Overactive bladder (OAB) is a highly prevalent condition that is frequently associated with diminished quality of life when inadequately treated. When OAB is refractory to oral medications, onabotulinumtoxinA (BTX) detrusor chemodenervation has been shown to be safe and efficacious, with symptomatic improvement rates as high as 65% when using the standard posterior-lateral injection template [1]. Interestingly, several investigational studies have suggested that inclusion of the bladder trigone, either alone, or in conjunction with the standard template, may provide adequate improvement in lower urinary tract symptoms for many patients [2]. However, despite proven clinical efficacy, placement of the cystoscope through the urethra with concurrent bladder injection is cumbersome, uncomfortable for patients, and labor intensive due to equipment turnover. In addition, transurethral cystoscopic injection of BTX carries a 22% risk of developing a urinary tract infection [3]. Despite proven clinical efficacy of BTX chemodenervation, many patients fail to seek additional treatment beyond their first injection as a result of the cystoscopic route of delivery. We sought to assess the feasibility of the transvaginal route of injection under ultrasound guidance in the pre-clinical stage of investigation, with the eventual goal to develop a novel route of administration for BTX to the bladder trigone and posterior wall. We hypothesized that the transvaginal route will be feasible to perform.

We performed a cadaver proof of feasibility study using a de-identified anonymous fresh female deceased donor cadaver pelvis. Deceased de-identified anonymous cadaver tissue research is exempt from IRB living human subject research at our institution. Our cadaver procedural protocol was approved by the division of clinical anatomy at our institution. The cadaver met our inclusion criteria of being female gender, having a patent vagina, and no prior pelvic surgery. The cadaver was placed in a supine split leg position. A 16 French Foley catheter was placed in the bladder and the bladder filled with 300 mL of water. With the bladder distended and palpable, we placed a suprapubic laparoscopic trochar into the bladder dome. A zero degree lens was used to visualize the bladder trigone and ureter orifices through the laparoscopic trochar. Next, a transvaginal ultrasound probe, approved for use in cadavers, was placed in the vagina. Using the Foley balloon to localize the bladder neck and trigone under ultrasound guidance, an 18 gauge, 25 cm needle was directed into the bladder trigone. The laparoscope confirmed appropriate targeting of the trigone (Figure 1). The combination of the laparoscopic view and the ultrasound guidance confirmed that the position of the ureteral orifices were identifiable via transvaginal ultrasound. We injected a total of 3 mL of dilute blue India ink (3 drops ink per 10 mL saline) under ultrasound guidance divided into three locations along the bladder trigone (1 mL per injection). Ultrasound images pre and post-injection were saved (Figure 1). We then injected 5 mL of dilute green India ink (3 drops ink per 10 mL saline), divided into three locations along the posterior bladder wall under ultrasound guidance (1.7 mL per injection). There was no dye extravasation into the lumen of the bladder on cystoscopy. Once injection was completed, a suprapubic cystotomy was performed and gross visualization of the location of the two dye colors was used to confirm if ultrasound targeting of the trigone and posterior bladder wall was accurate (Figure 1). Dissection confirmed there was no interposing bowel along the most apical extent of our injection. Full thickness bladder and vaginal wall tissue was obtained for histology using an 8 mm punch biopsy from the midline trigone, ureteral orifice, posterior wall and lateral wall in order to co-localize depth and diffusion of injection with muscle and nerve fibers. Tissue was fixed in formalin, paraffin embedded and processed for light microscopy staining of collagen, smooth muscle, nerves and anatomic layers of the bladder and vaginal wall.

We found that the trigone was effectively targeted along the interureteric ridge, with blue dye present and not involving the ureteral orifices. The presence of green dye on the posterior bladder wall confirmed access to this area via a transvaginal approach (Figure 2). Overall, a total of 8 mL of dilute dye was delivered accurately to the bladder trigone and posterior bladder wall.

We have shown that ultrasound guidance allows for accurate targeting of the bladder trigone and posterior bladder wall. A volume of 8 mL of solution used during BTX therapy could theoretically be injected transvaginally by including the posterior and lateral bladder walls in the injection template. Further studies are needed to quantify anatomic variability of the trigone in cadavers, and validate the anatomic landmarks for selecting the appropriate site and depth of injection for targeting the detrusor muscle and nerves.

Under transvaginal ultrasound guidance, the bladder trigone and posterior bladder wall can be accurately identified and targeted with an injectable solution. This early study has promising results for development of a novel route of administration of BTX in patients with refractory OAB.

Nitti VW, Dmochowski R, Herschorn S, Sand P, Thompson C, Nardo C, Yan X, Haag-Molkenteller C; EMBARK Study Group. J Urol. 2013 Jun;189(6):2186-93. doi: 10.1016/j.juro.2012.12.022. Epub 2012 Dec 14. OnabotulinumtoxinA for the treatment of patients with overactive bladder and urinary incontinence: results of a phase 3, randomized, placebo controlled trial.
Kuo HC. Neurourol Urodyn. 2011 Sep;30(7):1242-8. doi: 10.1002/nau.21054. Epub 2011 May 10. Bladder base/trigone injection is safe and as effective as bladder body injection of onabotulinumtoxinA for idiopathic detrusor overactivity refractory to antimuscarinics.
Sun Y, Luo D, Tang C, Yang L, Shen H. Int Urol Nephrol. 2015 Nov;47(11):1779-88. doi: 10.1007/s11255-015-1125-7. Epub 2015 Oct 3. The safety and efficiency of onabotulinumtoxinA for the treatment of overactive bladder: a systematic review and meta-analysis.