OVERACTIVE BLADDER IN MEN: SPECIAL CONSIDERATIONS FOR EVALUATION AND MANAGEMENT ROGER R. DMOCHOWSKI AND DAVID R. STASKIN ABSTRACT Lower urinary tract symptoms (LUTS) in men may arise from a variety of underlying causes, including benign prostatic hyperplasia. LUTS may have a significant component of storage symptoms (urgency, frequency, urge incontinence) at presentation; however, the absence of overactive bladder (OAB) symptoms does not necessarily imply pure outlet obstruction nor does their presence indicate the lack thereof. Symptomatic correlates to urodynamic findings are high when considering isolated OAB symptoms. However, mixed presentations or more overtly obstructive scenarios have less correlation with baseline symptom appraisal instruments. The ideal approach for diagnosis and management is predicated on a graded approach, with more invasive evaluation withheld for those men in whom presumptive therapy fails or who present with associated complex symptoms and in whom a higher level of intervention is being considered. The increasing incidence of LUTS with age implies a partial detrusor contribution, which must be considered in the overall management schema. UROLOGY 60 (Suppl 5A): 56–63, 2002. © 2002, Elsevier Science Inc. L ower urinary tract symptoms (LUTS) in men may be primarily obstructive or irritative in composition or may be a blend of obstruction and irritation. These symptoms have a significant effect on quality of life, and when present in a moderateto-severe degree, they portend poorer overall quality of life and general health status compared with the unaffected general population.1 Animal studies that have attempted to evaluate the effect of lower urinary tract outlet obstruction on storage and emptying parameters have demonstrated a variety of responses, although relatively recently, in both the rat and minipig. Increasing obstruction has been found to correlate with increasing bladder contractility until detrusor decompensation results. The chronicity by which this process occurs in humans and the variable naFrom the Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA (RRD); and Section of Voiding Dysfunction, New York Presbyterian Hospital, Weill Cornell Medical College, New York, New York, USA (DRS). Roger R. Dmochowski is on the medical advisory board for Lilly, Watson, and OMP Pharmaceuticals, and he is a study investigator funded by Surx, Lilly, Watson, Roche, and Schwartz. David R. Staskin is a paid consultant to Ortho-McNeil, Pfizer, Indevus, Kyowa, Yamanouchi, Roche, and Lilly. Reprint requests: Roger R. Dmochowski, MD, Department of Urologic Surgery, Room A1302, Medical Center North, Vanderbilt University Medical Center, Nashville, Tennessee 37232. Email: roger.dmochowski@mcmail.vanderbilt.edu 56 © 2002, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED ture of the symptoms associated with this spectrum of response imply the necessity of more than superficial evaluation of men with LUTS. Most of these men (approximately 70%) will be found to have bladder outlet obstruction on subsequent evaluation, and the incidence of outlet obstruction is similar in all men no matter what the primary complaint.2 Also, the incidence of LUTS increases with age; voiding and storage symptoms increase, with a more substantial increase in voiding abnormalities in men compared with women after the fifth decade of life.3 This finding does not appear to have Western cultural limitations, because the severity of voiding symptoms is also more frequent and of greater magnitude in Japanese men compared with Japanese women ⬎50 years old.4 The evaluation and management of men with symptoms consistent with overactive bladder (OAB), including urinary urgency, frequency, and urge urinary incontinence, hinge on the identification and assessment of the magnitude of concomitant lower urinary tract obstruction that may coexist with and be a cause (in part or in entirety) of the presenting symptoms. This obstruction may arise from benign prostatic hyperplasia (BPH), primary bladder neck dysfunction, or abnormal voiding dynamics on a learned or pathologic basis (pseudodyssynergia or true dyssynergia). Chronic prostatic pain syndromes (eg, abacterial chronic prostatitis) and other pelvic floor dysfunctions can 0090-4295/02/$22.00 PII S0090-4295(02)01797-1 also present with a component of symptoms compatible with OAB. The complexity of the presenting symptoms and the variety of entities that exist as possible differential diagnostic entities mandate a thorough and diligent evaluation of the lower urinary tract in men to plan optimal therapeutic intervention. Evaluation is predicated on a complete assessment of voiding dynamics and is best accomplished with urodynamic studies. These studies should provide a complete representation of filling characteristics, pressure and flow criteria, sphincteric activity, and postvoid residual determination. LUTS are also heterogeneous in their symptomatic impact. Urgency, nocturia, and hesitancy are most bothersome, whereas weak stream, urgency, and frequency are the most prevalent in pooled populations being evaluated for BPH.5 It is now well demonstrated that moderate-tosevere LUTS in men can result in urinary retention. The incidence of retention in men with untreated LUTS in community-based trials is 6.8 per 1000 during longitudinal follow-up of 4 years.6 If only patients with moderate-to-severe symptoms are considered, the rate of retention increases to 25 per 1000.7 Therefore, on the basis of these trials, untreated LUTS may place the patient at risk for potential clinical deterioration. Optimal therapy for these patients may rely on bladder outlet, bladder storage, or a combination of outlet and storage therapy to achieve optimal symptomatic response. However, reassessment may be required in the case of partial symptomatic response. The recognition of pelvic pain syndromes in men as contributory to urinary symptoms also requires therapy directed at this entity if identified by screening evaluation. EVALUATION OF MEN WITH LOWER URINARY TRACT SYMPTOMS Diagnostic evaluation of men with LUTS rests on an initial estimation of subjective bother and objective data on bladder emptying. Because the occurrence of LUTS does not necessarily indicate concomitant prostate enlargement and/or obstruction, specific modalities should be used to ascertain the potential for the etiologic role of these entities. Diary or voiding log completion by the patient provides substantial evidence about the normal urinary habits of that patient, including giving some estimate of functional bladder capacity and diurnal and nocturnal frequency. Frequency volume charts provide a strong correlation to cystometric capacities and are reasonably immune to the effect of detrusor instability in men with LUTS.8 The symptomatic appraisal serves as a correlate to UROLOGY 60 (Supplement 5A), November 2002 the diary and is assessed by any of several validated LUTS questionnaires. The American Urologic Association symptom score for BPH (AUA-7) is most commonly used in North America. However, equally reproducible data can be obtained from the International Prostate Symptom Score (IPSS), International Continence Society (ICS)-BPH, and Danish Prostate Symptom Score (DAN-PSS-1) scales. General quality-of-life instruments are less useful, although they do provide incidence assessments that are reproducible.9 Recent evaluation of the ICS male inventory, which is a derivative of the ICS-BPH, has shown sensitivity for both incidence assessment and bother quantification. Interestingly, whereas the highest prevalence of symptoms centered on voiding, the most bothersome were those symptoms related to storage. Obviously, bother is what matters to the patient, because the mere presence of symptoms of obstruction and urgency is not perceived as problematic by the individual.10 Disappointingly, numerous studies have failed to demonstrate diagnostic specificity for global LUTS and identifiable bladder outlet obstruction.11,12 The urinary flow test, which measures peak urinary flow rate and urinary residual volume, has been used as the objective testing modality for screening purposes. This modality provides relatively reasonable correlation with obstruction but may be misinterpreted in the presence of detrusor hypocontractility or high-flow, high-pressure voiding (as can be seen in early-phase outlet obstruction associated with detrusor compensatory changes). However, approximately 88% of men with peak flow rates of ⱕ10 mL/sec will be found to be obstructed on urodynamic evaluation.13 Furthermore, in considering symptoms and flow rate, approximately 1% of men in their fifth decade of life and 13% in their eighth decade of life will have combined peak urine flow (Qmax) rates of ⬍10 mL/ sec and IPSS values of ⬍7.14 Overall, therefore, 1% of men ⬍50 years and 13% of men ⬍80 years will be obstructed and asymptomatic.15 In considering men with reduced flow rates, symptoms, and increased age, without urodynamic evaluation, other parameters become independently predictive of the development of acute urinary retention. Roehrborn et al.,16 –18 in a metaanalysis of predictors of retention in pooled groups of placebo patients from clinical trials of men with LUTS undergoing active interventions (4300 patients), found prostate-specific antigen and prostate volume to be strong independent predictors of urinary retention in men followed up longitudinally in clinical trials. The implications for inclusion of these measures during long-term management of BPH are significant. 57 Greater diagnostic specificity is obviously mandated before interventions with permanent connotations (eg, thermotherapy or transurethral resection of the prostate [TURP]) are considered. So, the diagnostic paradigm continues to evolve. LUTS IN YOUNG MEN LUTS in younger men can arise from a multiplicity of causes, including chronic prostatitis, prostatodynia, and discrete bladder outflow obstruction. Primary bladder neck dysfunction is a common cause of LUTS in younger men, with or without pelvic pain.19,20 Functional abnormalities of striated sphincter relaxation may also occur, further obfuscating the patient’s presentation.21 Because of the bothersome nature of these symptoms, a variety of metrics have been used to quantitate symptom magnitude, including the AUA Symptom Index (AUASI) and the IPSS. Many experts advocate urodynamic evaluation of these patients to assess voiding parameters and also (when combined with fluoroscopy) to identify discrete areas of obstruction associated with causes, such as primary bladder neck dysfunction. In a study of 52 men with LUTS who were ⬍45 years, Nitti and Ficazzola,19 using videourodynamics and the AUASI, identified 3 distinct types of bladder neck obstruction. Type 1 included men with fluoroscopic evidence of focal obstruction or narrowing at the bladder neck with classic highpressure, low-flow voiding parameters (as defined by the Abrams-Griffiths nomogram). Type 2 had a similar radiographic appearance with sustained detrusor contraction pressures of ⬎30 cm H2O associated with reduced flows. Type 3 had sustained high-pressure voiding with delayed opening of the bladder neck. All had similar bother on the basis of AUASI; however, detrusor instability was statistically more likely to be associated with highpressure voiding as seen in types 1 and 2. They concluded that, although the symptomatic presentation was similar, the findings of the videourodynamics varied and that fluoroscopic evaluation was additive in discerning these varied voiding patterns.19 Earlier studies by Norlen and Blaivas22 in 23 younger men with a variety of referral diagnoses, including neurogenic and psychogenic voiding dysfunction, also found comprehensive videourodynamics to be of value, identifying 16 members of this group as having findings compatible with bladder neck obstruction (narrowed bladder neck, high detrusor voiding pressure). Likewise, Kaplan et al.,20,23,24 using similar evaluation techniques, identified this disorder in 31 of 34 patients referred for refractory prostatitis. Yalla et al.21,25 also identified a group of patients with slowed relaxation of the bladder neck in response to increased detrusor 58 pressure during the voiding event. These patients were found to have periurethral striated muscle extending to the bladder neck, which the clinicians postulated could be responsible for a pseudoobstructive initiation of voiding, much like that seen in the patients with type 3 obstruction described by Nitti and Ficazzola.19 Certainly, other pathophysiologic explanations can be advanced for the distinct entity of primary bladder neck obstruction, such as smooth muscle hyperplasia and neurologic dysfunction (sympathetic or neurotransmitter induced).26 Also, the recently described relation between increased intraprostatic pressures found in men with chronic pelvic pain and the high correlation of these symptoms with the inflammatory variant of this disorder would also tend to implicate the possible exacerbating potential of outlet obstruction in these patients.27 Options for therapy in this population include ␣-blockade and transurethral incision, both of which have demonstrated reasonable outcomes. However, results are consistently more significant and durable with incision of the bladder neck.28 Similarly, ␣-blockers have also been used successfully in men with chronic prostatitis syndromes.28 Pooled results indicate that most ␣-blockers have similar efficacy, with increasing adverse effects as dose is increased.29 Surgical therapy for primary bladder obstruction has produced sustained results in young men with primary bladder neck dysfunction. In all, 87% overall improvement in symptoms, urinary flow rate, and peak voiding pressures has been reported with unilateral bladder neck incision at a minimal follow-up time of 1 year in men with this diagnosis.28,30 For those men with functional pelvic floor dyssynergy, directed therapy for the pelvic floor may produce substantive resolution of symptoms. Symptomatic improvement in 83% of 35 men with pseudodyssynergia of the striated sphincter has been reported with combined behavioral and biofeedback modulations.24 LUTS IN OLDER MEN In older men, diagnostic concerns include detrusor hyperactivity, impaired contractility syndrome, detrusor failure, carcinoma of the prostate, and, of course, BPH. Between 50% and 75% of men with bladder outlet obstruction will have OAB symptoms31; however, the converse is not true, although some studies have failed to reveal as high a prevalence of detrusor overactivity with these symptoms.32 Moreover, the absence of symptoms in age-selected men with subsequent urodynamic evidence of outlet obstruction further lends credence to the significant symptomatic contribution that irritative complaints supply to global LUTS UROLOGY 60 (Supplement 5A), November 2002 scores. Walker et al.,15 evaluating a group of 24 men with no urinary symptoms, found 13% with unequivocal obstruction and another 29% with equivocal criteria for obstruction. The evaluation and treatment of older men, however, are hampered by the coexistent onset of age-related detrusor changes, which complicate interpretation of screening evaluations. The incidence of OAB in men increases with age, an effect seen in the absence of substantial change as documented on urodynamic evaluation.33–35 It is well documented that there is a decrease in Qmax attendant with advancing age, which simply may represent increased frequency in this age group or may represent true complex myogenic and neurogenic ultrastructural changes occurring in the bladder.36 –38 Madersbacher et al.39 have aptly demonstrated this decrease in flow in a cohort of urodynamically unobstructed men with adequate bladder contraction. Reductions in urine flow to 10 mL/sec of Qmax were shown, with no discernible obstruction in slightly ⬎60% of the study population. Severely depressed flow rates, are, however, more consistent with obstruction, with flow rates ⬍10 mL/sec associated with obstruction in 88% of patients.40,41 In the same analysis, however, patients with flow rates between 10 and 14 mL/sec (pressures generally considered to be in the equivocal range) showed essentially equivalent incidences of obstruction (57% obstructed vs 43% unobstructed). Therefore, standard threshold values for normal and abnormal flow rates may not apply in this group and also may not be representative of any outflow impedance. Longitudinal studies of men with untreated prostatic obstruction and men with detrusor underactivity have revealed significant worsening of OAB symptoms over baseline in the absence of discernible changes in these populations. Other urodynamic measures of outlet obstruction have also been used to assess symptomatic LUTS in older men with BPH. Sullivan and Yalla42 assessed bladder contractility and compliance in a group of 168 men with obstructive and nonobstructive voiding dysfunction (as defined by pressure differential between detrusor and urethra). They identified a significant correlation between maximal isovolumetric detrusor contraction in men with obstruction compared with men without obstruction, independent of detrusor instability. The lowest incidence of compliance abnormalities was seen in the unobstructed patients. The investigators believed that the detrusor contractility changes represented a detrusor compensation to obstruction. They also noted that detrusor reserve, as measured by contraction indices and postvoid residual volume, was lowest in the patients with chronic retention and indicated detruUROLOGY 60 (Supplement 5A), November 2002 sor decompensation. The concept of sustained isovolumetric contraction (stop-flow testing) has been shown to correlate with bladder outlet obstruction by other groups as well.43 LUTS correlate poorly with most urodynamic findings. Hyman et al.2 were only able to correlate urge incontinence with detrusor instability in 160 men with a mean age of 61 years who presented for evaluation of urinary symptoms. No other symptom correlated with urodynamic diagnosis. Of 109 patients with overt bladder outlet obstruction determined by pressure and flow criteria, 50 (46%) also had urodynamic evidence of detrusor instability. Similarly, in a group of 565 men with LUTS, 26% had significant residual volume (⬎20% functional capacity), 46% had instability, and 53% were obstructed.44 These investigators also concluded that the complexity of presentation of men with LUTS precluded presumptive diagnosis on the basis of symptoms alone. The disparity between presenting symptoms and urodynamic findings has also been seen in large groups of patients with mixed symptoms. Fusco et al.45 evaluated 541 neurologically normal men with LUTS and found 69% to have some element of obstruction. However, within the obstructed group, 47% had detrusor instability, and an additional 10% demonstrated poor bladder contractility, which, at least partially, was contributory to the overall symptomatic presentation. The autonomous development of OAB symptoms in the absence of obstructive components is accompanied by mural changes in the bladder, which are characteristically seen in aging bladders and also in obstructed bladders. These changes include loss of detrusor muscle volume, decreased neuronal density, and increased intramuscular fibrosis, implying a potentially similar pathophysiologic explanation arising from seemingly disparate causes.36,37 In this population, the overall response to medical therapy is interesting. Although overall symptomatic relief is often attained with ␣-blocker ingestion in men with LUTS, whether they are obstructed or unobstructed, persistent irritative symptoms may continue and may worsen with time. Witjes et al.46 found that medical ␣-blockade provided symptomatic and urine flow rate improvements in men who were obstructed on the basis of urodynamic investigation and also in those who were not obstructed. Interestingly, no significant changes were seen in the peak voiding pressures in the unobstructed group, despite the symptomatic change. Gerber et al.47,48 showed similar results with short-term (3-month) doxazosin use. However, with longer follow-up (15 months) time, symptoms again deteriorated toward baseline. The combination of isometric detrusor contraction and 59 maximum urinary flow rate has also been shown to be predictive of obstructive voiding dysfunction in men with obstructive symptoms and has been advocated as a guide for directed intervention designed to ameliorate those symptoms. Comiter et al.49 found that this combined value accurately predicted obstruction in 141 (93%) of 151 symptomatic men with infravesical obstruction. Recent evaluation of tamsulosin in men unequivocally obstructed on the basis of pressure-flow evaluation has demonstrated significant decreases in peak voiding pressures, with concomitant parallelism in symptomatic response in the study population. Surprisingly, men with no urodynamic evidence of obstruction had a similar clinical response with short-term (3-month) treatment protocols, again underscoring the reasonability of restricting complex evaluation to those men who do not respond to presumptive medical therapy.50 The role of ␣-blockade in stimulating prostatic apoptosis, thereby producing clinical effect, is now gaining currency in addition to its accepted smooth muscle relaxation properties.51 Another subgroup of the older male population that presents a diagnostic challenge is those men who have had prior prostate intervention (such as TURP). Altogether, 19% of men will have persistent OAB symptoms after TURP, an effect more marked in men ⬎80 years old; of these, a significant number are often again treated with surgical intervention.52 Abrams53 and Nitti et al.,30 in separate analyses, have shown that ⬍20% of these men have any evidence of recurrent or persistent bladder outlet obstruction. Also, Thomas et al.54 have recently shown that even in men who have had resolution of OAB symptoms after TURP, 48 (83%) of 58 experienced return of their symptoms at long-term follow-up (mean, 12.6 years after surgery). They also found that even a few men with no OAB symptoms preoperatively developed de novo OAB (39 [48%] of 82). No correlation between age and time since surgery was able to be made in this cohort. Most of those men with OAB symptoms preoperatively, who had initial symptomatic resolution after surgery, experienced recurrence of their symptoms with time. Similar to previously noted findings in men with untreated obstruction or underactive detrusor function, OAB symptoms in these patients worsened in the absence of any definable urodynamic change. This occurred despite sustained improvement in peak voiding pressures compared with preoperative values (Qmax, 100 vs 45 cm H2O; P ⬍0.05). Others have noted similar early resolution of detrusor instability after TURP, although this is not a universal result in all studies. Pressure flow studies are particularly useful in this population as a means to compare therapies. These studies are reproducible and sensitive 60 for persistent outlet obstruction and provide adequate discrimination from placebo interventions.55 Moreover, the degree of symptomatic and urodynamic improvement with various interventions for BPH correlates with the magnitude of intervention, further lending reasonability to the observational value of urodynamics in the initial and subsequent evaluation of BPH.14 The pressure flow analysis also has reliability and minimal intratest variability.56 The role of ambulatory urodynamics may also further elucidate occult diagnoses in men with LUTS. Rosario et al.57 found that 24% of 69 men with LUTS were reclassified by ambulatory studies compared with findings on complex, nonambulatory study as to presence and degree of obstruction. This finding suggests several issues. Surgical intervention clearly produces early symptomatic benefit for irritative symptoms, which may only partially be because of relief of obstruction. The potential for some form of deafferentation being accomplished by these procedures (eg, TURP or any bladder neck and proximal urethral intervention), leading to improvement in OAB symptoms, must also be considered. Finally, the disappointing long-term benefit for symptoms must be weighed against the extended longitudinal nature of this study—the fact that presumably ongoing age-related changes continued to occur in these men and that other factors had potentially become overt, such as the occurrence of neurologic diseases or other confounding variables likely because of the elapsed time of study. CONCLUSION The presence of OAB symptoms in men is indicative of many possible origins. Straightforward screening techniques (quality-of-life assessment, flow rate, residual urine volume determination) are useful first-line segregating instruments. However, failure of presumptive medical therapy (or other targeted therapies) should instigate more formal evaluation to identify subtle detrusor or bladder outlet factors that may masquerade as bladder outlet obstruction, OAB, or both. Both younger and older men present with unique etiologic possibilities that should be assiduously investigated to initiate apropos salvage therapies. The role of urinary tract evaluation, as provided by complex urodynamics, is paramount for a successful diagnostic paradigm to be applied to these patients. Further knowledge about long-term results of therapy and about chronic lower urinary tract changes experienced with aging has demonstrated the necessity for careful discrimination of presenting OAB symptoms. 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Rosario DJ, MacDiarmid SA, Radley SC, et al: A comparison of ambulatory and conventional urodynamic studies in men with borderline outlet obstruction. Br J Urol 83: 400 – 409, 1999. DISCUSSION FOLLOWING DR. DMOCHOWSKI’S PRESENTATION Alan J. Wein, MD (Philadelphia, PA): How many male patients with symptoms of overactive bladder (OAB) do you see? Roger R. Dmochowski, MD (Nashville, TN): I think ⱖ60% of my patients have storage abnormalities in terms of OAB– like symptoms. David R. Staskin, MD (New York, NY): If these patients are not obstructed and ␣-blockers are not working centrally, should you treat them with an anticholinergic agent? I think choosing ␣-blockers versus anticholinergics is based on whether there is an obstruction. Dr. Wein: I would not treat an older man with an antimuscarinic without giving him an ␣-blocker. Dr. Staskin: What about the men between 40 and 60 years of age? They are treated differently from women in the same age group, despite the fact that the chance that they are obstructed is very low. Christopher R. Chapple, MD (Sheffield, England): Many of these men between 40 and 60 years of age do have a bladder 62 neck obstruction or related symptoms. The additional factor, of course, is that many of these people have a degree of prostatitis. We all see the younger men with bladder neck obstruction with prostatitis, and often, a very pressured lifestyle seems to relate in some way. So, there is some potential benefit for using a combination of an anticholinergic agent and an ␣-blocker. Then, of course, clouding the issue even further is that men with bladder neck obstruction do not do very well with ␣-blockers as a rule. Joseph G. Ouslander, MD (Atlanta, GA): I think both drugs, ␣-blockers and antimuscarinics, are problematic in older patients with comorbidities. The ␣-blockers make these people susceptible to falls, and with the antimuscarinics, it is impossible to tell whether there is any significant degree of obstruction that puts them at risk for bladder decompensation. Dr. Wein: I know the type of patient you are talking about. I tell those patients they need to ask their internist first whether they can take an ␣-blocker. UROLOGY 60 (Supplement 5A), November 2002
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