COLLAGEN INJECTION FOR THE TREATMENT OF INCONTINENCE AFTER CYSTECTOMY AND ORTHOTOPIC NEOBLADDER RECONSTRUCTION IN WOMEN

0022-5347/00/1631-0212/0 THE JOURNAL OF UROLOGY® Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 163, 212–214, January 2000 Printed in U.S.A.

COLLAGEN INJECTION FOR THE TREATMENT OF INCONTINENCE AFTER CYSTECTOMY AND ORTHOTOPIC NEOBLADDER RECONSTRUCTION IN WOMEN MARIE-BLANCHE TCHETGEN, MARTIN G. SANDA, JAMES E. MONTIE*

AND

GARY J. FAERBER

From the Section of Urology, Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan KEY WORDS: bladder, cystectomy, urinary diversion, urinary incontinence, collagen

ABSTRACT

Purpose: We determine the clinical efficacy of endoscopically injected collagen for the treatment of new onset urinary incontinence in women following cystectomy and orthotopic neobladder. Materials and Methods: Three women 58 to 74 years old underwent transurethral collagen injection for stress urinary incontinence following cystectomy and orthotopic neobladder. Before cystectomy 2 women denied having any stress urinary incontinence while 1 complained of mild incontinence. Onset of incontinence following cystectomy and neobladder formation ranged from 8 months to 3 years, and average pad use ranged from 3 to 5 per 24-hour period. All patients underwent video urodynamic evaluation before collagen injection. Neobladder capacity was 180 to 400 cc and Valsalva leak point pressures ranged from 30 to 60 cm. water. Results: A total of 6 injections were given, including 3 injections in 1 patient, 2 in 1 and 1 in 1. All 3 women had significant improvement or became dry with initial injection but required repeat injections to maintain improved continence status. At 7 to 8 months after the last injection 1 woman was dry, 1 used 1 or no pad daily and 1 reported no durable change in stress urinary incontinence. Conclusions: Collagen injection appears to be a successful, minimally invasive treatment for new onset stress urinary incontinence following cystectomy and orthotopic neobladder in women. We report our experience with managing new onset stress urinary incontinence secondary to intrinsic sphincter deficiency in 3 women after radical cystectomy and orthotopic neobladder diversion. CASE HISTORIES

Case 1. B. D., a 74-year-old woman, underwent radical cystectomy and ileal neobladder reconstruction for muscle invasive transitional cell carcinoma of the bladder. Preoperative voiding history was significant only for mild irritative voiding symptoms attributable to bladder cancer. The patient denied urge or stress urinary incontinence. Postoperatively she reported immediate stress urinary incontinence requiring 4 or 5 pads daily. Pelvic examination revealed no evidence of pelvic prolapse or a neobladder-vaginal fistula. Video urodynamic evaluation demonstrated minimal post-void residual urine and a reservoir capacity of 400 cc with no evidence of significant contractile waves. Maximum intravesical filling pressure was 8 to 10 cm. water. Other findings included a slightly open bladder neck at rest and a well supported urethra during the Valsalva maneuver but significant urethral sphincter incompetence with a Valsalva leak point pressure of 30 to 45 cm. water, consistent with intrinsic sphincter deficiency. The patient elected collagen injection therapy. After a negative skin test a total of 3 treatments of 2.5 to 3.5 cc collagen were injected at 1-month intervals. The patient remained dry 3 months after the last injection. She subsequently underwent ureteroileal anastomosis revision secondary to ureteral stricture. Postoperatively an indwelling Foley catheter remained in place for approximately 10 days. After catheter removal the patient reported recurrent stress urinary incon-

tinence. She underwent repeat collagen injection, after which she became dry, although she required short-term intermittent catheterization because of elevated post-void residual urine. The patient continues to be dry 7 months later. Case 2. N. C., a 70-year-old woman, underwent cystectomy and orthotopic ileal neobladder for definitive management of refractory carcinoma in situ. Before cystectomy she had urinary frequency, voiding up to once hourly and urgency. She denied any urinary urge or stress incontinence. However, postoperatively stress and urge incontinence developed. Urodynamic evaluation 8 months after surgery revealed an open bladder neck and a reservoir capacity of 180 cc with a filling pressure of less than 20 cm. water. Phasic contractions up to 60 cm. water were noted during which urethral pressure remained from at 23 to 29 cm. water. These contractions were associated with leakage when vesical pressure exceeded 50 cm. water. In addition, leakage was noted with the Valsalva maneuver, particularly when standing (Valsalva leak point pressure 50 to 60 cm. water). No urethral hypermobility was observed. Peristaltic contractions, and decreased neobladder capacity and outlet resistance were thought to be factors contributing to incontinence. Initial treatment with diphenoxylate and atropine to inhibit phasic contractions of the reservoir resulted in shortterm improvement in urge incontinence. However, stress urinary incontinence persisted, requiring the use of 3 or 4 pads daily. Transurethral collagen injection was performed in an attempt to increase outlet resistance and accelerate the rate of neobladder enlargement. The patient received 2 collagen injections at 1-month intervals. After the initial injection she was completely dry for 10 days until incontinence recurred, requiring 3 pads daily. Repeat injection provided no significant improvement. A pubovaginal sling procedure was discussed but the patient was reluctant to undergo another operation.

Accepted for publication July 30, 1999. * Financial interest and/or other relationship with Introcell and Urocor. 212

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Case 3. J. L., a 58-year-old woman, underwent radical cystectomy and orthotopic ileal neobladder for muscle invasive transitional cell carcinoma 3 years before presentation. Before cystectomy she had had mild stress urinary incontinence with only occasional need for a pad and no nocturnal enuresis. Postoperatively persistent nocturnal enuresis developed and the patient noticed gradually worsening stress urinary incontinence. At presentation 3 years postoperatively 2 or 3 pads nightly were soaked and 1 or 2 pads were used during the day. Physical examination revealed a well supported anterior vaginal wall and urethra. Stress urinary incontinence was demonstrated by the Valsalva maneuver. Video urodynamic evaluation showed a closed bladder neck, a post-void residual urine of 25 cc and a capacity of approximately 325 cc. There were some nonsustained peristaltic waves generating pressure up to 25 cm. water. The patient underwent 1 transurethral collagen injection of 3.5 cc and noticed significant improvement in symptoms. At 8-month followup she reported complete resolution of nocturnal enuresis and mild stress leakage necessitating 0 or 1 pad daily.

DISCUSSION

Intrinsic sphincter deficiency is characterized by poor or minimal urethral resistance, resulting in urinary leakage at a low abdominal or Valsalva pressure.1 Urethral properties reported to have a role in the continence mechanism are the mucosal seal and inner wall softness, which facilitate urethral coaptation,2 smooth muscle and striated muscle function, which lead to urethral compression,3 length of the functional urethra and anatomical position of the proximal urethra, such that intra-abdominal pressure is transferred to the bladder neck and proximal urethra.4 Other factors, such as collagen and elastin content, as well as neural control also have important roles. Impairment of any of these urethral properties may lead to various degrees of urethral dysfunction and an associated loss of continence. Conditions, such as aging, pelvic surgery, levator weakness and urethral scarring, may have a deleterious effect on the urethral continence mechanism.5 Characteristic fluoroscopic guided urodynamic findings in patients with intrinsic sphincter deficiency include an open bladder neck and proximal urethra (internal sphincter), a Valsalva leak point pressure of less than 60 cm. water and minimal to absent urethral hypermobility.1 We report new onset or worsening stress urinary incontinence in 3 women after cystectomy and orthotopic neobladder diversion, and review our use of collagen injection therapy in this clinical setting. Traditionally orthotopic neobladder reconstruction is not performed in women because of concerns about postoperative continence and urethral disease recurrence.6 These assumptions were due to limited understanding of the female continence mechanism and relative ignorance of the pathological characteristics predictive of urethral involvement in women with transitional cell carcinoma of the bladder.7 Experience accumulated during the last few years indicates that, contrary to previous assumptions, incontinence is not an expected outcome of orthotopic neobladder reconstruction in women.7–9 Stein et al reported their experience with orthotopic reconstruction in 34 women.8 Complete daytime and nighttime continence was achieved in 88% and 82% of patients, respectively, and 15% required some form of intermittent catheterization to empty the neobladder. Of the 5 patients with daytime incontinence 1 responded favorably to collagen injection and became completely continent. The remaining 4 women were incontinent only during a major Valsalva effort and they were not interested in further treatment. In most patients optimal continence was achieved within 6 months postoperatively. These favorable results were attributed to

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limited dissection of the urethra, and resulting preservation of the rhabdosphincter and its pudendal innervation. As demonstrated by Colleselli et al, preservation of the musculature and innervation of the distal two-thirds of the urethra are crucial and sufficient for maintaining continence in women.10 It was further suggested by Grossfeld et al that preservation of the neurovascular bundles lateral to the uterus, vagina and bladder neck, which carry sympathetic innervation to the bladder neck and proximal urethra, is not necessary for achieving satisfactory continence in women after orthotopic neobladder reconstruction.7 They reported complete daytime continence in 14 of 15 patients who underwent en bloc anterior pelvic exenteration with orthotopic Koch ileal neobladder reconstruction. Video urodynamic evaluation of these continent patients revealed an open bladder neck and proximal urethra, suggesting that sympathetic denervation of the proximal urethra and associated smooth musculature does not necessarily lead to incontinence. These findings contradict previous reports that this autonomic innervation is crucial for maintaining continence.11, 12 From an anatomical perspective the margin between the bladder neck and proximal urethral smooth muscle, and the distal striated muscle is not well defined. Studies of female fetal specimens reveal a progressive and variable intermingling of smooth and striated muscle fibers starting in the mid portion of the urethra,10 with each type of muscles contributing to urethral closing pressure in association with other urethral properties, such as the mucosal seal, inner wall softness and anatomical position.2, 4 Therefore, incontinence secondary to urethral factors may develop after orthotopic reconstruction even in the setting of a technically sound operation. Surgical technique in our 3 patients included complete resection of the bladder neck with urethral transection at least 1 cm. distal to the bladder neck. The endopelvic fascia was not incised to avoid injury to the external urethral sphincter, and lateral dissection of the vaginal wall was also avoided to prevent damage to the innervation of the proximal urethra and external urethral sphincter.9 Neobladder factors may also contribute to incontinence after orthotopic reconstruction. Recently Park and Montie reviewed the mechanisms of urinary incontinence and retention in 15 men and 4 women who underwent neobladder diversion at our institution.13 All patients had nocturnal incontinence but complete daytime continence. Cases were classified as failure to store and failure to empty. Patients with failure to empty had a significantly longer functional urethra that prohibited efficient voiding by the Valsalva maneuver. Anterior vaginal prolapse resulting in a “pouchocele” effect with associated urinary retention has also been reported.13, 14 This phenomenon of hypercontinence has been noted to develop more frequently in women than men,6, 14 and it would explain the higher incidence of urinary retention necessitating intermittent catheterization in women.6 Incomplete removal of the bladder neck may be a contributing factor because increased outlet resistance may impede efficient Valsalva maneuver voiding.9 As a result, surgeons have been reluctant to advocate any procedure aimed at increasing outlet resistance, such as urethropexy or collagen injection, for fear of precipitating hypercontinence.9 Interestingly Kutta and Haupt recently proposed a technique of “rotundovaginopexy” as a method of stabilizing the vagina after cystectomy to avoid pouchocele development.15 Park and Montie reported on 11 patients with failure to store problems presumably due to insufficient sphincter function in 8 (73%) and poor reservoir function caused by high pressure contraction waves in 3 (27%).13 None of the patients with a failure to store problem had stress incontinence even when the Valsalva pressure exceeded 80 to 100

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cm. water. All patients had a corresponding increase in external urethral closure pressure that prevented urinary leakage. Park and Montie concluded that nocturnal incontinence in these patients was likely due to the loss of external sphincter tone during sleep. In this setting a minimal increase in intra-abdominal pressure would overcome outlet resistance and result in urinary leakage. Causes of failure to store after neobladder diversion may be classified as reservoir failure due to poor compliance or contraction waves, leading to detrusor incontinence similar to that in myelodysplasia, and sphincter failure secondary to external urethral sphincter injury, an inadequate proximal urethra or loss of sphincter tone during sleep.13 Urodynamic evaluation of our 3 patients revealed leakage at a low Valsalva pressure of 60 cm. water or less and no urethral hypermobility. Patient B. D. had evidence of failure to store secondary to sphincter incompetence. Leakage occurred at a low Valsalva leak point pressure in the absence of reservoir contractions. Continence was achieved by periurethral injection of collagen as a bulking agent to increase outlet resistance. Patient N. C. had components of reservoir and urethral failure. Incontinence was improved by a combined antimotility agent and collagen injection, although results were not durable. Patient J. L. appeared to have combined urethral and reservoir failure as well, although to a lesser degree than patient N. C. She improved with collagen injection only. Despite the small number of patients our study provides insight into the unique anatomical and functional characteristics of incontinence after orthotopic neobladder reconstruction. These characteristics must be considered when contemplating treatment. There are few reports of incontinence procedures performed in women in this clinical setting, which is likely associated with the traditional paucity of female orthotopic reconstruction and the relatively high incidence of hypercontinence.

4. 5. 6. 7.

8.

9. 10. 11. 12. 13. 14. 15.

Urinary Incontinence. Edited by P. O’ Donnell. St Louis: Mosby-Year Book, 1997. DeLancey, J. O.: Structural support of the urethra as it relates to stress urinary incontinence: the hammock hypothesis. Am J Obstet Gynecol, 170: 1713, 1994. McGuire, E. J.: Urethral dysfunction. In: Female Urology. Edited by E. D. Kursh and E. J. McGuire. Philadelphia: Lippincott, 1994. Hautmann, R. E., Paiss, T. and De Petriconi, R.: The ileal neobladder in women: 9 years of experience with 18 patients. J Urol, 155: 76, 1995. Grossfeld, G. D., Stein, J. P., Bennett, C. J. et al: Lower urinary tract reconstruction in the female using the Kock ileal reservoir with bilateral ureteroileal urethrostomy: update of continence results and fluorodynamic findings. Urology, 48: 383, 1996. Stein, J. P., Grossfeld. G. D., Freeman. J. A. et al: Orthotopic lower urinary tract reconstruction in women using the kock ileal neobladder: updated experience in 34 patients. J Urol, 158: 400, 1997. Park, J. M. and Montie, J. E.: Orthotopic diversion in men and women. Atlas Urol Clin North Am, 5: 65, 1997. Colleselli, K., Strasser, H., Moriggl, B. et al: The female urethra: a morphological and topographical study. J Urol, 160: 49, 1998. Hubner, W. and Pfluger, H.: Functional replacement of bladder and urethra after cystectomy for bladder cancer in a female patient. J Urol, 153: 1043, 1995. Cancrini, A., deCarli, P., Fattahi, H. et al: Orthotopic ileal neobladder in female patients after radical cystectomy: 2-year experience. J Urol, 153: 956, 1995. Park, J. M. and Montie, J. E.: Mechanisms of incontinence and retention after orthotopic neobladder diversion. Urology, 51: 601, 1998. Stenzl, A., Colleselli, K., Poisel, S. et al: Rationale and technique of nerve sparing radical cystectomy before an orthotopic neobladder procedure in women. J Urol, 154: 2044, 1995. Kutta, A. and Haupt, G.: Rotundovaginopexy in orthotopic ileal neobladder following radical cystectomy in women. Eur Urol, 33: 308, 1998.

CONCLUSIONS

The long-term outcome of transurethral collagen injection for managing urethral deficiency in women after orthotopic neobladder diversion is unclear. It is likely that repeat injections are necessary for maintaining continence, as is generally the case in type III stress urinary incontinence. However, the low morbidity of this minimally invasive procedure makes it an attractive treatment option in patients with bothersome stress urinary incontinence after orthotopic neobladder reconstruction. REFERENCES

1. McGuire, E. J., Fitzpatrick, C. C., Wan J. et al: Clinical assessment of urethral sphincter function. J Urol, 150: 1452, 1993. 2. Zinner, N. R., Sterling, A. M. and Ritter R. C.: Role of inner urethral softness and urinary continence. Urology, 16: 115, 1980. 3. Baldwin, D. D. and Hadley, R.: Stress urinary incontinence. In:

EDITORIAL COMMENT Collagen injection is an effective treatment for stress incontinence in women although it usually requires 2 treatments for a success rate of 50% to 60%. This study demonstrates the use of collagen in a small number of patients with intrinsic sphincter deficiency after ileal neobladder formation. The short-term success rate is similar to that reported in the literature. These patients need to undergo precollagen urodynamics to ensure that no storage or hypermobility problems are contributing to incontinence. Stress incontinence after neobladder formation in women is uncommon and hypercontinence is more common. To answer the question of whether collagen is effective for stress incontinence after orthotopic reconstruction a study with more patients followed for at least 2 years would need to be performed. I do not think that this study has answered the question but it has provided food for thought. Sharon English St. George’s Hospital Christ Church, New Zealand