Non-Inflammatory Chronic Pelvic Pain Syndrome Can Be Caused by Bladder Neck Hypertrophy

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1 European Urology European Urology 44 (2003) Non-Inflammatory Chronic Pelvic Pain Syndrome Can Be Caused by Bladder Neck Hypertrophy Petr Hruz, Hansjörg Danuser, Urs E. Studer, Werner W. Hochreiter * Department of Urology, University of Bern, Anna-Seiler-Haus, Inselspital, CH-3010 Bern, Switzerland Accepted 8 April 2003 Abstract Purpose: Little is known about the etiology of the non-inflammatory Chronic Pelvic Pain Syndrome (CPPS, NIH category IIIb). We conducted this study to determine whether endoscopic and urodynamic evaluation provide objectively measurable parameters that may support the rationale of therapeutic strategies for patients who failed to respond to medical treatment of non-inflammatory CPPS. Materials and Methods: The 48 patients included in this study fulfilled the NIH criteria for non-inflammatory chronic pelvic pain syndrome category IIIb. All patients had received multiple courses of antimicrobial and/or antiinflammatory drugs, but suffered recurrent symptoms. An endoscopic and urodynamic evaluation was performed after any medical treatment had been discontinued for at least 6 weeks. Results: At urethrocystoscopy, no patient had endoscopic evidence of obstruction due to urethral stricture, but 29 patients (60%) were found to have significant bladder neck hypertrophy. At urodynamic evaluation, these 29 patients had an increased detrusor opening pressure DOP (49 vs. 29 cmh 2 O), an increased detrusor pressure at maximal flow P det;qmax (55 vs. 34 cmh 2 O), a decreased maximal flow Q max (10 vs. 17 ml/s) and an increased postvoid residual urine PVR (67 vs. 17 ml) when compared to the 19 patients with a normal appearing bladder neck. These differences were statistically significant ( p < 0:05). When assessed with the NIH Chronic Prostatitis Symptom Index (CPSI) the two groups showed no difference in the domains of pain and quality of life impact but urinary symptoms were significantly more pronounced in the presence of bladder neck alterations. Conclusions: Patients with non-inflammatory CPPS who fail to respond to medical treatment with antibiotics and/or anti-inflammatory drugs may have morphological alterations in form of bladder neck hypertrophy. This can be suspected when urinary symptoms, residual urine and decreased Q max are present. These can be assessed by noninvasive methods. Endoscopic and/or urodynamic evaluation seem to be justified in these patients in order to establish the diagnosis, consider a-adrenergic blockade and avoid unnecessary antibiotic treatment. # 2003 Elsevier Science B.V. All rights reserved. Keywords: Chronic pelvic pain syndrome; Urodynamic investigation; Bladder neck hypertrophy 1. Introduction Prostatitis is one of the most common entities encountered in urological practice. A US national survey of physician visits from 1990 to 1994 compiled almost 2 million office visits yearly where the diagnosis of prostatitis was made [1]. Only 5% to 10% of cases * Corresponding author. Tel. þ /21; Fax: þ address: werner.hochreiter@insel.ch (W.W. Hochreiter). are known to have a bacterial etiology. In about 90% of cases the cause is unknown [2]. The most common form is the chronic abacterial prostatitis or type III prostatitis, according to the National Institutes of Health (NIH) prostatitis classification system called Chronic Pelvic Pain Syndrome (CPPS) [3]. Numerous studies on prostatitis syndromes have focussed on an infectious etiology suggesting that microorganisms may be important causative agents [4 7]. However, many patients are not cured by antimicrobial therapy and both patients and physicians are often frustrated in /03/$ see front matter # 2003 Elsevier Science B.V. All rights reserved. doi: /s (03)

2 P. Hruz et al. / European Urology 44 (2003) dealing with this condition. Although antimicrobial treatment is recommended as first line approach in patients with inflammatory CPPS (NIH category IIIa), there are still few evidence-based recommendations on how to proceed in patients with the non-inflammatory syndrome (NIH category IIIb) [8] since characteristic objective findings are missing. It is a common belief that probably various mechanisms may lead to the development of symptoms in CPPS IIIb. The present study was conducted to determine if these patients have functional and/or anatomical alterations of the lower urinary tract which could constitute pathophysiological mechanisms of their disease. 2. Materials and methods From March 2001 to August 2002, 634 patients were evaluated for symptoms suggestive for chronic prostatitis/cpps. After exclusion of patients with other pathologies, 416 men met the criteria for the diagnosis of CPPS category III, as outlined by the National Institutes of Health Steering Committee [3]. To distinguish between categories IIIa and IIIb we used the presence of white blood cells/ high power field (WBC/HPF) whereas CPPS IIIb was defined as <10 WBC/HPF (400) in urine after prostatic massage (VB3) and/ or <10 WBC/HPF (1000) in expressed prostatic secretions (EPS). Two hundred and seventy three patients (66%) were diagnosed with CPPS IIIa and 143 patients (34%) with CPPS IIIb. Of the latter group, 77 patients had received at least 2 courses of antimicrobial and/or anti-inflammatory therapy by their treating physician but suffered persisting or recurrent symptoms which were assessed using the German version of the NIH Chronic Prostatitis Symptom Index (CPSI) [9]. Of these, 48 patients were willing to undergo both urodynamic investigation and urethrocystoscopy. The median age of the patients was 48 years (range 22 77) and the duration of symptoms was at least 3 months. A complete physical examination was followed by uroflowmetry measuring the free urinary flow and ultrasound determination of postvoid residual urine (PVR). The 3-glass urine analysis (or 4-glass urine analysis when expressed prostatic secretions were available) according to Meares and Stamey [10] was performed as well as routine microbiological cultures. Urodynamic and endoscopic evaluation were scheduled after any medication had been discontinued for at least 6 weeks. Pressure flow investigation was performed with a SediaNT 1 urodynamic unit (Sedia, Givisiez, Switzerland) using an 8-French Gaeltec catheter tip pressure transducer (Gaeltec Ltd., Dunvegan, Scotland). Assessment included detrusor opening pressure (DOP), maximal detrusor pressure (P det;max ), detrusor pressure at maximal flow (P det;qmax ) and maximal urinary flow (Q max ). Urodynamic examination was followed by urethrocystoscopy with a 16-French flexible scope (Olympus, Volketswil, Switzerland). The appearance of the bladder neck was assessed dynamically during the bladder filling phase as well as statically when the patient had the sensation of a full bladder Statistical analysis Statistical analysis was performed with the Wilcoxon signed rank test, distributions were tested for normality by QQ-plots. Calculations were performed with the SPSS for Windows package. Differences were considered significant if p < 0: Results At urethrocystoscopy no patient had endoscopic evidence of obstruction due to urethral stricture but 29 patients were found to have significant bladder neck hypertrophy (BNH). Since there is no standardized method to evaluate the degree of obstruction at the level of the bladder neck, BNH was defined according to the endoscopic appearance as none, moderate or severe (Fig. 1). Moderate or severe BNH was defined only if the appearance of the bladder neck remained the same dynamically during bladder filling with endoscopic water flow as well as statically when the bladder was full. Patients with moderate or severe BNH were assigned to group I (29 patients), whereas patients with no BNH were assigned to group II (19 patients). When compared to the 19 patients with a normal appearing bladder neck, the group with BNH had increased mean values of DOP (49 vs. 29 cmh 2 O), P det;max (67 vs. 43 cmh 2 O), P det;qmax (55 vs. 34 cmh 2 O), and PVR (64 vs. 18 ml) while the mean Q max was decreased during free flow (15 vs. 23 ml/s) as well as during pressure flow investigation with the 8-French catheter Fig. 1. Definition of bladder neck hypertrophy (BNH) by endoscopic appearance.

3 108 P. Hruz et al. / European Urology 44 (2003) in situ (10 vs. 17 ml/s). Except for Q max during free flow these differences were all statistically significant ( p < 0:05) (Fig. 2a c). Assessment with the NIH CPSI showed no difference in the domains of pain and quality of life impact but patients with BNH had a statistically significant higher mean score regarding urinary symptoms (Table 1) which was primarily due to differences in the obstructive question. 4. Discussion Fig. 2. (a c) Comparison of urodynamic results in patients with noninflammatory CPPS with and without bladder neck hypertrophy. The non-inflammatory chronic pelvic pain syndrome remains a diagnostic and therapeutic challenge. Several studies using specific culturing and molecular biological techniques indicate that this syndrome may actually be a cryptic bacterial infection of the prostate gland that is usually missed or undetected by conventional routine cultures in clinical microbiology laboratories [5 7,11]. It is surprising that almost all patients who receive the diagnosis of chronic prostatitis/chronic pelvic pain syndrome are treated with at least 1 course of antibiotics [12 14]. This is the case regardless of what the prostate-specific specimen showed and even when no such specimen was examined. While this practical approach may benefit many patients, not all patients improve. In cases of antibiotic therapy failure the diagnostic efforts should be directed towards a possible urodynamic cause such as functional and/or anatomical alterations. In our study we found that 60% of the patients had an endoscopically narrow appearing bladder neck (group I). Whether this is due to fibrosis as a result of possible previous inflammation or to bladder neck dysfunction as a result of increased adrenergic stimulation is unknown. We are aware that estimating the degree of bladder neck obstruction is physician dependent since there are no objectively measurable parameters. However, the urodynamic parameters of bladder outlet obstruction, judged by the pressure flow parameters, were significantly correlated with the urethrocystoscopic findings of a narrow appearing bladder neck. When compared to the patients with a normal appearing bladder neck (group II), patients in group I showed abnormalities of almost all urodynamic parameters measured with statistically significant differences (Fig. 2(a c)). These findings are consistent with bladder outlet obstruction (BOO) based on criteria established by the International Continence Society [15]. Thus, it is not surprising that patients with BNH complain of more severe urinary symptoms when assessed with the CPSI. However, the relationship between endoscopic and urodynamic findings alone does not explain the etiology of the pain which was found to be of similar intensity in both groups. Increased tension and spasm of the smooth muscle in the bladder neck produce increased pressure in the

4 P. Hruz et al. / European Urology 44 (2003) Table 1 Comparison of symptoms assessed with the Chronic Prostatitis Symptom Index (CPSI) N Mean S.E.M. 95% confidence interval for mean p-value Lower bound Upper bound Pain 29 a n.s. (Questions 1 4) 19 b Urinary symptoms 29 a (Questions 5 6) 19 b Quality of life impact 29 a n.s. (Questions 7 9) 19 b Significance determined by Wilcoxon signed rank test. a non-inflammatory CPPS with bladder neck hyperplasia. b non-inflammatory CPPS without bladder neck hyperplasia. prostatic urethra with consequent reflux of urine into the prostatic ducts [16]. Mehik showed that patients with CPPS have higher intraprostatic pressure values than normal individuals suggesting that the increased tissue pressure causes pain similar to a compartmental syndrome in traumatology [17]. Our observation of increased DOP in group I is in line with the high maximal urethral closure pressure found by Barbalias in patients with CPPS [18,19] which corroborates the theory of intraprostatic reflux. In patients with BNH this might be due to morphological alterations while a functional obstruction may be caused by a form of detrusor/internal sphincter dyssynergy in patients with an endoscopically normal appearing bladder neck. Since the bladder neck area is known to be rich in alpha adrenergic receptors, the therapeutic approach with a-blockers seems to be reasonable. It has been shown that a-adrenergic blockade not only leads to an improvement of the urodynamic abnormalities but also to relief of symptoms [19,20]. Although most investigators believe that CPPS IIIb is not an infectious process, this has never been proven conclusively in any clinical study. Therefore, it may be appropriate to start the patient on a 4-week course of antimicrobial therapy at least once and then to reassess him after this period. If there is no response to the antimicrobials, such treatment should be discontinued. Based on our observations the use of a-blockers seems to be the next logical step in treating such patients with CPPS IIIb. Some limitations of the present study have to be mentioned. Since we included only patients with CPPS IIIb, the role of BNH in patients with CPPS IIIa remains unknown. The issue whether the presence or absence of BNH may eventually lead to different treatment results with a-blockers needs to be addressed in further studies including a control group. However, the results of the present study provide an objective basis for a-blocker treatment at least in a subgroup of patients with CPPS IIIb. 5. Conclusions A large number of patients with non-inflammatory chronic pelvic pain syndrome have endoscopic and urodynamic evidence of bladder outlet obstruction due to bladder neck hypertrophy. This can be suspected in the presence of urinary symptoms, postvoid residual urine and decreased Q max, all of which can be assessed by non-invasive methods. When antimicrobial therapy fails treatment should be directed towards a-adrenergic blockade. Our findings may contribute to a more rational and evidence-based management of this frequent and often difficult to treat syndrome. References [1] Collins MM, Stafford RS, O Leary MP, Barry MJ. How common is prostatitis? A national survey of physician visits. J Urol 1998;159: [2] de la Rosette JJ, Hubregtse MR, Meuleman EJ, Stolk-Engelaar MV, Debruyne FM. Diagnosis and treatment of 409 patients with prostatitis syndromes. Urology 1993;41: [3] Krieger JN, Nyberg Jr L, Nickel JC. NIH consensus definition and classification of prostatitis. JAMA 1999;282: [4] Weidner W, Schiefer HG, Krauss H. Role of Chlamydia trachomatis and mycoplasmas in chronic prostatitis. A review. Urol Int 1988;43: [5] Nickel JC, Costerton JW. Coagulase-negative staphylococcus in chronic prostatitis. J Urol 1992;147: [Discussion ]. [6] Krieger JN, Riley DE, Vesella RL, Miner DC, Ross SO, Lange PH. Bacterial DNA sequences in prostate tissue from patients with prostate cancer and chronic prostatitis. J Urol 2000;164: [7] Tanner MA, Shoskes D, Shahed A, Pace NR. Prevalence of corynebacterial 16S rrna sequences in patients with bacterial and nonbacterial prostatitis. J Clin Microbiol 1999;37: [8] Nickel JC. Prostatitis: lessons from the 20th century. BJU Int 2000; 85:

5 110 P. Hruz et al. / European Urology 44 (2003) [9] Hochreiter W, Ludwig M, Weidner W, Wagenlehner F, Naber K, Eremenco S, et al. National Institutes of Health (NIH) Chronic Prostatitis Symptom Index. Deutsche Version. Urologe A 2001;40: 16 7 [in German]. [10] Meares EM, Stamey TA. Bacteriologic localization patterns in bacterial prostatitis and urethritis. Invest Urol 1968;5: [11] Weidner W, Schiefer HG, Krauss H, Jantos C, Friedrich HJ, Altmannsberger M. Chronic prostatitis: a thorough search for etiologically involved microorganisms in 1,461 patients. Infection 1991;19(Suppl 3):S [12] McNaughton Collins M, Fowler Jr FJ, Elliott DB, Albertsen PC, Barry MJ. Diagnosing and treating chronic prostatitis: do urologists use the four-glass test? Urology 2000;55: [13] Nickel JC, Nigro M, Valiquette L, Anderson P, Patrick A, Mahoney J, et al. Diagnosisand treatment of prostatitis in Canada. Urology 1998; 52: [14] Moon TD. Questionnaire survey of urologists and primary care physicians diagnostic and treatment practices for prostatitis. Urology 1997;50: [15] Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, 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: [16] Roberts RO, Lieber MM, Bostwick DG, Jacobsen SJ. A review of clinical and pathological prostatitis syndromes. Urology 1997;49: [17] Mehik A, Hellstrom P, Lukkarinen O, Sarpola A, Alfthan O. Increased intraprostatic pressure in patients with chronic prostatitis. Urol Res 1999;27: [18] Barbalias GA. Prostatodynia or painful male urethral syndrome? Urology 1990;36: [19] Barbalias GA. Clinical and therapeutical guidelines for chronic prostatitis. from bacteriological importance to neuromuscular considerations. Eur Urol 2000;37: [20] de la Rosette JJ, Karthaus HF, van Kerrebroeck PE, de Boo T, Debruyne FM. Research in prostatitis syndromes : the use of alfuzosin (a new alpha 1-receptor-blocking agent) in patients mainly presenting with micturition complaints of an irritative nature and confirmed urodynamic abnormalities. Eur Urol 1992;22: Editorial Comment J.C. Nickel, Kingston, Ont., Canada The investigators attempted to determine whether endoscopic and urodynamic evaluation provides objectively measurable parameters that may support the rationale for specific therapeutic strategies for patients diagnosed with non-inflammatory chronic pelvic pain syndrome (NIH category IIIB CPPS) who fail to respond to medical treatment. The 48 patients evaluated with urodynamics and cystoscopy were culled from 634 patients being evaluated for possible chronic prostatitis/cpps (416 were eventually diagnosed with CPPS category III). The authors subjectively determined that 29 of the patients had significant bladder neck hypertrophy (BNH) based on their definition of the endoscopic appearance of the bladder neck. When compared to the 19 patients with a normal looking bladder neck, the group with BNH had urodynamic parameters suggestive of obstruction. There was no difference between the two groups in terms of pain or quality of life scores using the NIH chronic prostatitis symptom index but there was significantly higher urinary symptom scores, primarily due to differences in a single obstructive question. This is an interesting and potentially important observation, but must be analysed with some critical reservations. Only a small number of patients from the larger cohort of CPPS patients underwent urodynamic and cystoscopic evaluation. It is certain that these men were not randomly selected for these evaluations. It is very probable that there was some selection bias, either on the part of the patient (more severe symptoms?) or the urologist (identification of obstructive voiding symptoms?). The cystoscopic diagnosis of bladder neck obstruction secondary to BNH is very subjective and there is no doubt that there would be significant variability in rating BNH among urologists. In this study the urodynamic parameters of bladder outlet obstruction did significantly correlate with the cystoscopic findings of a narrow appearing bladder neck, substantiating the claim of the authors that this diagnosis can be adequately discriminated by cystoscopy alone. The efficacy of alpha-blocker therapy in CPPS has been shown to be modest, at best, and it would certainly be an important finding, if the authors were able to unequivally demonstrate that patients with BNH had a significantly better response to alpha-blockade than patients without BNH. Unfortunately this very important evaluation was either not done or not reported. Since the patients with an endoscopic observation of BNH and urodynamic finding of bladder outlet obstruction had a significantly higher voiding score (primarily driven by an obstructive symptom item), it might be feasible to differentiate patients with BNH and/or bladder outlet obstruction who would potentially respond to alpha-blocker therapy by only asking this single obstructive voiding question. The authors only reported on patients with CPPS IIIB (non-inflammatory CPPS), although many researchers now feel that there is very little validation in differentiating patients with inflammatory (IIIA) from non-inflammatory (IIIB) CPPS and there has definitely been no agreement as to the white blood cell count cut off point for differentiating these two categories. This study is an important first step, but the results must be followed up to determine if the methods suggested by the authors really do make a difference in selecting both NIH category IIIA and IIIB CPPS patients who will have a more significant response to alpha-blocker therapy.