Sacral nerve stimulation in patients with detrusor overactivity

Peer review Sacral nerve stimulation in patients with detrusor overactivity Abstract Detrusor overactivity, particularly with symptoms of urge incontinence, can be a debilitating and embarrassing condition. Sacral nerve stimulation (SNS), or sacral neuromodulation, provides a minimally invasive treatment option for those patients refractory to conventional behavioural and anticholinergic therapy. A review was performed of major studies evaluating the use of SNS for patients with refractory urge incontinence. Factors including therapy technique, efficacy, safety and cost-effectiveness were assessed. The review showed that advances in implant technique have improved both efficacy and safety for SNS. Screening with percutaneous nerve evaluation obtains a positive response in 51-63% of patients. Of the patients that receive permanent implants with a neuromodulating device, complete dryness is obtained in 40-59% of patients and 59-76% of patients report a >50% reduction in incontinence symptoms. The most common adverse events included pain at the implant site and lead migration. A surgical revision rate of 33-51.6% to overcome adverse events was reported with up to 10% requiring permanent explantation. The cost of SNS is estimated at A$9,866 per year of patient complete dryness but long-term cost-effectiveness studies are yet to be performed. In conclusion, SNS appears to be a safe and effective option for patients with refractory urge incontinence. A more detailed cost analysis needs to be conducted before cost-effectiveness can be ascertained. Keywords: urinary incontinence, detrusor overactivity, sacral nerve stimulation, neuromodulation Introduction Sacral nerve stimulation (SNS), or sacral neuromodulation, was introduced in 1994 as a treatment for various voiding and storage dysfunctions 1. Its indications include those of refractory urinary urge incontinence, urge frequency, non-obstructive urinary retention, faecal incontinence, pelvic pain and interstitial cystitis 1-3. This review will focus on the use of SNS in female patients suffering from urinary urge incontinence or detrusor overactivity (DO). In patients with symptoms of DO but no urodynamic testing, the term overactive bladder syndrome is used 4. Yufei Chen The Pelvic Floor Unit, St George Hospital University of New South Wales, Sydney, NSW Competing interests: None declared Acknowledgements: Assistance of A/Prof Kate H Moore, Director, The Pelvic Floor Unit, St George Hospital, University of New South Wales, Sydney & Member (Co-opted) Australian and New Zealand Continence Journal Editorial Committee DO in females is often refractory to conservative management 2, 4, 5. Front-line treatment usually includes behavioural therapy, pelvic floor exercises, dietary modifications (for example, fluid and caffeine reduction) and anticholinergic medication 4. Behavioural therapy such as bladder training has shown varying results, with cure rates ranging from 25% to 97%, possibly related to patient understanding and motivation 5. Anticholinergic medications, although effective, are limited by their side effects, such as a dry mouth and dyspepsia, which can often be intolerable 5, 6. Furthermore, there is a financial barrier to compliance with medical therapy, as most medications in this class are not subsidised within Australia. Intradetrusor injections of botulinum toxin have been shown to be effective in a significant portion of patients with DO, but requires recurrent administration and carries a risk of over paralysis, leading to high rates of intermittent selfcatheterisation 7. Surgical interventions are also available for DO, including bladder augmentation and urinary diversion, but these tend to be saved as a last resort for they are irreversible and are associated with considerable side effects 2, 6, 7. Volume 16 Number 1 Autumn 2010 15

As a minimally invasive procedure, SNS provides a promising intermediate option for patients with DO refractory to standard treatment or where these options are medically contraindicated 8. SNS induces neuromodulation through using mild electrical pulses to continuously stimulate sacral nerves that innervate the lower urinary tract 5. The mechanism underlying the action of SNS on the overactive bladder is thought to arise from stimulation of the A delta afferent fibres of the sacral dorsal root, which simultaneously excite central micturition inhibitory pathways as well as blocking the procontractile effect of neuropeptide release from C fibres. SNS may also stimulate urethral sphincter activity, the contraction of which inhibits detrusor contraction 9, 10. How SNS seems to paradoxically work for patients with non-obstructive urinary retention is poorly understood 11. Implant technique There have been major technical advances in recent years regarding the design and insertion of the implantable pulse generator (IPG). The exclusive supplier of IPGs is currently InterStim TM with their devices allowing external, patientcontrolled regulation of stimulation amplitude within a preprogrammed range 2, 8. The introduction of this patient-directed therapy has reduced patient discomfort and subsequent clinic visits 1, 2. InterStim TM implantation requires a two-stage process. An initial test phase with percutaneous nerve evaluation (PNE) conducted on an out-patient basis is then followed by either permanent implantation or lead removal based on PNE response 4, 11. (Figure 1) which has resulted in an increase in positive screening results 11. The tined-lead approach, with self-anchoring tine elements, allows for a longer screening duration and is less susceptible to lead migration. Furthermore, the tined-lead can be reutilised for the permanent IPG, negating the need for a second stage lead change 2, 5, 12. Since 2002, a minimally invasive procedure has been developed for tined-lead implantation under local anaesthetic, requiring no incision or additional fascial anchoring 12. The nerve supply to the majority of the pelvic organs arises from the S2-4 sacral roots. Despite S2 containing the majority of pudendal afferents, S3 is the target for SNS as its stimulation results in less undesired leg muscle contraction 11. However, pudendal afferents have been found to be limited to solely S2 in 18% 13 of patients which may account for the lack of response to S3 stimulation in certain candidates 11. During PNE, the correct sacral level can be localised by observing patient response; a successful S3 electrode placement should elicit appropriate motor and sensory responses including a bellows movement of the perineum (inward movement of anus and deepening of gluteal cleft), plantar flexion of the great toe and a pulling sensation in the vagina 1, 8, 14. The IPG has traditionally been implanted in the anterior abdominal wall through a flank incision, which required complete turning of the patient during surgery (Figure 2). Scheepens et al. 15 performed a case series of 39 patients PNE originally involved the insertion of an electrode wire through a needle probe, which is subsequently secured by adhesive tapes 1. This has been replaced by the tined-lead test Figure 1. Tined lead approach to PNE. Courtesy of Medtronic, Inc. Figure 2. InterStim TM therapy with device implanted into buttock innervating S3. Courtesy of Medtronic, Inc. 16 Volume 16 Number 1 Autumn 2010

Table 1. Efficacy of SNS for DO. Baseline versus last follow-up. Therapy success is defined as a >50% improvement in symptoms over baseline at last follow-up. Follow-up leaks Pad or diapers % patients % patients with duration per day per day completely dry therapy success Schmidt et al. 6 months 9.7 ±6.3 to 2.6 ±5.1 6.2 ±5.0 to 1.1 ±2.0 52% 76% (1999) * (p<0.0001) (p<0.0001) (at 18 months) (at 18 months) Spinelli et al. 12 months 5.4 ±3.9 to 1.1 ±1.6 NR 59% NR (2001) (p<0.001) Siegel et al. 3 years 11.6 ±6.6 to 5.0 ±6.1 6.7 ±4.6 to 3.4 ±4.9 NR 59% (2000) (p<0.0001) (p<0.0001) Bosch & Groen 5 years 7.1 to 0.7 5.4 to 1.3 40% 60% (2000) (p=0.0001) (p=0.0001) van Kerrebroeck 5 years 9.6 ±6.0 to 4.7 ±4.9 >5 to 1.8 NR 68% et al. (2007) (p<0.001) (p<0.001) * = RCT, = patients with >90% improvement in symptoms, NR = not reported who underwent buttock implantation of the IPG and found that the procedure was simpler with considerably reduced operating time (from 2.5 to 1.5 hours). More importantly, this led to decreased postoperative pain, fewer infections and a lower reoperation rate 15. Buttock placement has now become the standard approach to IPG implantation, despite a lack of highlevel evidence 2. Efficacy To be eligible for SNS therapy, patients must respond positively to PNE. A successful response is defined in most studies as a greater than 50% improvement in incontinence symptoms by bladder diary over the 3- to 7-day screening period 8, 16. In studies comprised solely of patients with DO, the positive screening rate was 51-63% 16-19. This screening rate seems to have increased with the use of the tined-lead electrode, but has not been evaluated in patients solely with DO 20. Follow-up duration and study design often varied among studies, making comparisons difficult. A prospective randomised study in patients with refractory urge incontinence showed a significant improvement in all symptoms for patients within the stimulation group after 6 months of SNS (Table 1) 19. Patients allocated to the control group who received 6 months of conventional therapy before crossing over to the stimulation group had significantly worse voiding diary parameters 19. Overall, at 18 months post-implantation, 52% of patients were completely dry, with a further 24% having >50% improvement in symptoms and 57% of patients had eliminated pads with a further 19% having a >50% reduction in pad use 19. A similar RCT by Weil et al. showed a 59% dry rate after 6 months for the implantation group, compared with 5% of patients being dry in the delay group 21. Several other prospective and retrospective studies 3, 8, 19, 22, 23 of patients with refractory DO who underwent SNS also based clinical success on voiding diary parameters (Table 1). Stable, long-term control at 1 and 5 years of all symptoms of DO was shown by two separate studies 3, 23. Only a few studies reported on postoperative urodynamic results. Shaker and Hassouna 24 found that bladder volume at initial urge increased 50% from 133.17ml to 203.75ml and maximum bladder capacity increased 15% from 291.93ml to 335.83ml following SNS. At 6-months post implantation, Bosch and Groen 25 found a significant increase in bladder volume at normal desire (213ml to 291ml; p=0.04) and a reduction in the severity of unstable detrusor contractions. Despite the general improvement in urodynamic variables, it has been shown to correlate poorly with symptomatic success 25, 26. Another measure of outcome is patient assessment of quality of life (QoL). Amundsen et al. evaluated patients using the sevenitem Incontinence Impact Questionnaire from 0-100 with higher scores indicating a negative impact on QoL. They found a significant post-implantation drop in score from 74.3 to 6.8 in 18 Volume 16 Number 1 Autumn 2010

Table 2. Effect on QoL scores in patients who underwent SNS for DO. Baseline versus last follow-up. Follow-up duration QoL score (0 to 100) Amundsen et al. (2005) 29 months (range 8 to 48) 74.3 to 6.8 82.2 to 16.6 (patients age <55) (patients age >55) Spinelli et al. (2001) 12 months 33.1 to 69.6 (p<0.001) Aboseif et al. (2007) 18 months 34.4 ±22.8 to 83.8 ± 16.6 (p<0.01) = high score is worse, = higher score is better younger patients and from 82.2 to 16.6 in patients older than 55 (Table 2). Two studies with separate incontinent specific questionnaires where 0 corresponded to poor QoL and 100 to no impact on QoL from incontinence both revealed a significant improvement in scores following SNS 22, 27 (Table 2). Adverse events Despite the minimally-invasive nature of SNS, it is not without its risks and side effects. Adverse events can accompany the initial test stimulation procedure or the IPG implantation. In a study comprising 914 test stimulation procedures, 166 (18.2%) had an associated adverse event 8. The most common issues were lead migration (11.8%), technical problems including incorrect lead placement (2.6%) and pain (2.1%) 8. Adverse events following IPG implantation occur in up to 71% of patients 2, 3. Common complications include new pain or undesirable change in sensation (27-42%) pain at the implant site (21-27%), lead migration (5-10%), infection (6-8%), bowel dysfunction (3-10%) and mechanical problems with the IPG device (2-6%) 2, 3, 8. Adverse effects on bowel function were more often reported in studies with patients aged over 75, suggesting that age affects the clinical outcomes of SNS 14. There were no severe or irreversible adverse events reported 2, 3, 8. Reoperation is often needed to overcome adverse events unable to be managed by antibiotics and local wound care 14, 27. A high overall surgical revision rate of 33-51.6% has been reported by several studies 2, 3, 8. In up to 10% of patients, permanent explantation of the IPG was required 3. Reoperations also occur for battery depletion. Expected battery life for the InterStim TM device is 6-10 years, after which time the pacemaker portion of the device needs to be replaced 7. By itself, this is a fairly small procedure but undoubtedly carries with it further risks. In view of the reported complications, one needs to realise that, in most studies, the safety data often grouped together patients of both genders with diagnoses including urge incontinence, frequency, interstitial cystitis and urinary retention. It may be argued that pooling of data may be justified based on the identical nature of the device and procedure for all patient groups and in one study no significant difference in safety profile was found between the patients with urinary urge incontinence, urgency-frequency and non-obstructive urinary retention 8. Cost-effectiveness Healthcare economics forms the crux of many treatment decisions, but few studies have looked at the cost-effectiveness of SNS. Aboseif et al. 27 conducted a retrospective study of patients who had received InterStim TM therapy, comparing healthcare costs for the year before and after implantation. They found that following InterStim TM insertion, there was a significant decrease per patient in outpatient visit expenses for urinary symptoms (US$994 to US$265), therapeutic and diagnostic procedures including cystoscopy and urodynamics (US$733 to US$59) as well as medication costs (US$693 to US$483) 27. This is in addition to the significant cost of multiple failed therapies which these patients would have undergone prior to undergoing SNS. These figures do not account for the indirect and intangible costs (including loss of productivity and QoL) that form a considerable burden in patients with urinary incontinence 28. However, considering the success of SNS and improvement in patient satisfaction, these costs are likely to be also reduced considerably 1. The cost-benefits of SNS are further improved by the initial test stimulation screening which identifies responders suitable for implantation 1. Long-term cost-benefit research has not yet been performed 27. Longitudinal studies are needed to incorporate the considerable up-front costs of surgical implantation (in excess of A$23,000 for a successful PNE and InterStim TM implantation 29 ) into the true cost-benefit analysis of SNS over time. A government assessment report performed a cost-effectiveness evaluation of SNS for DO estimating a cost of A$9,866 per additional year of patient complete dryness 29. This figure did not take into account patients who achieve partial improvements in urinary symptoms. 20 Volume 16 Number 1 Autumn 2010

There is no comparative cost data for SNS versus other treatment options 29. Future long-term cost comparisons between a single SNS operation versus recurrent botulinum injections may be valuable as they both provide minimally-invasive options for patients with urinary incontinence refractory to front-line treatments. Conclusion DO is an increasingly common diagnosis, due to both growing public awareness and the ageing population. Conservative treatments have been found to be generally effective, but in patients whose symptoms are refractory to this approach, SNS provides an alternative option to more invasive surgical procedures. The techniques behind SNS have evolved over the past decade to make it a quick and safe procedure. SNS has been shown to have long-term efficacy in terms of reducing symptoms of urge incontinence and improving quality of life. The recent approval by the Australian Therapeutic Goods Administration of SNS for the treatment of refractory urge incontinence will now allow physicians to offer this therapy to patients who have failed conservative measures. References 1. Shaker H & Hassouna M. Sacal Root Neuromodulation in the Treatment of Various Voiding and Storage Problems. Int Urogynecol J 1999; 10:336-343. 2. van Voskuilen A, Oerlemans D, Weil E, de Bie R & van Kerrebroeck P. Long Term Results of Neuromodulation by Sacral Nerve Stimulation for Lower Urinary Tract Symptoms: A Retrospective Single Center Study. Eur Urol 2006; 49:366-372. 3. van Kerrebroeck P, van Voskuilen A, Heesakkers J et al. Results of Sacral Neuromodulation Therapy for Urinary Voiding Dysfunction: Outcomes of a Prospective, Worldwide Clinical Study. J Urol 2007; 178:2029-2034. 4. Kohli N & Patterson D. InterStim Therapy: A Contemporary Approach to Overactive Bladder. Rev Obstet Gynecol 2009; 2(1):18-27. 5. Yamanishi T, Kamai T & Yoshida K. Neuromodulation for the treatment of urinary incontinence. Int J Urol 2008; 15:665-672. 6. Chartier-Kastler E, Bosch J, Perrigot M, Chancellor M, Richard F & Denys P. Long-term results of sacral nerve stimulation (S3) for the treatment of neurogenic refractory urge incontinence related to detrusor hyperreflexia. J Urol 2000; 164:1476-1480. 7. McKertich K. Urinary Incontinence Procedural and Surgical Treatments for Women. Aust Fam Physician 2008; 37(3):122-131. 8. Siegel S, Catanzaro F, Dijkema H et al. Long-term result of a multicenter study on sacral nerve stimulation for treatment of urinary urge incontinence, urgency-frequency and retention. Urology 2000; 56(Supplement 6A):87-91. 9. Malossi J & Chai T. Sacral Neuromodulation for the Treatment of Bladder Dysfunction. Current Urology Reports 2002; 3:61-66. 10. Vignes J, Deloire M & Petry K. Animal Models of Sacral Neuromodulation for Detrusor Overactivity. Neurourol Urodyn 2009; 28:8-12. 11. Bosch J. Electrical neuromodulatory therapy in female voiding dysfunction. BJU International 2006; 98(Supplement 1):43-48. 12. Spinelli M, Giardiello G, Gerber M, Arduini A, van den Hombergh U & Malaguti S. New Sacral Neuromodulation Lead for Percutaneous Implantation Using Local Anesthesia: Description and First Experience. J Urol 2003; 170(5):1905-1907. 13. Huang J, Deletis V, Vodusek D & Abbott R. Preservation of pudendal afferents in sacral rhizotomies. Neurosurgery 1997; 41:411-415. 14. Brazzelli M, Murray A & Fraser C. Efficacy and Safety of Sacral Nerve Stimulation for Urinary Urge Incontinence: A Systematic Review. J Urol 2006; 175:835-841. 15. Scheepens W, Weil E, van Koeveringe G et al. Buttock Placement of the Implantable Pulse Generator: A New Implantation Technique for Sacral Neuromodulation A Multicenter Study. Eur Urol 2001; 40:434-438. 16. Amundsen C, Romero A, Jamison M & Webster G. Sacral Neuromodulation for Intractable Urge Incontinence: Are There Factors Associated With Cure? Urology 2005; 66(4):746-750. 17. Bosch J & Groen J. Sacral (S3) segmental nerve stimulation as a treatment for urge incontinence in patients with detrusor instability: results of chronic electrical stimulation using an implantable neural prosthesis. J Urol 1995; 154:504-507. 18. Hasan S, Robon W, Pride A & Neal D. Transcutaneous electrical nerve stimulation and temporary S3 neuromodulation in idiopathic detrusor instability. J Urol 1996; 155:2005-2011. 19. Schmidt R, Jonas U, Oleson K et al. Sacral Nerve Stimulation for Treatment of Refractory Urinary Urge Incontinence. J Urol 1999; 162:352-357. 20. Spinelli M, Weil E, Ostardo E et al. New tined lead electrode in sacral neuromodulation: experience from a multicentre European study. World J Urol 2005; 23:225-229. 21. Weil E, Ruiz-Cerdá J, Eerdmans P, Janknegt R, Bemelmans B, & van Kerrebroeck P. Sacral root neuromodulation in the treatment of refractory urinary urge incontinence: a prospective randomized clinical trial. Eur Urol 2000; 37(2):161-171. 22. Spinelli M, Bertapelle P, Cappellano F et al. Chronic sacral neuromodulation in patients with lower urinary tract symptoms: results from a national register. J Urol 2001; 166(2):541-545. 23. Bosch J & Groen J. Sacral nerve neuromodulation in the treatment of patients with refractory motor urge incontinence: long-term results of a prospective longitudinal study. J Urol 2000; 163(4):1219-1222. 24. Shaker H & Hassouna M. Sacral nerve root neuromodulation: effective treatment for refractory urge incontinence. J Urol 1998; 159:1516-1519. 25. Bosch J & Groen J. Neuromodulation: urodynamic effects of sacral (S3) spinal nerve stimulation in patients with detrusor instability or detrusor hyperflexia. Behav Brain Res 1998; 92:141-150. 26. Bosch R & Groen J. Complete 5-year follow-up of sacral (S3) segmental nerve stimulation with an implantable electrode and pulse generator in 36 consecutive patients with refractory detrusor overactivity incontinence. Neurourol Urodyn 2002; 21:390-391. 27. Aboseif S, Kim D, Rieder J et al. Sacral Neuromodulation: Cost Considerations and Clinical Benefits. Urology 2007; 70(6):1069-1073. 28. Moore K. The costs of urinary incontinence. MJA 2001; 174:436-437. 29. Sacral Nerve Stimulation for Urinary Indications: Commonwealth of Australia, 2008. Volume 16 Number 1 Autumn 2010 21