3.2.5. Long-Term Therapeutic Effects of BoNT-A in IC/BPS

BoNT turnover in neurons is primarily mediated by the lysosomal/autophagic and ubiquitin-proteasome systems [71]. Most studies have shown persistent muscle paralysis in humans for four to six months following treatment with BoNT-A [72,73]. The persistence of the therapeutic effect after a single BoN-A injection in patients with LUTDs has varied among studies. In a study comparing the different types of BoNT-A injection for patients with neurogenic detrusor overactivity, approximately half of the patients (53.4%) exhibited continence at three months postinjection [74]. The mean interval of on-demand repeated injection was eight months, and no significant differences were found among types of BoNT-A injections. When assessing the therapeutic effect of a single BoNT-A injection in patients with IC/BPS, the longest follow-up duration in published studies is currently one year [52,62]. In 2008, Giannantoni et al. reported significant symptomatic relapse at five months after 200 U BoNT-A injection in the trigone and lateral wall, in terms of bladder pain, urinary frequency, and bladder capacity [62]. All patients exhibited recurrent pain at 12 months postinjection. In 2015, Akiyama et al. used 100 U BoNT-A trigone injections and reported similar results.[52] The response rates (global response assessment ≥+1: slightly improved) were 38.2% at six months postinjection and 20.6% at 12 months postinjection [52]. Although BoNT-A injection was effective for symptomatic relief in IC/BPS, remission was common and repeated injection was necessary for most patients.

Because symptomatic relapse is common, the persistence of therapeutic effects after repeated BoNT-A injection is an important issue. Evidence from cosmetic use of BoNT-A showed that treatment failure may occur after repeated injections [52,75]. The formation of neutralizing antibodies after repeated BoNT-A injections could include antibodies that target the functionally active part of BoNT-A, thereby leading to treatment failure [76]. In a human study, the formation of neutralizing antibodies after Botox®injection was observed in an estimated 5–15% of patients [77]. In cosmetic use, potential risk factors for development of neutralizing antibodies included a single injection of >200 U and repeated injection within one month [75]. For BoNT-A injection in patients with LUTDs, current evidence suggests that the therapeutic effect could persist after repeated injections. Kennelly et al. performed a prospective study of 240 neurogenic detrusor overactivity patients who underwent up to six repeated BoNT-A injections within a four-year period [60]. Symptomatic improvement among injections did not reach statistical significance, particularly in terms of incontinence episodes and voided volume. For patients with IC/BPS, studies also showed that repeated BoNT-A injections could provide persistent symptomatic relief [78–80]. Notably, beginning in 2006, we performed a BoNT-A injection of 100 U every six months in patients with refractory IC/BPS until they wished to discontinue treatment [78]. Significant symptomatic improvement, including to bladder pain, O'Leary–Sant scores, and global response assessment, persisted after the fourth BoNT-A injection. Within a follow-up period of up to 79 months, patients who received repeated injections had a better success rate and longer therapeutic duration than those who received a single injection. The rate of adverse effects did not increase with the number of BoNT-A injections. Therefore, repeated BoNT-A injections may be both effective and safe for patients with IC/BPS.

However, one study detected serum BoNT-A antibodies in patients who received bladder BoNT-A injections, and the presence of such antibodies was associated with treatment failure [81]. Although repeated BoNT-A injections in the bladder are generally effective, the formation of neutralizing antibodies might cause treatment failure in some patients. Further study is necessary to investigate whether the neutralizing antibodies are present in the bladder after repeated BoNT-A injection.

#### 3.2.6. BoNT-A Injection for IC/BPS with Hunner's Lesion

Hunner's lesion is a specific cystoscopic finding that is characterized by a circumscript, reddened mucosa with small vessels radiating toward a central scar [82]. Patients with IC/BPS and Hunner's lesion (HIC) typically experience significant sharp bladder pain and require cystoscopic bladder electrocauterization [1,82]. The efficacy of BoNT-A injection in HIC is controversial. Our study used diffuse bladder-body injection of BoNT-A in patients with HIC; notably, these patients showed no significant changes in any clinical or urodynamic variables [83]. Another study reported that the efficacy of BoNT-A injection in patients with HIC was not superior to treatment with hydrodistention alone [84]. In contrast, Pinto et al. compared the treatment outcomes of intratrigonal BoNT-A injection between patients with HIC and patients with IC/BPS without Hunner's lesion [85]. Both groups had equal responses to BoNT-A, as well as significant improvement that included lessening of bladder pain, urinary frequency, and O'Leary–Sant scores. In another study, complete remission of Hunner's lesion was observed in three of five patients with HIC after BoNT-A injection [86]. All of the abovementioned studies were limited to small numbers of patients (≤0 patients with HIC per study), and the results were conflicting among studies. In the past, the definition of Hunner's lesion might have differed among countries [82]; hence, the characteristics of patients with HIC included in previous studies may lack consistency. In the study by Pinto, the patients with HIC and patients with IC/BPS without Hunner's lesion had similar symptom severity at baseline; in contrast, the patients with HIC in our study had much more severe baseline symptoms. From our perspective, BoNT-A injection alone is insufficient for satisfactory symptomatic relief in patients with severe HIC. Further studies with larger numbers of patients and clear definitions of Hunner's lesion are necessary.
