Hyaluronic Acid Copolymer in Patients with Neurogenic Bladder

Bladder

Long-Term Followup After Endoscopic Treatment of Vesicoureteral Reflux with Dextranomer/Hyaluronic Acid Copolymer in Patients with Neurogenic Bladder A. S. Polackwich, S. J. Skoog and J. C. Austin* From the Division of Urology, Oregon Health & Science University, Portland, Oregon

Purpose: Subureteral injection of dextranomer/hyaluronic acid copolymer is a minimally invasive method to treat vesicoureteral reflux. We report short and long-term success in treating secondary vesicoureteral reflux in patients with neurogenic bladder dysfunction or severe voiding dysfunction. Materials and Methods: We performed a retrospective chart review of all subureteral injection procedures done to identify patients with neurogenic bladder or severe voiding dysfunction. Short (less than 12 months) and long-term vesicoureteral reflux results for patients and ureters were recorded. Preoperative urodynamics and radiographic findings were reviewed. Preoperative factors were evaluated to identify patients with greater chances of success. Results: A total of 12 patients (17 ureters) were identified (10 with neurogenic bladder and 2 with Hinman syndrome). Short-term success (no vesicoureteral reflux) was achieved in 50% of patients and 58% of ureters. At a median followup of 4.5 years (range 1 to 9) success decreased to 35% of ureters. Overall, long-term success was found in 25% of patients who were free of vesicoureteral reflux and required no additional surgery. Of the patients 41% required additional urological surgery for vesicoureteral reflux or related conditions. Conclusions: With long-term followup many patients who had initial improvement in vesicoureteral reflux ultimately experienced treatment failure and recurrence of reflux. At a median of 4.5 years 25% of patients with neurogenic bladder and vesicoureteral reflux were successfully treated with endoscopic injection of dextranomer/hyaluronic acid copolymer.

Abbreviations and Acronyms CIC ⫽ clean intermittent catheterization Dx/HA ⫽ dextranomer/hyaluronic acid copolymer NGB ⫽ neurogenic bladder SB ⫽ spina bifida SUI ⫽ subureteral injection UDS ⫽ urodynamics UTI ⫽ urinary tract infection VCUG ⫽ voiding cystourethrogram VUDS ⫽ videourodynamics VUR ⫽ vesicoureteral reflux Study received institutional review board approval. * Correspondence: Department of Surgery, Division of Urology, CDW-6, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, Oregon 97239 (telephone: 503-494-4808; FAX: 503-494-4743; e-mail: [email protected]).

Key Words: urinary bladder, neurogenic; vesico-ureteral reflux; surgical procedures, operative SECONDARY vesicoureteral reflux may develop in children with neurogenic bladder dysfunction or severe refractory voiding dysfunction. When present this condition can increase the risk of pyelonephritis, and in severe cases lead to hydronephrosis and renal damage. The treatment of secondary VUR initially relied on optimizing the management of bladder dysfunction with anticholinergic medication and clean intermittent catheterization.

The need to treat secondary VUR surgically after managing bladder dysfunction is more controversial. Historically this has relied on bladder augmentation with a good success rate.1 Subureteral injection has been performed more recently in these patients. The minimally invasive nature makes SUI an attractive alternative to open procedures in this patient population, who often have significant medical comorbidities. Endoscopic treatment of secondary VUR

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ENDOSCOPIC TREATMENT OF VESICOURETERAL REFLUX IN NEUROGENIC BLADDER CASES

has decreased success rates compared to treatment with ureteral reimplantation (60% vs 85%) and less success than treatment of primary VUR with SUI.2– 4 We reviewed our experience with patients with secondary VUR and endoscopic injection of Dx/HA with a focus on the short and long-term success of VUR treatment as well as the ability to avoid major surgical treatment in the future.

MATERIALS This study received institutional internal review board approval. We performed a retrospective review of all patients treated at our institution with a subureteral injection of Dx/HA from 2001 to 2010 to identify those who had secondary VUR associated with NGB dysfunction. We included patients with nonneurogenic neurogenic bladder dysfunction in the study (Hinman syndrome). Patients were identified through a billing database to identify those with neurogenic bladder who had endoscopic treatment of VUR (CPT code 52327 paired with 1 of the ICD-9 codes of 344.61(other paralytic syndromes with NGB), 596.54 (NGB not otherwise specified), or 741.90, 741.91, 741.92, 741.93, 741.00 or 741.03 (range of spina bifida codes). Records of all patients who underwent endoscopic treatment of VUR were also screened to identify additional patients who met the study inclusion criteria. Medical records were reviewed to ensure that they met entry criteria. Patients with VUR in the presence of overt bladder dysfunction as noted in the inclusion criteria were defined as having secondary VUR. Demographic and medical data were collected on patients by reviewing institutional and scanned external records. Data recorded included age, gender, use of anticholinergics, bladder capacity, urodynamic study results, need for additional surgical treatment and bladder management. Radiographic data included VCUG results (often in conjunction with UDS) and renal ultrasound before SUI of Dx/HA, less than 12 months after SUI, at last followup and length of total followup. VUR was graded I to V in the standard fashion. Patients without SB underwent spinal magnetic resonance imaging to evaluate for spinal cord tethering. Length of followup was defined as the time from SUI to the latest pediatric urology visit. Initial, interim and postoperative VUR were obtained through VCUG or videourodynamic studies. In cases with more than 1 preoperative UDS, results were used from the UDS that were performed most closely to SUI (imaging or UDS were done within 6 months of the procedure). All patients were thoroughly evaluated and bladder dysfunction was managed as optimally as possible with CIC, anticholinergics and other pharmacotherapy, and voiding training as appropriate for the etiology of the bladder dysfunction. They did not undergo SUI until bladder dysfunction was considered managed short of bladder augmentation. Results were analyzed by individual ureters and patients. Success was defined at the absence of any VUR (including new contralateral VUR if single ureter was treated). Short-term success was defined by the absence of VUR less than 12 months after injection and long-term successes included studies performed more than 12 months postoperatively.

All patients underwent upper tract imaging to rule out obstruction, and VCUG or VUDS 6 to 12 weeks after the procedure. Patients underwent repeat imaging after that based on clinical signs or symptoms at the discretion of the physician. Long-term VCUGs were performed when patients needed VUDS, had febrile UTIs or if there was new hydronephrosis on upper tract imaging. In addition to long-term resolution of VUR, we evaluated for febrile UTIs during followup as well as the need for further reconstructive surgery of the urinary tract. Rates of long-term success were further evaluated by potential risk factors for failure to see if one could better predict in which patients treatment would succeed. Preoperative risk factors analyzed included the presence of bladder trabeculations on cystogram, bladder capacity before SUI less than 75% of predicted and bladder compliance 20 ml/cm H2O or less. Bladder capacity was normalized to percent predicted bladder capacity based on age using the formula, Capacity ⫽ (Age ⫹ 2) * 30 ml. Success vs failure was evaluated for patients with 1, 2 or all 3 risk factors. Those patients who did not undergo UDS preoperatively were excluded from the analysis of multiple risk factors. Groups were evaluated using Fisher’s exact test and p ⬍0.05 was considered statistically significant.

RESULTS A total of 242 patients underwent subureteral Dx/HA injection from 2001 to 2010. Twelve patients with 17 refluxing ureters and associated neurogenic bladder dysfunction were identified. The technique of SUI was done using the hydrodistention implantation technique in 11 and classic subureteral polytetrafluoroethylene injection in 1. There were no repeat injections. Indications for SUI were a history of febrile UTI in 11 patients and worsening VUR in 1 (patient number 4 in tables 1 and 2). Median patient age at SUI was 5.5 years (range 2 to 18). Of the patients 7 were male and 5 were female. Median VUR grade before SUI was III (range I to V). Median followup from SUI was 4.5 years (range 1 to 9). Bladder dysfunction in 7 patients was due to SB, 1 had NGB related to VACTERL (vertebral, anal, cardiac, tracheal, esophageal, renal and limb abnormalities) syndrome, 2 had NGB related to severe spastic quadriplegia and 2 males had Hinman syndrome. Bladder management at SUI included CIC in 4 patients, vesicostomy in 4 (3 of which were closed at time of SUI) and 4 patients voided spontaneously (none with normal bladder function). Of the patients 61% (7 of 12) were taking anticholinergics. Patients were not treated with anticholinergics if they had a large capacity, poorly emptying bladder (Hinman syndrome) or if they voided spontaneously with good emptying with severe neurological impairment (spastic quadriplegia). VUDS were not done in 3 of the patients. Of these patients 1 had SB with a permanent vesicostomy and the other 2 had spastic quadriplegia. These 2

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Table 1. Patient demographics and reflux grade before and after Dx/HA injection Pt No.—Age—Gender at SUI 1—6—F 2—11—M 3—14—F 4—2—F 5—5—F 6—3—M 7—14—M 8—12—M 9—2—M 10—4—F 11—18—M 12—15—M

Diagnosis

Ml UDS Preop Capacity (% predicted)

Compliance (ml/cm H2O)

Bladder Wall

Rt/Lt Preop VUR Grade

Rt/Lt Short-Term VUR Grade

Rt/Lt Long-Term VUR Grade

SB SB SB SB SB SB VACTERL SB Spastic quadriplegia Spastic quadriplegia Hinman syndrome Hinman syndrome

240 (85) 220 (70) 300 (88) 140 (55) 165 (55) 160 (54) 140 (36) Not applicable Not applicable Not applicable 820 (199) 810 (199)

8.5 8.7 35 54 6.7 2.7 6.2 Not applicable Not applicable Not applicable 33 20

Smooth Smooth Trabeculated Smooth Trabeculated Trabeculated Smooth Smooth Smooth Smooth Trabeculated Trabeculated

1/1 _ /3 4/_ 3/3 _ /2 _ /4 4/_ 4/_ 4/4 2/3 _ /4 5/5

4/4 1/0 5/_ 3/0 _ /0 _ /0 0/_ 0/_ 0/2 0/0 _ /0 5/5

4/4 1/0 5/3 2/1 _ /4 1/4 0/_ 0/_ 0/2 0/0 _ /4 5/5

patients were judged to have adequate bladder capacity and emptying based on VCUG alone, and were 2 of the long-term successes (patients 8 and 10). Of the 12 patients and 17 ureters identified, 50% of patients (6 of 12) and 58% of ureters (10 of 17) had short-term resolution of VUR. At a median of 4.5 years (range 1 to 9) long-term success decreased to 25% of patients (3 of 12) and 35% of ureters (6 of 17). Additional procedures were required in 41% (5 of 12) of patients. These procedures were performed at a median of 4 years (range 1.5 to 5). The procedures included bladder augmentation with ureteral reimplantation in 3, bladder augmentation alone in 1 and nephroureterectomy in 1. One patient died of complications related to bowel obstruction 1 year postoperatively. Patient demographics, preoperative UDS findings, and short-term and long-term results are summarized in tables 1 and 2. Overall at a median of 4.5 years of followup 25% of patients (3 of 12) were free of VUR, clinically well and needed no

additional surgical treatment for VUR or bladder dysfunction. Patients 1, 4, 5 and 6 had febrile UTIs after SUI as indications for their last VCUG/VUDS. The initial SUI procedure failed in 1 of these patients and the other 3 were short-term successes with recurrent VUR at long-term followup. Of those patients treated with a vesicostomy which was taken down at the SUI of Dx/HA, 1 of 3 did not go on to require additional surgery and is free of VUR. The analysis of patient outcomes for the presence of multiple or single presumed risk factors for failure or success showed no significant difference in success (table 3).

DISCUSSION With long-term followup we found that there is a decreased success rate with endoscopic treatment of VUR with Dx/HA in patients with NGB compared to previously published success rates in patients with-

Table 2. Bladder management, SUI success and additional procedures Pt No.

Diagnosis

1

SB

2 3

SB SB

4 5

SB SB

6 7 8

SB VACTERL SB

9 10 11 12

Spastic quadriplegia Spastic quadriplegia Hinman syndrome Hinman syndrome

Preop Bladder Managment

Postop Bladder Managment

Short-Term Success

Long-Term Success

Vesicostomy ⫹ anticholinergics CIC ⫹ anticholinergics CIC ⫹ anticholinergics

CIC ⫹ anticholinergics

No

No

5

CIC ⫹ anticholinergics CIC ⫹ anticholinergics

No No

No No

1.5 2

CIC ⫹ anticholinergics Vesicostomy ⫹ anticholinergics CIC ⫹ anticholinergics Vesicostomy Vesicostomy ⫹ anticholinergics Voiding Voiding Timed voiding Timed voiding ␣-blockers

CIC ⫹ anticholinergics CIC ⫹ anticholinergics

No Yes

No No

6 8

CIC ⫹ anticholinergics CIC ⫹ anticholinergics Vesicostomy ⫹ anticholinergics Voiding Voiding CIC CIC

Yes Yes Yes

No Yes Yes

9 2 1*

No Yes Yes No

No Yes No No

5 6 3 1

* Patient died 1 year after surgery of unrelated cause, no UTI or VUR.

Yrs Followup

Followup Procedures Bladder augmentation, reimplantation Bladder augmentation, reimplantation Bladder augmentation, reimplantation Bladder augmentation

Nephroureterectomy

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Table 3. Long-term success stratified by risk factors

Trabeculations Capacity less than 75% Compliance less than 20 ml/cm H2O

% Success With Risk Factors

% Success Without Risk Factors

p Value

0 25 20

42 0 0

0.08 0.5 1

out bladder dysfunction. More importantly, we found that many patients who originally had improvement in VUR went on to have recurrence of reflux. Of the patients 41% ultimately required subsequent operations to definitively treat bladder dysfunction. Our cohort of patients was treated for VUR after an effort to maximize bladder management short of augmentation (which many surgeons would automatically do in a patient undergoing takedown of a vesicostomy and initiation of CIC) and then treat the VUR. We did not simply treat the VUR and ignore the bladder dysfunction. We report these results to document the outcomes when complicated cases such as these are managed with SUI alone. VUR has been treated endoscopically with Dx/HA with good results in patients with primary VUR at our institution and, thus, we believe our results indicate poor success with the patient population rather than a poor technique.5 Of our patients 6 ultimately required bladder augmentation or a significant change in bladder management (4 augmentation, 2 starting CIC), which suggests that ongoing bladder dysfunction and deterioration may have a role in outcomes. We tried to evaluate for risk factors to predict in which bladders treatment was more likely to fail but our numbers were too small. The decrease in success rates, regardless of cause, demonstrates the limitations of minimally invasive SUI in patients with NGB. Prior studies that have examined the endoscopic treatment of secondary VUR have had 2 major issues. Followup is often short and cases of NGB are included with nonneurogenic cases. We found that the median time to require an additional procedure is 4 years. Studies with limited followup may be classifying patients as successes in whom failure will occur with extended followup. Given that endoscopic management is less morbid than open reimplantion, it has been tempting to use this as first line therapy in patients. Indeed some studies have shown re-treatment of these patients as many as 5 times to achieve a rate of success that is still inferior to open management.6 Early studies demonstrated that this treatment may not be as effective for VUR in the setting of NGB. In a large meta-analysis Elder et al showed decreased effectiveness, 62% vs 74%, of SUI with a bulking agent in those patients with neurogenic bladder vs those

with normal bladder.4 In a comparison of SUI of Teflon® and ureteral implantation in patients with NGB, ureteroneocystostomy was shown to be more effective than initial and repeat SUI.2,7 Likewise, Capozza et al demonstrated lower success rates in patients with preoperative voiding dysfunction.8 In a study of 93 ureters in complex cases, which included 11 cases of NGB, Perez-Brayfield et al found only a 68% success rate at 3 months using VCUGs.9 Our results would suggest that the success rate would be less with continued followup. Estornell Moragues et al evaluated patients with NGB and severe voiding dysfunction after SUI with a variety of bulking agents.10 While the success rate of 71% at an average of 52 months appears strong, evaluation of the individual patients showed that many of these successes have shorter term followup. Haferkamp et al examined short-term and longterm outcomes of SUI of collagen in children and adults with NGB.11 They found an immediate success of 90%, which decreased to 15% at 2 years. While this may have been due to the nature of the material that was injected, the nature of disease may have also contributed to the results. The high long-term failure rate of endoscopic management of VUR in patients with NGB is in contrast to the high success rate of open ureteral reimplantation. This was shown by Jeffs et al who reported an 89% success rate,12 and was reiterated when Engel et al showed an 83.7% success rate of reimplantation in patients with NGB.7 Recent studies have demonstrated that augmentation alone may be enough to correct VUR, except in those patients in whom reflux occurs at low bladder pressures and early in bladder filling (ie low volumes).13,14 This was not specifically evaluated in our study. It may be an important factor in determining when ureteral reimplantation is needed during bladder augmentation and deserves continued investigation. Limitations of our study include that it is retrospective with small patient numbers and, thus, our conclusions are limited. Study strengths include the followup length and its comprehensive nature. Many of our patients had a variant of SB and received long-term care at our spina bifida center. Patients with neurogenic bladder and VUR are often less than ideal candidates for surgery. Many have had prior abdominal operations and ventriculoperitoneal shunts. They frequently have severe kyphoscoliosis and contractures that make positioning, surgical exposure and anatomy difficult. There is a temptation to use SUI as a simple alternative to open surgery. Our findings would suggest that SUI should be used with caution because the short-term and long-term rates of success are low. Prior SUI may make later ureteral reimplantation more challenging, and this should be considered given the high

ENDOSCOPIC TREATMENT OF VESICOURETERAL REFLUX IN NEUROGENIC BLADDER CASES

rate of reoperation in our patients. We would only further consider SUI in patients in whom bladder dysfunction is well managed, those with good bladder capacity and compliance, and those with mild VUR with a history of febrile UTIs for whom clinical evaluation would strongly suggest that bladder augmentation is unlikely to be needed yet there is an indication to treat the VUR. Families should be informed that the expected chance of success is lower in these patients and that there is a significant risk of recurrence if the procedure is initially successful.

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CONCLUSIONS On long-term followup we found that in many patients with initial improvement in VUR, treatment ultimately fails and reflux recurs. This necessitated more definitive surgical treatment in 41% of our patients. At a median of 4.5 years only 25% of patients with NGB and VUR were successfully treated with endoscopic injection of Dx/HA, were free of VUR and did not require any further urological surgery.

REFERENCES 1. Simforoosh N, Tabibi A, Basiri A et al: Is ureteral reimplantation necessary during augmentation cystoplasty in patients with neurogenic bladder and vesicoureteral reflux? J Urol 2002; 168: 1439. 2. Granata C, Buffa P, Di Rovasenda E et al: Treatment of vesico-ureteric reflux in children with neuropathic bladder: comparison of surgical and endoscopic correction. J Pediatr Surg 1999; 34: 1836. 3. Routh JC, Inman BA and Reinberg Y: Dextranomer/hyaluronic acid for pediatric vesicoureteral reflux: systematic review. Pediatrics 2010; 125: 1010. 4. Elder JS, Diaz M, Caldamone AA et al: Endoscopic therapy for vesicoureteral reflux: a metaanalysis. I. Reflux resolution and urinary tract infection. J Urol 2006; 175: 716. 5. Lavelle MT, Conlin MJ and Skoog SJ: Subureteral injection of Deflux for correction of re-

flux: analysis of factors predicting success. Urology 2005; 65: 564. 6. Misra D, Potts SR, Brown S et al: Endoscopic treatment of vesico-ureteric reflux in neurogenic bladder– 8 years’ experience. J Pediatr Surg 1996; 31: 1262. 7. Engel JD, Palmer LS, Cheng EY et al: Surgical versus endoscopic correction of vesicoureteral reflux in children with neurogenic bladder dysfunction. J Urol 1997; 157: 2291. 8. Capozza N, Lais A, Nappo S et al: The role of endoscopic treatment of vesicoureteral reflux: a 17-year experience. J Urol 2004; 172: 1626. 9. Perez-Brayfield M, Kirsch AJ, Hensle TW et al: Endoscopic treatment with dextranomer/hyaluronic acid for complex cases of vesicoureteral reflux. J Urol 2004; 172: 1614.

10. Estornell Moragues R, Serrano Durba A, Dominguez Hinarejos C et al: Endoscopic treatment of vesicoureteral reflux in pediatric patients with the diagnosis of neurogenic bladder. Results and long-term outcome. Arch Esp Urol 2008; 61: 278. 11. Haferkamp A, Mohring K, Staehler G et al: Longterm efficacy of subureteral collagen injection for endoscopic treatment of vesicoureteral reflux in neurogenic bladder cases. J Urol 2000; 163: 274. 12. Jeffs RD, Jonas P and Schillinger JF: Surgical correction of vesicoureteral reflux in children with neurogenic bladder. J Urol 1976; 115: 449. 13. Biers SM, Venn SN and Greenwell TJ: The past, present and future of augmentation cystoplasty. BJU Int 2012; 109: 1280. 14. Soygur T, Burgu B, Zümrütbas A et al: The need for ureteric re-implantation during augmentation cystoplasty: video-urodynamic evaluation. BJU Int 2010; 105: 530.