**2. Results**

From July 2017 to June 2019, a total of 73 women with moderate to severe MUI were included in this observational study. The median age was 54.78 (range, 33 to 78) years. Of these, 38 patients underwent MUS only (group 1). Thirty-five patients received simultaneous MUS and intravesical injection of 80 units of BoNT-A (group 2). Detailed patient characteristics were shown in Table 1. Three months after the operation, 27 (71%) and 31 (88%) patients in group 1 and group 2 both scored 0 in the Urinary Incontinence Outcome Score (UIOS) [8] (*p* = 0.085, Table 2).


**Table 1.** Patient characteristics.

MUS: Mid-urethral sling, BoNT-A: botulinum toxin A, OABSS: Overactive Bladder Symptom Score.



UIOS: Urinary Incontinence Outcome Score, OAB: overactive bladder.

Seventeen of the 38 patients in group 1 had detrusor overactivity (DO), and 16 (94%) of them indicated that they wanted to receive treatment for OAB 3 weeks after surgery. On the contrary, 10 (48%) of the 21 patients without DO wanted to receive treatment for OAB. In group 2, 16 women had DO, and five patients wanted to receive medication treatment for OAB. In 19 patients without DO, only four patients wanted to receive medication treatment (Table 3).


**Table 3.** Surgical outcomes of patients with and without detrusor overactivity.

DO: detrusor overactivity, UIOS: Urinary Incontinence Outcome Score.

The Overactive Bladder Symptom Scores (OABSS) in the MUS only group before and after 3 weeks of management were 8.5 and 6.1, which were not statistically different (*p* = 0.084). The OABSS in the MUS with BoNT-A group were 9.3 before surgery and 3.5 after 3 weeks of surgery, which showed significant improvement (*p* < 0.001, Table 4). Three months after surgery, patients with persistent bladder symptoms have been treated with oral medications, and the OABSS in groups 1 and 2 were 4.2 and 3.3, respectively.

**Table 4.** Evaluation of overactive bladder symptoms score at three weeks.


OABSS: Overactive Bladder Symptoms Score.

Based on further analysis of the data on week 12 after surgery, it was found that DO and OABSS ≥11 (area under the curve = 0.96, *p* = 0.003, 95% confidence interval, 0.893–1.000) were predictors of successful treatment when MUS was combined with BoNT-A injection (Table 5).



DO: detrusor overactivity, OABSS: Overactive Bladder Symptoms Score.

The complication rates between the two groups were similar (Table 6). In the MUS with BoNT-A group, eight of the 35 patients complained of difficulty in urination. Six of them showed impaired detrusor contractility (bladder contractility index <100) in the urodynamic study before surgery [9]. These symptoms improved 12 weeks after the operation.



PVR: post voiding residual urine volume.

#### **3. Discussion**

Urinary incontinence has a considerable impact on quality of life and significantly affects morbidity [10,11]. In women with urinary incontinence, approximately 50% and 30–40% have SUI and MUI, respectively [12]. Coexistence of SUI and UUI could increase the severity of leakage and significantly affect the patients' quality of life. Besides nonsurgical management, MUS for SUI is considered significantly effective in the treatment of storage symptoms [13,14]. On the contrary, conservative treatments for UUI mainly include behavioral modification, pelvic floor muscle training, and administration of oral medication [15]. New treatment modality should be considered considering that there is no single treatment applicable to treat both symptoms simultaneously.

Clinically, treatment decision will be determined according to the predominance of SUI or UUI. For example, if SUI is predominant, MUS surgery will be arranged, and patient may receive antimuscarinic agent after surgery [13,14]. However, some studies have pointed out that surgery for SUI is considered not beneficial or can even worsen the symptoms of OAB [16,17]. Moreover, approximately 6–8% of women treated with MUS will develop de novo OAB. On the contrary, if patient's symptom is UUI predominant, surgery is generally not recommended. Antimuscarinic agent and beta-3 agonist are administered to treat symptoms, but these patients often still experience persistent urinary leakage because of SUI. It is difficult for women to evaluate themselves whether SUI or UUI is more predominant. In some of these women, only SUI is treated; thus, they still experience UUI.

Intravesical injection of BoNT-A is also relatively effective for OAB-wet and has been approved by the Food and Drug Administration [18]. To the best of our knowledge, this is the first study to compare MUS with concomitant BoNT-A intravesical injection with MUS only to treat MUI. If two types of urinary incontinence can be treated simultaneously, it should be a good choice for patients. This study successfully expanded the clinical indication of BoNT-A in treating MUI.

Our results show that the continence rate of patients with moderate to severe MUI who received BoNT-A while undergoing MUS was slightly better than that of patients receiving MUS only (cure rate 88% vs. 71%, respectively), but the difference was statistically insignificant. More importantly, not only the symptoms of urinary leakage but also the symptoms of OAB improved in patients receiving both MUS and BoNT-A intravesical injection.

The possible complication of urinary retention is a great concern of patients with MUI receiving MUS and BoNT-A intravesical injection simultaneously. Sun et al. reported that the complication risks of 100 units of BoNT-A intravesical injection included UTI (35%) and urinary retention (8–10%) [18]. In our previous pilot study, five patients received 100 units of BoNT-A intravesical injection. All of them experienced difficulty in voiding and had postvoid residual urine greater than 150 mL. Moreover, three of these five patients required single catheterization after receiving MUS combined with 100 units of BoNT-A intravesical injection. Kuo et al. reported that the range of BoNT-A dosage from 50 U to 300 U showed significant improvement in OAB and urinary incontinence and in urodynamic measures, but receiving >100 units of BoNT-A (*p* = 0.029) was considered a predictor for the increasing incidence of adverse event such as straining to void [19]. Thus, we decreased the BoNT-A dosage to 80 units in this study, and patients did not experience urinary retention. Although 23% of the patients had transient difficulty in urination, these symptoms all improved 12 weeks after the operation.

We found that using a lower dose of 80 units of BoNT-A prevents urinary retention. Previous studies have pointed out that the lower BoNT-A dose has shorter efficacy [20]. Hence, proper explanation regarding the possible reinjection of BoNT-A in 3 months after surgery was provided to patients before surgery. We comprehensively discussed with the patients whether they needed to receive another BoNT-A intravesical injection or to undergo behavioral therapy combined with the administration of oral medication. Finally, 35% of patients decided to continuously receive BoNT-A intravesical injection.

There are several ways to treat urgency symptoms in MUI such as behavioral therapy, pelvic floor muscle training, and administration of oral medication [21]. Most MUI patients initially receive oral medications for their symptoms. However, these oral medications such as anticholinergic agents or beta-3 agonists have significant side effects. Side effects of anticholinergic agents include dry mouth, constipation, and cognitive problems in the elderly [22]. Although beta-3 agonists have relatively lesser side effects than anticholinergic agents, blood pressure may increase in some patients after receiving beta-3 agonists, and the long-term effects of beta-3 agonists on the elderly are still unclear [23,24]. In our study, only 26% continued to take the medication for OAB. Therefore, MUS combined with BoNT-A intravesical injection is considered beneficial in reducing the side effects of oral medications.

In our study, decreasing urination flow rate after surgery was associated with MUS or BoNT-A intravesical injection. However, none of the patients required urinary catheterization in our study. Moreover, adjusting the tension of the sling was not needed while we performed MUS surgery combined with BoNT-A intravesical injection, although BoNT-A may strongly reduce the contractility of the bladder. Previous studies pointed out that the mechanism of MUS was supported by a "tension-free" method instead of urethral obstruction [25].

In our study, all of the patients experienced MUI, but the proportion of DO that was observed during the urodynamic examination before surgery was 45%. According to the definition of the ICS [26], the diagnosis of UUI is based on the patient's symptoms. During the preoperative evaluation, the patient stated that it was difficult to distinguish whether SUI or UUI was predominant. For example, during certain movements, such as brisk walking or small jogging, increased abdominal pressure was accompanied by urgency to leak urine. In our study, we found that in patients who received both treatments, the symptoms still improve in patients without DO. However, patients with DO receiving MUS alone had higher risk of persistent UUI after surgery than patients receiving MUS combined with BoNT-A intravesical injection. We recommend that patients with MUI combined with DO should appropriately receive MUS and BoNT-A intravesical injection.

There were some limitations to this study. First, this was an observation study instead of a randomized controlled trial. According to the guideline of European Association of Urology and American Urological Association, both MUS and BoNT-A intravesical injection are standard treatments for urinary incontinence. In preoperative counseling we explained to every patient that BoNT-A intravesical injection carried 5% incidence of urinary retention and clean intermittent catheterization might be necessary [5]. Based on patients' autonomy, we let them choose whether to receive the BoNT-A intravesical injection or not. There was no significant difference in age, BMI, and OABSS between the two groups. Second, the case number was small. In addition, currently there is no objective and universally accepted tool to evaluate treatment outcomes of MUI. Nevertheless, the promising results shown in OABSS and UIOS improvement as well as freedom from OAB medications could support the rationale to conduct a prospective, large-scaled, randomized study to confirm the efficacy and safety of MUS combined with BoNT-A intravesical injection in treating MUI.
