Ravi Kacker1 and Anurag K. Das2
(1)
Division of Urology, Department of Surgery, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Rabb 440, Boston, MA 02115, USA
(2)
Department of Urology, Center for Neuro-urology and Continence, Beth Israel Deaconess Medical Center, Boston, MA, USA
Ravi Kacker
Email: rkacker@bidmc.harvard.edu
Abstract
Sacral neurostimulation (SNS) is a minimally invasive, reversible treatment option that has been approved by the United States Food and Drug Administration for patients with urgency/frequency and urge incontinence refractory to medical therapy. SNS may work through somatic afferents to modulate bladder and sphincter function. A test stimulation trial using an external neurostimulator can help identify patients who are most likely to respond to the procedure. In this chapter, we examine the indications for SNS and the options for a test stimulation using either temporary or permanent leads. The implantation procedure and previous studies on outcomes after SNS are discussed in addition to cost considerations.
Urinary frequency, urgency, and urge incontinence represent common problems in the urologist’s practice. The term overactive bladder (OAB) is defined by the International Continence Society as “urgency or frequency with or without urge incontinence in the absence of other pathological or metabolic conditions to explain these symptoms” [1]. Although pharmaceutical management and pelvic floor rehabilitation combined with behavioral modification provide relief to many patients with symptoms of OAB, many patients have insufficient improvement or are unable to tolerate pharmacologic therapy [2]. By some estimates, up to 40 % of patients either are refractory to primary management or have an unsatisfactory response. In such cases, sacral neuromodulation (SNS) is a minimally invasive and reversible treatment with a high rate of success that is an attractive option before consideration of more invasive and permanent treatment modalities.
Neuromodulation therapy for OAB symptoms represents a recent step in the long history of the use of electrical stimulation for medical purposes. Early medical applications of electrical stimulation in the nineteenth century were aimed at a broad range of disorders including depression and excess libido. Over the next half century, pioneering applications in urology applied electrical stimulation to the bladder, pelvic floor, or sacral roots for neurogenic urinary retention or neurogenic overactivity. Advances in cardiac pacing and miniaturization of electrical instruments led to a resurgence of interest in neuromodulation of bladder function. The Department of Urology at the University of California, San Francisco led by Drs. Richard Schmidt and Emil Tanagho was instrumental in performing some of the early work and laying the foundation for the use of SNS for the treatment of refractory voiding dysfunction. Drs. Craggs and Fowler in London [3] and Drs. DeGroat and Chancellor [4] at the University of Pittsburgh have performed further work on the mechanism of action of SNS.
Initial large-scale trials were funded by Medtronic (Minneapolis, MN, USA) in the mid-1990s and led to approval from the United States Food and Drug Administration of InterStim for SNS for urge incontinence in 1997 and for urgency/frequency and nonobstructive urinary retention in 1999. Since then, over 25,000 patients have undergone SNS [5]. A systematic literature review by Brazelli [6] demonstrated evidence for safety and efficacy of SNS for neuromodulation in both randomized controlled trials (RCTs) and case series. For the RCTs, 80 % of patients achieved either 90 % continence or a 50 % improvement in their urge incontinence symptoms after SNS.
Mechanism of Action
The exact mechanism of action of SNS is unknown, but it may restore the balance of inhibitory and excitatory influences on bladder and sphincter function controlled by spino-bulbo-spinal pathways. Bladder afferents project to the pontine micturition center which then modulate micturition reflexes. In this theory, sensory somatic input from the pelvic floor acts to inhibit bladder afferents and may be deficient in the OAB syndrome [7]. SNS acts by somehow restoring these inhibitory pathways at the level of S2–4 which provide the primary autonomic (pelvic nerve) and somatic (pudendal nerve) innervation for the bladder, urethra, and pelvic floor. Studies on the latency of the motor response to SNS after chronic treatment have suggested that somatic afferents, in particular, are activated [8].
Cortical sensory changes are also observed during SNS. EEG studies show activity that best correlates with the sensory cortex and combined PET/MRI (magnetic resonance imaging) studies do not show activation of the areas associated with bladder filling sensation and micturition. These findings support the theory that SNS modulates somatic sensory pathways rather than directly influencing bladder and sphincter function. Neural plasticity may also play a role over the course of SNS and PET studies show an initial activation of areas associated with motor learning, followed by activation of motor areas associated with pelvic floor and abdominal musculature [9].
Such PET findings may relate to another theory that the mechanism of action of SNS lies in efferent-mediated augmentation of the guarding reflex [10]. Indeed, in animal models, chronic SNS leads to hypertrophy of striated external sphincter muscle fibers and increased urethral closure pressures [11]. It is, however, unclear if these changes are secondary to modulation of somatic afferents or direct stimulation of motor pathways via Onuf’s nucleus. Recent studies have also investigated the neurotransmitters that mediate the effect of SNS and found that both non-NMDA and vanilloid receptors play a role [3].
Case Studies
Here we present two illustrative cases of patients with refractory OAB symptoms treated with SNS.
Case 1
A 35-year-old G2P2 white female presents with a 5-year history of urinary frequency and urgency. She denies hematuria or significant pain component and has never had urge incontinence. She voids every 45 min to hourly during the day and has nocturia about twice a night. She dates her urinary symptoms as starting soon after undergoing hysterectomy for fibroids. Medical and surgical history otherwise is remarkable only for constipation and appendectomy. There are no culture-proven urinary tract infections, but the patient has tried several courses of antibiotics without significant improvement. She has tried anticholinergics without any significant improvement of her urinary symptoms and worsening of her constipation. Physical examination is unremarkable and pelvic examination shows normal external genitalia without significant prolapse or estrogenized introitus. Neurological examination including perianal sensation and rectal sphincter tone is normal.
Voiding diary reveals a functional capacity of 220 mL with an average void of 125 mL. There are 16 and 18 voids on two 24-h diaries. Urodynamics reveals first sensation at 40 mL, with a strong desire at 75 mL and a capacity of 130 mL. Emptying is normal, but there is some Valsalva augmentation during voiding. There is no evidence of detrusor overactivity. Cystoscopy is unremarkable and essentially normal except for hypersensitivity and limited capacity.
Case 2
A 55-year-old white female presents with complaints of inability to make it to the bathroom in time. She has accidents where she loses large amounts of urine 2–3 times weekly, but more commonly (3–4 times daily), she will lose up to three tablespoons as she is entering the bathroom or trying to undress. The urge incontinence has been present for 5–6 years but the large volume incontinence is new. She denies any bowel incontinence, has mild constipation, and denies any neurologic disease. She is otherwise healthy, with mild hypertension, and is G3P3 (all deliveries were performed with Caesarean section); she denies any stress incontinence or fecal incontinence.
Her examination essentially is unremarkable, with no evidence for any prolapse and a normal abdominal and neurological examination. Urine is clear with no hematuria or pyuria. Cystoscopy is normal and urodynamics reveals terminal detrusor overactivity with inability to inhibit the detrusor contraction. Anticholinergic medications are of minimal help.
Indications
SNS is indicated for the treatment of refractory urge incontinence and refractory urinary frequency/urgency syndromes, or refractory OAB, depending on one’s terminology. Generally, patients who have failed or could not tolerate more conservative therapy, such as behavioral modification, pelvic floor rehabilitation (including pelvic floor biofeedback/muscular vaginal electrical stimulation), and anticholinergic/antimuscarinic medications, are given a trial of SNS. Some physicians exhaust all possible options, including high-dose combinations of antimuscarinics and tricyclic antidepressants, before considering neuromodulation as an option; others will move to SNS earlier.
In 2009, the International Consortium on Incontinence published an algorithm for the management of patient with OAB [12]. SNS is the only minimally invasive treatment option for refractory OAB to be granted a level A recommendation (high level of evidence) by the International Consortium on Incontinence. These recommendations are based on RCTs of SNS for urgency/frequency and urge incontinence demonstrating safety and efficacy along with subsequent follow-up studies demonstrating a durable response. These studies are reviewed later in this chapter.
In the United States, the current approval is for the treatment of refractory urinary frequency/urgency syndromes, urinary urge incontinence, and nonobstructive urinary retention of a nonneurogenic etiology. However, since the introduction of SNS for OAB, there has been growing recognition of the potential benefit of SNS for a broader range of pelvic disorders that may involve some OAB symptoms. Although these applications are investigational, research is ongoing into the potential use of SNS for interstitial cystitis/painful bladder syndrome and neurogenic voiding dysfunction among others.
It is important to remember that patients with neurologic disease were excluded from the initial industry-sponsored trials and subsequent follow-up studies. There is some evidence for patients benefiting from SNS, particularly for early intervention for patients with spinal cord injury, but SNS has not been studied in a systematic fashion for these applications [13]. One major practical limitation of SNS for neurologic disorders is the need of many of these patients to undergo MRI studies.
Terminology is evolving for the condition known as interstitial cystitis/painful bladder syndrome, and the diagnosis is certainly applied to many patients with severe urgency and frequency and minimal pelvic pain. Urinary symptoms in these patients may respond better to SNS than do pain symptoms [14]. Multiple small series have demonstrated short-term efficacy. The highest response rates were reported by Comiter for carefully selected patients who underwent a successful period of test stimulation [15]. In this study, only 27 of 39 patients progressed from test stimulation to permanent implantation, but the rate of success was 94 % among those patients undergoing permanent implantation. A recent series by Powell with an average of 59.9-month follow-up had a low rate of loss of benefit over time for patients who underwent a test stimulation before implantation. However, 50 % of patients underwent explantation due to technical reasons, infection, battery depletion, or pain at the implantation site [16].
Psychological Considerations
A history of psychological disorders is common among candidates for SNS therapy and can pose a challenge for the clinician. While many patients will have substantial physical and psychological benefit from successful therapy, a history of psychiatric disorders may influence the rate and duration of a successful response to SNS therapy.
Weil et al. found that patients with a history of psychological dysfunction were more likely to fail implantation after a successful test procedure than patients without such a history (82 % versus 28 %). Among patients with an initially successful implantation, the duration of the therapeutic effect was shorter for patients with a history of psychological disorders (12 versus 36 months) [17]. Other publications also have speculated that psychological disorders may interfere with the patient’s voiding symptoms and, ultimately, the patient’s response to therapy.
Conversely, voiding symptoms impose a clear burden on quality of life and may contribute to the presence or severity of psychological or mental disorders. The MDT-103 trial demonstrated a clear benefit in terms of depression and health-related quality of life after SNS therapy. Of the 89 patients in the trial, 73 % had some degree of depression at baseline. Patients assigned to direct implantation showed significant improvement in the Beck Depression Index after SNS therapy at 3, 6, and 12 months after starting therapy, while patients in the delayed group showed a slight worsening of depression symptoms [18].
These data suggest that significant psychological benefit may be gained from successful SNS therapy. However, in some cases, such as when there is concern that preexisting psychological disorders may interfere with response to therapy, a psychiatric evaluation may be warranted.
Test Procedure
A test procedure provides a short-term trial of SNS and is important to patient selection before permanent implantation of an implantable pulse generator (IPG). The response during the test period can be used to select the optimal lead position (left versus right, S3 versus S4) and establish patient expectations for symptomatic improvement. The test procedure can be performed in the office, ambulatory-surgery unit, or operating room, and lets the patient and physician decide whether the benefits of permanent implantation are worth the risk and costs of the therapy.
The patient performs a 2- to 3-day voiding diary before the test procedure. In the test procedure one or more leads are placed into the sacral foramina based on the appropriate neural response (discussed later). When planning for a “one-stage” SNS placement, temporary insulated wires are placed in the office setting. In the “two-stage” procedure, permanent quadripolar tined leads are placed in the ambulatory-surgery unit or the operating room. The test period lasts for a few days up to 1 week for temporary and 2 weeks for permanent leads. In both cases, the wires are attached to an external stimulator. The patient maintains stimulation at a comfortable level (it should not be painful) and completes a voiding diary in order to provide objective data while undergoing neuromodulation. Based on the patient’s subjective experience and the objective data obtained through the voiding diary, a final decision is made to proceed or not proceed with permanent implantation. Usually, the patient needs to exhibit significant subjective improvement, and the voiding diary should show at least 50 % improvement in voiding parameters to warrant proceeding to implantation of the IPG.
Test Procedure with Temporary Leads
The office-based test procedure sometimes is referred to as percutaneous nerve evaluation (PNE). While the pioneers of SNS performed this test procedure without fluoroscopy, most practitioners perform it under straight local anesthesia under fluoroscopic guidance. The patient is placed in the prone position with one or two pillows under the lower abdomen to improve the sacral approach. The sacrum is prepped with antiseptic solution and the sacral notches and coccygeal drop-off are identified by palpation or fluoroscopy. S3 usually is located 1.5–2 cm lateral to the midline at the level of the sacral notches, or about 9 cm above the coccygeal drop-off. Local anesthesia is achieved from S2 to S4 over the underlying skin and subcutaneous tissue, making certain not to enter the foramen.
Utilizing the previously mentioned landmarks and fluoroscopic guidance, primarily with lateral imaging, insulated foramen needles are placed percutaneously in the S3 and S4 foramen, and the sensory and motor responses are identified. Once the appropriate responses have been obtained, an insulated wire is placed through the 18-gauge needle in the foramen and the needle is removed. These temporary wires are inexpensive and easy to place. For patients without a clear optimal site of lead placement, two or more such wires can be taped in place and attached to an external stimulator. The patient is taught how to adjust for optimal results and can try out left and right sides or S3 and S4 and decide on the best response. Bilateral test stimulation may be helpful for some patients who fail an initial trial with unilateral placement [19].
Test Procedure with Permanent Leads for Two-Stage SNS
In equivocal cases, or if the insulated wires move, a trial can be carried out with a quadripolar tined lead. The initial procedure is similar to the test stimulation described but cannot be performed in the office setting. Broad spectrum antibiotics are given, and adequate monitored anesthesia care is obtained. Once the needles have been placed in the appropriate foramen and the motor and sensory responses have been obtained, a decision is made to use the best responses. The needle’s stylet is removed, a guide wire is inserted, and the tract is dilated over the guide wire under fluoroscopic guidance once the needle has been removed. The sheath from the dilating apparatus is then left in place; the tined lead (so called as it has tines that hold it in place) is inserted and the position optimized by checking for neural responses. The sheath then is removed, and the tines hold the lead in place. The tined lead now is tunneled to the location of the eventual IPG, where it is connected to an externalizing wire, and then another tunnel is created to externalize the connection and to prevent infection.
Neural Response
Intraoperative motor and sensory neural responses guide lead positioning during the test stimulation. Sensory responses generally include a tingling, pulling, or vibratory sensation in the vagina and rectum in women and in the scrotum, phallus, and rectum in men. Motor responses include levator tightening (bellows response) and plantar flexion of the big toe. Sometimes at S3, a plantar flexion of the entire foot is noted. In such cases, S4 may be the more appropriate foramen, as most patients are significantly bothered by such a foot response.
An intraoperative motor response during the test procedure generally is considered to be more predictive of success after IPG implantation than a sensory response. Cohen et al. followed 35 patients, of which 21 progressed to permanent IPG implantation after a test procedure using quadripolar tined leads. A positive motor response was observed in 95 % of those progressing to permanent implantation versus only 21.4 % of patients who failed the test procedure. Patients with a positive sensory response in the absence of a motor response had only a 4.7 % chance of having a positive result after implantation [20]. Another recent study examined the role of sensory testing in patients with both OAB and pain symptoms, a group that might be expected to benefit from sensory testing. There was no difference in the rate of symptomatic improvement or explantation for patients who did or did not have sensory testing [21].
While intraoperative motor responses are the primary neural responses used to locate the ideal site of electrode implantation, neuromodulation is usually applied at a level below that needed to stimulate a motor response. The patient may use sensory perception to stimulation as an indicator of continued neuromodulation. Loss of sensory perception after implantation may herald a loss in benefit from neurostimulation.
Permanent Versus Temporary-Lead Test Procedure
Before the development of a test procedure with permanent quadripolar leads, use of a temporary lead was the only means for patient selection for SNS. The test procedure itself is considered safe, and complications at the pre-implantation stage are rare. However, lead migration and the risk of infection limit the trial period to about 1 week. Lead migration often presents with pain and decreased efficacy and occurs at a rate of about 10–15 %. In a series by Siegel et al. the rate of temporary-lead migration was 11.8 % of 918 test stimulations. Other complications reported were pain in 2.1 % and technical problems in 2.6 % [22]. Short-term failure rates of up to 27 % have been reported for IPG implantation after successful temporary-lead placement [23]. It is not clear if these failures are due to lead migration, an inadequate test period, or other reasons.
Since the introduction of permanent quadripolar tined leads for test stimulation in 1997, multiple groups have published on the successful use of these leads. Today, most physicians in the United States perform a test procedure with these leads. One advantage of the quadripolar-lead test procedure is that the same responses should be obtained once the external neurostimulator is replaced by the permanent IPG because the lead–nerve interface does not change. The tined lead rarely migrates, and thus a 1- to 2-week or longer trial can easily be done.
A prospective trial by Everaert et al. [24] randomized 41 patients who had a successful trial procedure with temporary leads to either direct (one-stage) IPG implantation or undergo a test procedure with tined leads before implantation (two-stage). Patients in the two-stage group worse an external pulse generator for 3–5 weeks until there was a greater than 50 % improvement in urinary symptoms. All patients in this group progressed to IPG implantation. At 24 months of follow-up, patients who underwent a two-stage procedure had a lower rate of failure compared to the patients who had undergone a single-stage procedure (14 % versus 33 %). This study suggests that temporary-lead test stimulation may have a significant false-positive rate, although it is interesting to note that all patients in the two-stage group eventually progressed to IPG implantation.
There is some evidence that there also may be a significant false-negative rate with a temporary-lead test procedure. Temporary leads are likely to migrate during such a long test procedure and only quadripolar tined leads can be used for a longer test period. Van Voskuilen et al. reported an 80 % rate for a successful test procedure with quadripolar leads, which is considerably higher than published rates for successful test procedures with temporary leads [25]. There may be a significant number of false-negative test procedures with temporary leads due to undetected lead migration or insufficient length of the test period. Kessler et al. demonstrated the predictive benefit of a prolonged testing period. In a retrospective study of 20 patients (13 with urgency/frequency or urge incontinence), an increase in the testing period from 4 to 7 days to a minimum of 14 days increased the rate of eligibility for IPG implantation from 50 to 80 % (p = 0.031) [24].
While a longer test period may increase patient eligibility for neurostimulation, patients screened by either method have similar long-term outcomes. Hundred patients underwent either temporary or permanent lead placement and proceeded to implantation only after a 50 % reduction in symptoms during the test period. The rate of progression to implantation was higher for patients who had permanent leads placed (69 % versus 47 %). However, there was no difference in the rate of failure after implementation. Patients who were screened using either test procedure had about a 2 % rate of failure over 2-year follow-up [26]. While this study included both patients with OAB symptoms and urinary retention, it suggests that the method of test stimulation does not affect long-term outcomes after implantation.
Rarely, lead migration may occur with tined leads for particularly thin patients, either before or after IPG implantation. Overall, lead migration after implantation occurred for 16 % of patients in Brazelli’s [6] review of SNS trials. Hijaz and Vasavada suggested that the risk of lead migration after IPG implantation may be reduced but not eliminated when tined leads are used during the test procedure [27]. Infection is an additional risk of longer trial periods with tined leads due to the percutaneous passage of an extension wire to an external neurostimulator. Huyler et al. performed a microbiologic examination of explanted tined leads from 20 patients who underwent an unsuccessful test period for 2 weeks or longer and identified Staphylococcus species growth in four patients. However, these bacteria were susceptible to perioperative antibiotics and only one of these patients had clinical signs of infection [28]. Similarly, a review of complications in series of 44 patients undergoing a test procedure for at least 14 days identified one case of lead migration, one patient who required revision for pain, and no cases of infection [29]. Overall, these reports suggest a complication rate for a prolonged testing period comparable to a shorter period with temporary leads.
Implantation Procedure
After successful test stimulation, patients may be considered for IPG implantation after being counseled on the risks and benefits. The foreseeable need for an MRI is a contraindication to IPG implantation. The risks of the neurostimulator to a fetus are unknown and patients who are or may become pregnant should consider delaying therapy or choosing alternative therapies. The currently available neurostimulator is the InterStim® device manufactured by Medtronic, Inc. with a battery life of 6–10 years depending on the settings. Medtronic recently introduced the InterStim II, which received regulatory approval in both the United States and Europe in 2006. The new version is smaller in volume and lighter and does not require an extension cable to connect to the tined leads [30]. The implantation procedure itself is for the most part unchanged.
The procedure is performed under general anesthesia using short-acting or nonparalytic anesthetic agents. Perioperative prophylactic broad-spectrum antibiotics are provided and strict antiseptic precautions are maintained. The patient is positioned prone and prepped with multiple layers of providone-iodine, and a midline sacral incision is made. The incision is carried down to the level of the lumbodorsal fascia and this is opened sharply about 1.5 cm from the midline. The underlying paravertebral muscles are separated or divided, and the sacral periosteum is identified. The sacral foramen can be palpated as dimples or a marbling effect on the sacral surface. An insulated needle is placed into the appropriate foramen as determined during the test period. Neural responses are evaluated as discussed earlier until the appropriate foramen is located.
A quadripolar tined lead is placed in the foramen and secured in place by suturing the fixed collar on the lead to the periosteum. Neural motor responses are again tested and excellent motor responses in the form of levator bellows and big toe movement should be obtained in at least three of the four leads. A second incision is then made over the upper buttock 3–5 cm below with superior posterior iliac crest. This position should be planned so as to minimize the risk of discomfort with sitting and daily activities. For the original InterStim® model, a tunneling tool is used to transfer the free end of the lead to the buttock incision. Using a short 10-cm connecting lead, the appropriate connections are now made between the extension lead and the stimulating quadripolar lead and between the connecting lead and the IPG. In the InterStim II® model, the neurostimulator is directly connected to the tined lead. For both models, the incisions are closed in layers generally without drain placement. A confirmatory radiograph is obtained. The patient is discharged home usually within 23 h and returns 1 week later for activation of the neurostimulator.
In some cases, buttock placement of the IPG is not possible due to previous infection, sacral wounds, or other reasons. Alternatively, the IPG can be placed in the anterior abdomen either subcutaneously or under the rectus for very thin patients. While this procedure is similar, a much longer 50-cm extension lead is used. The technique is described in detail by Siegel et al. [31]. The neurostimulator may be controlled using an external programmer allowing adjustment of the amplitude of stimulation within a defined range. The patient should set the amplitude to a comfortable level. Periodic adjustments can be performed as needed.
Most physicians use this implantation procedure with only small variations in technique, but some variations such as bilateral SNS and the use of guarded cuff electrodes deserve further attention. Guarded cuff electrodes have the potential to maintain a fixed distance between electrode and nerve root and prevent any lead movement. Because implantation requires a sacral laminectomy and there is limited availability of guarded cuff electrodes this procedure is rarely done in the United States.
In some patients, bilateral temporary leads as part of a test procedure may be helpful in identifying the lead placement with the optimal response, particularly for patients who fail a unilateral test procedure [32]. However, the value of continued bilateral stimulation and bilateral IPG implantation remains unclear. Kaufmann et al. studied the value of bilateral stimulation in a porcine model of OAB by inducing detrusor hyperactivity using formalin. Bilateral stimulation in this model appeared to increase the chance of stimulating the relevant fibers over a unilateral approach [33]. The clinical relevance of this study is unclear and there is little clinical evidence of any advantage to bilateral over unilateral IPG placement.
The IPG produces a square waveform and can be set to various pulse rates (2.1–130 Hz), amplitudes (0.005–10.55 V), and pulse widths (60–450 μs). An initial pulse rate can be determined during the test period and adjusted after implantation to obtain the appropriate response. Urethral closure pressure studies suggest an initial pulse rate of 10 and 16 Hz [34]. Natural stimuli of C fibers, Aδ fibers, and Aβ fibers occur at different pulse rates, suggesting that different pulse rates may lead to different clinical outcomes [35]. While a study of pulse rate changes did not result in better clinical outcomes on average for a cohort of patients with suboptimal responses to SNS, individual patients did benefit from changes in pulse rate [36].
Cost Considerations
SNS is associated with high initial treatment costs due to device costs, costs related to the test procedure, and operating room and anesthesia costs for implantation. A recent study by Wantanabe and colleagues estimated that these initial costs amounted $22,226 [37]. Treatment failures, while uncommon, involve additional cost for explantation, usually done in the operating room under local or general anesthesia. These high costs, particularly in the current economic environment, require that both patient and provider carefully consider the costs of treatment before proceeding.
One important question is whether the increased costs of the use of permanent leads, in the so-called two-stage procedure, justify the potentially lower risk of treatment failure after implantation. While permanent leads cost about $2,000 each, the cumulative difference in cost between a test procedure with permanent and temporary leads also depends heavily on operative costs, which vary in different health care environments. In the randomized trial by Everaert et al. costs per patient were about €2,000 higher for patients undergoing a two-stage versus a one-stage procedure [25]. To our knowledge, no cost–benefit analysis has yet demonstrated an advantage for a two-stage procedure due to a lower rate of treatment failure.
A few studies have examined the costs of SNS versus comparable treatments for anticholinergic refractory OAB symptoms. Not surprisingly, the initial costs of SNS exceed initial costs for intra-detrussor botox and augmentation cystoplasty. In the cost-analysis by Wantanabe et al. SNS therapy remained the most expensive form of therapy after 3 years with cumulative costs of $26,269 versus $7,651 for intra-detrussor Botox and $14,377 for augmentation cystoplasty.
Leong et al. developed a Markov decision model with either SNS or botox therapy as treatment options to determine cost-effectiveness of each therapy. In the model where both procedures are done under general anesthesia, SNS achieved cost-effectiveness (defined as under €40,000 per QALY) over botox after 4 years. Interestingly, SNS was no longer cost-effective if a test procedure or two-stage procedure was used [38]. In a similar Markov model using the US cost data, the societal costs of SNS over botox exceeded $100,000 per QALY at 2 years of therapy [39]. These studies have significant limitations including the lack of long-term efficacy data for both therapies, but overall these studies suggest that SNS must have excellent long-term efficacy in order to justify high initial costs.
Outcomes
A recent review of the initial RCTs of SNS for urgency/frequency and urge incontinence and multiple subsequent observational studies reported an initial response rate of between 64 and 88 % of all patients [38]. A similar repose rate of 80 % was found in a review by Brazelli et al. defined by either 90 % continence or a 50 % improvement in their urge incontinence symptoms after SNS [6]. Recent follow-up data demonstrate a durable response. These data for 121 patients showed a persistent response at 5 years after initial 1-year success for 84 % of patient with urge incontinence and 71 % with urgency/frequency [40]. A successful clinical response is defined as a greater than 50 % response in urgency, frequency (or normalization), or urge incontinence.
Three prospective randomized trials of SNS for urgency/frequency or urge incontinence merit mention. A study by Schmidt et al. enrolled 155 patients from 16 international centers with urge incontinence refractory to medications and without pelvic pain or known neurologic conditions. All patients underwent a test period of 3–7 days and 98 patients had a greater than 50 % improvement in their symptoms. These patients were randomized to undergo either immediate IPG implantation or delayed implantation after 6 months of medical therapy. After 6 months of SNS for the immediate implantation group, 47 % of patients were completely dry and 29 % had a greater than 50 % reduction in incontinence with efficacy retained at 18 months of follow-up. Urodynamic parameters improved for the immediate versus delayed implantation group at 6 months with a higher percentage demonstrating stable detrusor function (56 % versus 16 %; p = 0.014). For all patients, 32.5 % underwent surgical revision for generator or implant site pain or lead migration [10].
A second trial on SNS for urge incontinence randomized 44 patients to SNS or medical management with an average reduction of 88 % in episodes of incontinence and 90 % in leakage severity. 56 % of implant patients versus 4 % of controls had complete resolution of incontinence and urodynamics demonstrated by roughly quadrupling the volume at first contraction. Based on long-term follow-up, the 3-year actuarial estimate for treatment failure was 32.4 % [41].
The effectiveness of SNS for urgency/frequency was evaluated in a later multicenter trial that randomized 51 patients after a successful test stimulation to immediate InterStim® implantation or a control group. In the treatment group, 56 % of patients achieved either a 50 % reduction in symptoms or less than 7 voids per day. Eight percentage of patients had no improvement in voiding symptoms at all. After 6 months, voiding diary, quality of life, and urodynamic parameters were significantly improved on average in the implant group versus no improvement in the control group. After 6 months of therapy the neurostimulator was turned off and symptoms returned to baseline [42].
A few studies have attempted to identify factors that predict success or failure of SNS. Amundsen et al. prospectively evaluated patients with medication refractory urge incontinence who underwent SNS with a mean follow-up of 29 months. Cure, as defined by no resolution of daily incontinence, was associated with age less than 55 and lack of comorbidities. Patients above 75 years of age had less than a 30 % cure compared to over 80 % of patients under 45. No patients with three or more comorbidities were cured. However, it should be noted that some patients in the study had known neurologic comorbidities, unlike the patients in the previously mentioned clinical trials [43]. Along these lines, another study of patients who failed sacral neuromodulation found that many such patients had some degree of pudendal neuropathy [44].
Algorithm for Management of OAB with SNS
There are multiple acceptable algorithms for management of patients considered for management of OAB. Optimal management is patient specific. We present our standard algorithm here.
All patients considered for SNS must have a complete history and physical examination, including a genital, rectal, and neurological examination. These patients should perform accurate voiding diaries and undergo urodynamic studies to confirm the diagnosis and ascertain whether they are suitable candidates. These patients should have failed or could not tolerate more conservative therapies such as behavioral modification or appropriate medication.
All patients initially undergo a test stimulation with temporary leads placed in the office. Temporary wires are tested bilaterally at S3 or at S3 and S4 (if there is significant foot flexion at S3) looking for the best sensory and motor responses as described earlier. The temporary lead is left in at least two separate foramina and sometimes more; it is rare for us to leave only one wire. A voiding diary is kept for 3–5 days. Patients with a 50 % improvement in symptoms or normalization are considered successful and progress to a one-stage procedure. As discussed above, the permanent quadripolar lead and the IPG then are implanted in the same setting.
If the results of the test are equivocal or if there is suspicion of lead migration during the test procedure, we proceed to a two-stage procedure. A quadripolar lead is implanted in the operating room in the first stage and the patient will wear an external generator and maintain a voiding diary for 2 weeks. At this point, if there is greater than 50 % improvement in symptoms, we proceed to IPG implantation.
Patients may return with recurrent symptoms. In this case, reprogramming of the device is the first step in troubleshooting the generator. First, we cycle through each of the setting levels to see if the patient regains the target sensation. Next, pulse width and amplitude are varied. If there is no success, the patient may need revision with repeat lead placement in the operating room.
Case Study
Returning to the case study presented earlier, the first patient presented with urgency and frequency and had hypersensitivity and low capacity. She underwent a test placement of temporary leads in the office. Under local anesthesia and fluoroscopic guidance, wires were placed at the left and right S3 foramen. Sensory responses were obtained toward the vagina and rectum, and there was a good levator response with very slight toe flexion. Voiding diary during the 5-day test stimulation showed improvement in voided volume to 220 mL, with the number of voids decreasing to 10 or 11. The patient slept through the night with a functional capacity of 320 mL. The patient had an overall better response on the left side and was implanted on the left with continued improvement. At 6 months, voiding function was essentially normal, with voided volume per void of 250 mL and 8–10 voids daily. The patient also thought her constipation was improved, although this was just an observation.
The second patient presented with urge incontinence not helped with anticholinergics and had terminal detrusor overactivity on urodynamics. She underwent a trial of office-based test stimulation. At the S3 level, bilaterally, there is not only a levator response but also a strong foot response involving all toes. She feels the response primarily in the perineum. At S4, she has a levator response with no foot or toe response and feels the response primarily in the rectum and perineum. Wires are left at left S3 and S4 and she responds at both leads, although at S3, the foot movement is bothersome for her. She has no large volume leakage and has a decrease in small volume leakage to 1–2 times daily. She is implanted at left S4, and, at 6 months postprocedure, had no large volume leakage and rare episodes (2–3 times weekly) of a few drops of leakage.
These cases represent good results obtained with SNS with an office-based test procedure followed by permanent lead placement and IPG implantation in one stage in the operating room. Certainly, there are many patients who either do not respond during a test stimulation with either temporary or permanent leads, or have a loss of efficacy after a successful test stimulation. Nonetheless, in this difficult population with limited therapeutic choices, SNS is a promising therapeutic option once behavior treatments and pharmacotherapy have failed.
Conclusions
Since approval of SNS for OAB symptoms, the procedure has grown in popularity, with multiple case series and RCTs demonstrating safety and efficacy of the procedure. Given the high cost of the procedure, the selection of patients most likely to have a sustained benefit is important. At this time, few studies have determined factors that predict a response to SNS for OAB symptoms. In some cases, the etiology of urinary symptoms may not be known. The response rate to SNS is unclear for patients with a neurogenic or pain component to their symptoms. Previous studies on SNS outcomes have focused on patients without known neurologic deficits and current approval is for urgency/frequency and urge incontinence of a nonneurogenic etiology.
A test procedure is helpful in determining the optimum site of lead placement in addition to screening patients before implantation. Only patients who have a successful response with test stimulation should progress to implantation of the neurostimulator. A test procedure may be performed either with temporary leads placed in the office or with permanent leads placed in the OR. There are advantages and disadvantages to either approach. The placement of permanent tined leads allows a longer test period but is substantially more costly. There is some evidence that a longer test period may improve patient selection. However, patients who proceed to implantation after either test stimulation seem to have similar long-term outcomes. Further study is needed to determine if permanent lead placement is cost-effective.
Overall, the rate of successful resolution of urgency/frequency and urge incontinence is high with SNS, in terms of patient symptoms, satisfaction, and urodynamic parameters. Technologic advances have led to leads that are less likely to change position and smaller neurostimulators. Future advancement may better define pulse rate and other stimulation parameters that are tailored to address an expanding set of indications.
Disclosure
Dr. Anurag Das has received compensation for teaching courses, proctoring, and developing teaching materials for Medtronic, Inc.
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