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27. Contemporary Management of Urinary Incontinence
Keywords
Stress urinary incontinenceAutologous stem cell transplantUrgency urinary incontinenceMixed urinary incontinenceMidurethral slingSacral neuromodulationBeta-3 AgonistUrodynamicsOnabotulinumtoxinAVaginal laser therapyIntroduction
Urinary incontinence is defined by the international continence society as the complaint of involuntary leakage of urine [1]. It can be broken down into two categories: urgency urinary incontinence (UUI) and stress urinary incontinence (SUI). Urgency urinary incontinence is defined as the observation of involuntary leakage form the urethra synchronous with the sensation of sudden, compelling desire to void that is difficult to defer. Stress urinary incontinence is defined as the involuntary loss of urine on effort or physical exertion [2]. Wu and associates estimate that the prevalence of urinary incontinence in U.S. women is about 17.1%. This is associated with a significant cost burden to both the healthcare system and individual patients [3]. The annual cost related to urinary incontinence is estimated at 27.8 billion in the US [4, 5]. Compounding this is the significantly diminished reported healthcare related quality of life in these patients [6]. The goal of this chapter is to review the contemporary treatment options for the management of urinary incontinence.
SUI
SUI is experienced by approximately 35% of women >18 in the US [4, 5]. Fifty percent of women reporting urinary incontinence, report SUI. The main risk factors for developing SUI include parity, obesity and increased age [7]. It is more commonly seen in non-Hispanic, white women and is worsened with chronic medical conditions such as asthma, diabetes and physical inactivity [7–9]. Briefly, we will review the diagnosis and contemporary treatment options for SUI.
Diagnosis
SUI can be broken down into two subcategories: midurethral hypermobility or intrinsic sphincter deficiency (ISD). Midurethral hypermobility results in a lack of support of the urethral sphincter which does not allow it to close during moments of high intraabdominal pressure [10]. This can be diagnosed by performing a Q-tip test in which a cotton swab is placed in the urethra and the patient is asked to strain. If there is greater than a 30-degree change from the original position of the cotton swab, hypermobility is present. In contrast, ISD is a failure of the sphincter mechanism of the urethra to function without the presences of hypermobility. Difficulties arise more often in management of ISD than hypermobility [11].
If urodynamics is done and the urethral pressure profile (UPP) is obtained, ISD can be diagnosed if the maximal urethral closing pressure (MUCP) is below 20 cm H2O. To date, there is not a cut-off point of the MUCP which is a predictor for success with surgical management [12, 13]. Valsalva leak point pressure (VLPP) measures the intraabdominal or intravesical pressure required to overcome urethral resistance ultimately leading to urinary incontinence. McGuire described that VLPP <60 was often associated with ISD [14]. It is uncertain what the clinical significance is by distinguishing between the two different forms of SUI.
It is important to obtain a thorough history and physical exam when evaluating a patient with SUI. In history taking, it is crucial to assess if there are components of UUI associated with leakage and which symptoms are predominant as 20–36% of patients experience mixed urinary incontinence (MUI) [15]. Supplemental information may be obtained via a voiding diary, imaging, cystoscopy or urodynamics depending on the clinician’s index of suspicion.
A thorough physical exam is necessary to support the medical history. Inspection of the external genitals for signs of pelvic organ prolapse, vaginal atrophy, urethral hypermobility, and abnormalities in the urethra (patulous, prolapse etc.) is a crucial part of patient assessment [16]. Additionally, SUI should be confirmed with a negative Marshall/Booney test (urine leakage on straining or coughing with a moderately filled bladder.) This test can be done in supine position and standing if leakage is not visualized in supine position.
Pelvic organ prolapse is an essential part of the physical exam as it may influence the treatment plan. There are several ways to quantify the degree and location of prolapse with the Pelvic Organ Qualification score (POP-Q) being one of the most common tools used [16]. This scoring system assesses the level of anterior, posterior and apical prolapse as it relates to the hymenal ring. If there is concomitant anterior prolapse or significant apical prolapse, assessing SUI with reduction of prolapse should be done. This can be done with manual reduction or with use of a pessary.
As an adjunct to the history and physical exam, pad weight testing and voiding diaries can offer valuable information though is only obtained by <10% of urologist evaluating patients for SUI. While patients are more compliant with shorter testing periods (1-hour for pad test), the longer the testing (48–72 h), the more reproducible the results [17]. Validated questionnaires can be another source of supplemental information.
Urodynamics (UDS) seemed to be commonly performed before surgery for SUI without much evidence supporting its use. Nager et al. performed a study randomly assigning women to undergo office evaluation with UDS versus office evaluation only in women with uncomplicated SUI. They found treatment success at 1 year was 76.9% in the UDS testing group versus 77.2% in the evaluation only group. They concluded that in women with uncomplicated, demonstrable SUI, office examination alone was not inferior to evaluation with UDS [18].
Management
Non-Invasive Management of SUI
Management options for SUI range widely from conservative to invasive. Treatment options include physical therapy, weight loss, vaginal estrogen cream, urethral inserts, pessary, periurethral bulking, midurethral sling, burch colposuspension, and autologous pubovaginal sling.
As stated earlier in the chapter, obesity is significantly associated with SUI [7, 19]. Subak and associates demonstrated that 8.0% weight loss had a significant impact on decreasing SUI episodes in obese women in comparison to women who did not lose weight [6]. Given these findings, lifestyle modification aimed at weight loss is recommended in obese patients as an initial treatment option for SUI [20].
It stands to reason that a decrease in fluid intake will result in decreased urine production and thus a decrease in volume or overall incontinence episodes however no clinical trials have confirmed the effect of fluid management on SUI [21]. It is recommended that patients maintain fluid hydration.
Pelvic floor physical therapy (PFPT) is often recommended as a first line treatment for patients with SUI. The oldest form of PFPT for SUI is kegel exercises consisting of sets of 8–12 contractions of the pelvic floor sustained for 10 s. This should be repeated multiple times per day for 4–5 months to assess efficacy [22]. Several studies have looked at the efficacy of PFPT on SUI. Dumoulin et al. after reviewing the outcomes of 18 studies found that following PFPT, 56% of patients are cured in the treatment group compared to 6% in the non-treatment group [23].Long term follow up is not available on PFPT and the rate of adherence to treatment has been demonstrated to rage from 10 to 70% [24]. A randomized control trial in which women were randomized between PFPT and midurethral sling surgery (MUS) showed that initial surgical treatment gave significantly higher objective (77% vs. 59%) and subjective cure rate (85% vs. 53%) at one-year follow-up. When patients crossed over to the MUS group, no additional benefit was found from undergoing PFPT beforehand [25]. Initial treatment with PFPT is a Grade A recommendation by the European Urologic Association (EUA) as a first line therapy given its non-invasive nature, safety and cost-effectiveness [20].
While some studies have demonstrated that vaginal estrace cream or oral conjugated estrogen can result in improvement or cure of SUI in post-menopausal women, the data is lacking and recent publications indicate no difference in improvement between placebo and estrogen supplementation groups.
Several urethral inserts exist on the market as a non-surgical alternative to management of SUI. The Reliance Insert was the first FDA approved urethral insert designed to function as an occlusive device. It is composed of an external meatal tab, a rigid stem and a proximal balloon inflated with 3 cc. Varying sizes are available ranging from 3.0 to 5.0 cm. It is not a reusable device and must be changed after voiding [26]. Statskin et al. studied this device in 135 women with SUI or mixed incontinence and found that at 4 months 80–95% of patients reported complete dryness to significant improvement of their symptoms [27]. Similarly Miller and associates reported at 1 year follow up 79% of women were completely dry and an addition 16% reported significant improvement [28].These types of devices are intended for use in highly motivated patients who do not desire surgery, have good manual dexterity and are tolerate of a urethral device. Other urethral inserts include the Viva Plug, FemSoft Insert, Relax, Influence and AutoCath® 100 [26]. The latter three are valve activated prosthetics that require surgeon application and exchange every month to several months.
Commercially available vaginal devices such as the Impressa® is another conservative treatment source for SUI that can be used in patients desiring control of incontinence without medical or surgical intervention. Unfortunately, too few studies have been done to assess the efficacy of this device [29].
Pessaries are classically used for the management of pelvic organ prolapse (POP) however certain pessaries are designed with the intent of reducing POP and controlling SUI. Ring pessaries with knobs and Mar-land pessaries are used for concomitant management of Stage I/II prolapse and SUI. They are designed to decrease urethral hypermobility by compressing the urethra against the posterior pubic symphysis. The contraindications to using these devices include pelvic/vaginal infection, vaginal ulcerations and poor patient compliance [30]. The Uresta® is a bell shaped pessary recently introduced into the market. A short term randomized control trial was done assessing the efficacy of the device. A total of 36 patients were enrolled into the study with 18 patients in each arm. Treatment success was defined as ≥50% decrease in pad weight following placement of device. Success was achieved in 66.7% of the Uresta® group and 22.2% of the placebo group, (p = 0.01) [29]. A follow up study showed that at 12 months, 76% of participants successfully fitted in the treatment group continued use, while 50% of overall fitted participants continued use [31].
Minimally Invasive Management of SUI
Minimally invasive procedural treatment options include urethral bulking agents (UBAs). UBAs are injectable natural or synthetic substances that are injected to the periurethral space for treatment of bothersome SUI. They work by increasing the resistance of the urethra and increasing urethral support [32]. Most bulking agents consist of a biodegradable carrier gel which is degraded by the body allowing scar tissue to form around the particles yielding a lasting effect. The effect diminishes over time, however, due to the degradation of the gel. Though minimally invasive, efficacy has not been shown to be great with UBAs. There is a lower success rate compared to surgical procedures and their long term effect is limited often requiring reinjections [33, 34]. Complications associated with UBAs include bleeding, tissue migration, allergic reactions and formation of sterile abscess [34]. UBAs can also be mistaken on cross sectional imaging for bladder stones. No bulking agents has been proven to be superior to another [33]. The preferred location for injection is the mid urethra [35]. Although widely skewed ranging from 10 to 83%, this can be a valuable treatment options for older patients and patients who are not good surgical candidates [36, 37].
Stem cell injection therapy has been considered for the potential regenerative repair of ISD. Scientist postulate that autologous stem cell transplantation may persist longer than injected foreign substances given that the cell based therapy will not cause an immunogenic or allergic reaction [38]. A recent study published by Carr et al. demonstrated the injection of high dose autologous muscle derived cells for 12 or more months resulted in a >50% improvement in pad weight and >50% reduction in diary reported stress leaks. No major treatment related adverse events were reported in this study [39]. This is still largely under investigation but provides an interesting concept and shows promise for the management of SUI in the future.
Surgical Management of SUI
Colposuspension
Surgical management of SUI should be considered after failure of conservative and minimally invasive options have been exhausted or as a primary treatment option once an informed discussion is held between the patient and provider. Traditional surgical treatment options consisted of Marshall-Marchetti-Krantz (MMK), Burch colposuspension and the pubovaginal sling modified and improved by McGuire in the late 1970s [40]. In the late 1990s the synthetic midurethral sling (MUS) was introduced into the market radically changing the treatment of SUI. Since then, the mini-sling and single incision sling have been introduced into the market.
The MMK procedure is a bladder neck colposuspension designed to stabilize the urethra and reposition the bladder neck and proximal urethral intra-abdominally restoring original anatomy using absorbable or non-absorbable suture to tack the aforementioned tissue to the periosteum of the pubic bone. This was first described in 1949 [41]. Complications following this procedure were noted in 20% of patients and included bladder neck obstruction, worsening SUI and osteitis pubis occurring in 0.9–3.2% of patients [42]. These results lead to modification of the procedure and development of the Burch colposuspension.
The Burch colposuspension first described in 1961, the paravaginal fascia is attached to coopers ligament in lieu of the pubic symphysis. Cure rates using this procedure approach 70–90% with the effects diminishing down to 85% at 1 year and 70% at 5-year follow-up [43].
Pubovaginal Sling
The pubovaginal sling has undergone many iterations with the most accepted technique described by McGuire in 1970 [40]. Traditionally, it was not considered a first line treatment, but an option after treatment failure of colposuspension or MUS. It is now considered a treatment option for index SUI patients. Materials for PVS can be autologous, allograft, xenograft or synthetic. Fascia lata and rectus fascia are the most common autologous materials used and are typically 8 cm × 2 cm in size. The graft material is placed at the bladder neck, in contrast to the mid-urethra. Tensioning of the sling is clinician dependent, however the general rule is to allow a two-fingerbreath space between the suture and the fascia when tensioning [44]. Cystourethroscopy is recommended following passing trocars and sling placement to assess for bladder perforation. The literature suggests a cure rate of 46–97% in patients undergoing autologous fascia slings [43]. It is unclear what the cure rates are for non-autologous PVS. Several studies suggest that PVS and Burch colposuspension have similar cure rates [45]. Schimpf et al. showed evidence to the contrary suggesting PVS had a superior cure rate compared to Burch colposuspension [46]. Short term complications include wound infection, seroma, hematoma and urinary retention. Long term complications associated with PVS include sling erosion or extrusion, followed by de novo urgency and UUI.
Midurethral Sling
The goal of the midurethral sling is for it to be placed at the highest pressure part of the urethra to mimic the function of the pubourethral ligament [47]. Most tapes consist of polyprolene in contrast to the polyethylene and polytetrafluoroethylene materials which were associated with erosion. MUS are macropourous with pore size of >75 μm resulting in better incorporation into native tissue.
In comparison to the PVS, operating time tends to be shorter for this procedure accompanied by a shorter recovery with similar clinal outcomes. Documented cure rates of retropubic tape range from 71 to 97% at 1 year and 51 to 88% at the 5- year mark [48].
Complications following this procedure include mesh erosion, extrusion, urinary retention and perforation of the bladder. The most common intraoperative complication is bladder perforation (6.6%) Cystourethroscopy is required following MUS placement to assess for bladder perforation. Post operatively, retention was noted at 16.6% [49].
Transobturator tapes (TOT) were created in an attempt to decrease rates of bladder perforation and vascular injury associated with retropubic tape. The TOT is midurethral and tension free similar to retropubic tape however the arms of the sling are fixed in the obturator foramen. The subjective cure rate following TOT is 62–98% at one year follow-up and 43–92% at >5 years [48]. Groin pain and sexual dysfunction are more commonly seen after TOT [50].
Following failure of any type of MUS, it is recommended that if mesh is to be used again, a retropubic route be done [51].
Transobturator Versus Retropubic MUS
Richter et all compared the transobturator approach to the retropubic approach and demonstrated an objective equivalence in treatment outcomes. Subjectively, there was a slight increase in efficacy with the retropubic sling (62.2%) versus the transobturator (55.8%). The complication seen more commonly in the retropubic group was voiding dysfunction while neurologic symptoms were more often experienced in transobturator group neurologic symptoms [52].
Single Incision Slings
Single Incision Mini Slings (SIMS) were introduced into the market in 2006 to provide a less invasive, less morbid means of managing SUI. This required no blind passage and one single incision to the midline of the vagina. Initial review of efficacy demonstrated clear inferiority to the traditional MUS. Recent reviews of newer products have demonstrated similar efficacy between SIMS and MUS [53]. An adjustable SIMS which was introduced in to the market in 2009. This allows for anchoring of one arm of the sling while adjusting tension and securing the tape only after adequate tensioning is achieved. SIMS-adjust was compared to TVT-O and TVT and no significant difference in cure rates was appreciated [54]. The main advantage for SIMS over TVT-O/TVT was the shorter operative time. Long term outcomes are still not known and not enough data exists to reliably compare SIMS to MUS [55].
Urethral Compression
The artificial urinary sphincter (AUS) may be considered for management of SUI in patients who have failed all other treatments and should be considered a last resort. This is a three-piece device that has an intraabdominal pressure regulating balloon, a urethral cuff and a labial pump. It is estimated that 1% of women with refractory SUI have AUSs implanted. There are many different approaches to placement of the AUS including transvaginal, abdominal/retropubic, laparoscopic, and robotic. The most commonly accepted approach is the retropubic approach [56]. The overall cure rates are reported at 76–89%. One long term study showed that after 20 years, 32.4% of women still had durable success [57]. Explant of the device can be necessary secondary to infection, erosion or device failure [58, 59]. Urethral atrophy does occur frequently in male patients, however there is lack of data on the incidence of atrophy in female patients. If this is a surgical consideration for a patient, they should be referred to a specialized center for placement.
Several European countries have adopted the use of external compression devices. The Adjustable Continence Therapy (ACT®) was designed as a minimally invasive mechanisms to manage refractory SUI in patients with ISD who were previously operated on while avoiding the retropubic space and abdominal cavity. Its major advantage is the ability to adjust the periurethral balloon fluid to fine tune the balance between incontinence and obstruction [60]. The ACT kit contains two silicone elastomer balloons connected to a titanium port along with a syringe and a puncture needle used to inflate the device. Balloons are placed alongside the bladder neck at the 5–7 o’clock position under fluoroscopy and flexible cystoscopy. The balloons are then filled with a radiopaque solution to 0.6 mL. A urethral catheter is left in place for 12 h. This is done as an outpatient procedure. The balloon can be filled 0.6 mL at a time until maximum efficacy is achieved with a maximum fill of 7 mL [58, 60, 61]. A single center retrospective trial focusing on patients with ISD compared ACT® with the AUS in 61 women, 25 undergoing ACT and 36 undergoing AUS. Those in the ACT group had prior history of pelvic radiation, more comorbidities and were older. Overall, the operative time and length of hospitalization were lower in the ACT group (P < 0.001). A higher rate of intraoperative complications were noted in the AUS group (47% vs. 8%, p < 0.001). The rate of post-operative complications did not differ between the two groups. Two members of the ACT group required explant due to vaginal erosion associated with device infection in comparison to seven explants required in the AUS group. The decrease in stress urinary incontinence subscore was significantly greater in the AUS group (−7.6 vs. −3.2; p < 0.01) as was the decrease in mean number of pads per 2 h (−4.6 vs. −2.3; p = 0.002). The patient global impression of improvement was better in the AUS group (p < 0.001). While the AUA does not mention use of the ACT in their treatment algorithm for complicated SUI, the EUA considers that it might play a role, however recommend a secondary sling, autologous PVS or colposuspension as first line in complex patients [20, 62].
Urgency Urinary Incontinence
Urgency urinary incontinence (UUI) impacts 17% of women over the age of 45 in the US and 27% of all women over the age of 75 in the US [63]. UUI can have a significant impact on quality of life with the clinical manifestations depending on the severity of detrusor instability, integrity of the external sphincter and patients functional status [64]. The vast majority of treatment options are aimed at management of detrusor instability. Much like SUI, UUI can be managed conservatively, followed by more invasive measures. We will review the diagnosis and contemporary treatment options for the management of UUI.
Diagnosis
As with diagnosis of most medical conditions, a thorough history and physical exam in a crucial component. History taking should encompass past medical history, surgical history, gynecologic history, duration of symptoms, frequency of symptoms, and current medications. Providers may obtain a post void residual to rule out overflow incontinence however this is not mandated and is a Grade B/C recommendation. A pelvic exam encompassing a perineal and rectal exam is necessary. Providers should also assess for pelvic floor muscle strength. Voiding diaries can also be used to assess storage and filling and to determine functional bladder capacity [20]. The presence of an active urinary tract infection may worsen urinary incontinence, thus a urinalysis is recommended ± urine culture if indicated [65]. Urodynamics may influence clinical decision making, however the evidence suggests that it does not change treatment outcomes therefore is left to the discretion of the treating clinician [66]. Little evidence exists to suggest that imaging contributes to improved clinic outcomes thus routine imaging is not recommended (Grade A) [20].
There is weak evidence suggesting that taking alpha-blockers in women may precipitate or worsen urinary incontinence [67]. Additionally, systemic estrogen doubles the prevalence of UI in previously continent women, and worsens UI in 30% of women [68]. Diuretics given to elderly patients do not worsen or cause UI however central nervous system agents, may cause UI [69, 70].
Minimally Invasive Management UUI
Unlike pelvic floor physical therapy in SUI, there is little evidence to suggest that PFPT improves UUI in patients with primary UUI or mixed incontinence. When comparing PFPT to use of anticholinergics, there was no benefit to PFPT alone or in conjunction with oral agents [71].
Pelvic floor physical therapy addresses both the external sphincter and, theoretically, detrusor instability. Clinicians suggest the use of “quick-flicks” to inhibit bladder contractions when they start addressing the detrusor instability component of UUI. The quick flick exercise involves taking slow deep breaths, while contracting the pelvic floor muscles rapidly 3–5 times when the sudden urge to void is felt. This has been found to suppress the urge to void [72]. Additionally, kegel exercises aimed at pelvic floor strengthening assist in improving external sphincter resistance during involuntary bladder contractions [64].
Medical Management UUI
Antimuscarinics are widely used for the management of overactive bladder and UI aimed primary at decreasing detrusor activity via cholinergic blockade. Acetylcholine (ACh) is released from cholinergic nerves and stimulates muscarinic receptors. Five subtypes of muscarinic receptors exist and two, M2 and M3, have a predominance in the bladder. Stimulation of these receptors result in detrusor contraction [73–75]. Several formulations of anticholinergic medications exist with two of the most commonly used anticholinergics being Tolterodine and Oxybutynin.
Oxybutynin is offered in several different formulations and can be distributed orally, transdermal, rectally or intravesically. Oral oxybutynin is distributed in two forms: Controlled release (CR) and immediate release (IR). Studies have found that both forms lead to a reduction in 24-h incontinence episodes by 84–88% in the controlled and immediate release treatment groups, respectively. In either regimen, total continence was found to be achieved in 40% of patients. Dry mouth, however is more frequently reported in the IR group (87%) than the CR group (68) p = 0.04 [76].
A systematic review of the literature performed by Harvey et al. compared tolterodine 1–2 mg twice per day to oxybutynin 2.5–5 mg three times per day. Both drugs were found to have similar rates of decreased micturition in 24-h period. Oxybutynin, however, was found to have a marginally decreased rate of incontinence episodes over 24 h and an increased mean voided volume per micturition. The study noted that fewer patients experienced dry mouth with the use of tolterodine. While there was a statistically significant increase in improvement seen in the oxybutynin group, this was not clinically relevant and patients overall tolerated tolterodine better [77].
Potential adverse effects of this drug class include urinary retention, constipation, pruritus, erythema, dry mouth and blurred vision. The central nervous system (CNS) is largely unaffected by anticholinergic agents, however, in elderly patients, due to the increase in the blood brain barrier, they should be prescribed with caution [78]. The M1 selectivity of oxybutynin together with its high permeability for the BBB results in higher CNS effects than quaternary amines such as trospium and non-selective anthicholinergics such as tolterodine [79, 80].
Several studies have been published addressing patient adherence to anticholinergics. Medical claims studies have shown that within 30 days of prescription, 43–83% of patients discontinue use of medications. These studies also show that over half of patients never refill their medications. This low level of compliance lead clinicians and researchers to development of treatments with fewer side effects and similar or improve efficacy.
β3 adrenergic receptors are expressed on nerve fibers in the mucosa and muscular layers of the bladder and are predominant in the human detrusor muscle. They are activated by adrenergic stimulation resulting in detrusor relaxation [81, 82]. This knowledge lead to the development of the β3 agonist mirabegron for the management of frequency, urgency and UUI.
In a pooled analysis of three clinical trials, Chapple et al. compared placebo to mirabegron 50 mg and 100 mg. Compared to 59.6% of patients in the placebo group, 69.5% of patients in the 50 mg group and 70.5% of patients in the 100 mg group reported ≥50% reduction in incontinence from baseline (p ≤ 0.001) [83].
Studies have reported the adverse events associated with mirabegron treatment, however the reported rate of serious events is low. The DRAGON investigator group found that the incidence of treatment related adverse events in patients receiving mirabegron doses ranging from 25 to 100 mg was comparable to placebo with serious adverse effects reported at a rate of <2% [84]. HR was found to increase in a dose dependent fashion and only in patients receiving mirabegron doses 100 mg or higher. Special attention should be noted when administering this drug to patients with chronic kidney disease and advanced liver disease. The accepted dose recommendations in the US are 25 mg and 50 mg based on balance between efficacy and side effect profile.
While monotherapy with either drug is efficacious in patients with OAB, combination therapy provides increased improvement in symptoms. Side effects are appreciated in all groups with no greater side effects noted in the combination group compared to mirabegron alone [85, 86].
Treatment compliance to mirabegron in comparison to anticholinergics differs depending on patient experience. In patients with ≥1 prior treatment for OAB at 12 months compliance was noted in 39% in mirabegron group vs. 14–35% in the anticholinergics group. In treatment naïve patients, adherence at 12 months was 30% in mirabegron group, vs. 14–21% anticholinergic group [87]. Anticholinergics and mirabegron appear to have similar efficacy in the treatment and management of OAB. Overall, there is a higher reporting of AEs in the anticholinergic groups.
Burglo et al. assessed whether combining drug therapy with behavioral training compared to drug therapy alone would achieve a sustainable reduction in incontinence after discontinuation of medications and found that the addition of behavioral training to drug therapy reduced incontinence frequency during treatment but this was not sustained following discontinuation. This suggests combination therapy has a beneficial impact on patients. Seventy percent of patients who received combination therapy vs. 58% had a reduction in UUI episodes at ten weeks [88].
Third Line therapy UUI
Posterior Tibial Nerve Stimulation and Sacral Neuromodulation
While there are many minimally invasive measures to address OAB and UUI, patients who are treatment refractory may elect to proceed with third line treatment.
Bladder innervation is controlled by the sympathetic and parasympathetic nervous systems. Under normal circumstances, excitation of the parasympathetic system results in effective bladder wall contraction and complete bladder emptying. Conversely, excitation of the sympathetic system enables bladder wall relaxation and subsequent storage of urine via activation of β -adrenoceptors.
Posterior tibial nerve stimulation (PTNS) is another treatment option for UUI. The posterior tibial nerve has both motor and sensory function and arises from the same spinal segment as the nerves which innervate the bladder and pelvic floor [72]. The stimulation of the posterior tibial nerve results in retrograde stimulation of the sacral nerve plexus with neuromodulatory effects that can result in improvement in bladder overactivity. The exact mechanism of action of neuromodulation is unclear. In a randomized control trial (RCT) comparing PTNS to sham therapy, 54.5% of patients reported moderate to marked improvement from baseline compared to 20.9% of sham subjects. (p < 0.001) (Peters) Another randomized controlled trial comparing the anticholinergic tolteridine to PTNS, 79.5% of patients undergoing PTNS and 54.8% of patients undergoing oral treatment considered themselves cured or improved (p = 0.01). The study found that both groups experienced similar improvements in UI, urgency, frequency and quality of life [89].
Sacral neuromodulation (SNM)is also considered a third-line therapy for patients with overactive bladder [62]. InterStim® therapy was introduced after approval by the FDA in 1997 for the use of treatment of refractory UUI. It is a permanent implanted neuromodulator device that is placed via the sacral foramen along the sacral nerve, typically S-3. It is a staged procedure with the first stage attaching the lead to a temporary test stimulator and the second stage attaching the lead to an implanted pulse generator if patients achieve a >50% improvement in their symptoms during the first stage. The InSite study was a multicenter, prospective, RCT comparing standard medical treatment to SNM. The study found that at 6 months, OAB therapeutic success was 49% in the medical therapy group and 76% in SNM group (p = 0.002). The SNM group also showed significant improvement in quality of life compared to medical therapy (p < 0.001). Adverse events were noted in 30.5% of SNM group and 27.3% of medical therapy group demonstrating the superiority of SNM to medical management of OAB [89].
Several studies have been published reporting the rate of adverse events following SNM. Seigel et al. report a revision rate of 32% with 33% of patients requiring revision for battery replacement. He also reports a permanent removal rate of 13% compared to the 8.6% rate reported in the Rosetta trial [90]. While the Rosetta trial reports that 58% of patients will require re-programming at 24 month follow-up, they only report a revision rate of 3%. The authors postulate that this stark contrast may be secondary to improved clinical technique with lead placement. Following SNM, the Rosetta trial reports a UTI rate of 11%.
OnabotulinumtoxinA (Botox A®) is a neurotoxic protein produced by the bacterium Clostridium botulinum. It functions by preventing the release of acetylcholine neurotransmitter from the axon endings at the neuromuscular junction causing flaccid paralysis [91]. When used in the bladder, this causes detrusor relaxation. It was first described for use in patients with detrusor hyperreflexia following spinal cord injury in 2000. Patients were injected with 200–300 units of OnabotulinumtoxinA. Nineteen out of 21 patients were evaluated 6 weeks following injection. Of those patients, 89% were completely continent, the patients that were found to have persistent incontinence received the 200 unit dose. There was an overall decrease in mean voiding pressures (p < 0.016) and an increase in cystometric bladder capacity 296.3 ± 145.2 to 480.5 ± 134.1 (p < 0.016) The mean PVR increased from 261.8 ± 241.3 to 490.5 ± 204.8 (p < 0.016). Duration of treatment lasted for at least 9 months following initial injection. Safe and effective treatment was proven in SCI patients with incontinence refractory to anticholinergics with a dose of 300 units providing the best chance at counteracting incontinence episodes. Three patients with tetraplegia experienced autonomic dysreflexia and were responsive to treatment [92].
The use and efficacy of this drug have been studied in the neurogenic and idiopathic OAB group. A double-blind, placebo-controlled, randomized dose ranging trial was done assessing safety and efficacy of Botox A® on idiopathic OAB patients with UUI experienced eight or more times per week and eight or more micturitions daily at baseline. Subjects received doses ranging from 50 to 300 units or placebo. The primary end-point was determining improvement in weekly urinary incontinence episodes. Durable efficacy was found in all patients using doses of 100 units or higher. Efficacy was noted as early as week 2. Minimal additional benefit was seen in patients treated with doses greater than 150 U. A dose dependent increase in PVR was noted with the greatest increase in PVR at the 200 U dose, with peak PVR reached at 2 weeks post treatment. Patients with PVRs >200 cc were associated with increased risk of UTI and need for CIC. The authors conclude that 100 U may be the recommended starting dose for idiopathic patients where they may see the ideal balance between efficacy and side effects [93]. Patients with neurogenic detrusor overactivity have chronic conditions requiring life-long treatment. Kennelly and associates demonstrated that long-term use of Botox A® in this patient population is both efficacious and well tolerated when treated with 200 units of onobotulinumtoxinA [94].
The rate of urinary retention following Botox injection is highly variable largely due to how retention is defined by clinicians, the patient population and units administered. Osborne et al. sought to determine the true rate of post-Botox urinary retention defining retention as any patient started on daily intermittent catheterization or had an indwelling catheter placed following Botox injection [95]. In this retrospective study with a median follow up of 12.5 months, patients were excluded if they had pre-operative PVR >200, history of neurogenic bladder or neurologic disorder known to affect voiding, history of urinary retention, had less than 4-week follow-up following Botox injection, received Botox at an outside institution and received more than 200 units during their first treatment. Seventy-six percent of the patients were female with a mean age of 64 ± 13.2 years. Post-operatively, 35% of patients experienced urinary retention requiring catheterization for a mean duration of 16 weeks. They found that patients who received 100 units and had preoperative PVR of <100 mL had a 21% rate of retention. The authors also reported a postoperative urinary tract infection rate of 16% and an efficacy rate of 74%. This is in contrast to the Rosetta trial 6-month follow-up which reported a urinary retention rate of 8% with the median duration of catheterization being 37 days. Additionally, they reported a urinary retention rate of 35% with 39% of patients who did have an infection having multiple infections within a 6-month follow-up period [90].
Botox Versus SNM
Botox and SNM are well accepted as third line therapy options for refractory OAB [62]. The Rosetta trial was a randomized control trial comparing the two treatment options and evaluating for efficacy. The study defined success as ≥50% improvement in symptoms and found that SNM and Botox 200 Units had similar rates of efficacy at 84 and 83%, respectively at two-year follow-up [91]. No difference was found in the mean episodes of urgency urinary incontinence episodes (−3.88 vs. −3.50; p = 0.2). While the 6 month follow up showed an increase in cure rate in the Botox group versus the SNM group, at 24 months both groups had a cure rate approaching 5%. The Botox group did report a higher rate of treatment satisfaction (p < 0.001) and treatment endorsement (p < 0.002). Interestingly, while the Botox group had a higher rate of urinary retention following a second treatment (6%), this rate is lower than that reported in the literature (0–30%). Additionally, patients undergoing the 200 Unit Botox treatment had an median interval from first and second injection of 350 days suggesting a higher dose may correspond to longer duration of efficacy. This study confers that both treatment options are effective and sustainable in the management of OAB.
Fourth Line Therapy UUI
Augmentation Cystoplasty
While most patients with overactive bladder and associated urinary incontinence may be managed with the treatment measures detailed above, a small subset of patients are refractory. In patients with low compliance, low capacity, unstable bladders who fail third line treatments, augmentation cystoplasty (AC) may be considered.
This technique was first described in 1888 by Foggi and Tizzoni and later gained popularity in the 1950s with Couvelaire [96, 97]. Traditionally ileum, stomach, cecum, ascending colon and sigmoid colon have all been used in differing forms to augment the bladder [98]. Other tissues have been used for augmentation however are associated with a high failure or complication rate. Synthetic materials including Teflon, polyvinyl sponge, silastic and collagen have also been used without great success rates and are associated with complications including stone formation, UTI’s, contracture and fistulae [99, 100].
Contraindications to augmentation cystoplasty include patient unwillingness to intermittent catheterize, chronic bowel disease, exposure to radiation with result compromised bowel segments, or short bowel syndrome. In patients with compromised bowel, gastrocystoplasty or autoaugmentation with bladder may be considered. Autoaugmentation has not had long term follow-up and has been reported to have moderate success ranging from 50% in neurogenic detrusor hyperreflexia to 70% in idiopathic DO [101]. While renal insufficiency is not a contraindication, it is a relative contraindication and should be considered as patients who undergo augmentation cystoplasty may have slightly worsening renal function following the procedure [102–104].
Success rates following AC are higher in neurogenic patients (92%) than they are in idiopathic detrusor overactivity patients (53–58%). There is a wide failure rate ranging from 5to 42% [105–107].
AC is a major abdominal surgery and as such has significant short-term complications including wound infections, prolonged ileus, urine leak, small bowel obstruction, hemorrhage VP shunt infections and common complications seen with all major abdominal surgeries. Long term complications include, but are not limited to, metabolic disturbance, stone formation, renal impairment, bacteriuria, need for intermittent catheterization, perforation, vesicoureteric reflux, and nighttime incontinence. Malignancy has been reported in up to 30 patients to date following AC [108].
In rare instances, cystectomy and urinary diversion can be offered in patients with severe, refractory, complicated OAB with no other treatment alternatives [62].
Mixed Incontinence
Mixed urinary incontinence , defined by a combination of involuntary leakage of urine secondary to urgency and exertion, occurs in 30% of all women who report incontinence [109–112]. Accurately defining the cause and pathophysiology of MUI is difficult resulting in challenges in patient management [113]. Historically, management of urgency component was done primarily, followed by potential surgical management of SUI component if conservative measures failed [114]. Management of the SUI component primarily has the potential of treating both issues or causing de novo or worsening lower urinary tract symptoms. Ultimately the treatment plan is designed based on the degree of bother of each individual component and shared decision making.
Diagnosis
The diagnosis of MUI relies on clinical judgment as well as diagnostic tools. UDS should be considered given the complex nature of these patients however, it should be noted that not all patients who report UUI in their day-to-day life will experience detrusor overactivity with or without leakage on UDS [115]. Detection of DO on UDS in patients who report UUI can be as low as 8%. UDS may be used as a tool but should be supplemented with patient history, physical exam, validated questionnaires and voiding diaries.
Non-Surgical Treatment of MUI
Some effective first-line treatment options for MUI include behavioral modification, PFPT and weight loss. Timed voiding, double voiding and fluid restriction may offer patients with significant improvements in quality of life [113]. PFPT was found to be better than no treatment in a Cochrane review on management of MUI [23]. A study done by Subak et al. demonstrated that weight loss had a significant impact on the number of weekly incontinence episodes with resultant improved patient satisfaction compared to no weight loss [6].
Medical Management of MUI
The Mixed Incontinence Effectiveness Research Investigation Tolterodine (MERIT) trial was a double-blinded , randomized, multicenter control trial which recruited 854 women with MUI to assess the impact on tolterodine ER on MUI. The study found that after eight weeks of treatment while there was no improvement in SUI episodes, there was a statistically significant reduction in UUI episodes compared to placebo (−12.3 vs. −8.0; p < 0.0001). Additionally, the tolterodine ER group experienced statistically significant improvements in quality of life domains and overall reported improvement in their bladder condition [116]. Similarly, Dmochowski et al. reported use of 3.9 mg of transdermal oxybutynin in patients with MUI versus placebo resulted in significant improvements in urinary frequency, mean voided volume, quality of life and weekly incontinence episodes [117].
As mentioned above, high quality studies for the impact of estrogen on the management of UUI and SUI is lacking. To date, studies have shown that estrogen supplementation in post-menopausal women for the management of urinary symptoms demonstrates similar outcomes to treatment with placebo [113].
Surgical Management of MUI
Surgical management of MUI can be challenging owing to the complex pathophysiology of the disease process. Traditionally, there were concerns that management of SUI without prior management of UUI could result in worsening or de novo symptoms. Langer et al. reported following colposuspension in women with MUI, DO decreased to 33.3% from 73.3% [118]. Other studies looking at 2-year outcomes give rise to concern that presents of DO at the time of SUI surgery could lead to decreased surgical efficacy as patients with pre-existing DO have a cure rate of 75% compared to 95% appreciated in women with pure SUI [119]. Studies have also shown that 45–69% of patients experience resolution of UUI following pubovaginal sling [120–123]. Caution should be taken when interpreting these studies given the variation in defining “cure”. Similar studies have found some improvement in DO in women with MUI undergoing MUS placement with 60% subjective cure rates reported at 4-years by Holmgren at al compared to 85% subjective cure rates in patients with pure SUI [124].
When assessing how anti-incontinence procedures measure against each other in women with MUI, Gamble et al. found that women who underwent bladder neck sling had the lowest rate of post procedural, UDS proven, DO in comparison to those women undergoing transobturator sling and retropubic sling [125].
Ultimately, the management of MUI is complex and can be approached in many different ways. It is crucial to carefully evaluate the patient and have an informed discussion regarding possible treatment options and outcomes with patients. Initial management may be conservative, surgical or medical depending on patient presentation and clinical factors.
Future Potential Treatment Modalities
There has been a lot of discussion regarding laser treatment of the vaginal epithelium for treatment of genitourinary syndrome of menopause (GSM). GSM encompasses post-menopausal lower urinary tract symptoms including urinary urgency and dysuria. As such, several studies have looked at the effect of vaginal laser therapy on lower urinary tract symptoms including stress urinary incontinence. Gambacciani et al. conducted a prospective, longitudinal study in postmenopausal women suffering from GSM. The study identified 19 post-menopausal women who had mild to moderate SUI. Participants were treated with vaginal erbium laser (VEL) with a wavelength of 2940 nm once monthly for three months. The control group was treated with vaginal gel containing estriol 50 mg twice weekly for three months. Treatment with VEL resulted in significant improvement in ICIQ-SF scores from baseline (p < 0.01) up to 24 weeks from initial treatment [126]. Fistonic et al. similarly used the Er:YAG laser at a wavelength of 2940 in women with SUI and found a statistical and clinically significant improvement in ICIQ-UI questionnaires compared to baseline. Several devices have been marketed for treatment of urinary incontinence however, the vaginal laser is not specifically indicated by the FDA for treatment of urinary incontinence at this time [127].
Urinary incontinence is highly prevalent and has be shown to significantly impact quality of life. Khurt and associates found that UUI impacts quality of life more so than SUI or mixed urinary incontinence [128]. This chapter outlines contemporary treatment options for the management of urinary incontinence.
