Neuromodulation in urology,state of the art

Abstract

Sacral neuromodulation is an approved and validated treatment for overactive bladder syndrome, chronic non-obstructive retention, and chronic pelvic pain. Percutaneous tibial nerve stimulation is a less invasive approach of neuromodulation. We performed a literature research to assess the current evidence available about neuromodulation. Both techniques appear to be effective and safe third-line treatments. The overall success rate ranges from 43% to 85% for sacral neuromodulation and from 40% to 79.5% for percutaneous tibial nerve stimulation. Sacral neuromodulation has a higher incidence of complications in comparison to percutaneous tibial nerve stimulation, due to the more invasive surgical technique and the presence of a permanent implant. The incidence of surgical revision ranges between 9% and 33%. The most frequent complication with sacral neuromodulation is pain at implant site (15%–42%), followed by lead migration (4%–21%), pain at lead site (5.4%–19.1%), leg pain (18%), and infection (5.7%–6.1%). The quality of the studies on sacral neuromodulation and percutaneous tibial nerve stimulation in literature is quite modest, because of the shortage of good randomized clinical trial; most of the studies are prospective observational studies with mid-term follow-up.

Keywords

Sacral neuromodulation percutanous tibial nerve stimulation overactive bladder non-obstructive urinary retention interstitial cystitis bladder pain syndrome

Introduction

Sacral neuromodulation (SNM) is an approved and validated treatment for overactive bladder syndrome (OAB), chronic non-obstructive retention, and chronic pelvic pain.^1,2 The Food and Drug Administration have approved this treatment for OAB in 1997 and for chronic non-obstructive retention in 1999.³ The application of SNM for interstitial cystitis/bladder pain syndrome (IC/BPS) has to be considered off label. An alternative neuromodulation technique is represented by percutaneous tibial nerve stimulation (PTNS).⁴ This treatment is usually offered as a third-line therapy after conservative treatments, lifestyle modification, and oral drugs have failed. A recent retrospective real-world analysis on the continuation rates of oral drugs for the treatment of overactive bladder evidenced that at 1 year, only 44% of patients treated with mirabegron and 31% of patients treated with anticholinergics were adherent to their indexed medications.⁴

The working mechanism of SNM is complex. The approved and most employed device is InterStim (Medtronic, Inc., Minneapolis, MN). SNM consists an electrical stimulation with a tined lead on the sacral roots, generally S3. The effect of SNM appears to be modulated by the activation of somatic afferents that in turn inhibit bladder sensory pathways and reflex bladder hyperactivity. A possible mechanism of action on pain relies on the gate control theory. The stimulation of bigger Aβ fibers, such as with pressure or tactile stimuli, may activate inhibiting interneurons that in turn reduce the activity of smaller nociceptive Aδ and C fibers.⁵ Cats models suggest that the inhibition of bladder activity occurs primarily in the central nervous system (CNS) by inhibition of the ascending or descending pathways of the spinobulbospinal micturition reflex. A recent work applying functional magnetic resonance on 13 women treated with SNM for overactive bladder evidenced that SNM may directly influence brain activity. The increasing of stimulation amplitude determined a progressive overall brain activation. A subsensory stimulation determined the deactivation of the pons and periaqueductal gray matter, with stable activation of the right inferior frontal gyrus. A sensory stimulation determined the activation of the insula and the deactivation of the medial and superior parietal lobes. A suprasensory stimulation determined the activation of multiple structures and the expected S3 somatosensory region.⁶

Urodynamic studies have revealed a clinical benefit with improvement in bladder capacity and reduction in detrusor pressures during filling with minimal effects on voiding parameters.⁷ The clinical effect is considered significant when there is at least a 50% improvement in the mail symptom.

PTNS implies an intermittent weekly stimulation of the tibial nerve (a mixed sensory-motor nerve, containing axons passing through the L4–S3 spinal roots) at the ankle without any permanent lead or stimulator implanted. The electrical stimulation of these nerves stimulates large somatic afferent fibers that determine a central inhibition of the micturition reflex pathway at the level of the spinal cord or the brain.⁸

The aim of this study is to review the available good quality literature on SNM and PTNS with respect to efficacy and safety.

Search strategy

The literature search was conducted on PubMed/Medline and Scopus in December 2018. The search strategy included the following terms: “sacral neuromodulation,” “tibial neuromodulation,” “overactive bladder,” “lower urinary tract symptoms,” “urinary retention,” “chronic pelvic pain,” “painful bladder syndrome.” We limited the research to retrospective and prospective trials with at least 20 adult patients enrolled, in English language, with at least 3 months of follow-up, published between January 1998 and December 2018. All studies had to precisely indicate data on efficacy and safety of the aforementioned techniques. We first read all abstracts to select the studies that required a full-text evaluation. We evaluated the presence of a description of the study design, the characteristics of patients at baseline, perioperative data, the outcomes selected to evaluate efficacy and safety, the length of follow-up, the ethical committee approval (if required), and results at last follow-up. We finally pooled together and analyzed efficacy and safety data for the two techniques, SNM and PTNS.

SNM

Our literature search evidenced some good quality RCT comparing the results of SNM in patients with OAB symptoms with patients treated with standard medical therapy (SMT). Siegel et al. conducted the InSite study trial, including 128 enrolled patients (51 SNM, 71 SMT). At 6 months follow-up, they evaluated the clinical benefit with voiding diaries, considering success as a reduction of >50% of urinary leaks and/or number of voids or the return to a normal voiding frequency. SNM had a success rate of 76%, compared to SMT that assessed at 49% (p = 0.002).³ This trail continued with a prospective evaluation of efficacy and safety of the SNM arm with a follow-up of 3 years. This study had different inclusion criteria and included a larger cohort of patients (n = 272). In this study, clinical success was evaluated with a comparison from baseline in terms of number of voids or leakage episodes or the return to normal voiding frequency. In the group of patients suffering of urgency incontinence, 43% returned to complete continence (p < 0.0010), and there was a significant reduction of leaks episodes (from 3.1 ± 2.7 to 2.1 ± 2.3/24 h, p < 0.001). In the group of patients suffering of urgency without incontinence episodes, 66% of patients returned to a normal voiding frequency, with a significant reduction in number of voids/day (from 12.6 ± 4.5 to 4.8 ± 4.1).⁹ Another important randomized control trial (RCT) is the ROSETTA trial (Refractory Overactive Bladder: Sacral Neuromodulation vs Botulinum Toxin Assessment), which enrolled 381 women suffering of OAB and randomized to two arms, SNM, and botulinum toxin injection with a follow-up of 6 months. The results of this study showed that both techniques lead to a significant reduction in the main number of daily urgency incontinence episodes, which was greater for the Botulinum toxin arm (−3.89 (−4.26/−3.52) vs −3.25 (−3.64/−2.87)). This study also evidenced that, although having a greater clinical success, the Botulinum toxin arm was burdened by a greater incidence of urinary tract infections (UTI), probably due to the higher need of self-intermittent catheterization.¹⁰ In a smaller RCT with 43 patients, Weil et al. compared the results of SNM (n = 20) versus SMT (n = 22) with a median follow-up of 18 months. The study evidenced that there was a significant (>90%) improvement in pad use in 85% of patients, with a significant reduction in leakage severity and mean number of leakage episodes.¹¹ Two smaller RCT by Hassouna et al.¹² and Schmidt et al.,¹³ with 51 and 76 patients, respectively, compared the results of SNM to SMT with 6 months follow-up. The first study showed a significant reduction of daily number of voids in 56% of patients (vs 4% in the SMT group) and degree of urgency and a significant increase of voided volume per void (226 ± 124 vs 123 ± 75, p < 0.0001).¹² The second study demonstrated a significant reduction in the daily number of urinary leakage (2.6 ± 5.1 vs 11.3 ± 5.9, p < 0.001) and leakage severity (0.03 ± 0.9 vs 3.9 ± 3.8, p < 0.0001).¹³ After the turn off of the stimulation, the results were comparable to baseline, indicating that an active stimulation may be needed to achieve the curative effect of SNM.^11–13 In a cohort of 99 consecutive patients with 47% response after first stage tined lead placement, Nobrega et al. demonstrated that there was no significant difference in any urodynamic parameter between first stage success and failure groups. There was a tendency of having a lower compliance in the failure group, but it did not reach statistical significance.¹⁴ In an interesting prospective study on 43 female patients with pelvic floor dysfunction, Jadav et al.¹⁵ demonstrated after a median 6.8 months follow-up a reduction on OAB symptoms from baseline with the use of ePAQ-PF score (20.9 ± 19.7 vs 28.5 ± 21.5, p < 0.05) with clinical benefit also in other domains such as bowel and sexual function. Sutherland at al.¹⁶ in retrospective series of 83 patients treated with SNM with a mean follow-up of 22 months evidenced a reduction in daily mean number of voids (8.5 ± 5.0 vs 12.4 ± 5.1, p < 0.0001), mean night voids (1.6 ± 2.2 vs 2.3 ± 1.8, p = 0.0091), mean daily leakage episodes (1.0 ± 1.4 vs 5.0 ± 4.7, p < 0.0001), and number of daily pads (0.3 ± 0.7 vs 2.3 ± 2.6, p < 0.0001). In another retrospective study, Peeters et al. evidenced in a cohort of 104 patients, with a mean follow-up of 46.8 months, a significant reduction in urinary incontinence (70%) and urgency/frequency symptoms (68%). A smaller group of 94 patients suffered of idiopathic retention (32 patients with a diagnosis of Fowler’s syndrome) and showed good results even in this peculiar subgroup with a success rate (symptom reduction > 50%) of 73% in idiopathic retention and a cure rate of 62.5% in the Fowler’s syndrome group and 53% in the remainder patients.¹⁷ Another prospective study on 31 patients with non-obstructive urinary retention with a follow-up of 49.3 months showed a success rate of 58% with regard to the average number of daily catheters (1.9 ± 2.8 vs 5.3 ± 2.8, p < 0.001) and of 71% with regard to the average volume per catheter (109.2 ± 184.3 vs 379.9 ± 183.8, p < 0.001).¹⁸

There is a lower number of good quality studies on the treatment of IC/BPS with SNM. In a small retrospective study on 44 patients with IC/BPS with a long follow-up of 61.5 months, Gajewski and Al-Zahrani reported an 80% improvement of the global response assessment (GRA) and a 43% clinical success. They reported the need of surgical revision in 50% of patients, with an explant rate of 28%, in four cases due to painful stimulation.¹⁹ The results appear lower than those of OAB treatment and may be partly due to the nature of a retrospective study with a small population and partly due to the multifactorial nature of IC/BPS that usually requires a multidisciplinary treatment.

SNM appears to be a safe surgical procedure with mostly minor complications. The incidence of surgical revision ranges between 9% and 33%. The most frequent complication is pain at implant site with variable incidence between 15% and 42%. Lead migration is less frequent (4%–21%). Other complications are pain at lead site (5.4%–19.1%), leg pain (18%), and infection (5.7%–6.1%).^9,11–13 The ROSETTA study evidenced that SNM carries a risk of device removal of 3% and a lower risk of UTI when compared to botulinum toxin injection (11% vs 35%). A possible explanation may be, at least in part, the higher risk of intermittent self-catheterization with botulinum toxin injection (8% at 1 month, 4% at 3 months, and 2% at 6 months).¹⁰ In a retrospective multicenter case-control study on 1930 implants, Myer et al. reported an incidence of infection requiring explants of 1.97%. They demonstrated that hematoma formation (p < 0.004) and a pocket depth >3 cm (p < 0.031) were independent risk factors for infection requiring device explants. The most common organism identified in cultures from explanted materials was methicillin-resistant Staphylococcus aureus (38%).²⁰

In a prospective observational study, Peters et al. analyzed risk factors for reoperation after SNM in a cohort of 407 patients: they showed a greater risk of reoperation in patients undergoing other pelvic surgery, with diagnosis of IC/BPS, female patients under hormonal therapy, and with a high number of reprogramming needed. Furthermore, patients requiring reoperation had a higher incidence of wound infection (6.7%), back pain (3%), leg pain (3.7%), lead migration (6.7%), lead breakage (9%), and device malfunction (13.4%).²¹

Technology innovation is developing new devices with improved characteristics, even though studies with new devices still have a short follow-up. The RELAX-OAB study is a prospective, multicenter post-market clinical follow-up study investigating efficacy and safety of the Axonics r-SNM System, a novel miniaturized rechargeable SNM device. The system includes an implantable stimulator that is 5 cc in volume and that has been tested to deliver therapy for at least 15 years, connected to a four-contact tined lead implanted in the sacral foramen. The patient can recharge the neurostimulator by applying an external charging unit. The 3 months follow-up of this 2 years planned study evidenced an effective response of the device; 71% of subjects were test-responders at 1 month and 91% of them continued to respond at 3 months. In all, 75% of test responders reduced urinary urgency incontinence episodes and 53% reduced urinary frequency. The device appeared to be safe with absence of serious adverse events, accounting 19.6% of adverse events related to the therapy, mostly undesirable stimulation (7.8%) that resolved with device programming.²²

A multicenter cross-sectional observational study evaluated the impact of pregnancy in SNM treatment. Roulette et al. enrolled a group of 21 women with SNM implant carrying 27 pregnancies. In all, 18.5% of women turned off the device while trying to conceive, all the remainder in the first trimester and during all pregnancy. Before pregnancy, SNM was effective in 76.19% of patients; during pregnancy, urinary symptoms were recurrent in all but one patient. In all, 74% of patients reactivated the SNM after pregnancy and 20% reported a reduction in efficacy, in two of four cases due to a displacement of the electrode. Three of four patients with chronic retention resumed self-catheterization and 25.9% of patients had complications, mainly UTI and one case of pelvic pain.²³

PTNS

PTNS is a less invasive approach of neuromodulation. Most of the studies in this field have a short-term follow-up that is correlated to the standard duration of treatment of weekly stimulations for 3 months or 12 weeks. Kabay et al.²⁴ conducted a RCT comparing PTNS to sham stimulation in a population of 89 patients with chronic prostatitis/chronic pelvic pain, and they showed a reduction in pain in the PTNS arm (Visual Analogue Scale (VAS) response 40%, National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) questionnaire response 66.6%). In another RCT, Gungor Ugurlucan et al.²⁵ conducted another RCT on a population of 52 patients treated with PTNS or vaginal electrical stimulation: they showed a significant reduction in mean daily micturictions in both arms, but the reduction was higher in the vaginal stimulation arm. In a prospective randomized study, Finazzi-Agrò et al.²⁶ demonstrated the efficacy of PTNS stimulation compared to placebo after 12 weekly treatments with a significant improvement in incontinence episodes (71% vs 0%). Peters et al. conducted two prospective randomized studies on a cohort of 84 and 220 patients, comparing PTNS and oral tolterodine in the first cohort, and PTNS and sham stimulation in the second cohort. Both studies evidenced a significant response in the PTNS arm (79.5% vs 54.8%; 54.5% vs 20.9%).^27,28 In a prospective study on 39 patients treated with PTNS for chronic nonobstructive retention, Vandoninck et al.²⁹ demonstrated a significant benefit of the treatment as 59% of patients requested continuation of the treatment and 41% reported improvement in voiding diaries.

In a retrospective chart review on a large cohort of 162 patients treated with PTNS for OAB, Rostaminia et al. demonstrated that a history of depression and anxiety was associated with subjective improvement, whether a history of hypertension, prior intravesical onabotulinumtoxinA injection, and SNM are associated with a reduced subjective improvement. After defining a significant improvement in a >50% of symptoms, they demonstrated that a baseline history of depression/anxiety, a higher first sensation to void during urodynamics, and baseline urgency urinary incontinence have a higher chance to reach a significant improvement; on the contrary, a higher maximum pressure during urodynamics and severe baseline nocturia seemed to be correlated to a lower likelihood to reach a significant improvement.³⁰ Almost all studies included patients with idiopathic OAB; Tudor et al. conducted a study to compare results of PTNS in idiopathic OAB (n = 25) and neurogenic OAB (n = 49, mostly multiple sclerosis, 19, and Parkinson’s disease, 7). The overall cohort showed a significant improvement in symptoms after a 12 weeks treatment as indicated by ICIQ-OAB score [−3 (−11.5, 5) (p = 0.01)], ICIQ-LUTSqol [−16 (−57, 6.5) (p = 0.004)], change in 24 h urinary frequency [−1.67 (−3.0, 0.33) (p = 0.002)], and incontinence episodes [−0.0 (−1, 0) (p = 0.01)] on voiding diaries. There were no significant differences in outcomes between the two groups, idiopathic and neurogenic (all p > 0.19). Patients with multiple sclerosis had a higher probability to require a top-up maintenance treatment, compared to the rest of neurogenic patients and idiopathic patients.³¹

The efficacy of a combination therapy with PTNS was analyzed in a prospective randomized controlled study on 105 women with OAB by Vecchioli-Scaldazza et al. They divided the group into three treatment subgroups: solifenacin, PTNS, and combination therapy of solifenacin and PTNS. They found no statistical differences between solifenacin and PTNS group in terms of daily and night time micturiction frequency, urgency, urgency incontinence, and quality of life; on the contrary, they found a significant difference between the combination therapy group and the other two in all aforementioned domains (all p < 0.05).³²

In a large prospective cohort of 200 patients, Del Río-Gonzales et al. evaluated the durability of PTNS. They demonstrated the efficacy of PTNS with a success rate of 73.5% and a symptom improvement in 20.5%; 90.5% of patients reached a clinical improvement >50%. At 24 and 30 months follow-up, there was no statistically difference in daily urinary frequency compared to results immediately after PTNS treatment (p > 0.05) evidencing sustainable results with time; however, they observed a significant worsening in mean night-time urinary frequency and OAB-q SS (p < 0.05), indicating a possible subsequent need of retreatment.³³

Conclusion

This review shows that SNM and PTNS are effective and safe third-line treatments for OAB, non-obstructive urinary retention, and chronic pelvic pain/IC. The overall success rate of SNM ranges from 43% to 85%.^{3,11–13,17–19} The overall success rate of PTNS ranges from 40% to 79.5%.^24,26–29 Both techniques have demonstrated to be safe, with a low rate of complications and need of reintervention. SNM implant appears to maintain its benefit after pregnancy in the vast majority of patients, but studies with a longer follow-up and a larger size of the cohort are required. PTNS requires multiple treatment schedules to maintain the clinical benefit.

The quality of the studies on SNM and PTNS in literature is quite modest, because of the shortage of good RCT; most of the studies are prospective observational studies with mid-term follow-up. It is difficult due to the peculiar surgical technique and mechanism of action to have a placebo arm in studies; most studies include oral antimuscarinic therapy as control arm, but it should be underlined that patients have already failed medical treatment when given the indication to SNM. Good quality studies on PTNS mostly have a short follow-up, so we lack information on the long-term durability of efficacy.

There is no uniformity among studies in expressing the main outcome as it may be indicated by urinary frequency, number of leakage episodes, or the score of a questionnaire, making it difficult to compare the results between studies. The most employed definition of therapeutic success is a >50% reduction in the main symptom.

We need good-quality randomized and prospective studies to assess long-term results of neuromodulation with a clear and uniform indication of the main outcomes, to compare the results of different clinical experiences. Continence definitions should be univocal, avoiding terms that may not refer to a precise data, such as “social continence” or “>50% improvement.” Researchers should use validated questionnaires to evaluate the objective clinical response, the subjective satisfaction of the patient, and the impact on the quality of life.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Enrico Ammirati

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