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PurposeWe evaluated and identified baseline factors associated with change in health related quality of life among patients with interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome.Materials and methodsA total of 191 men and 233 women with interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome (collectively referred to as urologic chronic pelvic pain syndrome) were followed for 12 months with bimonthly completion of the Short Form 12 to assess general mental and physical health related quality of life, and with biweekly assessment of condition specific health related quality of life using the Genitourinary Pain Index. A functional clustering algorithm was used to classify participants as improved, stable or worsened for each health related quality of life measure. Ordinal logistic regression was used to determine baseline factors associated with change.ResultsPhysical health related quality of life improved in 22% of the participants, mental health related quality of life improved in 25% and condition specific health related quality of life improved in 47%. Better baseline physical health related quality of life, older age and the presence of nonurological symptoms were associated with lower likelihood of improvement in physical health related quality of life. Better baseline mental health related quality of life, female sex, and greater baseline depression and stress were associated with a lower likelihood of improvement in mental health related quality of life. Better baseline condition specific health related quality of life and more severe baseline urologic chronic pelvic pain syndrome pain symptoms were associated with a lower likelihood of improvement in condition specific health related quality of life.ConclusionsWhile several nonurologic chronic pelvic pain syndrome factors influenced the trajectory of general health related quality of life over time, only condition specific baseline health related quality of life and urologic chronic pelvic pain syndrome symptoms were associated with urologic chronic pelvic pain syndrome specific health related quality of life change. Significant differences in how urologic chronic pelvic pain syndrome impacts various aspects of health related quality of life suggest a multidisciplinary approach to assessment and treatment of these patients.

Purpose: We developed prediction models for severe pain and urinary symptoms after ureteroscopy with ureteral stent placement., Materials and Methods: The development cohort included 424 adults and adolescents enrolled in the multicenter STENTS prospective cohort study who underwent ureteroscopy with stent placement for urinary stones. The validation cohort was an independent prospective cohort of 115 adults. The outcomes were severe pain intensity and pain interference, measured by Patient-Reported Outcomes Measurement Information System, and severe urinary symptoms, measured by the Ureteral Stent Symptom Questionnaire. The top quartile of symptoms on postoperative days 1 and 3 were defined as severe. Generalized estimating equation models were used to predict severe symptoms on postoperative days 1, 3, 5, and 7 to 9 in the development cohort and severe pain interference on days 1 and 7 in the validation cohort., Results: Female sex, younger age, higher BMI, baseline pain interference, number of chronic pain conditions, renal stone location, and history of anxiety predicted severe pain. In the development cohort, the C-statistics were 0.83 (95% CI 0.80-0.85) for severe pain interference and 0.82 (95% CI 0.79-0.84) for severe pain intensity. A model in which baseline urinary symptoms replaced pain interference had excellent discrimination for severe urinary symptoms (C-statistic 0.83; 95% CI 0.81-0.85). In the validation cohort, the C-statistic was 0.7 for severe pain interference (95% CI 0.54-0.78)., Conclusions: Preoperative characteristics accurately predicted severe pain and urinary symptoms after ureteroscopy with stent placement. On further validation, these models could guide clinical decisions to improve surgical outcomes.

Purpose: Our objective was to investigate structural changes in brain white matter tracts using diffusion tensor imaging (DTI) in patients with overactive bladder (OAB)., Materials and Methods: Treatment-seeking OAB patients and matched controls enrolled in the cross-sectional case-control LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) Neuroimaging Study received a brain DTI scan. Microstructural integrity of brain white matter was assessed using fractional anisotropy (FA) and mean diffusivity. OAB and urgency urinary incontinence (UUI) symptoms were assessed using the OAB Questionnaire Short-Form and International Consultation on Incontinence Questionnaire-Urinary Incontinence. The Lower Urinary Tract Symptoms Tool UUI questions and responses were correlated with FA values., Results: Among 221 participants with evaluable DTI data, 146 had OAB (66 urinary urgency-only without UUI, 80 with UUI); 75 were controls. Compared with controls, participants with OAB showed decreased FA and increased mean diffusivity, representing greater microstructural abnormalities of brain white matter tracts among OAB participants. These abnormalities occurred in the corpus callosum, bilateral anterior thalamic radiation and superior longitudinal fasciculus tracts, and bilateral insula and parahippocampal region. Among participants with OAB, higher OAB Questionnaire Short-Form scores were associated with decreased FA in the left inferior fronto-occipital fasciculus, P < .0001. DTI differences between OAB and controls were driven by the urinary urgency-only (OAB-dry) but not the UUI (OAB-wet) subgroup., Conclusions: Abnormalities in microstructural integrity in specific brain white matter tracts were more frequent in OAB patients. More severe OAB symptoms were correlated with greater degree of microstructural abnormalities in brain white matter tracts in patients with OAB., Trial Registration: ClinicalTrials.gov: NCT02485808.

Purpose: We sought to systematically review and summarize the peer-reviewed literature on urologic chronic pelvic pain syndrome flares, including their terminology, manifestation, perceived triggers, management and prevention strategies, impact on quality of life, and insights into pathophysiologic mechanisms, as a foundation for future empirical research., Materials and Methods: We searched 6 medical databases for articles related to any aspect of symptom exacerbations for interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. A total of 1486 abstracts and 398 full-text articles were reviewed, and data were extracted by at least 2 individuals., Results: Overall, we identified 59 articles, including 36 qualitative, cross-sectional, or case-control; 15 cohort-based; and 8 experimental articles. The majority of studies described North American patients with confirmed diagnoses. "Flare" was a commonly used term, but additional terminology (eg, exacerbation) was also used. Most flares involved significant increases in pain intensity, but less data were available on flare frequency and duration. Painful, frequent, long-lasting, and unpredictable flares were highly impactful, even over and above participants' nonflare symptoms. A large number of perceived triggers (eg, diet, stress) and management/prevention strategies (eg, analgesics, thermal therapy, rest) were proposed by participants, but few had empirical support. In addition, few studies explored underlying biologic mechanisms., Conclusions: Overall, we found that flares are painful and impactful, but otherwise poorly understood in terms of manifestation (frequency and duration), triggers, treatment, prevention, and pathophysiology. These summary findings provide a foundation for future flare-related research and highlight gaps that warrant additional empirical studies.

Purpose: Overactive bladder (OAB) may be attributed to dysfunction in supraspinal brain circuits. Overactive bladder participants enrolled in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) study reported sensations of urinary urgency during a bladder-filling paradigm while undergoing brain functional MRI to map supraspinal dysfunction., Materials and Methods: OAB participants and controls (CONs) completed 2 resting-state functional MRI scans following consumption of 350 mL water. Scans were conducted at fuller and emptier bladder states, interleaved with voiding. Urgency ratings (0-10) were assessed. Patterns of urgency during bladder filling were investigated using latent class trajectory models. Clusters of participants encompassing each pattern (ie, subtype) were derived from aggregated groups of OAB and CON independent of diagnosis., Results: Two distinct patterns of urgency trajectories were revealed: first subtype with OAB and CON who were unresponsive to bladder filling (OAB-1 and CON-1) and second highly responsive subtype predominantly containing OAB (OAB-2). OAB-2 participants scored significantly higher on urinary symptoms but not pain or psychosocial measures. Neuroimaging analyses showed change in urgency due to both bladder filling and voided volume related to multiple loci of brain network connectivity in OAB-2, and in some cases, different than OAB-1 and/or CON-1. Sensorimotor to dorsomedial/dorsolateral prefrontal connectivity mediated the relationship between stimulus (voided volume) and percept (urgency) in OAB-2., Conclusions: Our results reveal different OAB subtypes with latent class trajectory models of urgency ratings during natural bladder filling. Functional MRI revealed differences in pathophysiology between subtypes, namely sensorimotor-prefrontal connectivity is a key locus in OAB patients with higher urinary symptoms.

Purpose: Interstitial cystitis/bladder pain syndrome patients can experience overactive pelvic floor muscle activity at rest. While the frequency power spectrum of pelvic floor muscle has briefly been explored, intermuscular connectivity of the pelvic floor muscle has yet to be studied, which may provide useful insight into the neurological component, ie, neural drive to muscles, in interstitial cystitis/bladder pain syndrome., Materials and Methods: High-density surface electromyography was collected from 15 female interstitial cystitis/bladder pain syndrome patients with pelvic floor tenderness and 15 urologically healthy female controls. Intermuscular connectivity was calculated across the maximally active locations of the left and right sides of the pelvic floor muscle as identified from the root mean squared amplitude at rest and compared with Student t tests for common sensorimotor rhythms involved in motor control: alpha (8-12 Hz), beta (13-30 Hz), and gamma (31-70 Hz) frequency bands. The root mean squared amplitudes at rest were also compared across groups., Results: The resting root mean squared amplitude of the pelvic floor muscle was significantly greater in female interstitial cystitis/bladder pain syndrome patients compared to healthy female controls ( P = .0046). The gamma-band intermuscular connectivity was significantly different between rest and pelvic floor muscle contraction ( P = .0001) for healthy female controls, but not for female patients with interstitial cystitis/bladder pain syndrome ( P = .1214). Both results indicate an elevated neural drive to pelvic floor muscle at rest in female interstitial cystitis/bladder pain syndrome patients., Conclusions: Gamma-band pelvic floor muscle connectivity in female interstitial cystitis/bladder pain syndrome patients is increased at rest. The results of this study may provide insight into the impaired neural drive to pelvic floor muscle implicated with interstitial cystitis/bladder pain syndrome.

Purpose: Symptom heterogeneity in interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, collectively termed urological chronic pelvic pain syndrome, has resulted in difficulty in defining appropriate clinical trial endpoints. We determine clinically important differences for 2 primary symptom measures, pelvic pain severity and urinary symptom severity, and evaluate subgroup differences., Materials and Methods: The Multidisciplinary Approach to the Study of Chronic Pelvic Pain Symptom Patterns Study enrolled individuals with urological chronic pelvic pain syndrome. We defined clinically important differences by associating changes in pelvic pain severity and urinary symptom severity over 3 to 6 months with marked improvement on a global response assessment using regression and receiver operating characteristic curves. We evaluated clinically important differences for absolute and percent change and examined differences in clinically important differences by sex-diagnosis, presence of Hunner lesions, pain type, pain widespreadness, and baseline symptom severity., Results: An absolute change of -4 was clinically important in pelvic pain severity among all patients, but clinically important difference estimates differed by pain type, presence of Hunner lesions, and baseline severity. Pelvic pain severity clinically important difference estimates for percent change were more consistent across subgroups and ranged from 30% to 57%. The absolute change urinary symptom severity clinically important difference was -3 for female participants and -2 for male participants with chronic prostatitis/chronic pelvic pain syndrome only. Patients with greater baseline severity required larger decreases in symptoms to feel improved. Estimated clinically important differences had lower accuracy among participants with low baseline symptoms., Conclusions: A reduction of 30%-50% in pelvic pain severity is a clinically meaningful endpoint for future therapeutic trials in urological chronic pelvic pain syndrome. Urinary symptom severity clinically important differences are more appropriately defined separately for male and female participants.

Purpose: The STudy to Enhance uNderstanding of sTent-associated Symptoms sought to identify risk factors for pain and urinary symptoms, as well as how these symptoms interfere with daily activities after ureteroscopy for stone treatment., Materials and Methods: This prospective observational cohort study enrolled patients aged ≥12 years undergoing ureteroscopy with ureteral stent for stone treatment at 4 clinical centers. Participants reported symptoms at baseline; on postoperative days 1, 3, 5; at stent removal; and day 30 post-stent removal. Outcomes of pain intensity, pain interference, urinary symptoms, and bother were captured with multiple instruments. Multivariable analyses using mixed-effects linear regression models were identified characteristics associated with increased stent-associated symptoms., Results: A total of 424 participants were enrolled. Mean age was 49 years (SD 17); 47% were female. Participants experienced a marked increase in stent-associated symptoms on postoperative day 1. While pain intensity decreased ∼50% from postoperative day 1 to postoperative day 5, interference due to pain remained persistently elevated. In multivariable analysis, older age was associated with lower pain intensity ( P = .004). Having chronic pain conditions ( P < .001), prior severe stent pain ( P = .021), and depressive symptoms at baseline ( P < .001) were each associated with higher pain intensity. Neither sex, stone location, ureteral access sheath use, nor stent characteristics were drivers of stent-associated symptoms., Conclusions: In this multicenter cohort, interference persisted even as pain intensity decreased. Patient factors (eg, age, depression) rather than surgical factors were associated with symptom intensity. These findings provide a foundation for patient-centered care and highlight potential targets for efforts to mitigate the burden of stent-associated symptoms.

Purpose: Most studies on interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome use typical or average levels of pelvic pain or urological symptom intensity as their outcome, as both are associated with reduced quality of life. Symptom exacerbations or "flares" have also been found to be associated with reduced quality of life, but no studies, to our knowledge, have investigated whether these associations are independent of typical pelvic pain levels and thus might be useful additional outcome measures (or stated differently, whether reducing flare frequency even without reducing mean pain intensity may be important to patients)., Materials and Methods: We used screening visit and weekly run-in period data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Symptom Patterns Study to investigate associations between flare frequency and multiple measures of illness impact and health care seeking activity, independent of typical nonflare and overall pelvic pain levels., Results: Among the 613 eligible participants, greater flare frequency was associated with worse condition-specific illness impact (standardized β coefficients=0.11-0.68, P trends < .0001) and health care seeking activity (odds ratios=1.52-3.94, P trends .0039 to < .0001) in analyses adjusted for typical nonflare and overall pelvic pain levels. Experiencing ≥1/d was also independently associated with worse general illness impact (standardized β coefficients=0.11-0.25)., Conclusions: Our findings suggest that flare frequency and possibly other flare characteristics may be worth considering as additional outcome measures in urological chronic pelvic pain syndrome research to support the development of new preventive and therapeutic flare strategies.

Purpose: We characterize patients with urinary urgency with vs without urgency urinary incontinence who presented to clinics actively seeking treatment for their symptoms., Materials and Methods: Participants who enrolled in the Symptoms of Lower Urinary Tract Dysfunction Research Network were categorized into urinary urgency with vs without urgency urinary incontinence. Participants were followed for 1 year; their urinary symptoms, urological pain, psychosocial factors, bowel function, sleep disturbance, physical activity levels, physical function, and quality of life were compared. Mixed effects linear regression models were used to examine the relationships between urgency urinary incontinence and these factors., Results: Among 683 participants with urinary urgency at baseline, two-thirds (n=453) also had urgency urinary incontinence; one-third (n=230) had urinary urgency-only without urgency urinary incontinence. No differences were detected in urological pain between urinary urgency-only and urgency urinary incontinence. Those with urgency urinary incontinence had more severe urgency and frequency symptoms, higher depression, anxiety, perceived stress scores, more severe bowel dysfunction and sleep disturbance, lower physical activity levels, lower physical function, and worse quality of life than those with urinary urgency-only. Among those with urinary urgency-only at baseline, 40% continued to have urinary urgency-only, 15% progressed to urgency urinary incontinence, and 45% had no urgency at 12 months. Fifty-eight percent with urgency urinary incontinence at baseline continued to report urgency urinary incontinence at 12 months, while 15% improved to urinary urgency-only, and 27% had no urgency., Conclusions: Patients with urgency urinary incontinence have severe storage symptoms, more psychosocial symptoms, poorer physical functioning, and worse quality of life. Our data suggested urgency urinary incontinence may be a more severe manifestation of urinary urgency, rather than urinary urgency and urgency urinary incontinence being distinct entities.

Purpose: The impact of nonurological factors on male lower urinary tract symptoms (LUTS) remains unclear. We investigated cross-sectional and longitudinal associations among anxiety, depression, physical function, sleep quality and urinary symptom subdomains., Materials and Methods: Data from 518 men in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) study were analyzed to identify associations between Patient-Reported Outcomes Measurement Information System® (PROMIS®) depression, anxiety, sleep disturbance and physical function measures and LUTS subdomains, as derived from the American Urological Association Symptom Index and LUTS Tool. Multivariable linear regression was used to assess the relationships between PROMIS measures and LUTS subdomains at baseline and at 3- and 12-month followup., Results: Baseline depression and anxiety were associated with urinary incontinence (p <0.001), voiding symptoms (p <0.001) and quality of life (p=0.002), whereas baseline sleep disturbance was associated with voiding and storage symptoms and quality of life (p <0.001 for all). Urinary symptom severity improved in all subdomains at 3 and 12 months. Similar associations between PROMIS measures and LUTS subdomains were observed at all time points, but baseline depression, anxiety, sleep disturbance and physical function measures were not associated with longitudinal trajectories of LUTS., Conclusions: Urinary symptom subdomains are independently associated with modifiable clinical variables including sleep quality and depression at all time points, but these variables do not predict the degree of improvement in LUTS following urological evaluation and treatment over the medium term. Bidirectional assessment and randomized experiments may improve our understanding of these relationships.

Purpose: We assessed the reliability and validity of an efficient severity assessment for pelvic pain and urinary symptoms in urological chronic pelvic pain syndrome, which consists of interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome., Materials and Methods: A total of 578 patients were assessed using brief, empirically derived self-report scales for pelvic pain severity (PPS) and urinary symptom severity (USS) 4 times during a 1-month period and baseline clinic visit that included urological, pain and illness-impact measures. Mild, moderate and severe categories on each dimension were examined for measurement stability and construct validity., Results: PPS and USS severity categories had adequate reliability and both discriminant validity (differential relationships with specific clinical and self-report measures) and convergent validity (common association with nonurological somatic symptoms). For example, increasing PPS was associated with pelvic tenderness and widespread pelvic pain, whereas USS was associated with urgency during a bladder filling test and increased sensory sensitivity. PPS and USS categories were independently associated with nonurological pain and emotional distress. A descriptive analysis identified higher likelihood characteristics associated with having moderate to severe PPS or USS or both. Lack of sex interactions indicated that the measures are comparable in interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome., Conclusions: Women and men with urological chronic pelvic pain syndrome can be reliably subgrouped using brief self-report measures of mild, moderate or severe pelvic pain and urinary symptoms. Comparisons with a broad range of clinical variables demonstrate the validity and potential clinical utility of these classifications, including use in clinical trials, health services and biological research.

Purpose: The objective of this study was to investigate the presence of nonbladder sensory abnormalities in participants with overactive bladder syndrome (OAB)., Materials and Methods: Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) study participants with OAB symptoms and controls were recruited from 6 U.S. tertiary referral centers. Quantitative sensory testing (QST) was performed to determine pressure pain sensitivity at the thumbnail bed and auditory sensitivity. Fixed and mixed effect multivariable linear regressions and Weibull models were used to compare QST responses between groups. Pearson correlations were used to assess the relationship between QST measures. Associations between QST and self-reported symptoms were explored with linear regression., Results: A total of 297 participants were analyzed (191 OAB, 106 controls; 76% white, 51% male). OAB cases were older than controls (57.4 vs 52.2 years, p=0.015). No significant differences in experimental thumbnail (nonbladder) pain or auditory sensitivity were detected between OAB cases and controls. Correlations between pressure and auditory derived metrics were weak to moderate overall for both groups, with some significantly stronger correlations for cases. Exploratory analyses indicated increased pressure pain and auditory sensitivity were modestly associated with greater self-reported bladder pain and pain interference with physical function., Conclusions: As a group, no significant differences between OAB cases and controls were observed in experimental nonbladder pain or auditory sensitivity during QST. Associations between QST outcomes and clinical pain raise the possibility of centrally mediated sensory amplification in some individuals with OAB.

Purpose: We sought to determine whether pollen triggers urological chronic pelvic pain syndrome flares., Materials and Methods: We assessed flare status every 2 weeks for 1 year as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain case-crossover analysis of flare triggers (NCT01098279). Flare symptoms, flare start date and exposures in the 3 days before a flare were queried for the first 3 flares and at 3 randomly selected nonflare times. These data were linked to daily pollen count by date and the first 3 digits of participants' zip codes. Pollen count in the 3 days before and day of a flare, as well as pollen rises past established thresholds, were compared to nonflare values by conditional logistic regression. Poisson regression was used to estimate flare rates in the 3 weeks following pollen rises past established thresholds in the full longitudinal study. Analyses were performed in all participants and separately in those who reported allergies or respiratory tract disorders., Results: Although no associations were observed for daily pollen count and flare onset, positive associations were observed for pollen count rises past medium or higher thresholds in participants with allergies or respiratory tract disorders in the case-crossover (OR 1.31, 95% CI 1.04-1.66) and full longitudinal (RR 1.23, 95% CI 1.03-1.46) samples., Conclusions: We found some evidence to suggest that rising pollen count may trigger flares of urological chronic pelvic pain syndrome. If confirmed in future studies, these findings may help to inform flare pathophysiology, prevention and treatment, and control over the unpredictability of flares.

Purpose: Up to 85% of women with interstitial cystitis/bladder pain syndrome have pelvic floor dysfunction and hypertonicity. Current evaluation methodologies lack objective measures of pelvic floor muscle activity. We examined the ability of using intravaginal high-density surface electromyography to quantitatively, objectively and noninvasively map pelvic floor muscle activity and innervation zone locations in patients with interstitial cystitis/bladder pain syndrome., Materials and Methods: Fifteen women with interstitial cystitis/bladder pain syndrome and 15 controls underwent 2 sessions of digital pelvic examinations and high-density surface electromyography assessments. The root mean squared amplitude of high-density surface electromyography was first calculated, and the resting root mean squared ratio was then calculated by normalizing the resting electromyography root mean squared to the peak electromyography amplitude reached during maximum voluntary contraction. Innervation zone distributions were obtained from decomposed high-density surface electromyography signals. The correlation between the root mean squared ratio and interstitial cystitis/bladder pain syndrome symptom scores and pelvic floor muscle alignment were investigated in patients with interstitial cystitis/bladder pain syndrome and healthy controls., Results: Women with interstitial cystitis/bladder pain syndrome demonstrated significantly increased resting root mean squared ratios compared to controls (0.155±0.048 vs 0.099±0.041, p=0.0019). Significant correlations were found between resting root mean squared ratio and patient reported pain (r s =0.523, p=0.003), interstitial cystitis symptom (r s =0.521, p=0.003) and problem indices (r s =0.60, p <0.001). In addition, women with interstitial cystitis/bladder pain syndrome were more likely to have shortened pelvic floor muscles (80%, 12 vs 13.3%, 2, p <0.01). Women with shortened pelvic floor muscles demonstrated significantly higher resting root mean squared ratio compared to those with normal pelvic floor muscle length (0.155±0.046 vs 0.107±0.040, p=0.0058)., Conclusions: Intravaginal high-density surface electromyography offers an objective and quantitative strategy to noninvasively assess pelvic floor muscle dysfunction in women with interstitial cystitis/bladder pain syndrome. Abundant spatiotemporal muscle activity information captured by high-density surface electromyography allows for mapping innervation zone distributions for major pelvic floor muscles.

Purpose: We compared demographics, clinical presentation, comorbidities, urinary profiles, and treatment responses between patients with interstitial cystitis/bladder pain syndrome with and without Hunner lesions., Materials and Methods: We performed a systematic review of the literature in PubMed® in February 2019. Publications were included if they compared data between patients with interstitial cystitis/bladder pain syndrome with and without Hunner lesions, yielding 59 articles. Meta-analysis was performed on a subset of clinical characteristics., Results: Meta-analysis showed that patients with interstitial cystitis/bladder pain syndrome with Hunner lesions were significantly older (MD 6.7 years, 95% CI 2.0-11.3, p=0.005), reported higher urinary frequency (MD 3.2 per day, 95% CI 1.1-5.4, p=0.003), nocturia (MD 1.0 per night, 95% CI 0.1-2.0, p=0.034) and Interstitial Cystitis Symptom Index (MD 2.2, 95% CI 1.4-3.0, p <0.001), but lower cystometric bladder capacity (MD -113 ml, 95% CI -164 to -61 ml, p <0.001) compared to those with interstitial cystitis/bladder pain syndrome without Hunner lesions. There were no differences in pain scores (p=0.105), symptom duration (p=0.2) or sex (p=0.83) between the 2 groups. While some studies reported higher rates of comorbid pain syndromes (eg fibromyalgia) among patients without Hunner lesions, overall results were conflicting. Patients with Hunner lesions had higher urinary levels of pro-inflammatory cytokines/chemokines (CXCL10, NGF, IL-6, IL-8, MIF), luminal nitric oxide and responded well to endoscopic treatment of the Hunner lesions (eg fulguration or triamcinolone injection). In comparative studies patients with interstitial cystitis/bladder pain syndrome with Hunner lesions responded better to oral cyclosporine A than those without Hunner lesions., Conclusions: Systematic review and meta-analysis demonstrated significant differences in demographics, clinical presentation, urinary marker profiles, and treatment responses between patients with and without Hunner lesions, suggesting that they may represent 2 distinct clinical phenotypes. Studies are needed to investigate their mechanistic differences.

Purpose: Conventional classification of patients with lower urinary tract symptoms into diagnostic categories based on a predefined symptom complex or predominant symptom appears inadequate. This is due to the frequent presentation of patients with multiple urinary symptoms which could not be perfectly categorized into traditional diagnostic groups. We used a novel clustering method to identify subtypes of male patients with lower urinary tract symptoms based on detailed multisymptom information., Materials and Methods: We analyzed baseline data on 503 care seeking men in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) Observational Cohort Study. Symptoms and symptom severity were assessed using the LUTS (Lower Urinary Tract Symptoms) Tool and the AUA SI (American Urological Association Symptom Index), which include a total of 52 questions. We used a resampling based consensus clustering algorithm to identify patient subtypes with distinct symptom signatures., Results: Four distinct symptom clusters were identified. The 166 patients in cluster M1 had predominant symptoms of frequency, nocturia, hesitancy, straining, weak stream, intermittency and incomplete bladder emptying suggestive of bladder outlet obstruction. The 93 patients in cluster M2 mainly endorsed post-micturition symptoms (eg post-void dribbling and post-void leakage) with some weak stream. The 114 patients in cluster M3 reported mostly urinary frequency without incontinence. The 130 patients in cluster M4 reported severe frequency, urgency and urgency incontinence. Most other urinary symptoms statistically differed between cluster pairs. Patient reported outcomes of bowel symptoms, mental health, sleep dysfunction, erectile function and urological pain significantly differed across the clusters., Conclusions: We identified 4 data derived clusters among men seeking care for lower urinary tract symptoms. The clusters differed from traditional diagnostic categories. Further subtype refinement will be done to incorporate clinical data and nonurinary patient reported outcomes.

Purpose: Lower urinary tract symptoms are prevalent and burdensome, yet methods to enhance diagnosis and appropriately guide therapies are lacking. We systematically reviewed the literature for human studies of biomarkers associated with lower urinary tract symptoms., Materials and Methods: PubMed®, EMBASE® and Web of Science® were searched from inception to February 13, 2018. Articles were included if they were in English, performed in benign urological populations without neurological disorders or interstitial cystitis/bladder pain syndrome, and assessed a biomarker's association with or ability to predict specific lower urinary tract symptoms or urological conditions. Bioinformatic pathway analyses were conducted to determine whether individual biomarkers associated with symptoms are present in unifying pathways., Results: Of 6,150 citations identified 125 met the inclusion criteria. Most studies (93.6%) assessed biomarkers at 1 time point and were cross-sectional in nature. Few studies adjusted for potentially confounding clinical variables or assessed biomarkers in an individual over time. No individual biomarkers are currently validated as diagnostic tools for lower urinary tract symptoms. Compared to controls, pathway analyses identified multiple immune response pathways that were enriched in overactive bladder syndrome and cell migration/cytoskeleton remodeling pathways that were enriched in female stress incontinence., Conclusions: Major deficiencies in the existing biomarker literature include poor reproducibility of laboratory data, unclear classification of patients with lower urinary tract symptoms and lack of adjustment for clinical covariates. Despite these limitations we identified multiple putative pathways in which panels of biological markers need further research.

Purpose: Self-reported measurement tools often provide a recall period, eg "In the past 7 days…" For lower urinary tract symptoms the concordance of end of day (daily) reports with 7 and 30-day recalled reports is unknown to our knowledge. We evaluated how accurately 7 or 30-day recall questions capture lower urinary tract symptoms., Materials and Methods: The 261 female and 254 male participants were recruited from a total of 6 United States tertiary care sites. We evaluated 18 items representing 7 symptoms covering storage, voiding and post-micturition symptoms. Item responses on the daily forms were averaged for a 7 or a 30-day period and compared to the corresponding 7 or 30-day recall version of the item. Analyses were item and gender specific. Within person concordance was assessed using the Pearson correlation. Bias (systematic overreporting or underreporting) was calculated as the difference between the recalled item and the averaged daily item score, and reported as a percent of the item scale., Results: All correlations exceeded 0.60. Correlations between averaged daily reports and recalled reports ranged from 0.72 to 0.89 for 7 days and from 0.71 to 0.91 for 30 days among women, and from 0.68 to 0.90 and 0.68 to 0.95, respectively, among men. Most items did not show systematic bias and the median percent bias did not exceed 10% for any item. However, bias exceeding ±10% for some items was observed in a subset of individuals., Conclusions: Recalled reports during the 7 and 30 days tracked well with averaged daily reports for men and women. Systematic bias was minimal, suggesting that 7 and 30-day recall periods for self-reported lower urinary tract symptoms are reasonable.

Purpose: We performed clustering analysis of patient symptoms to discover common patient subtypes in females and males with interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome., Materials and Methods: The clinical variables included in k-means clustering were urological pain severity, urinary urgency, frequency and nonurological pain, each on a 0 to 10 numerical rating scale, and a yes or no response to each of the 6 UPOINT (Urological Treatment Program for Chronic Prostatitis) domains, including the urinary, psychosocial, organ specific, infection, neurological/systemic and skeletal muscle tenderness domains., Results: Included in study were 211 patients seeking care of interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome. The k-means clustering algorithm identified 3 clusters of patients with interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, including 1) a mild pelvic symptom cluster in about 30% of patients, 2) a severe pelvic symptom cluster in about 40% and 3) a systemic symptom cluster in about 30%. Patients in the systemic cluster were younger by about 5 to 7 years and more likely to be female. They had the most severe urinary symptoms (urgency, frequency and painful bladder filling), and the most severe pelvic and nonpelvic pain. They were also more likely to have chronic overlapping pain conditions, psychosocial issues (depression, anxiety and somatic symptoms) and poorer quality of life than patients in the 2 other pelvic clusters. They were not less likely to have Hunner lesions in the bladder., Conclusions: Symptom based clustering identified 3 clusters of patients with interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. These patient subtypes had different pelvic and systemic presentations. Patients in the systemic cluster may benefit from interdisciplinary therapies. Future studies are needed to elucidate differences in pathophysiology among these clusters.

Purpose: Some patients continue to have bothersome lower urinary tract symptoms despite treatment. We examined characteristics associated with bother from lower urinary tract symptoms in a prospective cohort., Materials and Methods: In this 1-year prospective, observational cohort study we obtained data on patients with lower urinary tract symptoms who were seeking care at a total of 6 tertiary care centers in the United States. Participants answered the AUA-SI (American Urological Association Symptom Index) global urinary bother question at study entry and 12 months later. Multilevel logistic and linear regression was used to identify factors associated with worsening bother and bother at 12 months, respectively., Results: Of the 756 participants 121 (16%) had worsened lower urinary tract symptom bother during the study period. When adjusted for other variables, worsened lower urinary tract symptom bother was more likely among men who were nonwhite (OR 1.79, 95% CI 0.94-3.40) or who had diabetes (OR 1.68, 95% CI 0.86-3.27) and among women with diabetes (OR 1.77, 95% CI 0.85-3.67), prior treatment of lower urinary tract symptoms (OR 2.58, 95% CI 1.22-5.46) or a higher depression level (OR 1.29, 95% CI 1.10-1.52). Baseline factors associated with more severe bother at 12 months in men included more severe bother at baseline, nonwhite race, worse urinary frequency and incontinence, and higher levels of stress (p <0.05). Among women more severe bother at baseline, urinary urgency and frequency, and worse physical function were associated with more severe bother at 12 months., Conclusions: Urinary symptom severity at baseline, race, depression and psychological stress were associated with the bother of lower urinary tract symptoms in a prospective cohort of men and women treated at tertiary care facilities. These findings may inform the clinical care of patients with bothersome lower urinary tract symptoms and direct providers to better prognosticate for patients with challenging lower urinary tract symptoms cases.

Purpose: To improve the potential for finding clinically important subtypes of patients with lower urinary tract symptoms we developed the CASUS (Comprehensive Assessment of Self-reported Urinary Symptoms). We used it to present data on the experiences of lower urinary tract symptoms in treatment seeking women and men from a prospective observational cohort., Materials and Methods: We created an initial list of lower urinary tract symptoms that were confirmed in 22 qualitative interviews with providers, and 88 qualitative interviews with care seeking and noncare seeking women and men with lower urinary tract symptoms. Items from extant measures were adopted and revised, and new items were developed. All items were evaluated for understanding in 64 cognitive interviews. Items were administered to a prospective cohort of female and male patients with lower urinary tract symptoms who were seeking care. Analyses were done to describe item response distributions and correlations among item responses separately for women and men., Results: A total of 444 males and 372 females provided responses to the CASUS. Several sets of items showed different relationships for women compared to men. In particular the associations between sensation related items and incontinence related items were generally positive among females but often negative among males., Conclusions: After using an intensive development process the CASUS addresses a wide range of lower urinary tract symptoms. It should help identify clinically important subtypes of patients. Further, item collection can provide the foundation for shorter measures for use in the clinic and as trial end points.

Purpose: Women with lower urinary tract symptoms are often diagnosed based on a predefined symptom complex or a predominant symptom. There are many limitations to this paradigm as often patients present with multiple urinary symptoms which do not perfectly fit the preestablished diagnoses. We used cluster analysis to identify novel, symptom based subtypes of women with lower urinary tract symptoms., Materials and Methods: We analyzed baseline urinary symptom questionnaire data obtained from 545 care seeking female participants enrolled in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) Observational Cohort Study. Symptoms were measured with the LUTS (lower urinary tract symptoms) Tool and the AUA SI (American Urological Association Symptom Index), and analyzed using a probability based consensus clustering algorithm., Results: Four clusters were identified. The 138 women in cluster F1 did not report incontinence but experienced post-void dribbling, frequency and voiding symptoms. The 80 women in cluster F2 reported urgency incontinence as well as urgency and frequency but minimal voiding symptoms or stress incontinence. Cluster F3 included 244 women who reported all types of incontinence, urgency, frequency and mild voiding symptoms. The 83 women in cluster F4 reported all lower urinary tract symptoms at uniformly high levels. All but 2 of 44 LUTS Tool and 8 AUA SI questions significantly differed between at least 2 clusters (p <0.05). All clusters contained at least 1 member from each conventional group, including continence, and stress, urgency, mixed and other incontinence., Conclusions: Women seeking care for lower urinary tract symptoms cluster into 4 distinct symptom groups which differ from conventional clinical diagnostic groups. Further validation is needed to determine whether management improves using this new classification., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We examined how mental health measures, sleep and physical function are associated with the presence and type of urinary incontinence and severity in women seeking treatment for lower urinary tract symptoms., Materials and Methods: This baseline cross-sectional analysis was performed in treatment seeking women with lower urinary tract symptoms. All participants completed the LUTS (Lower Urinary Tract Symptoms) Tool (Pfizer, New York, New York), which was used to classify women based on urinary incontinence symptoms and measure severity. The PROMIS (Patient-Reported Outcomes Measurement Information System) questionnaire for depression, anxiety, sleep disturbance and physical function, the PSS (Perceived Stress Scale) and the IPAQ-SF (International Physical Activity Questionnaire Short Form) were administered. Multivariable regression modeling was done to assess associations with urinary symptom presence, type and severity., Results: We studied 510 women with a mean ± SD age of 56 ± 14 years. Of the women 82% were Caucasian, 47% were obese and 14% reported diabetes. Urinary incontinence was reported by 420 women (82.4%), including stress urinary incontinence in 70, urgency urinary incontinence in 85, mixed urinary incontinence in 240 and other urinary incontinence in 25. On adjusted analyses there was no difference in any mental health, sleep or physical function measure based on the presence vs the absence of urinary incontinence. Among women with urinary incontinence PROMIS anxiety and sleep disturbance scores were higher in those with mixed urinary incontinence than stress urinary incontinence. Increasing urinary incontinence severity was associated with higher PROMIS depression and anxiety scores, and higher PSS scores. However, higher urinary incontinence severity was not associated with a difference in sleep or physical function., Conclusions: Among treatment seeking women with lower urinary tract symptoms, increasing urinary incontinence severity rather than the presence or type of urinary incontinence was associated with increased depression, anxiety and stress., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Male urinary incontinence is thought to be infrequent. We sought to describe the prevalence of urinary incontinence in a male treatment seeking cohort enrolled in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network)., Materials and Methods: Study inclusion and exclusion criteria, including men with prostate cancer or neurogenic bladder, were previously reported. LURN participants prospectively completed questionnaires regarding lower urinary tract symptoms and other clinical variables. Men were grouped based on incontinence type, including 1) no urinary incontinence, 2) post-void dribbling only and 3) urinary incontinence. Comparisons were made using ANOVA and multivariable regression., Results: Of the 477 men 24% reported no urinary incontinence, 44% reported post-void dribbling only and 32% reported urinary incontinence. African American men and those with sleep apnea were more likely to be in the urinary incontinence group than in the no urinary incontinence group (OR 3.2, p = 0.02 and OR 2.73, p = 0.003, respectively). Urinary incontinence was associated with significantly higher bother compared to men without leakage (p <0.001). Compared to men without urinary incontinence and men with only post-void dribbling those with urinary incontinence were significantly more likely to report higher scores (more severe symptoms) on the PROMIS (Patient-Reported Outcomes Measurement Information System) questionnaires regarding bowel issues, depression and anxiety than men without urinary incontinence (p <0.01)., Conclusions: Urinary incontinence is common among treatment seeking men. This is concerning because the guideline recommended questionnaires to assess male lower urinary tract symptoms do not query for urinary incontinence. Thus, clinicians may be missing an opportunity to intervene and improve patient care. This provides a substantial rationale for a new or updated symptom questionnaire which provides a more comprehensive symptom assessment., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We examined health care seeking activities during a 12-month period in a cohort of men and women with urological chronic pelvic pain syndromes., Materials and Methods: A total of 191 men and 233 women with urological chronic pelvic pain syndrome were followed with biweekly, Internet based questionnaires about symptoms and health care seeking activities, including 1) health care provider contacts, 2) office visits, 3) emergency room/urgent care visits, 4) medication changes and 5) medical procedures. Multivariable modeling was used to determine the association of demographic and clinical variables with health care seeking. Super users were defined as individuals who reported health care seeking activity at least 11 times during the 23 biweekly assessments., Results: Health care seeking activities included a mean of 2.4 office contacts, 2.5 office visits, 1.9 medication changes, 0.9 medical procedures and 0.3 emergency room/urgent care visits. A total of 31 health care seeking super users accounted for 26% of health care seeking activities. Worse baseline pain severity and female gender were associated with a higher rate of all health care seeking activities except emergency room/urgent care visits. A nonurological chronic pain condition was associated with more provider contacts, office visits and medical procedures. Greater baseline depression symptoms were associated with more provider contacts, office visits and medication changes. Other examined variables, including patient age, symptom duration, catastrophizing, anxiety, urinary symptom severity and symptom variability, had a minimal association with health care seeking., Conclusions: Health care seeking activities were strongly influenced by the severity of pain in patients with urological chronic pelvic pain syndromes but not by urinary symptom severity. Women and patients with nonurological overlapping pain conditions were more likely to be seen and treated for symptoms., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Although many factors have been proposed to trigger symptom exacerbations (flares) in patients with interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, few studies have investigated these factors empirically. Therefore, we embedded a case-crossover study in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain longitudinal study to evaluate a range of patient reported triggers., Materials and Methods: We assessed exposure to proposed triggers, including diet, physical activities, sedentary behaviors, stress, sexual activities, infection-like symptoms and allergies, by questionnaire a maximum of 3 times when participants reported flares and at 3 randomly selected times. We compared participant preflare to nonflare exposures by conditional logistic regression., Results: In our full analytical sample of 292 participants only 2 factors, including recent sexual activity (OR 1.44, 95% CI 1.06-1.96) and urinary tract infection symptoms (OR 3.39, 95% CI 2.02-5.68), which may overlap with those of flares, were associated with flare onset. On subanalyses restricted to flares with specific suspected triggers additional positive associations were observed for some factors such as certain dietary factors, abdominal muscle exercises, and vaginal infection-like symptoms and fever, but not for other factors (eg stress)., Conclusions: Except for sexual activity our findings suggest that patient reported triggers may be individual or group specific, or they may not contribute to flares. These findings suggest caution in following rigid, global flare prevention strategies and support additional research to develop evidence-based strategies., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We described and compared the frequency and type of lower urinary tract symptoms reported by men and women at the time that they were recruited from urology and urogynecology clinics into the Symptoms of Lower Urinary Tract Dysfunction Research Network multicenter, prospective, observational cohort study., Materials and Methods: At 6 research sites treatment seeking men and women were enrolled who reported any lower urinary tract symptoms at a frequency more than rarely during the last month on the LUTS (Lower Urinary Tract Symptoms) Tool. At baseline the study participants underwent a standardized clinical evaluation and completed validated questionnaires. Urological tests were performed, including pelvic/rectal examination, post-void residual urine measurement and urinalysis., Results: A total of 545 women and 519 men were enrolled in the study. Mean ± SD age was 58.8 ± 14.1 years. At baseline nocturia, frequency and a sensation of incomplete emptying were similar in men and women but men experienced more voiding symptoms (90% vs 85%, p = 0.007) and women reported more urgency (85% vs 66%, p <0.001). Women also reported more of any type of urinary incontinence than men (82% vs 51% p <0.001), which was mixed incontinence in 57%. Only 1% of men reported stress incontinence but they had other urinary incontinence, including post-void dribbling in 44% and urgency incontinence in 46%. Older participants had higher odds of reporting symptoms of nocturia and urgency., Conclusions: In this large, treatment seeking cohort of men and women lower urinary tract symptoms varied widely by gender and age. Men reported more voiding symptoms and nonstress or urgency urinary incontinence while women reported more incontinence overall and urgency. Older participants had greater odds of urgency and nocturia., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Diet, fluid intake and caffeine, alcohol and tobacco use may have effects on lower urinary tract symptoms. Constructive changes in these modifiable nonurological factors are suggested to improve lower urinary tract symptoms. To better understand the relationship between nonurological factors and lower urinary tract symptoms, we performed a systematic literature review to examine, grade and summarize reported associations between lower urinary tract symptoms and diet, fluid intake and caffeine, tobacco and alcohol use., Materials and Methods: We performed PubMed® searches for eligible articles providing evidence on associations between 1 or more nonurological factors and lower urinary tract symptoms. A modified Oxford scale was used to grade the evidence., Results: We reviewed 111 articles addressing diet (28 studies), fluid intake (21) and caffeine (21), alcohol (26) and tobacco use (44). The evidence grade was generally low (6% level 1, 24% level 2, 11% level 3 and 59% level 4). Fluid intake and caffeine use were associated with urinary frequency and urgency in men and women. Modest alcohol use was associated with decreased likelihood of benign prostatic hyperplasia diagnosis and reduced lower urinary tract symptoms in men. Associations between lower urinary tract symptoms and ingestion of certain foods and tobacco were inconsistent., Conclusions: Evidence of associations between lower urinary tract symptoms and diet, fluid intake and caffeine, alcohol and tobacco use is sparse and mostly observational. However, there is evidence of associations between increased fluid and caffeine intake and urinary frequency/urgency, and between modest alcohol intake and decreased benign prostatic hyperplasia diagnosis and lower urinary tract symptoms. Given the importance of these nonurological factors in daily life, and their perceived impact on lower urinary tract symptoms, higher quality evidence is needed., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We examined baseline clinical and psychosocial characteristics that predict 12-month symptom change in men and women with urological chronic pelvic pain syndromes., Materials and Methods: A total of 221 female and 176 male patients with urological chronic pelvic pain syndromes were recruited from 6 academic medical centers in the United States and evaluated at baseline with a comprehensive battery of symptom, psychosocial and illness-impact measures. Based on biweekly symptom reports, a functional clustering procedure classified participant outcome as worse, stable or improved on pain and urinary symptom severity. Cumulative logistic modeling was used to examine individual predictors associated with symptom change as well as multiple predictor combinations and interactions., Results: About 60% of participants had stable symptoms with smaller numbers (13% to 22%) showing clear symptom worsening or improvement. For pain and urinary outcomes the extent of widespread pain, amount of nonurological symptoms and poorer overall health were predictive of worsening outcomes. Anxiety, depression and general mental health were not significant predictors of outcomes but pain catastrophizing and self-reported stress were associated with pain outcome. Prediction models did not differ between men and women and for the most part they were independent of symptom duration and age., Conclusions: These results demonstrate for the first time in a large multisite prospective study that presence of widespread pain, nonurological symptoms and poorer general health are risk factors for poorer pain and urinary outcomes in men and women. The results point to the importance of broad based assessment for urological chronic pelvic pain syndromes and future studies of the mechanisms that underlie these findings., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We characterized the location and spatial distribution of whole body pain in patients with urological chronic pelvic pain syndrome using a body map. We also compared the severity of urinary symptoms, pelvic pain, nonpelvic pain and psychosocial health among patients with different pain patterns., Materials and Methods: A total of 233 women and 191 men with urological chronic pelvic pain syndrome enrolled in a multicenter, 1-year observational study completed a battery of baseline measures, including a body map describing the location of pain during the last week. Participants were categorized with pelvic pain if they reported pain in the abdomen and pelvis only. Participants who reported pain beyond the pelvis were further divided into 2 subgroups based on the number of broader body regions affected by pain, including an intermediate group with 1 or 2 additional regions outside the pelvis and a widespread pain group with 3 to 7 additional regions., Results: Of the 424 enrolled patients 25% reported pelvic pain only and 75% reported pain beyond the pelvis, of whom 38% reported widespread pain. Participants with a greater number of pain locations had greater nonpelvic pain severity (p <0.0001), sleep disturbance (p = 0.035), depression (p = 0.005), anxiety (p = 0.011), psychological stress (p = 0.005) and negative affect scores (p = 0.0004), and worse quality of life (p ≤0.021). No difference in pelvic pain and urinary symptom severity was observed according to increasing pain distribution., Conclusions: Three-quarters of the men and women with urological chronic pelvic pain syndrome reported pain outside the pelvis. Widespread pain was associated with greater severity of nonpelvic pain symptoms, poorer psychosocial health and worse quality of life but not with worse pelvic pain or urinary symptoms., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: In healthy control subjects certain brain regions of interest demonstrate increased regional cerebral blood flow in response to painful stimuli. We examined the effect of bladder distension on arterial spin label functional magnetic resonance imaging measures of regional cerebral blood flow in regions of interest in subjects with interstitial cystitis., Materials and Methods: A total of 11 female subjects with interstitial cystitis and 11 healthy controls underwent 3 brain perfusion scan studies using arterial spin label functional magnetic resonance imaging, including 1) with a full bladder, 2) with an empty bladder and 3) while experiencing heat pain. Regional cerebral blood flow was calculated using custom software and individual scans were spatially normalized to the MNI (Montreal Neurological Institute) template. Region of interest based, absolute regional cerebral blood flow was determined for each condition and for the within group/within subject regional cerebral blood flow distribution changes induced by each condition., Results: Bladder distension was associated with robust increases in regional cerebral blood flow in subjects with interstitial cystitis. The increases were greater than those in healthy controls in multiple regions of interest, including the supplemental motor area (mainly Brodmann area 6), the motor and sensory cortex, the insula bilaterally, the hippocampal structures bilaterally, and the middle and posterior cingulate areas bilaterally. During heat pain healthy controls had more robust regional cerebral blood flow increases in the amygdala bilaterally. At baseline with an empty bladder there was lower regional cerebral blood flow in the insula, and the mid and posterior cingulate cortex bilaterally in subjects with interstitial cystitis., Conclusions: Compared to healthy controls, subjects with interstitial cystitis have limited differences in regional cerebral blood flow in baseline (empty bladder) conditions as well as during heat pain. However, they had robust regional cerebral blood flow increases in the full bladder state in regions of interest typically associated with pain, emotion and/or motor control, indicating altered processing of bladder related sensations., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We compare the systemic (nonurological) symptoms between patients with overactive bladder and subjects without overactive bladder. We also compare the urinary symptoms, quality of life and psychosocial measures between the 2 subgroups of patients with overactive bladder with a high vs low systemic symptom burden., Materials and Methods: Patients diagnosed with overactive bladder (51) and age matched individuals without overactive bladder (30) were administered the polysymptomatic, polysyndromic questionnaire to assess the numbers and distribution of systemic symptoms across multiple organ systems. Validated instruments were administered to evaluate urinary symptoms (ICIQ-UI, ICIQ-OAB, OAB-q, USS), quality of life (UDI-6, IIQ-7, OAB-q) and psychosocial difficulties (depression, anxiety, stress, sexual trauma, sleep, fatigue). Patients with overactive bladder were divided into 2 subgroups (with and without widespread systemic symptoms) and their responses were compared., Results: Patients with overactive bladder reported significantly more systemic (nonurological) symptoms compared to controls (mean ± SD 17.5 ± 12.3 vs 6.4 ± 7.9 symptoms, p <0.001). Differences were observed across multiple organ systems (neurologic, cardiopulmonary, gastrointestinal, sexual, musculoskeletal and gynecologic, p <0.05). About a third of patients with overactive bladder (31.4%) reported widespread systemic symptoms across multiple organ systems (mean 32.0 symptoms). The presence of widespread systemic symptoms among patients with overactive bladder was correlated with worse incontinence/overactive bladder symptoms (ICIQ-UI, OAB-q), poorer quality of life (UDI-6, IIQ-7, OAB-q) and more psychosocial difficulties (depression, anxiety, fatigue and higher stress, p <0.05)., Conclusions: The increased presence of nonurological symptoms in overactive bladder suggests an underlying systemic etiology and pathogenetic mechanisms that may contribute to overactive bladder. This study highlights the importance of understanding systemic factors in urological conditions otherwise thought to be organ specific., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to create symptom indexes, that is scores derived from questionnaires to accurately and efficiently measure symptoms of interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, collectively referred to as urological chronic pelvic pain syndromes. We created these indexes empirically by investigating the structure of symptoms using exploratory factor analysis., Materials and Methods: As part of the MAPP (Multi-Disciplinary Approach to the Study of Chronic Pelvic Pain) Research Network 424 participants completed questionnaires, including GUPI (Genitourinary Pain Index), ICSI (Interstitial Cystitis Symptom Index) and ICPI (Interstitial Cystitis Problem Index). Individual items from questionnaires about bladder and pain symptoms were evaluated by principal component and exploratory factor analyses to identify indexes with fewer questions to comprehensively quantify symptom severity. Additional analyses included correlating symptom indexes with symptoms of depression, which is a known comorbidity of patients with pelvic pain., Results and Conclusions: Exploratory factor analyses suggested that the 2 factors pain severity and urinary severity provided the best psychometric description of items in GUPI, ICSI and ICPI. These factors were used to create 2 symptom indexes for pain and urinary symptoms. Pain, but not urinary symptoms, was associated with symptoms of depression on multiple regression analysis, suggesting that these symptoms may impact patients with urological chronic pelvic pain syndromes differently (B ± SE for pain severity = 0.24 ± 0.04, 95% CI 0.16-0.32, β = 0.32, p <0.001). Our results suggest that pain and urinary symptoms should be assessed separately rather than combined into 1 total score. Total scores that combine the separate factors of pain and urinary symptoms into 1 score may be limited for clinical and research purposes., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We describe bladder associated symptoms in patients with urological chronic pelvic pain syndromes. We correlated these symptoms with urological, nonurological, psychosocial and quality of life measures., Materials and Methods: Study participants included 233 women and 191 men with interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome in a multicenter study. They completed a battery of measures, including items asking whether pain worsened with bladder filling (painful filling) or whether the urge to urinate was due to pain, pressure or discomfort (painful urgency). Participants were categorized into 3 groups, including group 1-painful filling and painful urgency (both), 2-painful filling or painful urgency (either) and 3-no painful filling or painful urgency (neither)., Results: Of the men 75% and of the women 88% were categorized as both or either. These bladder characteristics were associated with more severe urological symptoms (increased pain, frequency and urgency), a higher somatic symptom burden, depression and worse quality of life (3-group trend test each p<0.01). A gradient effect was observed across the groups (both>either>neither). Compared to those in the neither group men categorized as both or either reported more frequent urological chronic pelvic pain syndrome symptom flares, catastrophizing and irritable bowel syndrome, and women categorized as both or either were more likely to have a negative affect and chronic fatigue syndrome., Conclusions: Men and women with bladder symptoms characterized as painful filling or painful urgency had more severe urological symptoms, more generalized symptoms and worse quality of life than participants who reported neither characteristic, suggesting that these symptom characteristics might represent important subsets of patients with urological chronic pelvic pain syndromes., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: The clinical features of the interstitial cystitis/bladder pain syndrome are similar to those of the chronic prostatitis/chronic pelvic pain syndrome. However, to our knowledge no studies have directly compared the characteristics of these syndromes in men and women., Materials and Methods: The MAPP Research Network recruited 191 men and 233 women with IC/BPS or CP/CPPS. Baseline data included demographics, Interstitial Cystitis Symptom Index and Problem Index scores; Genitourinary Pain Index score; American Urological Association Symptom Index score; Likert scales to assess urinary urgency, frequency, pain and overall symptom severity; and a single question about the most bothersome pelvic symptom., Results: After adjustment for age, income and symptom duration, measures of pain severity were similar across genders. Mean scores for the ICSI, ICPI and AUASI were significantly higher in women than in men, reflecting more bladder focused symptoms in women. The most bothersome single symptom in men as well as in women was pain in the pubic/bladder area (men 34%, women 58%). The characteristics of the men and women in the MAPP cohort were similar to those reported in other research cohorts for IC/BPS and CP/CPPS., Conclusions: Our findings indicate that pain severity is similar for both genders and that bladder focused symptoms (urgency, suprapubic pain, frequency) are more common in women. However, a substantial proportion of men also reported these types of bladder symptoms., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We used MAPP data to identify participants with urological chronic pelvic pain syndromes only or a chronic functional nonurological associated somatic syndrome in addition to urological chronic pelvic pain syndromes. We characterized these 2 subgroups and explored them using 3 criteria, including 1) MAPP eligibility criteria, 2) self-reported medical history or 3) RICE criteria., Materials and Methods: Self-reported cross-sectional data were collected on men and women with urological chronic pelvic pain syndromes, including predominant symptoms, symptom duration and severity, nonurological associated somatic syndrome symptoms and psychosocial factors., Results: Of 424 participants with urological chronic pelvic pain syndromes 162 (38%) had a nonurological associated somatic syndrome, including irritable bowel syndrome in 93 (22%), fibromyalgia in 15 (4%), chronic fatigue syndrome in 13 (3%) and multiple syndromes in 41 (10%). Of 233 females 103 (44%) had a nonurological associated somatic syndrome compared to 59 of 191 males (31%) (p = 0.006). Participants with a nonurological associated somatic syndrome had more severe urological symptoms and more frequent depression and anxiety. Of 424 participants 228 (54%) met RICE criteria. Of 228 RICE positive participants 108 (47%) had a nonurological associated somatic syndrome compared to 54 of 203 RICE negative patients (28%) with a nonurological associated somatic syndrome (p < 0.001)., Conclusions: Nonurological associated somatic syndromes represent important clinical characteristics of urological chronic pelvic pain syndromes. Participants with a nonurological associated somatic syndrome have more severe symptoms, longer duration and higher rates of depression and anxiety. RICE positive patients are more likely to have a nonurological associated somatic syndrome and more severe symptoms. Because nonurological associated somatic syndromes are more common in women, future studies must account for this potential confounding factor in urological chronic pelvic pain syndromes., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We compared symptoms between interstitial cystitis/bladder pain syndrome and overactive bladder based on patient self-reported symptoms on validated questionnaires., Materials and Methods: We prospectively recruited 26 patients diagnosed with interstitial cystitis/bladder pain syndrome, 53 diagnosed with overactive bladder and 30 healthy controls to participate in a questionnaire based study that inquired about lower urinary tract symptoms. The questionnaires used were GUPI, ICSI, ICPI, ICIQ-OAB, ICIQ-UI, IUSS, numerical rating scales of the severity of bladder pain, pressure or discomfort, and numerical rating scale of the severity of urgency and frequency symptoms., Results: On univariate analysis patients with interstitial cystitis/bladder pain syndrome reported significantly more severe pain symptoms than those with overactive bladder. Patients with overactive bladder reported significantly more severe urinary incontinence symptoms than those with interstitial cystitis/bladder pain syndrome. There was no difference in frequency and urgency severity between the groups. Surprisingly, 33% of patients with overactive bladder reported pain or discomfort when the bladder filled and 46% with interstitial cystitis/bladder pain syndrome reported urgency incontinence. On multivariate analysis ICIQ-UI total scores (p = 0.01) and bladder pain severity on the numerical rating scale (p <0.01) distinguished the 2 conditions with 90.6% sensitivity and 96.1% specificity. Overactive bladder had higher ICIQ-UI and lower numerical rating scale pain scores., Conclusions: There is considerable overlap of self-reported symptoms between interstitial cystitis/bladder pain syndrome and overactive bladder. This overlap raises the possibility that the 2 conditions represent a continuum of a bladder hypersensitivity syndrome., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We characterized urological symptoms in a subset of patients with urological chronic pelvic pain syndrome who have a high somatic symptom burden and a wide symptom distribution fitting a polysymptomatic, polysyndromic presentation pattern., Materials and Methods: A total of 81 patients with urological chronic pelvic pain syndrome enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases MAPP Research Network Study at Washington University in St. Louis and University of Alabama at Birmingham sites. They completed a symptom questionnaire to assess the somatic symptom burden and its distribution, and GUPI (Genitourinary Pain Index) to assess urological chronic pelvic pain syndrome symptoms, impact on quality of life and self-reported treatment seeking behaviors for urological chronic pelvic pain symptoms. The polysymptomatic, polysyndromic symptom pattern was defined by self-report of numerous painful and nonpainful somatic symptoms across many organ systems and by symptom categories on the polysymptomatic, polysyndromic questionnaire., Results: Patients with urological chronic pelvic pain syndrome and the symptom pattern reported more severe genitourinary pain on a Likert scale, more frequent pain in the last week and more widespread pain distribution in the genital and pelvic areas than patients with urological chronic pelvic pain syndrome without the pattern. Patients with the symptom pattern also had significantly higher scores on the GUPI pain subscale, quality of life subscale (worse) and total questionnaire scores than patients without the pattern. Patients with the pattern reported significantly more treatment seeking behavior than others., Conclusions: The polysymptomatic, polysyndromic pattern might be an important phenotypic factor to assess in the evaluation of urological chronic pelvic pain syndrome with clinical and research implications. This may be a distinct clinical subgroup among patients with urological chronic pelvic pain syndrome., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We investigate if subjects with interstitial cystitis/bladder pain syndrome demonstrate mechanical or thermal hyperalgesia, and whether the hyperalgesia is segmental or generalized (global)., Materials and Methods: Ten female subjects with interstitial cystitis/bladder pain syndrome and 10 age matched female controls without comorbid fibromyalgia or narcotic use were recruited for quantitative sensory testing. Using the method of limits, pressure pain and heat pain thresholds were measured. Using the method of fixed stimulus, the visual analog scale pain experienced was recorded when a fixed pressure/temperature was applied., Results: The visual analog scale pain rated by female subjects with interstitial cystitis/bladder pain syndrome was significantly higher than that rated by female control subjects when a fixed mechanical pressure (2 or 4 kg) was applied to the suprapubic (T11) area (p = 0.028). There was an up shift of the stimulus-response curve, which corresponded to the presence of mechanical hyperalgesia in the suprapubic area in interstitial cystitis/bladder pain syndrome. However, the visual analog scale pain rated by subjects with interstitial cystitis/bladder pain syndrome was not different from that rated by controls when a fixed pressure was applied at the other body sites (T1 arm, L4 leg, S2-3 sacral). No difference in visual analog scale pain rating was noted when a fixed heat stimulus (35C or 37C) was applied to any of the body sites tested (T1, T11, L4, S2). There was no difference in pressure pain thresholds or thermal pain thresholds between subjects with interstitial cystitis/bladder pain syndrome and controls., Conclusions: Female subjects with interstitial cystitis/bladder pain syndrome showed segmental hyperalgesia to mechanical pressure stimulation in the suprapubic area (T10-T12). This segmental hyperalgesia may be explained in part by spinal central sensitization., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We investigated the surgical learning curve of artificial urinary sphincter implantation using a large, consecutive, single surgeon series., Materials and Methods: We retrospectively reviewed the results of the first 150 consecutive, virgin artificial urinary sphincter implantations performed by a single surgeon between 1992 and 2003 for post-prostatectomy male stress urinary incontinence. Complication and reoperation rates, and continence outcomes (daily pad use and number of patients with a functional artificial urinary sphincter at last followup) were analyzed as a function of consecutive implant cases., Results: There was a significant decrease in the number of patients with complications (12 vs 3, relative risk 4.0, p = 0.012) and the number with reoperation (11 vs 3, relative risk 3.7, p = 0.026) when the first 25 patients who underwent artificial urinary sphincter implantation were compared to the second 25. No further decrease was noted beyond the first 25 cases. Despite significantly higher complication and reoperation rates in the first 25 cases, equivalent functional outcomes (same postoperative daily pad use and number of patients with a functional artificial urinary sphincter at last followup) were still achieved after artificial urinary sphincter revision., Conclusions: The surgical learning curve of placing a virgin artificial urinary sphincter was about 25 cases, as measured by complication and reoperation rates. This case number was high compared to typical exposure during residency and clinical practice. There is an urgent need to improve urological prosthetic training and emphasize the referral of artificial urinary sphincter cases to regional centers of excellence or to high volume, artificial urinary sphincter implanters to improve the surgical outcome., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We defined the relevant skin flora during genitourinary prosthetic surgery, evaluated the safety of chlorhexidine-alcohol for use on the male genitalia and compared chlorhexidine-alcohol to povidone-iodine in decreasing the rate of positive bacterial skin cultures at the surgical skin site before prosthetic device implantation., Materials and Methods: In this single institution, prospective, randomized, controlled study we evaluated 100 consecutive patients undergoing initial genitourinary prosthetic implantation. Patients were randomized to a standard skin preparation with povidone-iodine or chlorhexidine-alcohol. Skin cultures were obtained from the surgical site before and after skin preparation., Results: A total of 100 patients were randomized, with 50 in each arm. Pre-preparation cultures were positive in 79% of the patients. Post-preparation cultures were positive in 8% in the chlorhexidine-alcohol group compared to 32% in the povidone-iodine group (p = 0.0091). Coagulase-negative staphylococci were the most commonly isolated organisms in post-preparation cultures in the povidone-iodine group (13 of 16 patients) as opposed to propionibacterium in the chlorhexidine-alcohol group (3 of 4 patients). Clinical complications requiring additional operations or device removal occurred in 6 patients (6%) with no significant difference between the 2 groups. No urethral or genital skin complications occurred in either group., Conclusions: Chlorhexidine-alcohol was superior to povidone-iodine in eradicating skin flora at the surgical skin site before genitourinary prosthetic implantation. There does not appear to be any increased risk of urethral or genital skin irritation with the use of chlorhexidine compared to povidone-iodine. Chlorhexidine-alcohol appears to be the optimal agent for skin preparation before genitourinary prosthetic procedures., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Bladder pain is a debilitating symptom of many urological conditions. There is no generally effective treatment. Abnormal urothelial turnover is common to multiple disease states but the specific components of urothelial injury and the resulting molecular signals that lead to bladder pain are unknown. We examined mouse models of bladder injury induced by uropathogenic Escherichia coli, protamine sulfate (Sigma®) and bacterial lipopolysaccharide to identify cellular and molecular correlates underlying pain sensitization in response to the stimuli., Materials and Methods: C57BL/6 female mice (Jackson Laboratory, Bar Harbor, Maine) were given intravesicular protamine sulfate, lipopolysaccharide or uropathogenic E. coli. The impact of each on nociception was determined by measuring the evoked visceromotor response to bladder distention 24 hours after inoculation. Levels of pyuria and tissue inflammation were examined by urinary cytology and tissue histology. Quantitative polymerase chain reaction and gene expression analysis were used to identify injury profiles associated with nociception., Results: Protamine sulfate treatment was significantly analgesic upon bladder distention. Protamine treated bladders did not show pyuria or extensive tissue damage. Protamine injury was associated with a global decrease in the expression of inflammation associated genes. In contrast, uropathogenic E. coli injury significantly increased the nociceptive response to bladder distention. Lipopolysaccharide treatment did not affect nociception. Finally, injury induced expression of inflammation associated genes correlated with nociceptive responses., Conclusions: Protamine treatment of the bladder is analgesic and tissue protective, and it suppresses the inflammatory cytokine expression normally associated with nociception. Also, the injury modalities that result in differential tissue response patterns provide an innovative method for identifying mediators of visceral pain., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)