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Neurourology and Urodynamics 30:766770 (2011)

Neuromodulation for Intractable OAB

Apostolos Apostolidis*
2nd Department of Urology, Aristotle University of Thessaloniki, Thessaloniki, Greece To review the current status of sacral neuromodulation (SNM) in the treatment of intractable overactive bladder symptoms, the PubMed English-language literature was used to address efcacy, technical issues, alternative techniques, the mechanism of action, adverse events, the cost-effectiveness, and current considerations on the use of SNM as second-line treatment in OAB. Several studies attest to the short- and long-term efcacy of SNM in reducing urgency incontinence and the remaining OAB symptoms. Few, medium-sized sample, randomized controlled trials exist. Little is known about long-term patient satisfaction from SNM and prognostic factors have not been identied. Technical advances have signicantly improved patient selection and outcomes, as well as complication rates, but revision rates still remain high. The mechanism of action remains largely unknown, but appears to be associated with reorganization of spinal reexes and regulation of cortical activity. Reports on cost-effectiveness are conicting. Less invasive forms of SNM may offer a viable alternative to central SNM. In conclusion, current evidence supports the short- and long-term efcacy of SNM in treating intractable OAB, but further research is needed to improve patient selection, identify prognostic factors, clarify the mechanism of action and reduce complications and revision rates. Neurourol. Urodynam 30:766770, 2011. 2011 Wiley-Liss, Inc. Key words: incontinence; overactive bladder; pudendal nerve stimulation; sacral nerve stimulation; sacral neuromodulation; tibial nerve stimulation; urgency


Neuromodulation, in particular the continuous electrical stimulation of the sacral nervessacral neuromodulation (SNM)remains to date the only approved second line management for OAB symptoms refractory to conservative and pharmacological treatments. It has been reported that in the decade following the approval by FDA of the InterStimTM device (Medtronic, Inc., Minneapolis, MI) for the treatment of urgency incontinence (1997), the urgency-frequency syndrome and non-obstructive urinary retention (1999), more than 35,000 patients have been implanted worldwide.1 SNM is currently unanimously recommended by expert panels for the treatment of intractable detrusor overactivity (DO) associated incontinence and mixed incontinence in women.2,3 However, conicting recommendations exist for the use of neuromodulation in men with intractable urgency incontinence due to DO.2,3 Nevertheless, the treatment is still evolving in terms of patient selection, surgical technique, and technical characteristics of the implant in an effort to improve efcacy and minimize side-effects.

including the number of total micturition and leakage episodes, the number of pads used, the rating of urgency, the maximum bladder capacity and volume at rst detrusor contraction, as well as on quality of life parameters such as the SF-36 mental and physical component scales.4,5 When complete continence was studied, almost 50% of the implanted patients were continent at 6 months as opposed to 1.6% of patients in the delay group, while a total 87% showed a more than 50% improvement in the number of leakage episodes as opposed to 3% in the delay group.4 Validity of results was further supported as most outcomes returned to baseline values when the stimulators were switched off (level of evidence 12). Further to the results from the short-term randomized trials, SNM-induced symptomatic improvements appear to be conrmed in case series studies with longer follow-ups. A 5-year follow-up single center study of OAB patients showed complete or satisfactory symptom control in 64% of the implanted patients.9 A systematic review of the case series studies concludes that 67% of implanted patients beneted from a more than 50% reduction in incontinence episodes including 39% who achieved complete continence.4 Similarly, another systematic review performed in order to produce treatment guidelines for the National Institute for Health and Clinical Excellence (NICE, UK) showed that 67% of implanted

EFFICACY The Physicians Perspective

A number of reviews have looked into the efcacy of implanted devices to provide stimulation of sacral nerves for refractory OAB with or without incontinence.1,4,5 Only three randomized trials have reported results in full publications. They compared immediate versus delayed implants, the latter serving as control groups where the patients were implanted 6 months later.68 A clear benecial effect of the immediate implant was seen at 6 months on a number of outcomes

Conict of interest: none. Dirk De Ridder led the review process. *Correspondence to: Dr. Apostolos Apostolidis, 2nd Department of Urology, Papageorgiou General Hospital, Ring Road, Nea Efkarpia, 56403 Thessaloniki, Greece. E-mail: Received 7 February 2011; Accepted 8 March 2011
Published online 15 June 2011 in Wiley Online Library ( DOI 10.1002/nau.21123

2011 Wiley-Liss, Inc.

Neuromodulation for Intractable OAB

patients were either dry or had a greater than 50% reduction in incontinence episodes at a 3- to 5-year follow-up period.1 In a multicenter trial, 69% of patients were still beneting from a reduction in the degree of urgency 2 years after surgery.10
The Patients Perspective


In patients with urgency incontinence signicant benets were recorded using different condition-specic questionnaires to assess quality of life (QoL) associated parameters, such as the Incontinence Impact Questionnaire, the Beck Depression Inventory and other domain-specic QoL indices.1113 To date, only two studies have addressed longterm patient satisfaction from SNM; in mean follow-up periods of 18 and 27 months, 90% and 80% of patients would undergo the treatment again.12,14

Results appear to be conicting. A follow-up study of a multicenter randomized trial suggests some reduction of efcacy with time: a similar proportion (46%) of patients with urgency incontinence remained dry at 3 years and 6 months after surgery, but only 59% as opposed to 87% showed a greater than 50% improvement in the number of leakage episodes. Also, 32% of OAB-dry patients had retained a normal voiding pattern after 2 years of SNM as opposed to 59% at 6 months, although the percentage of patients who had experienced a greater than 50% reduction in the number of daily voids remained unchanged (56%).10 By contrast, the 2-year follow-up of a group of OAB patients who had participated in a multicenter randomized trial claimed sustained efcacy concerning the improvement in the number of total voids/day, the mean voided volume per micturition and the degree of urgency.7 Further, a multicenter 5-year prospective trial showed sustained reduction of the number of leakage episodes and pads used in patients with urgency incontinence; similarly, the decreases in micturition frequency and degree of urgency, and increases in mean voided volume per micturition episode were sustained in OAB-dry patients.15 However, of the patients with a successful clinical outcome 1 year post-implant only 71% were considered clinical responders at 5 years.
PROGNOSTIC FACTORS Urological Parameters

techniques showed similar improvements in clinical parameters.17 In conjunction with the use of the permanent tined lead,18 the two-staged technique reduced the risk of infection and lead migration, allowing for better clinical outcomes. Prolonged stimulation period: beneting from the technical advances of the two-staged technique, a prolonged test stimulation period24 weeks as opposed to the standard 1 weekwas feasible. It is thought to improve patient selection, as it appears to achieve higher rates of implanted patients as well as better long-term outcomes.19 Unilateral versus bilateral stimulation: despite the sound scientic basis of bilateral stimulation, currently there is no evidence to support bilateral as opposed to unilateral stimulation for OAB symptoms.20 Positioning of the hardware: placement of the pulse generator in the buttock as opposed to the abdominal area is seen as a signicant advance; it reduced the operative times and complications, mainly pain, related to the IPG, one of the major causes for reoperation. A number of studies have evaluated the right angle for the electrode insertion into the S3 foramen, but differences in bony pelvic oor anatomy between genders as well as within the same gender has not allowed for standardization of those angles. Whether insertion angle has a prognostic value for treatment success remains to be proven. In addition, some researchers challenge the currently dominant concept concerning stimulation of the S3 nerve root, suggesting that in some patients S4 stimulation may be used as either salvage or rst option, as it might be associated with lesser risk of leg pain whilst still achieving sufcient pelvic oor contractions and perianal sensations.16 Novel approaches in SNM, such as pudendal nerve stimulation, suggest that S2 stimulation is also associated with good clinical outcomes.21,22

Mechanistic Parameters

To-date no specic urological pre-treatment factors have been associated with response to SNM. The presence of detrusor overactivity upon urodynamic investigation failed to show some predictive value, neither did other urodynamic parameters.16 Post-treatment reduction in the severity and frequency of incontinence episodes were found to be associated with patient satisfaction and improved QoL, respectively.12,14
Technical Parameters

Technical parameters, however, appear to be associated with an improved clinical outcome. One- versus two-staged technique: when the two techniques were directly compared, the two-staged procedure was associated with signicantly higher rates of implanted patients, although responders to both test stimulation
Neurourology and Urodynamics DOI 10.1002/nau

Further to technical evolutions, factors associated with the mechanism of action, which has yet to be elucidated, may be involved in prognosis. A possible neuroplastic effect has been suggested; a positron emission tomography study has shown that acute and chronic SNM are associated with different effects on higher brain centers.23 In patients with urgency incontinence, acute SNM was associated with activation of areas involved in sensorimotor learning (postcentral gyrus, parietal cortex, medial prefrontal cortex, insula) while chronic SNM was associated with activation of areas involved in initiation of voiding and sensation of bladder fullness (associative sensory cortex, premotor cortex, medial cerebellum). Other researchers have proposed that SNMinduced plasticity occurs at the spinal cord level, whereby reorganization of reexes results in suppression of detrusor contraction and facilitation of urine storage. Modulation of excitatory or inhibitory interneurons involved in a bladderto-urethral sphincter excitatory reex and a urethral sphincter-to-bladder inhibitory reex is thought to have a central role in this mechanism.24,25 A plastic reorganization of somatosensory pathways involved in the cortical network has been suggested also by percutaneous tibial nerve stimulation (PTNS) studies.26 Whether plasticity of the CNS is also followed or complimented by peripheral receptor plasticity has yet to be proven, but could well be associated with differences in response between patients with same symptom severity, changes of efcacy with time and overall prognosis.


Psychosocial Factors

Interestingly, a PTNS study demonstrated that the mental component of the SF-36 was negatively associated with response to treatment independent of disease severity, and proposed that psychosocial variables could be taken into consideration for better patient selection.27

Adverse events associated with SNM have been extensively discussed in the literature and stimulated a series of technical advances aiming to reduce the universally accepted high rate of complications. Earlier reviews report a 33% reoperation rate in implanted patients, the most common complications being pain at the implant site (25% of cases), lead migration (16%), wound problems (7%), bowel dysfunction (6%), infection (5%), and generator problems (5%). Relocation or replacement of the pulse generator as opposed to permanent explantation was required in 15% and 9% of the patients, respectively.4 However, technical advances, such as the introduction of the tined lead and the two-staged procedure appear to have positively affected the adverse event and reoperation rates. Considerably reduced incidences of pain (2.5%), lead migration (0.6%), and infection (2.5%) were reported in a single-institution followup study; surgical revision was required in 16.1% of patients including those with reduced efcacy (10.5%).28 Other factors apart from technical advances, such as the learning curve and patient selection may have had an additional benecial effect in reoperation rates: a 5-year follow-up study from a singleinstitution found a 69% reduction in surgical revisions in patients implanted after 1995 as opposed to those before this date.9 By contrast, in a multicenter 5-year follow-up study the surgical revision rate was as high as 39.5% (60 out of 152 patients).15

S2 root though being the predominant (60%).34 Studies in IDO patients with follow-up times of up to 24 months have reported successful suppression of the sensation of urgency35,36 and urgency incontinence,21,36,37 using dorsal penile/clitoral nerve or pudendal nerve stimulation. A revived interest is now becoming apparent for less invasive forms of SNM, namely percutaneous tibial nerve stimulation (PTNS). A series of novel randomized controlled trials showed a clear benecial effect of PTNS over sham treatment.3840 Results were found to be comparable even to those of standard pharmacotherapy.41 Maintenance treatment appears to be necessary for sustained efcacy,42 but long-term studies are largely missing.43

Costs may vary between different countries. Current hardware costs in the UK are at 8,400, while battery costs, which would need to be replaced every 57 years, are at 5,300. Nevertheless, few studies have examined the cost-effectiveness of SNM in urological conditions as opposed to its use in faecal incontinence. A health care utilization study demonstrated signicant benets in ofce visit, therapeutic and diagnostic procedure costs as well as drug costs.29 Using quality-adjusted life years (QALY), however, another study suggested that, at 2 years post-treatment, SNM was not costeffective. The study, which included surgical costs for initial placement and possible revisions in association with clinical efcacy, estimated the incremental cost-effectiveness ratio per QALY to be at $116,427.30 Such estimates are considerably higher than those previously published for the use of SNM in faecal incontinence (s16,000 and 25,000 for Spain and the UK respectively).31,32 The study also adds to the conicting reports which aim to compare the cost-effectiveness of SNM versus that of BTX-A in idiopathic OAB. Equal numbers of studies support each treatment as more cost-effective, but a single full publication exists30 as opposed to three short reports.33

Despite the large number of stimulators implanted worldwide, reported results concern only a small proportion of patients, with an acknowledged overlap among patients participating in reports from the same centers. To date, only three randomized trials with small numbers of patients have supported the efcacy of SNM with central stimulation, although an additional 3 randomized studies provided high level of evidence for peripheral stimulation too. Moreover, almost 30% of enrolled patients fail stage 1 and a further 30% of those implanted fail to benet. Considering that the placebo effect in OAB studies has been reported to be as high as 4050%, it may be that a requirement for a greater than 50% symptomatic improvement in stage 1 is inadequate and a higher percentage improvement in OAB symptomspossibly 70% may be needed for a better patient selection. A number of other factors warrant further investigation when aiming to reduce the non-responders in either stage of the implantation, including prolonged test stimulation, bilateral versus unilateral test stimulation, as well as technical characteristics, in particular the stimulation parameter settings, the angle of electrode insertion, and the stimulated nerve (S3 vs. S4 or even S2) in conjunction with individual patient anatomy. Identication of clinical prognostic factors is of importance and could well be associated with the mechanism of action (MOA) of SNM. A better MOA knowledge combined with further ameliorations of technical parameters involving the batteries and the lead could also improve the short-term and long-term efcacy.
Safety and Quality of Life Issues

Pudendal nerve stimulation is being investigated as alternative to SNM. The background for its use is that the S2 and S3 roots contribute to 95% of the pudendal afferent activity, the
Neurourology and Urodynamics DOI 10.1002/nau

In a patient population, who have to undergo a two-staged operation in order to receive the implant and a further surgical revision 57 years later to replace the original pulse generator, even the currently reduced reoperation rate of 16% due to complications may not be appealing. Interestingly, the effect of adverse events on patients QoL has not been studied. This adds to the general scarcity of studies investigating the long-term patient satisfaction and QoL changes following SNM,8,12,14 which becomes even more evident when compared to the extensive relevant literature on the use of SNM for refractory faecal incontinence. Further, several studies reported on the use of SNM for a variety of indications without discriminating between possible differences in adverse events. Finally, complications such as referred pain and bowel dysfunction are amongst the side-effects of central SNM, it appears that other nerves or nerve branches apart from those associated with the bladder may be stimulated during SNM.

Neuromodulation for Intractable OAB

TABLE I. Pros and Contras for the Use of Neuromodulation and BTX-A in the Treatment of Intractable OAB Neuromodulation Licensed treatment Long-term efficacy Few RCTs Small patient numbers Invasive High reoperation rate Unknown MOA Unknown long-term effect on neurons Improved, but still high complication rate Cost-effectiveness issues unaddressed BTX-A Unlicensed treatment Little data on long-term efficacy Few RCTs Small patient numbers Minimally invasive Reversible effect/need for repeat sessions Unknown MOA Unknown long-term effect on bladder Need for CISC in a percentage of patients Concurrent use of antimuscarinics in 20% patients Cost-effectiveness issues unaddressed


Individualization of the treatment in terms of functional anatomy has not been investigated but could be the way towards a more specic stimulation of the nerves or nerve branches associated with bladder function, thus improving the complication rate.



Comparable efcacy rates have been reported for the two treatments in intractable OAB (Table I).1,4,5,44,45 As with SNM, a similar small number of RCTs with small patient numbers has been published to date on the use of BTX-A in idiopathic OAB45 and similar concerns exist regarding patient overlap in reports from same centers. Currently, however, SNM remains the only licensed treatment for intractable OAB symptoms. Despite the considerations raised above and its more invasive nature compared to the minimal invasiveness of the BTX-A treatment, SNM offers long-term efcacy and is fully reimbursable. By contrast, BTX-A remains an unlicensed treatment and needs repeat sessions on a less-than-a year basis for sustained efcacy, while almost 20% of the patients need to complement the treatment with concurrent oral antimuscarinics.46 In addition, there is little published data on the efcacy of repeat injections.47,48 The mechanism of action remains largely unknown in both treatments.24,26,49 Raised concerns about the long-term effect of BTX-A injections in the bladder have not been addressed to-date, but neither has the long-term neural effect of SNM. The benet-risk ratio of BTX-A has recently been investigated, but a risk of post-treatment need for self-catheterizations cannot be excluded.50 Studies comparing the cost-effectiveness of the two treatments have produced conicting results.30,33



6. 7.

show comparatively better efcacy based on retrospective database analysis. Specically designed RCTs should follow. Identify prognostic factors: multicenter analysis of existing databases for urodynamic, bladder diary and clinical/surgical factors associated with efcacy or adverse events would be of importance. Patient selection would also improve by such data. Clarify the mechanism of action: animal experiments are needed to shed more light into the role of interneurons and the organization of spinal reexes involved in bladder function and dysfunction. Further radiology and neurophysiology studies could be employed to provide more evidence on the mechanism of action. Functional and histological bladder studies are also needed. Reduce complications and revision rates: technological advances concerning the battery and lead in conjunction with information on the mechanism of action and prognostic factors should help reduce complications. Identify possible long-term effects on the CNS as well as peripheral organs receiving innervation from the sacral nerves: functional and histological bladder and bowel studies as well as neurophysiology studies are needed to address the peripheral effect of SNM. Animal and radiology studies would address the central effect. Study quality of life parameters: prospective studies using bladder and health-related quality of life tools are needed. Assess the cost-effectiveness, especially in comparison to botulinum toxin therapy: studies should compare the SNMplus-complications-related costs to those associated with the management of OAB/incontinence, including the use of pads, antimuscarinics, antibiotics, skin care costs, OABrelated fracture costs and hours of productivity as well as state benet costs.

Current evidence supports the short- and long-term efcacy of SNM in treating intractable OAB. Reviewing SNM outcome reports would benet from larger studies reporting on a single as opposed to all current LUT indications. Currently, SNM stands as the single licensed second-line treatment for OAB, but as novel, minimally invasive treatments emerge, namely intradetrusor botulinum toxin, comparative and/or cross-over studies and individualization of indications may be required. Further research in SNM is needed to: 1. Improve patient selection: selection based on a 70% as opposed to 50% response rate might optimize efcacy, provided future publications from centers of excellence
Neurourology and Urodynamics DOI 10.1002/nau

1. Chartier-Kastler E. Sacral neuromodulation for treating the symptoms of overactive bladder syndrome and non-obstructive urinary retention: >10 years of clinical experience. BJU Int 2008;101:41723. 2. Wyndaele JJ, Kovindha A, Madersbacher H, et al. Neurologic urinary and faecal incontinence. In: Abrams P, Cardozo L, Khoury S, Wein A, editors. Incontinence. Paris: Health Publication Ltd; 2009. p. 793960. 3. Stohrer M, Blok B, Castro-Diaz D, et al. EAU guidelines on neurogenic lower urinary tract dysfunction. Eur Urol 2009;56:818. 4. Brazzelli M, Murray A, Fraser C. Efcacy and safety of sacral nerve stimulation for urinary urge incontinence: A systematic review. J Urol 2006;175: 83541. 5. Herbison GP, Arnold EP. Sacral neuromodulation with implanted devices for urinary storage and voiding dysfunction in adults. Cochrane Database Syst Rev 2009; CD004202.


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6. Schmidt RA, Jonas U, Oleson KA, et al. Sacral nerve stimulation for treatment of refractory urinary urge incontinence. Sacral Nerve Stimulation Study Group. J Urol 1999;162:3527. 7. Hassouna MM, Siegel SW, Nyeholt AA, et al. Sacral neuromodulation in the treatment of urgency-frequency symptoms: A multicenter study on efcacy and safety. J Urol 2000;163:184954. 8. Weil EH, Ruiz-Cerda JL, Eerdmans PH, et al. Sacral root neuromodulation in the treatment of refractory urinary urge incontinence: A prospective randomized clinical trial. Eur Urol 2000;37:16171. 9. van Voskuilen AC, Oerlemans DJ, Weil EH, et al. Long term results of neuromodulation by sacral nerve stimulation for lower urinary tract symptoms: A retrospective single center study. Eur Urol 2006;49:36672. 10. Siegel SW, Catanzaro F, Dijkema HE, et al. Long-term results of a multicenter study on sacral nerve stimulation for treatment of urinary urge incontinence, urgency-frequency, and retention. Urology 2000;56:8791. 11. Shaker HS, Hassouna M. Sacral nerve root neuromodulation: An effective treatment for refractory urge incontinence. J Urol 1998;159:15169. 12. Cappellano F, Bertapelle P, Spinelli M, et al. Quality of life assessment in patients who undergo sacral neuromodulation implantation for urge incontinence: An additional tool for evaluating outcome. J Urol 2001;166: 227780. 13. Amundsen CL, Webster GD. Sacral neuromodulation in an older, urge-incontinent population. Am J Obstet Gynecol 2002;187:14625; discussion 1465. 14. Foster RT, Sr., Anoia EJ, Webster GD, et al. In patients undergoing neuromodulation for intractable urge incontinence a reduction in 24-hr pad weight after the initial test stimulation best predicts long-term patient satisfaction. Neurourol Urodyn 2007;26:2137. 15. van Kerrebroeck PE, van Voskuilen AC, Heesakkers JP, et al. Results of sacral neuromodulation therapy for urinary voiding dysfunction: Outcomes of a prospective, worldwide clinical study. J Urol 2007;178:202934. 16. Bolton JF, Harrison SC. Neuromodulation 10 years on: How widely should we use this technique in bladder dysfunction? Curr Opin Urol 2009;19: 3759. 17. Amundsen CL, Romero AA, Jamison MG, et al. Sacral neuromodulation for intractable urge incontinence: Are there factors associated with cure? Urology 2005;66:74650. 18. 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;23:2259. 19. Kessler TM, Madersbacher H, Kiss G. Prolonged sacral neuromodulation testing using permanent leads: A more reliable patient selection method? Eur Urol 2005;47:6605. 20. van Kerrebroeck EV, Scheepens WA, de Bie RA, et al. European experience with bilateral sacral neuromodulation in patients with chronic lower urinary tract dysfunction. Urol Clin North Am 2005;32:517. 21. Bosch JL. The bion device: A minimally invasive implantable ministimulator for pudendal nerve neuromodulation in patients with detrusor overactivity incontinence. Urol Clin North Am 2005;32:10912. 22. Buchs NC, Dembe JC, Robert-Yap J, et al. Optimizing electrode implantation in sacral nerve stimulationAn anatomical cadaver study controlled by a laparoscopic camera. Int J Colorectal Dis 2008;23:8591. 23. Blok BF, Groen J, Bosch JL, et al. Different brain effects during chronic and acute sacral neuromodulation in urge incontinent patients with implanted neurostimulators. BJU Int 2006;98:123843. 24. de Groat WC. Integrative control of the lower urinary tract: Preclinical perspective. Br J Pharmacol 2006;147:S2540. 25. Grifths D, Apostolidis A. Neurological control of the bladder in health and disease. In: Fowler CJ, Panicker J, Emmanuel A, editors. Pelvic organ dysfunction in neurological disease: Clinical management and rehabilitation. Cambridge: Cambridge University Press; 2010. p. 124. 26. Finazzi-Agro E, Rocchi C, Pachatz C, et al. Percutaneous tibial nerve stimulation produces effects on brain activity: Study on the modications of the long latency somatosensory evoked potentials. Neurourol Urodyn 2009;28: 3204. 27. van Balken MR, Vergunst H, Bemelmans BL. Prognostic factors for successful percutaneous tibial nerve stimulation. Eur Urol 2006;49:3605. 28. Hijaz A, Vasavada SP, Daneshgari F, et al. Complications and troubleshooting of two-stage sacral neuromodulation therapy: A single-institution experience. Urology 2006;68:5337.

Neurourology and Urodynamics DOI 10.1002/nau