Overactive bladder (OAB) is commonly encountered in urologic practice. Treatment algorithms begin with conservative therapy and pharmacotherapy with antimuscarinics. Some patients do not receive adequate relief from these methods or they do not tolerate side effects from pharmacotherapy. A test stimulation for sacral neuromodulation and percutaneous tibial nerve stimulation are office-based techniques that are commonly used as the next step in the algorithm of care in patients with OAB. These techniques are efficacious and approved by the Food and Drug Administration for treatment of overactive bladder and its associated symptoms.
Key points
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Neuromodulation techniques, such as sacral neuromodulation (SNM) and percutaneous tibial nerve stimulation (PTNS), are treatment options for patients who fail behavioral therapy and pharmacotherapy.
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Neuromodulation may augment inhibitory bladder afferents and lead to cortical plasticity to inhibit bladder reflexes.
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A test sacral stimulation can be performed in the office with temporary leads and may help identify patients who are most likely to succeed with SNM.
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PTNS is an emerging therapy that may improve OAB symptoms in some patients through entirely office-based neuromodulation.
Introduction
Chronic 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 pathologic or metabolic conditions to explain these symptoms.” An estimated 34 million people in the United States have OAB, leading to significant impairment in quality of life, a higher risk of falls and other accidents, and lower self-esteem and health perception. Annual cost associated with OAB is estimated at more than $9 billion, including direct care, health consequences, and lost productivity.
For patients with OAB, first-line treatment options include conservative therapies, such as pelvic floor exercises and biofeedback, along with pharmacologic therapy. Although many patients find relief with these therapies, up to 40% of patients are either refractory to primary management or have an unsatisfactory response. Currently, several options exist for these patients, ranging from intradetrusor injection of botulinum toxin to irreversible surgical therapy, including detrusor myomectomy, augmentation cystoplasty, and urinary diversion. Neuromodulation represents a minimally invasive and reversible treatment with a high rate of success for patients who are refractory to first-line therapies for OAB.
In this review, we focus on office-based neuromodulation, specifically percutaneous tibial nerve stimulation (PTNS) and office-based test procedures for sacral neuromodulation (SNM). SNM refers to electrical stimulation of the S3 (or S4) sacral nerve root to modulate the micturition reflex. Initially, a test procedure is performed using either temporary leads placed in the office or, alternatively, permanent leads placed in the operating room (OR). After a successful test period, permanent leads and a pulse generator are implanted in the OR. PTNS is a less invasive, office-based therapy that applies electrical stimulation in a retrograde fashion through the tibial nerve to achieve neuromodulation of the sacral plexus. PTNS is typically applied weekly in the office for 12 weeks and responders continue with monthly therapies.
Historical Perspective
Neuromodulation therapy for OAB is a recent step in the long history of the use of electrical stimulation for medical purposes. In the nineteenth century, electrical stimulation was used for a broad range of psychiatric disorders and later applied to the bladder, pelvic floor, or sacral roots for neurogenic urinary retention or overactivity. Advances in cardiac pacing led to miniaturization of electrical instruments and the first demonstration of sacral neuromodulation by Drs Tanagho and Schmidt in the early 1980s. In patients with neuropathic voiding dysfunction, they showed that continuous stimulation of sacral root S3 modulated detrusor and sphincter activity, resulting in stabilization of micturition reflexes.
Further pioneering work on the mechanism of action of SNM was performed by Drs Craggs and Fowler in London and Drs DeGroat and Chancellor at the University of Pittsburgh. Initial large-scale trials (Medtronic [MDT]-130) demonstrating the efficacy of SNM in patients with non-neuropathic OAB were funded by Medtronic (Minneapolis, MN) in the mid-1990s. On the basis of these trials, the US Food and Drug Administration (FDA) approved SNM for urge incontinence in 1997, then urgency/frequency and nonobstructive urinary retention in 1999. Since then, SNM has been successfully used in about 25,000 patients with OAB.
More recently, PTNS has emerged as a lower-cost, office-based form of neuromodulation after pioneering work in the late 1980s by Dr Stoller at the University of California, San Francisco. Recently, a few randomized controlled trials have demonstrating improvements in urinary symptoms above those of placebo and similar to improvements with tolerodine. Subsequent studies have demonstrated a durable response in some patients. Currently, a commercial neuromodulation system is produced by Uroplasty, Inc (Minnetonka, MN), which received 501(k) FDA marketing clearance for urgency/frequency and urge incontinence in 2005.
Mechanism of Action
The exact mechanism of action of neuromodulation on micturition remains unclear. In theory, neuromodulation acts to augment inhibitory somatic afferents that are deficient in patients with OAB. These bladder afferents project to the pontine micturition center and, with chronic stimulation, lead to changes in suprapontine regions that ultimately modulate micturition reflexes. In SNM, electrical stimulation is directly applied to the sacral nerve root.
Chronic sacral nerve stimulation has been shown to lead to augmented somatosensory cortical responses to evoked potentials along the pudendal and posterior tibial nerves. PTNS aims to achieve an effect similar to SNM on micturition reflexes through electrostimulation of the posterior tibial nerves. Chronic electrostimulation of the pudendal nerve has also been shown to improve OAB symptoms in a few patients with neurogenic OAB.
Through positron emission tomography studies, additional neural plasticity is observed over the course of neuromodulation in cortical areas associated with motor learning and with pelvic floor and abdominal musculature. Thus, an additional theory is that neuromodulation also acts by augmenting of the guarding reflex. In animal models, neuromodulation leads to hypertrophy of striated external sphincter muscle fibers and to increased urethral closure pressures. It is unclear if these changes are due to the proposed neuromodulatory effect or simply due to direct stimulation of motor pathways by Onuf nucleus.
Introduction
Chronic 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 pathologic or metabolic conditions to explain these symptoms.” An estimated 34 million people in the United States have OAB, leading to significant impairment in quality of life, a higher risk of falls and other accidents, and lower self-esteem and health perception. Annual cost associated with OAB is estimated at more than $9 billion, including direct care, health consequences, and lost productivity.
For patients with OAB, first-line treatment options include conservative therapies, such as pelvic floor exercises and biofeedback, along with pharmacologic therapy. Although many patients find relief with these therapies, up to 40% of patients are either refractory to primary management or have an unsatisfactory response. Currently, several options exist for these patients, ranging from intradetrusor injection of botulinum toxin to irreversible surgical therapy, including detrusor myomectomy, augmentation cystoplasty, and urinary diversion. Neuromodulation represents a minimally invasive and reversible treatment with a high rate of success for patients who are refractory to first-line therapies for OAB.
In this review, we focus on office-based neuromodulation, specifically percutaneous tibial nerve stimulation (PTNS) and office-based test procedures for sacral neuromodulation (SNM). SNM refers to electrical stimulation of the S3 (or S4) sacral nerve root to modulate the micturition reflex. Initially, a test procedure is performed using either temporary leads placed in the office or, alternatively, permanent leads placed in the operating room (OR). After a successful test period, permanent leads and a pulse generator are implanted in the OR. PTNS is a less invasive, office-based therapy that applies electrical stimulation in a retrograde fashion through the tibial nerve to achieve neuromodulation of the sacral plexus. PTNS is typically applied weekly in the office for 12 weeks and responders continue with monthly therapies.
Historical Perspective
Neuromodulation therapy for OAB is a recent step in the long history of the use of electrical stimulation for medical purposes. In the nineteenth century, electrical stimulation was used for a broad range of psychiatric disorders and later applied to the bladder, pelvic floor, or sacral roots for neurogenic urinary retention or overactivity. Advances in cardiac pacing led to miniaturization of electrical instruments and the first demonstration of sacral neuromodulation by Drs Tanagho and Schmidt in the early 1980s. In patients with neuropathic voiding dysfunction, they showed that continuous stimulation of sacral root S3 modulated detrusor and sphincter activity, resulting in stabilization of micturition reflexes.
Further pioneering work on the mechanism of action of SNM was performed by Drs Craggs and Fowler in London and Drs DeGroat and Chancellor at the University of Pittsburgh. Initial large-scale trials (Medtronic [MDT]-130) demonstrating the efficacy of SNM in patients with non-neuropathic OAB were funded by Medtronic (Minneapolis, MN) in the mid-1990s. On the basis of these trials, the US Food and Drug Administration (FDA) approved SNM for urge incontinence in 1997, then urgency/frequency and nonobstructive urinary retention in 1999. Since then, SNM has been successfully used in about 25,000 patients with OAB.
More recently, PTNS has emerged as a lower-cost, office-based form of neuromodulation after pioneering work in the late 1980s by Dr Stoller at the University of California, San Francisco. Recently, a few randomized controlled trials have demonstrating improvements in urinary symptoms above those of placebo and similar to improvements with tolerodine. Subsequent studies have demonstrated a durable response in some patients. Currently, a commercial neuromodulation system is produced by Uroplasty, Inc (Minnetonka, MN), which received 501(k) FDA marketing clearance for urgency/frequency and urge incontinence in 2005.
Mechanism of Action
The exact mechanism of action of neuromodulation on micturition remains unclear. In theory, neuromodulation acts to augment inhibitory somatic afferents that are deficient in patients with OAB. These bladder afferents project to the pontine micturition center and, with chronic stimulation, lead to changes in suprapontine regions that ultimately modulate micturition reflexes. In SNM, electrical stimulation is directly applied to the sacral nerve root.
Chronic sacral nerve stimulation has been shown to lead to augmented somatosensory cortical responses to evoked potentials along the pudendal and posterior tibial nerves. PTNS aims to achieve an effect similar to SNM on micturition reflexes through electrostimulation of the posterior tibial nerves. Chronic electrostimulation of the pudendal nerve has also been shown to improve OAB symptoms in a few patients with neurogenic OAB.
Through positron emission tomography studies, additional neural plasticity is observed over the course of neuromodulation in cortical areas associated with motor learning and with pelvic floor and abdominal musculature. Thus, an additional theory is that neuromodulation also acts by augmenting of the guarding reflex. In animal models, neuromodulation leads to hypertrophy of striated external sphincter muscle fibers and to increased urethral closure pressures. It is unclear if these changes are due to the proposed neuromodulatory effect or simply due to direct stimulation of motor pathways by Onuf nucleus.
Indications
Neuromodulation is indicated for the treatment of refractory urge incontinence and urinary frequency/urgency syndromes. Generally, patients who have failed or who could not tolerate pharmacotherapy and conservative therapy are candidates for a trial of neuromodulation. Conservative therapy may include behavioral modification, pelvic floor rehabilitation (including pelvic floor biofeedback/muscular vaginal electrical stimulation). Some physicians exhaust all possible options, including high-dose combinations of antimuscarinics and tricyclic antidepressants, before considering neuromodulation; others will move to neruomodulation earlier. Bladder botox therapy has also been approved for these patients who have failed behavioral and pharmacotherapy.
The recently published American Urologic Association Guidelines include both SNM and PTNS as third-line, FDA-approved treatments for patients with non-neurogenic OAB. The Grade C recommendation applies to carefully selected patients who have severe refractory OAB symptoms or those who are not candidates for pharmacotherapy. In 2009, the International Consortium on Incontinence published an algorithm for the management of patients with OAB. SNM is the only minimally invasive treatment option for refractory OAB with a Grade A recommendation (high level of evidence). These recommendations are based on randomized controlled trials (reviewed later in this article) of SNM for urgency/frequency and urge incontinence demonstrating safety and efficacy along with subsequent follow-up studies demonstrating a durable response. Several randomized trials have shown short-term improvement in OAB symptoms with PTNS, although there are fewer data on long-term efficacy. European Association of Urology (EAU) guidelines gave a grade B recommendation to offer PTNS for improvement of urge incontinence in women who have not benefited from antimuscarinic medications.
Painful Bladder Syndrome and Neurogenic Voiding Dysfunction
In the United States, the current approval for SNM is for the treatment of refractory urinary frequency/urgency syndromes, urinary urge incontinence, and nonobstructive urinary retention of a non-neurogenic etiology. However, since the introduction of SNM for OAB, there has been growing recognition of the potential benefit of SNM for a broader range of pelvic disorders that may involve some OAB symptoms. Research is ongoing into the potential use of SNM for interstitial cystitis/painful bladder syndrome (IC/PBS) and neurogenic voiding dysfunction among others.
Patients with IC/PBS may experience an improvement in coexisting urinary symptoms with SNM. One series demonstrated short-term improvement in urinary symptoms along 27 carefully selected patients who had successful test stimulation. In another study of carefully selected patients with IC/PBS managed with SNM, 50% of patients underwent explantation for pain at the implantation site, infection, or other reasons. Of the patients who did not undergo implantation, there was minimal loss of benefit over 59.9 months of follow-up. SNM may be suitable for some patients with primarily urinary symptoms and minimal pain.
Patients with neurologic disease were excluded from the initial industry-sponsored trials and subsequent follow-up studies based on the belief that an intact spinal pathway was necessary for neuromodulation. However, similar success rates are observed in patients with neurogenic OAB and there is some evidence to support early intervention with SNM after spinal cord injury to prevent urinary incontinence. One major practical limitation of SNM for neurologic disorders is the need of many of these patients to undergo magnetic resonance imaging studies.
Psychiatric Considerations
Comorbid psychological disorders are common among patients who are candidates for SNM therapy. Although 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 SNM therapy. In an early study of 36 patients undergoing SNM, patients with a history of mental illness were more likely to fail implantation after a successful test procedure (82% vs 28%). Furthermore, patients with a history of mental illness had a shorter duration of therapeutic effect from SNM compared with patients with no history (12 vs 36 months).
Conversely, voiding symptoms impose a clear burden on quality of life and may contribute to the presence or severity of psychological or mental disorders. Improvement in OAB symptoms through neuromodulation may improve or prevent deterioration of mental health. The MDT-103 trial demonstrated a clear benefit in terms of depression and health-related quality of life after SNM 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 SNM therapy at 3, 6, and 12 months after starting therapy, whereas patients in the delayed group showed a slight worsening of depression symptoms.
These data suggest that significant psychological benefit may be gained from successful SNM 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.
Sacral neuromodulation test procedure
A test procedure provides a short-term trial of SNM 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 vs right, S3 vs S4) and establish patient expectations for symptomatic improvement. The test procedure can be performed with temporary leads in the office under local anesthesia. Although the pioneers of SNM performed this test procedure without fluoroscopy, most practitioners perform it under fluoroscopic guidance. Alternatively, a test procedure using permanent tined leads can be performed in the ambulatory-surgery unit or operating room.
In either case, the patient performs a 2- to 3-day voiding diary before the test procedure. The test period lasts for a few days up to 1 week for temporary and 2 weeks for permanent tined leads. 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 to provide objective data. Based on the patient’s experience and voiding diary, a final decision is made to proceed or not to 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.
Office-based Procedure
The office-based test procedure sometimes is referred to as percutaneous nerve evaluation. The patient is placed in the prone position with 1 or 2 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 to 2.0 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.
Insulated foramen needles are placed percutaneously in the S3 and S4 foramen using the previously mentioned landmarks and fluoroscopic guidance (with primarily lateral imaging). Appropriate 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, 2 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 of 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.
Sensory and Motor Neural Responses
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 and colleagues followed 35 patients, 21 of whom 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. 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.
Although 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.
Office-based Test Procedure Versus 2-Stage Implant
A major consideration for the clinician is whether to pursue an office-based test procedure, which if successful, is followed by a “1-stage” implant of permanent leads and an IPG in the OR. An alternative approach is the “2-stage” procedure, in which the patient has permanent quadripolar tined leads implanted in the OR. The patient undergoes a trial period, and if successful then returns to the OR for tunneling of the leads and placement of an IPG.
Before the development of a test procedure with permanent quadripolar leads, use of a temporary lead was the only means for patient selection for SNM. The test procedure itself is considered safe, and complications at the preimplantation 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% to 15%. Other complications, including pain, may occur at a lower rate (about 2%–3%). It is not clear if these failures are due to undetected lead migration, infection, or other reasons.
Since the introduction of permanent quadripolar tined leads for test stimulation in 1997, multiple groups have published on the successful use these leads. The major advantage of the 2-stage procedure is that the final lead-nerve interface is established before the test period. In theory, the tines should prevent lead migration and thereby allow a longer test period of up to 2 weeks. A recent meta-analysis of SNM trials found a 16% rate of lead migration. Overall, it appears that the use of tined leads may decrease, but not eliminate the risk of lead migration during the test period, particularly for thin patients. The primary disadvantage of a 2-stage procedure is that this procedure requires 2 trips to the OR and may be associated with a higher cost.
A few studies have directly compared outcomes using temporary leads in the office compared with permanent tined lead placement in the OR. In one recent nonrandomized study, patients undergoing a 3-day test period with temporary leads were less likely to progress to implantation than patients who underwent a test procedure with tined leads. However, among those patients who progressed to implantation, the type of test procedure did not impact failure rates, which were below 3% for both groups over 24 months of follow-up. Similar results were found in a smaller, randomized study involving only women.
A longer trial, up to 2 weeks, appears to increase eligibility for implantation, possibly because it takes some patients a longer time to adjust settings or otherwise achieve therapeutic benefit. Although a trial period of 1 to 2 weeks with tined leads does not seem to increase the specificity of a successful trial compared with an office-based trial, there may be a benefit from very long trial periods. Everaert and colleagues randomized 41 patients to either an office-based test procedure or to a 3-week to 5-week trial period after placement of tined leads in the OR. At 24 months of follow-up after implantation, there was a lower rate of failure for patients undergoing the prolonged test procedure compared with those who had only an office-based test procedure (14% vs 33%). In that study, the costs of an office-based test procedure were about $2,667 less than a test procedure initiated in the OR. Our own data ( Table 1 ) suggest that in experienced hands, an office-based fluoroscopically assisted test procedure provides excellent results, and can be performed in most patients at a much reduced cost to the health care system and is also an overall more efficient use of surgeon and OR time.
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