**3. Discussion**

The role of BoNT-A in treating refractory OAB is well established in both sexes [26,27]. However, studies focusing on efficacy and adverse events in the elderly population are limited [38]. In addition, with the extension of life expectancy, "75 years of age and over" is increasingly being used to define the elderly population [36]. Hence, our study defined the elderly population as patients aged 75 years or older. We aimed to determine the therapeutic outcome of intravesical BoNT-A in this population and identify valuable factors associated with adverse events. Our results revealed that although elderly bladders were more sensitive at baseline compared to young bladders, BoNT-A intravesical injection was equally effective for OAB symptom control. In addition, the prevalence of adverse events was equal in both age groups. Female sex, lower bladder compliance, and higher PdetQmax were associated with postoperative UTI, while DM and higher PdetQmax were associated with postoperative urinary retention in the elderly population.

Several possible pathophysiologies have been proposed to explain refractory OAB [39], including urothelial dysfunction with aging [40], undetected bladder outlet obstruction (BOO), chronic bladder ischemia or inflammation [41,42], and central sensitization [43,44]. These conditions are commonly found in the elderly population owing to aging-induced changes from the brain to the bladder itself [45–47]. In our study, more than 75% of patients in the elderly group were men, a proportion much higher than that in the young group. This may further emphasize the importance of chronic undetected BOO in bladder remodeling [48]. It is well-documented that the presence of BOO will result in large PVR and could be a risk of urinary retention after the intravesical BoNT-A injection, especially in the elderly [29,30]. Therefore, in our clinical practice, we will investigate patients with refractory OAB by video-urodynamic study to find if there is BOO, and the BoNT-A injection can only be performed in patients without BOO, or if their BOO has been welltreated. In addition, our findings of the preoperative multichannel urodynamic study in these elderly bladders, including increased bladder sensation and reduction in bladder capacity, were consistent with the known changes in the aging bladder [46]. Intravesical BoNT-A injection provides sensory blockade in addition to chemo-denervation of the bladder detrusor muscle [49,50]. This may explain why patients who are refractory to conventional OAB medications can be successfully treated with BoNT-A.

To the best of our knowledge, no case-control study has compared the therapeutic efficacy of BoNT-A between patients aged ≥75 years and those aged <75 years. White et al. [34] reported a case series of 21 refractory OAB patients aged 75 years and older and concluded that BoNT-A injection is efficacious, durable, and has a low incidence of adverse events in the short term. Frailty has been proposed as a negative factor for long-term treatment success, but this study used "age greater than 65 years" as the definition of elderly [29]. Our study demonstrated that the elderly population ( ≥75 years old) had similar subjective success rates at 3, 6, and 12 months postoperatively compared with the young population. Furthermore, with no between-group differences, >60% of patients in both groups eventually experienced a certain period of subjective dryness without urge incontinence. This highlights that age itself is not a direct factor that affects the bladder response to BoNT-A. Instead, the underlying pathophysiologies that develop during the aging process to induce refractory OAB are key factors in determining therapeutic outcomes.

Considering the direct chemo-denervation effect on the bladder detrusor muscle, PVR elevation and urinary retention are common concerns after intravesical BoNT-A injections [51]. A large PVR is commonly defined as a PVR greater than 150 or 200 mL,

and approximately 6–61% of patients with a mean age > 65 years have been reported to experience a large PVR after receiving injections [28–30,35]. Miotla et al. reported that female patients with PVR > 200 mL or retention after injections were older than those with PVR < 200 mL [52]. Liao and Kuo proposed that instead of age, frailty was associated with post-injection PVR > 150 mL [29]. In our elderly population ( ≥75 years old), 18 (27.7%) patients were found to have a large PVR > 200 ml after BoNT-A intravesical injection, and eight (12.3%) patients eventually experienced urinary retention and needed temporary Foley catheter indwelling. There was no difference in the prevalence of a large PVR and urinary retention between the elderly and young populations. Although no valuable factor could be found to be associated with large postoperative PVR in our elderly population, a higher baseline PdetQmax and a history of DM were identified as factors associated with postoperative urinary retention. DM is a well-known factor that induces overactive bladder and affects detrusor contractility during the voiding phase [53]. Wang et al. reported that intravesical BoNT-A successfully managed detrusor overactivity and achieved a similar treatment success rate in both DM and non-DM patients but with a higher risk of large PVR and general weakness in DM patients [54]. In elderly patients with DM, detailed consultation and close follow-up for postoperative PVR are necessary.

UTI is another common but frustrating unfavorable outcome after intravesical BoNT-A injections [55]. A recent systemic review revealed that the prevalence rate of UTI after intravesical BoNT-A injection for treating OAB is approximately 29.8% [56]. Both storage and emptying dysfunction have been proposed to impact UTI recurrence [57,58]. In our study, we found that female sex, lower bladder compliance, and a higher PdetQmax were associated with postoperative UTI in the elderly population. Lower bladder compliance and higher PdetQmax are common bladder dysfunctions that increase intravesical pressure during both the storage and emptying phases. Increased intravesical pressure is known to cause bladder ischemia, which may predispose the bladder to infection because of a delayed or insufficient immune response [59,60].

Although the present study successfully demonstrated the therapeutic outcomes and adverse events of intravesical BoNT-A injections in a population older than most of the published data, some limitations still exist. First, its retrospective design made it possible to involve biases during patient selection, data collection, and statistical analysis. Moreover, we could not further define 'frailty' by retrospectively reviewing the medical records. Instead, we believe that using 75 years as the cutoff value would be indeed a reasonable choice. Second, the small sample size in the elderly group limited the statistical power in multivariate logistic regression analyses, and also hindered the subgroup analysis for different sexes. Third, no postoperative multichannel urodynamic data were available to provide detailed bladder storage function after BoNT-A injection. Considering the invasiveness of the test, a simple uroflowmetry with PVR is commonly used to represent postoperative bladder function. Finally, in the long-term follow-up, we found only 29.7% of refractory OAB patients received subsequent BoNT-A injection in our hospital. This result indicates that the patients might not be satisfied with the unfavorable treatment outcome after the first BoNT-A injection and would choose medical therapy for their bothersome OAB symptoms. However, understanding the treatment effect of BoNT-A on the sensory blockade in the elderly population remains limited. Prospective case-control studies are necessary to evaluate treatment outcomes and outcome predictors in this population in detail.
