Functional Bladder Problems

Transcription

1 european urology supplements 6 (2007) available at journal homepage: Functional Bladder Problems Emmanuel Chartier-Kastler * Department of Urology, Hospital Pitié-Salpêtrière, University Paris VI, Boulevard de L Hôpital 83, Paris, France Article info Keywords: Bladder outlet obstruction (BOO) Interstitial cystitis (IC) Painful bladder syndrome (PBS) Tamsulosin Ultrasound Uroflowmetry Abstract Objectives: This paper summarises relevant new information on functional bladder problems presented during the New Horizons in Urology closed meeting, with special focus on bladder outlet obstruction (BOO) and painful bladder syndrome/interstitial cystitis (PBS/IC). Methods: Experts in the field of functional bladder problems selected and discussed the most relevant new findings during a closed meeting in Marbella, Spain. Furthermore, the delegates opinions on representative clinical case studies were assessed by interactive voting. Voting results were commented on by an expert panel. Results: Uroflowmetry and ultrasound hold promise as noninvasive tools to diagnose BOO. a 1 -Adrenoceptor antagonists can reduce bladder wall hypertrophy in patients with BOO. A very interesting finding for clinical practice is the evaluation of the tenderness on bladder palpation as initial screening for IC patients. Furthermore, botulinum toxin A and cyclosporine A seems promising in the treatment of patients with PBS/IC, but more data are needed to confirm these findings. Conclusion: New data on diagnosis and treatment of patients with BOO and PBS/IC, which seem promising for daily clinical practice, were discussed during the closed meeting. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Tel. +33 (1) ; Fax: +33 (1) address: emmanuel.chartier-kastler@psl.aphp.fr. 1. Introduction Functional bladder problems are common among men and women of all ages, and include overactive bladder, incontinence, bladder outlet obstruction (BOO), urinary tract infections, and painful bladder syndrome/interstitial cystitis (PBS/IC) [1]. This review paper will focus on diagnosis and management of patients with BOO and PBS/IC. The International Continence Society (ICS) defines BOO as the generic term for obstruction during voiding, characterised by increased detrusor pressure and reduced urine flow rate. It is usually diagnosed by studying the synchronous values of flow rate and detrusor pressure [2]. Benign prostatic obstruction is a form of bladder outlet obstruction caused by benign prostatic enlargement due to histologic benign prostatic hyperplasia (BPH) [2]. The most common causes of BOO in men are age-related bladder dysfunctions superimposed with pathologies such as BPH, urethral stricture, bladder stones, and bladder or pelvic tumours [3]. From the basic and animal literature, we have some information regarding the progressive response of the bladder to obstruction. Levin et al. [4] described the different steps of what happens regarding the bladder after /$ see front matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eursup

2 european urology supplements 6 (2007) obstruction. During the initial stage, men with BOO demonstrate a rapid enlargement of the bladder wall attributable to smooth muscle hypertrophy, urothelial and fibroblast hyperplasia, collagen deposition in the detrusor, and connective tissue reorganisation. Then, the bladder enters the compensated stage, which is characterised by a stable bladder mass and the bladder s function remains greater than 80% of normal. At some point thereafter, the bladder enters the decompensated stage because of ischemia; this period is characterised by a progressive increase in bladder mass and a progressive decrease of the bladder function and compliance. In general, if the obstruction is released during the compensated stage, there is a rapid and full restoration of normal, or nearly normal, bladder function. If the obstruction is released during the decompensated stage, there is only a partial recovery proportional to the level of decompensation. Until today, individual progression and time for decompensation were not predictable. The resulting obstruction often produces lower urinary tract symptoms (LUTS). The most common symptoms of BOO are classified as voiding symptoms including weak urinary flow, hesitancy, intermittency, terminal dribbling, incomplete bladder emptying, retention, and abdominal pain, and storage symptoms including nocturia, frequency, urgency, and urinary incontinence [2]. PBS/IC is a syndrome characterised by chronic irritative voiding symptoms, and suprapubic and/or pelvic pain without any known aetiologic factor [5]. This syndrome has clinically been considered a disorder affecting primarily women. However, the prevalence of PBS/IC symptoms varies considerably on the basis of its definition and is now known to be greater in men than was previously believed [6].Itis still not clear what should be the base definition of PBS. The ICS defined PBS as the complaint of suprapubic pain related to bladder filling, accompanied by other symptoms such as increased daytime and nighttime frequency, in the absence of proven urinary infection or other obvious pathology [2]. 2. Bladder outlet obstruction 2.1. Diagnosis of patients with BOO Assessment of medical history and physical examination are critical in the primary evaluation of patients with LUTS and BOO. Basic evaluation of these patients includes concomitant analysis of uroflowmetry and postvoid residual (PVR) analysis. In case of treatment failure or a doubtful diagnosis, further evaluation is indicated, which includes more invasive techniques, such as urodynamics with pressure-flow evaluation, cystoscopy, and ultrasound. An urodynamic evaluation is considered the gold standard to demonstrate the presence of BOO [3]. The invasive nature of urodynamics is often regarded as a disadvantage. Several noninvasive alternatives to determine BOO have been proposed. Already in 1996, the results of a study supported the use of the International Prostate Symptom Score (IPSS) to identify patients with BOO. There appeared to be a significant correlation between the IPSS score and the presence of BOO. When the total IPSS was >28 or the voiding subscore >15, the probability of BOO was >0.91 [7]. In an abstract presented during the American Urological Association conference, the potential of noninvasive uroflowmetry to predict the presence of BOO was evaluated [8]. In total, data from 3416 men who underwent uroflowmetry and pressure-flow studies during the last 12 yr were analysed. Of these men, 1535 were obstructed and had a BOO index >40. Multiple linear regression revealed that maximum urinary flow rate (Q max ), postvoid residual urine (PVR), and bladder-voiding efficiency, defined as voided volume/(voided volume + PVR), were significant variables to predict BOO (all p < 0.001) with a sensitivity of 69% and a specificity of 71%. On the basis of these variables, a table was developed that allows physicians to estimate the probability of BOO following uroflowmetry. This method can be particularly useful in units with limited access to urodynamics. Another promising, but not a new, tool to identify the presence of BOO is measurement of detrusor wall thickness (DWT) by means of ultrasound. Oelke et al. [9] performed DWT measurements at three different locations of the anterior bladder wall in 160 patients when their bladder was fully filled. A DWT cut-off value 2 mm can be used to classify the majority of patients with BOO. This accuracy seems to be high enough for a noninvasive classification of obstructed men in daily clinical practice. However, a lot of bias regarding this tool and its measurement technique can be reported Management of patients with BOO With regard to the management of patients with BOO, some recent studies specifically evaluated the effect of a 1 -adrenoceptor (AR) antagonists on DWT. Lluel et al. [10] observed that treatment with alfuzosin (3 mg/kg/d for 7 d) significantly reduced the increased bladder weight in obstructed rats ( p < 0.05). These results were in line with a multi-

3 712 european urology supplements 6 (2007) Fig. 1 The a 1 -adrenoceptor antagonist tamsulosin significantly reduced bladder wall hypertrophy in obstructed patients. Bladder wall hypertrophy was evaluated by ultrasound-estimated bladder weight (UEBW) [11]. NS = not significant. centre study evaluating the effect of tamsulosin on DWT of obstructed patients. After a 4-wk run-in period with no drug treatment, 9 nonobstructed patients and 18 obstructed patients received 0.4 mg once daily tamsulosin for a period of 6 mo [11]. The primary objective of the study was to evaluate the effect on bladder wall hypertrophy by using ultrasound-estimated bladder weight (UEBW). Treatment with tamsulosin significantly reduced UEBW in obstructed patients ( p < 0.05) (Fig. 1). These data suggest that a 1 -AR antagonists may have a direct effect on the obstructed bladder Clinical case study related to BOO The case of a 72-year-old man with storage and voiding symptoms and two episodes of haematospermia during the last year was discussed. The patient had been treated with dopamine therapy for Parkinson s disease during 4 yr and with angiotensin-converting enzyme inhibitors for high blood pressure. Several possible causes of voiding difficulties at nighttime (ie, reduced concentration or increased sympathetic tone) were pointed out during the panel discussion. The experts also referred to a recently published paper suggesting a possible physiologic cause of nocturia in some patients [12] Diagnostic evaluation Digital rectal examination of the patient revealed the presence of BPH with a prostate of about 40 g without other abnormalities. Neurologic examination of the patient revealed extrapyramidal syndrome related to Parkinson s with a tremor, but without evidence of other pathologies affecting the reflexes or perineal sensibility. In addition, the Fig. 2 Results from interactive voting on a representative case indicate that an urodynamic study is the preferred tool for diagnostic evaluation. Surprisingly, watchful waiting and cystoscopy are still frequently chosen. Only a minority of the participants chose urethrocystography as a diagnostic tool. patient had a PSA value of 5.2 ng/ml, no signs of prostate cancer, a Q max of 8 ml/s, a voided volume of 233 ml, and a PVR of 120 ml. Interactive voting revealed that about 14% of the delegates would advise watchful waiting, whereas 14% would perform a cystoscopy (Fig. 2). The majority of the delegates agreed with the proposition of the subject expert to perform a urodynamic study to further evaluate the patient. Urodynamic analysis showed that the patient had a high detrusor pressure during micturition, suggesting obstruction. During the panel discussion, it was stated that patients should first complete a voiding chart before a urodynamic study because the former gives information on the global diuresis of the patient, as well as of his nocturnal diuresis, which is essential to evaluate the patients nocturia. Therefore, the voiding chart should be the basis for further urodynamic analysis Treatment About half of the participants selected a transurethral resection of the prostate (TURP) as treatment option (Fig. 3). Surprisingly, only 9% would have performed a temporary prostatic stent. Nevertheless, the patient received a Fabian s stent (Urethrospiral 1, Porges, France), which is a temporary prostatic stent. The expert explained that this treatment was chosen to assess the outcome of the patient after surgery. Patients with neurologic diseases such as Parkinson s disease and extrapyramidal syndrome can develop sphincter deficiency after surgery. He advised to follow-up the clinical symptoms of the patient for a period of 3 mo, followed by another uroflowmetry and PVR analysis.

4 european urology supplements 6 (2007) is not only a PBS but is also associated with the presence of bladder pain, urgency, and submucosal haemorrhages, which means that not all patients with PBS have IC [5]. Recently, the presence of bladder tenderness on bladder palpation during vaginal examination seemed to be useful as initial screening tool for IC patients [16]. The sensitivity of tenderness on bladder palpation for the diagnosis of IC was 90.4%; specificity was 89.1%. This screening might be helpful to determine which patients need further evaluation or not. Fig. 3 Results from interactive voting indicate that about half of the participants chose a transurethral resection of the prostate (TURP) as treatment option for a patient with bladder outlet obstruction, whereas a prostatic stent was a less favoured option. In case of a positive result, a TURP could be performed at the same time of removal of the prostatic stent. There was some discussion on the use of a combination of anticholinergics and a 1 -AR antagonists, and depending on his nighttime voiding, antidiuretics to treat his Parkinson s disease and voiding difficulties. Most of the attendees agreed on a step-by-step management of these types of patients from diagnosis to treatment adapted to each patient. 3. Painful bladder syndrome/interstitial cystitis 3.1. Diagnosis of patients with PBS/IC PBS/IC is underestimated, underdiagnosed, and frequently inadequately treated in clinical practice. Most patients with PBS/IC will see at least five different physicians over a period of 5 yr before the correct diagnosis is made [13,14]. Nevertheless, it is important to know how to diagnose patients with PBS/IC because time delays in accurate diagnosis can worsen the patient s condition. However, since symptoms of PBS/IC are similar to those of other bladder disorders and because there is no definitive test to identify PBS/IC, diagnosis of PBS/IC is made by exclusion of other treatable conditions. Although there is some overlap between symptoms in patients with overactive bladder (OAB) and PBS, it is clear that patients with bladder pain must be classified as PBS [15]. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) developed diagnostic criteria to standardise the diagnosis of IC on the basis of patient s symptoms and cystoscopic findings [5].IC 3.2. Management of patients with PBS/IC Because of the elusive aetiology of PBS/IC, many forms of treatment have been attempted. Treatments for IC include behavioural therapies (eg, dietary modification and pelvic floor exercise), oral therapies (eg, pentosan polysulfate sodium [PPS], amitriptyline, and hydroxyzine), and intravesical therapies (eg, dimethylsulfoxide and heparin) (Table 1) [14]. The clinical efficacy of PPS for the treatment of IC has been demonstrated in several studies. In two randomised placebo-controlled studies, significant improvement in symptoms was reported after 3 mo of treatment with PPS [17]. Promising new medical treatments include botulinum toxin A (BTX-A) [18] and cyclosporine A [19] (Table 1). Giannantoni et al. [18] demonstrated that BTX-A intravesical injections are effective in the short-term management of PBS. In this study, 14 patients (12 women and 2 men) were prospectively included. Under short general anaesthesia, patients were given injections of 200 U of BTX-A diluted in 20 ml 0.9% NaCl. A voiding chart and the Visual Analog Scale (VAS) for pain quantification were completed before, and 1 and 3 mo after treatment. Table 1 Treatment of interstitial cystitis (IC) [14] Behavioural therapy Dietary modification Pelvic floor exercise Physical/emotional relief Oral therapy Pentosan polysulfate sodium (PPS) Tricyclic antidepressants (eg, amitriptyline, doxepin, imipramine) Antihistamines (eg, H 1 - and H 2 -receptor antagonists, hydroxyzine, cimetidine) Nonsteroidal anti-inflammatory drugs Bladder analgesics Intravesical therapy Dimethylsulfoxide (DMSO) Heparin Silver nitrate Other Botulinum toxin A (BTX-A) Cyclosporine A

5 714 european urology supplements 6 (2007) Fig. 4 Botulinum toxin A (BTX-A) injections significantly decreased daytime and nighttime urinary frequency as well as the Visual Analog Scale (VAS) score for bladder pain at 1- and 3-mo follow-up [18]. Before treatment, mean daytime and nighttime urinary frequencies were 14.2 and 4.5, respectively. The mean VAS score for bladder pain was 9.3 at baseline, but was significantly reduced at 1- and 3-mo follow-up ( p < 0.01) (Fig. 4). At the same time points, daytime and nighttime urinary frequency was significantly decreased ( p < 0.01 and p < 0.05, respectively). Sairanen et al. [19] compared cyclosporine A to PPS for the treatment of patients with IC in a randomised, open-label, prospective multicentre study. At 6 mo, treatment with 1.5 mg/kg cyclosporine A twice daily significantly reduced 24-h micturition frequency compared with 100 mg PPS three times daily ( p < 0.001) (Fig. 5). The clinical response rate was 75% for cyclosporine A compared with 19% for PPS ( p < 0.001). However, caution is warranted when using cyclosporine A for patients with IC because this drug is an immunosuppressive drug usually used for organ transplant patients. Because of potential toxicities, patients on cyclosporine A have to be carefully followed up. Surgery is another treatment alternative, but it is reserved for only patients who are refractory to conventional Fig. 5 Cyclosporine A significantly decreased 24-h micturition frequency compared with pentosan polysulfate sodium (PPS) in patients with interstitial cystitis (IC) [19]. Fig. 6 Results from interactive voting indicate that approximately an equal amount of participants chose between a urodynamic study and cystoscopy under general anaesthesia, and bladder biopsies as the tool for diagnostic evaluation of a patient with painful bladder syndrome/interstitial cystitis (PBS/IC). One of five delegates opted for the voiding diary. treatment. Nevertheless, optimal management of PBS/IC is limited by the fact that standardised guidelines have not been developed to ensure a consistent and effective approach for treatment. Neuromodulation is becoming increasingly important for the treatment of patients with PBS/IC who are refractory to conservative treatment. Sacral nerve stimulation, for example, has been successfully applied in PBS/IC patients in a number of studies [20] Clinical case study related to PBS/IC Another case discussed at the closed expert meeting was that of a 42-year-old woman with three children. The patient underwent a left oophorectomy at the age of 39 and was complaining of severe daytime and nighttime frequency, and a painful bladder. Furthermore, she had suprapubic pain, which was relieved by voiding Diagnostic evaluation Because of progressive aggravation of symptoms over 5 yr, the patient underwent several examinations and treatments (several cystoscopies, colonoscopy and laparoscopy, with multiple therapies), but they did not improve her symptoms. Clinical examination did not reveal any other abnormal features. The patient s intravenous pyelogram and urinalysis were normal. Interactive voting showed that about 40% of the delegates would evaluate this patient by means of urodynamics, whereas 35% would perform a cystoscopy under general anaesthesia and bladder biopsies. Only 19% would use a voiding diary (Fig. 6). The subject expert used a

6 european urology supplements 6 (2007) Fig. 7 Results from interactive voting on a representative case indicate that medical treatment, bladder hydrodistension, and bladder instillations are the preferred treatment options, whereas pelvic floor rehabilitation and surgery are less chosen therapies. voiding diary and performed uroflowmetry, urodynamics, and an outpatient visit cystoscopy. The latter was performed to obtain sufficient information before performing a cystoscopy under general anaesthesia. The outcomes of the urodynamic study revealed that the patient had no OAB, but a painful bladder with severe pain at about 150 ml of bladder filling, which was in line with her voiding diary. However, some delegates remarked that cystoscopy on an outpatient basis is a very painful procedure, which increases the risk that the patient will visit another physician Treatment About 38% of the delegates would have treated the patient with medical therapy such as cimetidine, benzodiazepines, and PPS, whereas 28% would have performed a bladder hydrodistension, and 24% would have performed a bladder instillation as initial treatment plan (Fig. 7). Some of the delegates would have started with a bladder hydrodistension and performed a bladder instillation afterwards. Nevertheless, most participants agreed that all available conservative treatments had to be tried first before initiating more invasive treatment. 4. Conclusions The outcomes of the closed expert meeting clearly demonstrate that there are large variations among urologists in the diagnosis and management of patients with functional bladder problems. This finding reveals the need for continued medical education of practising urologists. Ultrasound and uroflowmetry are noninvasive methods to determine BOO and can be used as initial screening of obstructed patients. New data have been presented, which show a direct effect of a 1 -AR antagonists on the obstructed bladder. In case of PBS/IC, there is clearly need for a standardised definition. The presence of bladder tenderness upon palpation can be useful in clinical practice for the initial screening of patients with IC. BTX-A and cyclosporine A seem promising in the treatment of patients with PBS/IC, but more data are needed to confirm this initial data and to reveal their long-term efficacy and safety. Although progress is being made in the diagnosis and treatment of patients with BOO and PBS/IC, more insight into the aetiology of different bladder problems as well as the development of standardised criteria for diagnosis of bladder problems is needed. Conflicts of interests The author is a consultant for Allergan and Coloplast, a lecturer for Astellas and Medtronic, and investigator of scientific trials for Allergan and Schwarz pharma. The author received financial compensation in all cases. References [1] Irwin DE, Milsom I, Hunskaar S, et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 2006;50: [2] Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21: [3] Dmochowski RR. Bladder outlet obstruction: etiology and evaluation. Rev Urol 2005;7(Suppl 6):S3 13. [4] Levin RM, Haugaard N, O Connor L, et al. Obstructive response of human bladder to BPH vs. rabbit bladder response to partial outlet obstruction: a direct comparison. Neurourol Urodyn 2000;19: [5] Gillenwater JY, Wein AJ. Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis, National Institutes of Health, Bethesda, Maryland, August 28 29, J Urol 1988;140: [6] Clemens JQ, Link CL, Eggers PW, et al. The effect of varying definitions on the prevalence of interstitial cystitis (IC)/ painful bladder syndrome (PBS) in a racially and ethnically diverse sample. J Urol 2006;175:94 (abstract no. 283). [7] Rodrigues NN, D ancona LCA, De Lima LM. Correlation between the prostatic symptom score and a pressure-flow study in the evaluation of symptomatic benign prostatic hyperplasia. J Urol 1996;155: [8] Al-Hayek S, Belal M, Abrams P. How reliable is non-invasive uroflowmetry in predicting the presence of bladder outlet obstruction in men? J Urol 2006;175:437 (abstract no. 1356).

7 716 european urology supplements 6 (2007) [9] Oelke M, Höfner K, de la Rosette JJ, et al. What is the most precise cut-off value of detrusor wall thickness measurement to classify bladder outlet obstruction? Neurourol Urodyn 2006;25 (abstract no. 28). [10] Lluel P, Méen M, Palea S. Alfuzosin reverses bladder hypertrophy induced by bladder outlet obstruction in rats. Eur Urol Suppl 2006;5:121 (abstract no. 396). [11] Tubaro A, Sironi D, Pizzoccaro M, et al. Effect of tamsulosin on bladder wall hypertrophy in patients with lower urinary tract symptoms suggestive of bladder outlet obstruction. Eur Urol Suppl 2003;2(1):158 (abstract no. 624). [12] Natsume O. A clinical investigation of nocturnal polyuria in patients with nocturia: a diurnal variation in arginine vasopressin secretion and its relevance to mean blood pressure. J Urol 2006;176: [13] Curhan GC, Speizer FE, Hunter DJ, et al. Epidemiology of interstitial cystitis: a population based study. J Urol 1999;161: [14] Metts JF. Interstitial cystitis: urgency and frequency syndrome. Am Fam Physician 2001;64: [15] Abrams P, Hanno P, Wein A. Overactive bladder and painful bladder syndrome: there need not be confusion. Neurourol Urodyn 2005;24: [16] Botros S, Miller J, Goldberg R, et al. A simple test to aid in the diagnosis of interstitial cystitis. Neurourol Urodyn 2006;25 (abstract no. 403). [17] In: Abrams P, Cardozo L, Khoury S, Wein A, editors. Incontinence. 3rd ed. Health Publication Ltd; p [18] Giannantoni A, Costantini E, Di Stasi SM, et al. Botulinum A toxin intravesical injections in the treatment of painful bladder syndrome: a pilot study. Eur Urol 2006;49: [19] Sairanen J, Tammela TL, Leppilahti M, et al. Cyclosporine A and pentosan polysulfate sodium for the treatment of interstitial cystitis: a randomized comparative study. J Urol 2005;174: [20] Bernstein AJ, Peters KM. Expanding indications for neuromodulation. Urol Clin North Am 2005;32:59 63.