A prospective, single-blind, randomized crossover trial of sacral vs pudendal nerve stimulation for interstitial cystitis

Authors

  • Kenneth M. Peters,

    1. Department of Urology, Ministrelli Program for Urologic Research and Education (MPURE), William Beaumont Hospital, Royal Oak, Michigan, USA
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  • Kevin M. Feber,

    1. Department of Urology, Ministrelli Program for Urologic Research and Education (MPURE), William Beaumont Hospital, Royal Oak, Michigan, USA
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  • Richard C. Bennett

    1. Department of Urology, Ministrelli Program for Urologic Research and Education (MPURE), William Beaumont Hospital, Royal Oak, Michigan, USA
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Kenneth M. Peters, Department of Urology, 3535 W 13 Mile Road, Suite 438, Royal Oak, MI, 48073, USA.e-mail: kmpeters@beaumont.edu

Abstract

OBJECTIVE

To compare sacral nerve stimulation (SNS) with pudendal nerve stimulation (PNS) for interstitial cystitis (IC).

PATIENTS AND METHODS

Twenty-two patients with well-documented, refractory IC had a tined lead placed at S3 and a second electrode implanted at the pudendal nerve via a posterior approach. In a blinded, randomized design, each lead was tested for 7 days. The best lead was implanted to a pulse generator and patients were followed at 1, 3 and 6 months.

RESULTS

The time required to place a sacral lead was 27.4 min, and a pudendal lead 19.6 min (P = 0.039). Of the 22 patients, 17 (77%) responded and had a permanent implant placed. PNS was chosen as the better lead in 77% and SNS in 24%. The order in which the lead was stimulated had no effect on the final lead implanted and there was no ‘carry-over’ effect. The overall reduction in symptoms was 59% for PNS and 44% for SNS (P = 0.05). At 6 months after implantation, voids improved by 41% (PNS) and 33% (SNS), and mean voided volume increased 95% and 21%, respectively; validated IC questionnaires improved markedly and complications were minimal.

CONCLUSIONS

This is the first ‘blinded’ study of SNS vs PNS for IC. A pudendal lead was implanted successfully in all patients, and most chose PNS as better than SNS; the improvement was sustained over time.

Abbreviations
IC

interstitial cystitis

FDA

Food and Drug Administration

(S)(P)NS

(sacral) (pudendal) nerve stimulation

HB-EGF

heparin-binding epidermal growth factor

ICSPI

O’Leary/Sant IC Symptom Problem Index

PUF

Pain Urgency and Frequency (questionnaire)

C-MAP

compound muscle action potential

IPG

implantable pulse generator.

INTRODUCTION

Interstitial cystitis (IC) remains one of the least understood and most difficult to treat urological conditions; there are >1000 000 cases of IC in the USA alone. It is well established that significantly many of these patients are refractory to oral medication and intravesical therapy [1,2]. Neuromodulation is not yet approved by the USA Food and Drug Administration (FDA) for treating IC, but it has been extensively studied. Patients with IC often qualify for neuromodulation on the basis of complaints of urgency and frequency, but the treatment of pelvic pain related to IC is not yet approved by the FDA as an indication for neuromodulation. The evidence that patients with IC benefit from sacral nerve stimulation (SNS) has been accumulating since the FDA first approved neuromodulation for treating urinary urge incontinence, urinary urgency-frequency, and unobstructive urinary retention, in 1997. In 2000 Chai et al.[3] showed the effect of temporary S3 SNS on frequency, urgency, pelvic pain, urinary levels of heparin-binding epidermal growth factor (HB-EGF) and antiproliferative factor. After 5 days of SNS, frequency halved, urgency decreased from 6.0 to 1.8 on a 10-point scale, and pain decreased from 7.0 to 2.3 on a 10-point scale. In addition, they showed that the HB-EGF concentration increased seven times and antiproliferative factor activity decreased. Maher et al.[4] and Comiter [5] reported similar findings in 2001 and 2003, with decreased urgency, frequency and pelvic pain. A more quantitative analysis of pelvic pain relief was reported by Peters and Konstandt in 2004 [6], showing a decrease in intramuscular morphine dose-equivalents used after permanent generator implantation in patients with refractory IC.

Neuromodulation techniques are developing constantly; the first major change was the acceptance and implementation of the staged procedure. Next came the invention of the tined lead, making the operation faster and less painful. Attention has now turned to the possibility of using the pudendal nerve as the site of neuromodulation (pudendal NS, PNS). The pudendal nerve might offer the benefit of increased afferent stimulation through S2–S4. The present study is a subset analysis of a prospective, single-blind, randomized, crossover trial which was designed to compare SNS with PNS for treating voiding dysfunction.

PATIENTS AND METHODS

This study was powered to determine a 40% response difference between SNS and PNS during the initial stage-one blinded phase of the study. With a power of 80% and α of 0.05 (two-tailed), 20 patients were required to determine any significant difference. In all, 22 patients with refractory IC who were receiving SNS to treat their voiding dysfunction consented to having a second electrode placed at the pudendal nerve as part of the present study, approved by the institutional review board. Baseline voiding diaries were obtained, including urinary frequency, voided volumes and incontinent episodes. In addition the O’Leary/Sant IC Symptom Problem Index (ICSPI) [7] and Pain Urgency and Frequency (PUF) questionnaires [8] were completed. All procedures were performed by one surgeon (K.M.P.).

The InterStim (Medtronic, Inc., Minneapolis, MN, USA) quadripolar tined lead was used. An electrode was placed at the S3 nerve root, in the standard fashion, and externalized. After placing a tined lead at S3, all patients had a second electrode placed on the same side at the pudendal nerve, via a posterior approach. Briefly, needle electrodes were placed in the external anal sphincter and compound muscle action potentials were measured (C-MAP). The ischial tuberosity was palpated and a foramen needle was passed medial to this toward the ischial spine, using fluoroscopic guidance. The needle was stimulated from 0 to 10 mA at 1 Hz until a C-MAP consistent with pudendal stimulation was found. The typical motor response was an anal contraction, and sensory response consisted of pulsating in the vaginal or scrotal area. Once the pudendal nerve was identified, the directional guidewire, followed by the lead introducer, was advanced toward the nerve and the quadripolar lead was positioned. Each electrode was stimulated, and after reconfirming pudendal stimulation in at least three of four electrodes, the tines were deployed. Radiographic films were taken to document the sacral and pudendal lead position (Fig. 1). The quadripolar lead was tunnelled to a mid-buttock incision, connected to a standard percutaneous extension lead and externalized. Each lead was marked as lead number 1 or lead number 2, to keep patients unaware of the type of implant. Patients were discharged with the standard external stimulation box, with a pulse width of 200µs and a rate at 16 Hz. Each patient was randomized, in a single-blinded design, to begin stimulation on either the sacral or pudendal electrode. Each lead was stimulated for 7 days, and patients completed voiding diaries and an overall response assessment which asked patients to rate frequency, urgency, pelvic pain and bowel function on a 7-point scale, from ‘markedly worse’ to ‘markedly better’. The primary outcome was the patient’s rating of their overall percentage improvement on each lead. They then chose the lead to be implanted to a permanent generator, based on clinical response, before knowing which was sacral and which was pudendal. The number of subjects choosing a sacral lead compared to a pudendal lead was assessed. An overall 50% improvement in symptoms was considered a positive response. Patients not responding to either lead had the electrodes explanted; the others had the best lead connected to the implantable pulse generator (IPG). Patients were then followed at 1, 3 and 6 months with voiding diaries, the overall response questionnaires and the ICSPI and PUF questionnaires.

Figure 1.

A plain film documenting the sacral and pudendal lead positions.

The independent t-test was used to analyse the time to implant, Fisher’s exact test to assess possible bias in choosing a lead, based on whether a particular lead was tested first or second, and an anova regression model, in a crossover design, to determine if there was a ‘carry-over’ effect based on which lead was initiated first or second.

RESULTS

In all, 22 patients with IC (19 women and three men) were enrolled (mean age 48 years, range 26–70); all had a previous hydrodistension documenting either petechial haemorrhages or Hunner’s ulcers, and in all conservative therapy for their voiding dysfunction had failed (Table 1).

Table 1. 
The baseline characteristics of the patients
CharacteristicRespondersNon-responders
Number 175
Mean (range):
Age, years 46 (26–70) 56 (45–66)
Years since IC diagnosis  6.4 (1–20) 4.2 (2–7)
Hydrodistension volume, mL605 (400–750)510 (200–1000)
No. of previous IC treatments  6 (4–8) 5.4 (4–6)

In the acute testing phase, a quadripolar tined lead was successfully placed at the sacral and pudendal sites in all patients. The time to place the sacral and pudendal leads was 27.4 and 19.6 min, respectively (P = 0.039). Of the 22 patients, 17 (77%) had a significant clinical response and had an IPG placed. While unaware of type, patients were asked to rate their overall improvement in voiding symptoms and to choose which lead they desired. In the 17 responding to neuromodulation, PNS gave an overall 59% improvement in symptoms, whereas SNS gave an overall 44% improvement (P = 0.05). Thirteen of 17 patients chose the pudendal lead for the final implant and four chose the sacral lead. Five patients had no response to either lead and had both explanted. The order in which the lead was stimulated had no effect on the final lead implanted, and there was no carry-over effect. On a 7-point scale from ‘markedly worse’ to ‘markedly better’, PNS was better than SNS for urgency (P = 0.028) and frequency (P = 0.030). There were no differences between SNS and PNS for pelvic pain, bowel function, vaginal pain or incontinence. Voiding diary data showed a significant improvement in voiding frequency and volumes over baseline for both SNS and PNS, but there was no statistically significant difference between each of these leads (Table 2). Two patients developed sterile seromas around the IPG that were drained, in the office, with a syringe and needle. All patients had follow-up X-rays before the stage II implant and no migration of the sacral or pudendal lead was found.

Table 2. 
Stage I voiding diary data
GroupMean (sem) voiding diary variable
Voids/24 hVolume, mLLeast volume, mL
  • *

    Both SNS and PNS are different from baseline but not from each other.

Baseline24.07 (14.5) 81.8 (28.7)24.8 (16.6)
SNS*13.94 (7.7)152.8 (65.8)42.8 (22.9)
P 0.001  0.001 0.021
PNS*12.84 (5.0)158.0 (91.1)60.9 (43.9)
P 0.001  0.001 0.012

Patients with either a sacral lead (four) or pudendal lead (13) were followed at 1, 3 and 6 months with voiding diaries. At each time the validated ICSPI and the PUF questionnaires were completed. Three of 17 patients failed to complete any follow-up questionnaires, but continued to use their devices and reported sustained improvement. On a 7-point scale, two-thirds of those using SNS and PNS reported a ‘moderate’ or ‘marked’ improvement in overall IC symptoms at 6 months. No patient reported a worsening of their symptoms. At 6 months after implantation, the voids per day decreased by 41% for PNS and 33% for SNS, mean voided volume increased by 95% and 21%, and incontinence decreased by 92% and 17%, respectively (Fig. 2). The 10-cm visual analogue scale scores for pain decreased by 49% for sacral (7.9 to 4.0) and 29% for pudendal (4.5 to 3.2). There was a sustained improvement in those treated with either SNS or PNS. The ICSPI improved by 44% and 38% for PNS and SNS, respectively, and the PUF questionnaire by 35% and 29% respectively (Table 3). When asked if they would undergo the implantation again, all those using SNS and 90% of those using PNS responded ‘yes’. Half of those using SNS and 38% of those using PNS required at least one reprogramming event. No significant adverse events were reported and there were no revisions or explants.

Figure 2.

The mean (sem) a, number of voids/day, and b, voided volume; and c, the mean incontinent episodes/day.

Table 3.  Validated IC questionnaire results at 6 months after implantation
GroupPUFICSPI
SymptomBotherTotalSymptomProblemTotal
Sacral
Baseline16.5 (3.04)7.67 (2.40)24.2 (5.42)14.3 (3.48)13.0 (2.08)27.3 (5.55)
6-month12.8 (3.63)5.5 (1.76)18.3 (5.21)10.7 (3.48) 7.8 (3.44)18.5 (6.90)
P 0.050.096 0.01 0.03 0.12 0.07
Pudendal
Baseline16.4 (1.12)8.64 (0.41)24.8 (1.39)15.7 (0.78)12.9 (0.72)28.4 (1.41)
6-month10.7 (1.98)5.3 (1.01)15.5 (2.90) 8.6 (1.93) 7.5 (1.40)15.6 (3.37)
P 0.020.001 0.008 0.009 0.002 0.006

DISCUSSION

IC is a challenging clinical syndrome to manage; the initial treatment involves dietary modification, stress reduction, and oral pharmacological therapies. Despite best efforts, many patients continue to have urinary urgency, frequency and pelvic pain. SNS has been used for years to treat voiding dysfunction and there is a growing body of evidence that it might be useful in managing the symptoms of IC [1–6]. Despite the clinical success of neuromodulation, the exact mechanism of action is unknown. The development of a tined electrode, not requiring suture fixation, makes it feasible to stimulate other nerves of interest. The pudendal nerve is a distal branch of S2, S3 and S4, and is a logical site to study for voiding dysfunction. A potential benefit is increased afferent stimulation to the micturition centre through all three sacral nerve roots. We recently reported our acute comparative results of SNS vs PNS for various voiding dysfunctions, and the present study is a subset analysis of those with IC in that trial [9]. There have been no reports of chronic PNS in patients with IC, but a recent small study on overactive bladder was reported [10]. In the present report we describe our experience using a tined quadripolar lead at either the sacral or pudendal nerve to treat the symptoms of IC in a well-defined group of patients with refractory IC.

All the present patients had bladder hydrodistension documenting either petechial haemorrhages or Hunner’s ulcers. They were ≈ 5 years from initial diagnosis, had a mean bladder capacity of ≈ 550 mL, and six previous treatments for IC had failed. All patients chose to have neuromodulation to try and control their symptoms, and they consented to have a sacral and pudendal electrode placed as part of an approved, physician-sponsored study.

The first part of the study was to test acutely the benefit of SNS vs PNS in each patient; as this was the first blinded, crossover comparative trial of SNS vs PNS for voiding dysfunction, we elected to use electrodiagnostic monitoring to achieve a C-MAP confirming PNS. This ensured that we were stimulating the pudendal nerve and not just the pelvic floor muscles. Each patient had both a sacral tined lead placed in the standard fashion and a pudendal lead placed via a posterior approach. The pudendal site was a new site of stimulation, but we were able to deploy a tined lead at the pudendal nerve in all patients more quickly than the sacral lead, confirming the feasibility of this approach. Patients were randomized to begin SNS or PNS while unaware of type. Each lead was tested for 7 days and diaries and questionnaires were maintained by the patients. It was important to be certain that the order of stimulation had no effect on the final lead chosen for implantation, and statistical testing confirmed this, and that there was no carry-over effect from the first lead stimulated.

Of the 22 patients, 17 (77%) responded to neuromodulation and had a permanent IPG placed. When patients rated the percentage improvement of symptoms with each lead the pudendal lead showed a greater overall symptom improvement than the sacral lead. Most patients chose the pudendal lead (13/17) over the sacral lead (4/17) for final implantation, and the study blinding was maintained until the decision about which lead to implant was made. This suggests that PNS might be an alternative approach to treat voiding dysfunction, and supports future testing of those who have in whom SNS has previously failed. Voiding diary variables improved over baseline for both sacral and pudendal leads, but there was no statistically significant difference between the sites.

Adverse events were minimal; there were no intraoperative complications while placing the sacral or pudendal electrode. As the tined lead was not designed to be placed in the ischial rectal fossa, follow-up radiographs were obtained in all patients after 14 days of testing, before the second-stage implant. All leads, whether sacral or pudendal, were stable. Two patients (one sacral, one pudendal) developed a sterile seroma around the IPG, which was drained with a needle and syringe, resolving the problem.

In the second part of the study patients were assessed at 1, 3 and 6 months, with voiding diaries and questionnaires, to provide data on chronic PNS in these patients with IC. The data are deceptive because the study was not powered to compare SNS and PNS during the follow-up, and there were too few patients (four) implanted with a sacral lead. Despite these limitations, each group had reductions in urinary frequency, increases in voided volumes and reductions in incontinent episodes. The IC database multicentre study found that incontinence was common in those with IC, particularly when the IC symptoms were more severe [11]. This was also the case in the present study, and although patients did not have neuromodulation because of complaints of incontinence, there was an improvement in this outcome during the follow-up. The improvement in voiding symptoms appeared to be more stable over time in the PNS group. The validated IC questionnaires also improved in both the SNS and PNS groups. Of interest, the PUF bother score improved by 38% in both the SNS and PNS groups, but the symptom score improved more in the PNS group (34%) than in the SNS group (25%). Similarly, the ICSPI problem score improved by 43% in SNS and 42% in PNS, but the symptom score improved more in the PNS group (45%) than the SNS group (32%). This supports what was seen in the voiding diary data, that PNS might have a more significant and sustained effect on voiding dysfunction than SNS. Reprogramming events were monitored and half of the SNS and 38% of the PNS group required at least one reprogramming during the 6-month follow-up. Further supporting the benefit of neuromodulation in patients with IC, all the SNS and 90% of the PNS group would undergo the implant again. Finally, there were no significant adverse events, no infections and no explantations throughout the study.

There are several limitations to this trial. First, this was a relatively small study, particularly during the 6-month follow-up. Only four of the 17 patients implanted had a sacral lead and caution is needed not to over-interpret the data. There is compelling evidence that PNS is feasible and effective but there were too few patients to conclude that PNS is better than SNS. A well-designed direct comparison trail should be conducted to compare PNS and SNS for treating IC and other voiding dysfunctions. Second, it could be argued that more patients chose PNS as superior during the acute testing because electromyographic monitoring was used while placing the pudendal lead and not the sacral. It was chosen to monitor placing the pudendal lead and obtain a C-MAP because this was a new site of stimulation, and we wanted to confirm that the pudendal nerve was actually being stimulated. Previous studies showed no improvement in clinical outcome with SNS if electromyography was used while placing the sacral lead, if appropriate sensory, motor and radiographic findings were shown. The principal surgeon reported excellent outcomes with SNS with no electrodiagnostic monitoring [12]. Third, the 6-month follow-up is relatively short and a longer follow-up would be appropriate to better understand the role of PNS in treating the IC symptom complex.

In conclusion, this is the first prospective, single-blind, cross-over trial of SNS vs PNS for patients with IC. The study showed that placing a tined quadripolar lead at the pudendal nerve is feasible and safe. Most patients who tested both a sacral and pudendal electrode while unaware of type chose PNS as the better site. The prospective follow-up showed marked improvements in voiding variables and validated IC symptom questionnaires. Over 90% of patients treated with neuromodulation would undergo the implant again. A well-powered comparative trial of SNS vs PNS is needed to determine the role of PNS in treating voiding dysfunction.

ACKNOWLEDGEMENTS

Source of Funding: Ministrelli Program for Urologic Research and Education; additional tined quadripolar lead provided by Medtronic Inc.

CONFLICT OF INTEREST

The authors state that there is no conflict of interest.

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