Accepted Manuscript. Does intraoperative success predict outcome in the treatment of urethral sphincter insufficiency with bulking agent?

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1 Accepted Manuscript Does intraoperative success predict outcome in the treatment of urethral sphincter insufficiency with bulking agent? Niklas Pakkasjärvi, Seppo Taskinen PII: S (18) DOI: /j.jpurol Reference: JPUROL 2713 To appear in: Journal of Pediatric Urology Received Date: 28 June 2017 Accepted Date: 22 October 2017 Please cite this article as: Pakkasjärvi N, Taskinen S, Does intraoperative success predict outcome in the treatment of urethral sphincter insufficiency with bulking agent?, Journal of Pediatric Urology (2018), doi: /j.jpurol This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Does intraoperative success predict outcome in the treatment of urethral sphincter insufficiency with bulking agent? Niklas Pakkasjärvi, Seppo Taskinen * Department of Pediatric Surgery, Children s Hospital, University of Helsinki, Helsinki, Finland * Corresponding author: Department of Pediatric Surgery, Children s Hospital, University of Helsinki, PL 281, HUS, Helsinki, Finland. Tel.: address: seppo.taskinen@hus.fi (S. Taskinen). Summary Introduction Sphincter insufficiency is mostly associated with neurogenic and some structural abnormalities in the pediatric population. As a mini-invasive treatment, urethral bulking agents have been used to treat this problem. Objective The aim was to evaluate if technical success, defined as intraoperative increase in abdominal leak point pressure (ALPP), predicts the outcome of the treatment of sphincter insufficiency with urethral bulking agent. Study design We reviewed all children treated first time with dextranomer/hyaluronic acid (Dx/HA) copolymer (Deflux) for urethral sphincter insufficiency and who intraoperatively had ALPPs measured during Patient characteristics, change in urinary continence and the duration of the possible response were evaluated in neurogenic and non-neurogenic cases. Results 1

3 The median age of the patients was 7.8 years (range ) at initial treatment and median volume of Dx/HA instilled was 3.5 ml (IQR 2 5). Twelve patients had neurogenic disease and 15 had non-neurogenic disease. Median ALPPs before and after the injections were 19 cmh 2 O (IQR 14 28) and 70 cmh 2 O (IQR 48 80), p < Increases in ALPPs were similar in both patient groups (p = 0.661) and in 17 patients with any response and 10 patients with no response (p = 0.267). In patients with any response the median duration of the response was only 0.8 years (IQR ). During a median follow-up of 4.9 years (range ), 15 patients received one to three repeat injections and eight patients went through sling or bladder neck operation. During repeat injections, the preoperative ALPPs had returned to the original levels. Currently, 20% are continent or almost continent with one or more Dx/HA injections. In half of the patients with neurogenic bladder, compliance or volume deteriorated slightly in follow-up. Five out of 15 patients who reached puberty become continent spontaneously after failed bladder neck injection. Discussion Intraoperative ALPPs increased significantly in most patients during the procedure. However, only 52% of the patients experienced more than 1 month of success after the procedure, and even in those the effect lasted mostly under a year. With one to four injections one-fifth seem to have had a good long-term result. Although the long-term success rate is limited, bulking agent injection allowed the patients with spontaneous voiding to continue it and the injection did not prevent future treatments. Conclusion Intraoperative increased ALPP does not predict a good long-term outcome after Dx/HA injection. At the end, only a fifth of our patients had good result with one or more Dx/HA injections. A change in bladder behavior is possible after treatment. KEYWORDS 2

4 Children; Bladder exstrophy; Deflux; Neurogenic bladder; Non-neurogenic bladder; Urethral sphincter insufficiency Introduction A cornerstone in the treatment of urinary continence in children relies on a low-pressure bladder with appropriate outlet resistance. Urethral sphincter insufficiency is one of the major determinants of urinary incontinence in children, mainly for neurogenic bladder and some rare structural abnormalities. Because procedures increasing the bladder outlet resistance may increase bladder pressures, they are recommended only when detrusor activity is controlled [1]. In addition to surgical therapies, such as sling operations and bladder neck operations, minimally invasive procedures with bulking agents have become options in the treatment of sphincteric insufficiency [2 4]. Previous reports on urethral bulking in children have presented improvement in continence in about half of patients with neurogenic bladder with various materials [4,5]. However, only limited value has been observed as a secondary operation after failed sling procedures [6]. We have treated children with sphincter insufficiency by dextranomer/hyaluronic acid copolymer (Dx/HA, Deflux) injections since In 2004 we started to register intraoperative abdominal leak point pressure (ALPP) measurements to improve the results and to validate that outlet resistance increases during the procedure. In this study, we wanted to determine if clinical success is dependent on initial intraoperative result or the in situ permanence of the bulking agent. The increase in ALPP intraoperatively was considered to reflect technical success. In addition, we wanted to evaluate the long-term benefits from the therapy and which patients may benefit from therapy. Materials and methods 3

5 We analyzed all 27 patients undergoing first time endoscopic injection by a single urologist (S.T.) with Dx/Ha for urethral sphincter insufficiency during , when ALPPs were measured before and after the injection during the procedure. The study was approved by the institutional ethics committee. The patients were divided to two groups: neurogenic (12 patients) and nonneurogenic (15 patients). Within the neurogenic group, nine patients had myelomeningocele and one each had either lipomeningocele, spinal trauma, or post-infectious paraparesis (9 were males and 3 females). Within the non-neurogenic group, there were five bladder exstrophy patients: nine had epispadias and one had been operated because of ectopic ureter (12 were males and 3 females). The inclusion criteria for injection therapy were symptoms suitable to sphincter insufficiency. In addition, adequate bladder volume for age (> 80 % of the expected capacity for the age) and lowpressure bladder in the neurogenic group. In the neurogenic group eight patients were on anticholinergic medication and three had undergone ileocystoplasty. Because leak point pressures were close to zero in all patients in the non-neurogenic group and the urodynamic studies were done without an occlusion catheter, we did not apply the criteria for bladder volume in that group. All patients in the neurogenic group were on clean intermittent catheterization (CIC) and all patients in the non-neurogenic group were voiding spontaneously. Prior bladder neck surgery was not done for any patients in the neurogenic group, nor for four out of nine patients in the epispadias group, because of distal epispadias and not for the patient with ectopic ureter. Two out of five patients with bladder exstrophy had had no bladder neck surgery after the primary reconstruction. The remaining three had undergone separate bladder neck reconstruction. Preoperatively, medical history, incontinence charts, urine cultures, urinary ultrasound, and urodynamic investigation were performed. Patients were under general anesthesia for endoscopic treatment. Injections were performed using pediatric urethrocystoscopes with a working channel and a 0-degree lens, with a 4

6 flexible needle (Cook Williams Cystoscopic Injection Needle, 3.7F 23G, Cook Medical, Bloomington, IN, USA), with a median instilled volume of 3.5 ml (range 0.8 6, IQR 2 5). Males were injected under the epithelium around the bladder neck in males if it was closing to some degree, and if the bladder neck was very wide along the prostatic urethra or external sphincter. Females were injected mid-urethra. ALPPs were intraoperatively measured before and after injections through a suprapubic catheter and manually compressing a half-full bladder until leakage occurred. A suprapubic catheter was left for 3 5 days to drain the bladder after the injection. Postoperative results were collected during the control visits, and voiding/catheterization charts were utilized to clarify incontinence. Also, urine cultures and ultrasound were analyzed at these visits. The incontinence score was recorded on a scale from 0 to 3 (0, completely dry; 1, wet less than once a day; 2, wet for less than 50% of the time between daily catheterizations/micturition; and 3, wet for more than 50% of the time between catheterizations/micturition) before treatment and at control visit 1 3 months after treatment [7]. In addition, initial success was evaluated according to the recommendation of the ICCS: Nonresponse (NR) 0 49% decrease, partial response (PR) 50 99%, and complete response (CR) is defined as a 100% decrease in symptoms [8]. The patient was considered to have any response, if the response was CR or PR at least for 2 weeks after the injection. In addition, follow-up data after the first treatment were collected (duration of response, number of patients having repeat injections, and number of patients requiring surgery). In the case of repeat injections the clinical result was reevaluated. Statistical analysis was performed using the Fisher exact test for categorical variables and the Mann Whitney test or Wilcoxon Signed rank test (in the case of repeat measurements) for continuous variables. A p value < 0.05 was taken to be significant. 5

7 Results The median age of the 27 patients was 7.8 years (range years) at initial treatment. The median bladder volume for all patients was 190 ml (IQR ml), and a median 97% (IQR ) in relation to the expected bladder volume. Bladder volumes were larger within the neurogenic group, 291 ml (IQR ) versus 133 ml (IQR ), p = 0.004). The median maximal detrusor pressure during cystometry was 14 cmh 2 O (IQR ) in the patients with neurogenic bladder. In patients with incontinence because of structural abnormality, the leak point pressures were close to zero and accordingly the detrusor pressures were close to zero. Median ALPPs before and after injections were 19 cmh 2 O (IQR 14 28) and 70 cmh 2 O (IQR 48 80), with a median increase of 41 cmh 2 O (IQR 22 64, p < 0.001). The increase in ALPP was similar in the patients in the neurogenic and non-neurogenic groups (median 48 (IQR 30 67) and 35 (IQR 19 69) respectively, p = 0.661). The ALPP was less than 40 cmh 2 O after Dx/HA injection in two patients, with no response and partial response, respectively. Any response was observed at 1 month in 14 out of 27 patients (52%) after the first Dx/HA injection (7 had complete response and 7 had partial response). There was no difference in the response between the neurogenic and non-neurogenic groups (Table 1, p = 0.704). Within the non-neurogenic group the results were similar between the patients with or without prior bladder neck surgery (p = 0.619); the median preoperative incontinence score improved after the first Dx/HA injection from 3 (IQR 2 3) to 2 (IQR ) respectively (p < 0.001). However, the duration of response was short: median 0.8 (IQR , range ,4) years in 17 patients who had any response. The pre-treatment continence scores were similar in patients with and without any response (p > 0.99). Only two males (1 with myelomeningocele and the other with epispadias) were still continent at their last control visit 6.4 and 4.9 years after first injection. Median postinjection ALPPs were similar in 17 patients with any response and 10 patients with no response (78 (IQR ) cmh 2 O and 60.5 (IQR 45 80) cmh 2 O, respectively (p = 0.267). 6

8 During a median follow-up of 4.9 years (range ) after the first treatment, 15 patients underwent one to three repeat Dx/HA injections. Also, during repeat injections there was a significant increase in ALPPs from 20 cmh 2 O (IQR 14 24) to 50 cmh 2 O (IQR 28 81) during the operation (p < After the second injection, 11 out 15 patients got some response with a median duration of 0.7 years (IQR ). The response was abated after the first injection in eight out the 11 patients who got a response after the second injection. Two patients have had longterm success after the second Dx/HA injection and they have been continent at the latest controls at 5.4 and 8.6 years after the injections, respectively. Only one out of six patients had some response after a third Dx/HA injection, but he has been continent now for 7.3 years after the injection. He also had had a response from the previous two injections. Compared with the situation before the first Dx/HA injection, the median continence score decreased from 3 (IQR 2 3) to 1 (IQR ) (p = 0.003) in 19 patients who did not undergo more invasive surgery. Currently, five out of the original 25 patients (20%) who had daily incontinence episodes before Dx/HA injections are continent or have less frequent than daily incontinence because of one or more Dx/HA injections (2/12, 17%, in the neurogenic group and 3/13, 23%) in the non-neurogenic group, p > 0.99). Two epispadias patients who originally had small weekly incontinence episodes remain unchanged, except they feel that the size of droplets is less. Eight patients have undergone sling or bladder neck operations. In the neurogenic group urodynamic studies after Dx/HA injection demonstrated slight deterioration in bladder behavior in six out of 12 patients. In five patients, maximal detrusor pressure at full bladder increased from 10 cmh 2 O (range 6 15) to 20 cmh 2 O (range 20 34). In addition, in one patient the bladder volume decreased from 87% to 36% of the expected volume. All six with bladder deterioration had daily incontinence episodes. Two of them underwent bladder augmentation in addition to the sling operation, two patients underwent Botox treatment, and two pubertal patients with incontinence refused further treatment. The other patient receiving Botox treatment became continent during daytime, but not during the night. Altogether 15 7

9 patients are currently at least 15 year old. Among those 15, five patients (2 males with epispadias, 1 male, and 1 female with bladder exstrophy, and 1 male with traumatic spinal cord injury) who had initially poor success (2 had no response and 3 had short-term response) after Dx/HA injections became continent or almost continent during pubertal development. No post-injection complications were detected and all patients who voided spontaneously before injections have been able to do so afterwards. We did not observe upper urinary tract deterioration after injection treatment during follow-up. We did not recognize special difficulties in further more invasive surgery because of previous Dx/HA. Discussion In this study, we treated 27 patients with urinary incontinence because of urethral sphincter insufficiency because of neurogenic or non-neurogenic reasons by using periurethral Dx/HA injections. We sought to determine if the injection was technically successful by measuring increases in ALPPs during the procedure. Satisfactory ALPP was achieved in most patients, and a response was observed in half of the patients 1 month after the first injection. The increase in intraoperative ALPPs, however, did not influence the outcome and the duration of the response was rather short in most patients. In patients with repeat Dx/HA injections, pre-treatment ALPP values had decreased to the same level as before the first treatment. During follow-up, only one-fifth of the patients had satisfactory results with one or more injections. The results were similar in the nonneurogenic and in the neurogenic groups. In previous studies, the success with bulking agents has been variable as are definitions for success in the treatment of urethral sphincter insufficiency [3 6]. In the study of Lottman et al. [3], the success rate decreased from 79% at 1 month to 40% at 7 years after the treatment. In that study, success was defined as a need of a maximum of one pad a day and there was no difference in the results between the patients with neuropathic bladder and bladder 8

10 exstrophy or epispadias, as it was not among our patients. Also Dean et al. [9] have reported good results, with 79% of the patients having significant improvement in incontinence with a mean follow-up of 11.7 months after Dx/HA injection using an antegrade technique. Benefit from Dx/HA injections has been observed in 70 86% of the patients also after bladder neck surgery to some degree, at least in the short term [10,11]. In both of these studies continence was defined as at least a 3-hour daytime dry interval and improvement as at least a 2-hour dry interval. In the study of Shah et al. [12], 42% of the patients with bladder exstrophy or epispadias became socially continent (> 3-hour dry intervals) after the injection of a bulking agent if the patients had had previous bladder neck surgery. In that study, there was no difference between collagen and DxHA injections, but those patients who had partial continence before the injection had a better response. All studies have, however, not shown satisfactory results after therapy with a bulking agent. In a study from The Netherlands only two out of 27 patients with neurogenic bladder became continent with DxHA injections after a failed sling procedure [6]. In the study of Dyer at al. [13], only four out of 14 patients with Dx/HA injection and one out of 20 patients with Teflon injection had any response in a patient study similar to ours. In a very recent study with 45 patients receiving a bladder neck injection with polydimethysiloxane or collagen, 45% of the patients with neurogenic bladder and 13% of the patients with bladder exstrophy became long-term continent [14]. In that study bladder exstrophy patients were also on CIC, unlike our patients. Intraoperative measurement of leak point pressures has been addressed in only one study as far as is known [9]. In that study it was observed that detrusor leak point pressure was always more than 60 cmh 2 O when good mucosal coaptation was achieved. However, there was no attempt to evaluate if this increase in LPP was associated with better outcome. In our study, most patients got good increases in ALPPs during the injection. Among those few who did not, the limiting factor was that the epithelium in the urethra started to tear during the procedure. Accordingly, the injections were stopped, as it was difficult to get satisfactory increases in ALPPs 9

11 with deeper injections. Sometimes we were satisfied with a very small injection volume if the macroscopic result was good and the ALPP increased markedly, because we wanted to avoid CIC in non-neurogenic patients voiding spontaneously. Apparently, the substance did not stay in place in many cases, because the duration of the response was short in many patients and the ALPP was decreased to the original level at the start of repeat injections. Our study has some limitations. Firstly, our material is rather small and heterogeneous. It remains difficult to collect large series because of the rarity of sphincter insufficiency in pediatric populations, as has been the case in the other published studies. Secondly, the effect of the diseased bladder on the results remains difficult to evaluate especially in patients with bladder exstrophy and epispadias. However, for the patients in the neurogenic group urodynamic follow-up was continued and we noticed small deterioration in bladder compliance or volume in half of our patients with neurogenic bladder after Dx/HA injections. A similar possibility has been reported also previously [3]. In out material, it was not possible to conclude if the deterioration was associated with Dx/HA injections or with the natural development of neurogenic bladder. Thirdly, we do not have objective measurements concerning the amount of incontinence. However, according to patient description, the amount on incontinence was mostly droplets in patients who did not have daily incontinence. The definition of success is not static in the patients, since it is affected at least by patient selection, an increase in outlet resistance, the quality of the bladder, patient compliance to scheduled voiding or catheterizations, follow-up time, the definition of response, and apparently even patient age. However, our material is unselected, since injection therapy was attempted as a first-line therapy for urethral sphincter insufficiency in all patients with neurogenic bladder. In addition, our patients have a rather long follow-up time. Surgical therapy is the mainstay of treatment for increasing outlet resistance. The benefits of endoscopic treatment lie in the minimally invasive nature, with short convalescence and few complications. While the long-term success rate is limited, bulking agent injection is still worth 10

12 consideration in the pediatric population, as it is repeatable and it apparently did not adversely affect future treatments in our study or in a previous study [15]. If the first treatment is unsuccessful, we discuss with the family and the patient whether a further attempt with a bulking agent or more invasive surgery should be carried out. Five of our patients became continent or almost continent during puberty after failed bladder neck injection. It is possible that this is due to hormone-induced changes in the urethra and bladder neck. In some patients, also the understanding of the bladder behavior increased in puberty, leading to better voiding or CIC habits. Dx/HA injections enables some patients to avoid surgery that mandates a catheterization program afterwards. Conclusion Most patients had improvement in ALPPs during the operation, indicating the apparent technical success of the procedure. However, the duration of the clinical response was often short and ALPPs had decreased to the original levels in patients undergoing repeat treatments, because Dx/HA had apparently disappeared from the initial correct place. Only two of 27 patients became long-term continent with a single injection. Only one-fifth of our patients had a satisfactory long-term continence situation with one or more Dx/HA injections. One-third of patients underwent subsequent operative treatment and one-third of the patients who reached puberty after unsuccessful bladder neck injection became continent or almost continent spontaneously during pubertal development. Conflict of interest None Funding 11

13 None References [1] Stöhrer M, Blok B, Castro-Diaz D, Chartier-Kastler E, Del Popolo G, Kramer G, et al. EAU guidelines on neurogenic lower urinary tract dysfunction. Eur Urol 2009;56:81 8. [2] Caione P, Capozza N. Endoscopic treatment of urinary incontinence in pediatric patients: 2-year experience with dextranomer/hyaluronic acid copolymer. J Urol 2002;168: [3] Lottmann HB, Margaryan M, Lortat-Jacob S, Bernuy M, Läckgren G. Long-term effects of dextranomer endoscopic injections for the treatment of urinary incontinence: an update of a prospective study of 61 patients. J Urol 2006;176(4 Pt 2): [4] Alova I, Margaryan M, Bernuy M, Lortat-Jacob S, Lottmann HB. Long-term effects of endoscopic injection of dextranomer/hyaluronic acid based implants for treatment of urinary incontinence in children with neurogenic bladder. J Urol 2012;188: [5] Guys JM, Breaud J, Hery G, Camerlo A, Le Hors H, De Lagausie P. Endoscopic injection with polydimethylsiloxane for the treatment of pediatric urinary incontinence in the neurogenic bladder: long-term results. J Urol 2006;175: [6] De Vocht TF, Chrzan R, Dik P, Klijn AJ, De Jong TP. Long-term results of bulking agent injection for persistent incontinence in cases of neurogenic bladder dysfunction. J Urol 2010;183: [7] Kask M, Rintala R, Taskinen S. Effect of onabotulinumtoxina treatment on symptoms and urodynamic findings in pediatric neurogenic bladder. J Pediatr Urol 2014;10: [8] Austin PF, Bauer SB, Bower W, Chase J, Franco I, Hoebeke P, et al. The standardization of terminology of lower urinary tract function in children and adolescents: 12

14 Update report from the standardization committee of the International Children's Continence Society. Neurourol Urodyn 2016;35: [9] Dean GE, Kirsch AJ, Packer MG, Scherz HC, Zaontz MR. Antegrade and retrograde endoscopic dextranomer/hyaluronic Acid bladder neck bulking for pediatric incontinence. J Urol 2007;178: [10] Kitchens DM, Minevich E, DeFoor WR, Reddy PP, Wacksman J, Koyle MA, et al. Incontinence following bladder neck reconstruction is there a role for endoscopic management? J Urol 2007;177: [11] Riachy E, Defoor WR, Reddy PP, Alam S, Noh PH, Sheldon C, et al. Endoscopic treatment with dextranomer/hyaluronic acid for persistent incontinence after continent urinary reconstruction. J Endourol 2015;29: [12] Shah BB, Massanyi EZ, Dicarlo H, Shear D, Kern A, Baradaran N, et al. Role of urethral bulking agents in epispadias-exstrophy complex patients. J Pediatr Urol 2014;10: [13] Dyer L, Franco I, Firlit CF, Reda EF, Levitt SB, Palmer LS. Endoscopic injection of bulking agents in children with incontinence: Dextranomer/hyaluronic acid copolymer versus polytetrafluoroethylene. J Urol 2007;178: [14] Faure A, Hery G, Mille E, Orillac P, Da Silva B, Merrot T, et al. Long-term efficacy of Young-Dees bladder neck reconstruction: Role of the associated bladder neck injection for the treatment of children with urinary incontinence. Urology 2017;108: [15] Alova I, Margaryan M, Verkarre V, Bernuy M, Lortat Jacob S, Lottmann HB. Outcome of continence procedures after failed endoscopic treatment with dextranomer-based implants (DEFLUX ). J Pediatr Urol 2012;8:

15 Table Response rates (any response) 1 month after repeat Dx/HA injections for urinary incontinence. Response rate (n) Patient group 1st injection 2nd injection 3rd injection Neurogenic 7/12 5/5 Male 5/9 4/4 Female 2/3 1/1 Non-neurogenic 7/15 6/10 1/6 Male 6/12 6/9 1/6 Female 1/3 0/1

16 Table 1. Response rates (any response) 1 month after repeat Dx/HA injections for urinary incontinence. Response rate (n) Patient group 1st injection 2nd injection 3rd injection Neurogenic 7/12 5/5 Male 5/9 4/4 Female 2/3 1/1 Non-neurogenic 7/15 6/10 1/6 Male 6/12 6/9 1/6 Epispadias with BNR 3/4 3/3 1/2 Epispadias without BNR 3/4 1/2 0/1 Exstrophy with BNR 0/3 1/3 0/3 Exstrophy without BNR 0/1 1/1 Female 1/3 0/1 Epispadias with BNR 0/1 Exstrophy without BNR 0/1 Ureteric ectopia 1/1 0/1 BNR = bladder neck reconstruction.