Low-Energy Shock Wave Plus Intravesical Instillation of Botulinum Toxin A for Interstitial Cystitis/Bladder Pain Syndrome: Pathophysiology and Preliminary Result of a Novel Minimally Invasive Treatment

Abstract

Low-energy shock wave (LESW) therapy is known to facilitate tissue regeneration with analgesic and anti-inflammatory effects. LESW treatment has been demonstrated to be effective in treating chronic prostatitis and pelvic pain syndrome as well as overactive bladder, and it has a potential effect on interstitial cystitis/bladder pain syndrome (IC/BPS) in humans. LESW reduces pain behavior, downregulates nerve growth factor expression, and suppresses bladder overactivity by decreasing the expression of inflammatory proteins. Previous rat IC models have shown that LESW can increase urothelial permeability, facilitate intravesical delivery of botulinum toxin A (BoNT-A), and block acetic acid-induced hyperactive bladder, suggesting that LESW might be a potential therapeutic module for relieving bladder inflammatory conditions, such as bladder oversensitivity, IC/BPS, and overactive bladder. A recent clinical trial showed that LESW monotherapy was associated with a significant reduction in pain scores and IC symptoms. BoNT-A detrusor injection or liposome-encapsulated BoNT-A instillation could also inhibit inflammation and improve IC symptoms. However, BoNT-A injection requires anesthesia and certain complications might occur. Our preliminary study using LESW plus intravesical BoNT-A instillation every week demonstrated an improvement in global response assessment without any adverse events. Moreover, an immunohistochemistry study revealed the presence of cleaved SNAP25 protein in the suburothelium of IC bladder tissue, indicating that BoNT-A could penetrate across the urothelial barrier after application of LESW. These results provide evidence for the efficacy and safety of this novel IC/BPS treatment by LESW plus BoNT-A instillation, without anesthesia, and no bladder injection. This article reviews the current evidence on LESW and LESW plus intravesical therapeutic agents on bladder disorders and the pathophysiology and pharmacological mechanism of this novel, minimally invasive treatment model for IC/BPS.

Keywords: botulinum toxin A; interstitial cystitis; low-energy shock wave; urothelium.

Figure 1

Expression of p53, CK5, CK14, CK20, and Shh proteins varies in different phenotypes of interstitial cystitis/bladder pain syndrome (IC/BPS). Hunner’s IC/BPS bladders had a low proliferative and differentiation ability, whereas the other non-Hunner’s IC/BPS bladders also had deficit proliferative and differentiation ability, both of which were also associated with the grade of glomerulations under hydrodistention.

Figure 2

Scanning electron micrographs (EM) of the urothelium cell layer in (A) normal bladder urothelial cell integrity, (B) transmission EM showing normal tight junction of umbrella cells, (C) interstitial cystitis/bladder pain syndrome (IC/BPS) bladder showing defective urothelial cell layer and loss of the integrity of apical umbrella cells. Transmission EM of (D) normal bladder and (E,F) bladders with IC/BPS, showing different degrees of deficient urothelial cell layers and loss of the integrity of umbrella cells.

Figure 3

Changes in urothelium cell markers Shh, CK5, CK14, CK20, and E-cadherin expression after repeated platelet-rich plasma injections in interstitial cystitis/bladder pain syndrome bladders.

Figure 4

Immunochemical staining showing that the cleaved SNAP25 was not detectable in the bladder specimen before treatment (upper) but was evident at 1 month after LESW treatment with intravesical botulinum toxin A instillation (lower).