Neuromodulation

Dayron Rodríguez¹ & Anurag K. Das²

¹ Harvard Massachusetts General Hospital Program in Urology, Boston, MA, USA

² Division of Urology, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

Introduction

Chronic urinary frequency, urgency, and urge incontinence, collectively referred to as overactive bladder (OAB), are a common cause of voiding dysfunction and a frequently seen problem in the urologist’s practice. Approximately 30 million people in the United States have OAB, leading to significant impairment in quality of life, a higher risk of falls, lower self‐esteem and health perception [1]. Annual cost associated with OAB, including direct care, health consequences, and lost productivity, is estimated at more than US$10 billion [2].

For patients with OAB, first‐line treatment options include conservative therapies, such as behavioral interventions, pelvic floor exercises, and biofeedback, followed by 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 [3], and other options must be considered. 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. Unfortunately, these procedures are also associated with significant morbidity. Bladder botulinum toxin injection recently received US Food and Drug Administration (FDA) approval for use in patients with neurogenic and idiopathic OAB. Although results have been promising, there is a need for repeat injections and data on long‐term results are lacking. Sacral nerve stimulation (SNS) as well as percutaneous tibial nerve stimulation (PTNS) offer attractive alternatives which are state‐of‐the‐art, minimally invasive, and reversible treatments with a high rate of success for patients with voiding dysfunction (urinary retention or OAB) for whom conservative therapies have failed prior to consideration of more invasive and irreversible treatment modalities.

In this chapter we review the history of these novel techniques, as well as the current state of electric neuromodulation (sacral and tibial) for the treatment of refractory voiding dysfunction, including a detailed description of the therapies, possible mechanisms of action, indications for the procedures, patient selection, surgical techniques, efficacy/outcomes, risks/benefits, and cost considerations.

Historical perspective

Neuromodulation therapy for voiding dysfunction and urinary incontinence represents a recent step in the long history of the use of electrical stimulation for medical purposes. Caldwell [4] reported (in 1963) the use of electrical stimulation of the pelvic floor by implanted electrodes to control stress urinary incontinence and attempted to treat neurogenic incontinence with an implantable stimulator. The instruments in that era were rudimentary; however, with advances in cardiac pacing and improved understanding and miniaturization of electronic instruments, interest in neuromodulation of bladder function was revived in the 1970s and 1980s. Most of the credit for laying the foundation of neuromodulation as it is performed today goes to Drs. Schmidt and Tanagho [5, 6] who did many of the early studies at the University of California, San Francisco. Their work was instrumental in advancing the use of SNS for the treatment of refractory voiding dysfunction. They demonstrated that by using an electrode connected to an implanted pulse generator to provide continuous stimulation of sacral root S3, detrusor and sphincter activity could be modulated and micturition reflexes stabilized. Further research in understanding the mechanism of neuromodulation was done by Drs. Craggs and Fowler in London and Drs. de Groat and Chancellor at the University of Pittsburgh in the mid‐1990s [7, 8].

Initially, SNS was performed as a two‐stage procedure, and the quadripolar lead electrode was placed through an open sacral incision; the implantable pulse generator (IPG) was placed in the abdomen. The procedure was relatively involved and took approximately 2 hours to perform. The first major change was placement of the IPG in the upper buttock region. This helped decrease both the time needed to perform the procedure and the rate of infection. The next major change was the development of the tined lead, allowing percutaneous lead placement under fluoroscopy. This change made the procedure less invasive and further decreased the time needed to perform it.

The initial large‐scale trials were performed in the mid‐1990s when Medtronic Incorporated bought the technology from a struggling startup company and completed FDA trials, leading to the approval of SNS for the treatment of urge incontinence in 1997 and for frequency/urgency as well as nonobstructive urinary retention in 1999. Since then, SNS has been used successfully in over 26 000 patients for lower urinary tract dysfunction [9].

Mechanism of action

The mechanism of action of neuromodulation on voiding dysfunction has not been fully elucidated. In general, neuromodulation works on the principle that activity in one neural pathway can influence activity in another neural pathway. The S2–S4 nerve roots provide the primary autonomic and somatic innervation to the bladder, urethra, and pelvic floor. It is known that contractions of the pelvic floor and voluntary external sphincter can abolish unstable bladder contractions. This may represent one of the mechanisms whereby stimulation of the S3 or S4 nerve root results in strengthening of the pelvic floor and sphincter, resulting in a more appropriate relaxation of the pelvic floor and urethra with less bladder instability.

Chancellor and de Groat [10, 11] have suggested SNS improves somatic afferent inhibition of sensory processing in the spinal cord, playing an important role in modulating abnormal micturition. Schmidt et al. [12] noticed significant improvement in voiding dysfunction through the strengthening of the pelvic floor and external sphincter through efferent‐mediated augmentation of the guarding reflex. Fowler and colleagues [8] suggested that neuromodulation affects afferent pathways through changes in the spino‐bulbospinal pathways to the pontine micturition center. Gronewald et al. [13] have noted that the beneficial effect of SNS can occur without efferent activation of muscle fibers. It is likely that both efferent and afferent mechanisms play a role, with patients primarily with frequency and urgency helped more through afferent sensory mechanisms, and those with primarily urge incontinence improving as a result of increased efferent activity.

Chronic SNS has been shown to lead to augmented somatosensory cortical responses to evoked potentials along the pudendal and posterior tibial nerves [14]. Furthermore, 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 [15]. Suffice it to say that modulation of the sacral nerve toots restores a more normal relationship between the excitatory and inhibitory urinary control systems, helping the two extremes of voiding dysfunction/urinary retention and urge incontinence.

Indications and efficacy of sacral neuromodulation

All patients considered for SNS should have a complete history and physical examination, including a genital, rectal, and neurological examination. These patients should perform accurate voiding diaries and generally undergo urodynamic studies to confirm the diagnosis and ascertain whether they are suitable candidates.

Overactive bladder

The first American Urological Association (AUA) guidelines on OAB released in 2009 focused on 13 studies in the literature of largely single‐group observational designs, which evaluated the efficacy and adverse events of SNS in patients with severe refractory OAB symptoms, many of whom had failed multiple other therapies. Greater than 50% improvement was observed at 5 years in 68% of patients with urgency incontinence and in 56% of those with frequency urgency in those who initially had success with the external testing and went on to pulse generator implantation [16].

The updated literature review, and most recently updated AUA guidelines on OAB (May 2014) examined an additional 16 relevant treatment studies, including one prospective randomized multicenter trial, one crossover study, and another 14 observational studies. These recent studies corroborated similar efficacy reported in the prior guidelines [17]. The guidelines concluded that clinicians may offer sacral neurostimulation (SNS) as third‐line treatment in a carefully selected patient population characterized by severe refractory OAB symptoms or patients who are not candidates for second‐line therapy and are willing to undergo a surgical procedure. Given its lower side‐effect profile, some experts argue that SNS should be offered as first‐line therapy for OAB in the elderly, who may experience significant mental status changes with anticholinergic therapy.

Nonobstructive urinary retention

Prior to the introduction of neuromodulation many of the patients with this disease entity were managed with intermittent catheterization and/or indwelling catheter, given that no pharmacologic therapy was found to be sufficiently efficacious to treat these patients. Recent studies have shown that a significant number of patients with nonobstructive urinary retention who have undergone SNS treatment have been able to eliminate catheterization in six months (50–69%) as well as decrease catheterization volumes (PVR) (70–80%) [18–20]. SNS has even been shown to be particularly efficacious in patients with Fowler’s syndrome (young women with idiopathic retention and specific EMG findings) [21].

Expanding indications

Since the introduction of SNS for OAB and nonobstructive urinary retention, 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 some these applications are investigational and represent off‐label use, research is ongoing into the potential use of SNS for interstitial cystitis/painful bladder syndrome (IC/PBS)/pelvic pain, neurogenic voiding dysfunction, and sexual dysfunction. Early evidence suggests that some patients with these conditions may also benefit from sacral neuromodulation, potentially further expanding the indications for SNS.

Interstitial cystitis/painful bladder syndrome

Urinary symptoms in patients with IC/PBS may respond better to SNS than do pain symptoms. Multiple small series have demonstrated at least significant short‐term efficacy [22, 23]. The highest response rates were reported by Comiter [22] for carefully selected patients who underwent a successful period of test stimulation. 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. Given the increasing evidence of the efficacy of sacral neuromodulation in patients with IC/PBS this treatment is currently considered part of the AUA and European Association of Urology (EAU) guidelines for the management of IC/PBS [24, 25].

Fecal incontinence

The FDA recently approved sacral neuromodulation for the treatment of refractory fecal incontinence. Several prospective studies have reported on the efficacy of SNS for the treatment of refractory fecal incontinence with or without sphincter defects [26, 27]. Wexner et al. [27] reported on outcomes of a large prospective cohort of 120 women with refractory fecal incontinence and showed a significant reduction in incontinence episodes from nine episodes at baseline to two episodes at 1 year. They also reported significant clinical improvements in Fecal Incontinence Severity Index scores, Fecal Incontinence Quality of Life Questionnaire, use of pads and other forms of protection, and overall self‐perception of bowel health.

Neurogenic bladder

Lombardi and Del Popolo [28] studied the efficacy and safety of SNS in patients with incomplete spinal cord injury suffering from neurogenic lower urinary tract symptoms with a mean follow‐up of 61 months. Those patients with urinary retention reported a 50% improvement in baseline voiding parameters, with a significant decrease in the number of catheterizations and a significant increase in the frequency of voids and voided volume. Furthermore, at the conclusion of the study, 38% of patients no longer required catheterization for bladder emptying. A major practical limitation of SNS for neurologic disorders (spinal cord injury and multiple sclerosis patients) is the need of many of these patients to undergo magnetic resonance imaging (MRI) studies. MRIs have been shown to cause heating of the leads, and may damage the IPG [29, 30]. It is contraindicated to perform a MRI in a patient who has undergone SNS with an IPG, with the exception of brain MRI. As such, it is important that the patient’s neurologist be informed and be part of the decision‐making process prior to performing SNS.

Sexual dysfunction

Improvement in female sexual function after SNS treatment has been suggested in recent studies in the literature in a subset of patients suffering from idiopathic and neurogenic detrusor overactivity. Statistically significant improvement has been noted in terms of desire, lubrication, orgasm, satisfaction, and pain [31]. Furthermore, studies have also reported improvement in Female Sexual Function Index (FSFI) and Female Sexual Distress (FSDS) scores [32, 33]. It is hypothesized that the mechanism of action of SNS on improvement of sexual dysfunction relies on pudendal nerve integrity [31]. However, this remains a debated topic in the literature, and large multicenter prospective controlled trials are needed to provide good‐quality results and demonstrate a possible direct effect of SNS and improvement in sexual dysfunction.

Sacral neuromodulation test procedure

A test procedure provides a short‐term trial of 3–7 days of SNS and is important to patient selection before permanent implantation of an IPG. This is sometimes referred to as percutaneous nerve evaluation (PNE). It lets the patient and physician decide whether the benefits of permanent IPG implantation are worthwhile while weighing the benefits, risks, and costs of the therapy. The test procedure can be performed in the office under straight local anesthesia using fluoroscopy guidance; alternatively, a test procedure using permanent tined leads can be performed in the ambulatory surgery unit or operating room. The patient should complete a 2‐ to 3‐day voiding diary before the test procedure.

Percutaneous nerve evaluation

The patient is placed in the prone position with one or two pillows under the lower abdomen to improve the sacral approach. The sacrum, buttocks, and perineum are sterilely prepped with antiseptic solution and the sterile drapes are placed to allow for visualization of the buttocks and gluteal crease, as well as the patient’s feet and toes, during the procedure (Figure 166.1). 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. Insulated foramen needles are inserted percutaneously into the foramen at a 60° angle relative to the skin in the S3 and S4 foramens, using the previously mentioned landmarks and fluoroscopic guidance (with primarily lateral imaging). The test stimulator is connected to the foramen needle via the test stimulation cable, and stimulation is applied (Figure 166.2).