an integral part of the SNM procedure. Although we present a large nationwide investigation, our study has some limitations. One main problem of a national registry is the varying degree of experience of the involved centres, which leads to a centre bias. Also in the present study, the majority of the procedures were performed in one centre where SNM was introduced in Switzerland. Other centres starting with SNM were gradually included in the registry. The patients were not randomized to a certain procedure but subjectively assigned to the different SNM techniques depending on the opinion and preferences of the treating physician. In addition, treatment strategies changed during the study period based on new developments regarding testing and surgical techniques as well as new hardware and software. Thus, to minimize false positive/negative testing responses, some patients with prior positive/negative PNE underwent additional SNM testing with definitive leads but others did not. Although the two-stage technique with tined leads has become the standard procedure in some centres in Switzerland, there is no consensus on the different SNM techniques or on the number of leads (unilateral vs bilateral) that should be used. These differences make interpretation of the results more difficult. Moreover, any registry depends upon the appropriateness and validity of the selected outcome measures. A selection bias by not reporting negative results or adverse events cannot be completely excluded. This problem is likely to be very limited in the present study, however, as SNM monitoring was compulsory and insurance companies would not reimburse for treatment unless the data were provided. 5. Conclusions SNM is an effective and safe treatment for lower urinary tract dysfunction refractory to conventional therapies. The most common adverse events such as lead migration, infection, and pain at the implantation site are transient and can be treated effectively. There are no permanent sequelae following adverse events, and the procedure itself is completely reversible. Conflicts of interest Thomas M. Kessler, Eric Buchser, and Fiona C. Burkhard have a consultancy agreement with Medtronic, and Stephane Zrehen is an employee of Medtronic.

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