Story of discovery: advancing understanding of lower urinary tract symptoms and associated conditions
Millions of women, men, and children in the United States currently experience symptoms affecting the lower urinary tract, including pain, bladder leakage, and problems urinating. For many years, research on treating these health problems focused predominantly on organs and structures of the lower urinary tract, such as the bladder, prostate, and urethra. A not unreasonable belief was that most symptoms attributed to the lower urinary tract would eventually correlate with a particular dysfunction rooted in those tissues. Evolutions in thought over the past two decades led researchers to appreciate that not only can similar lower urinary tract symptoms result from different problems within its organs and structures, but that not all symptoms may have their origin in the urinary tract itself.
One way that lower urinary tract symptoms, or LUTS, have traditionally been captured and their severity assessed has been through the use of questionnaires—also sometimes referred to as “tools” or “instruments,” depending upon the context—that allow individuals to self-report their symptoms and related issues, such as how much they are bothered by their symptoms. A question may require a person to report frequency of a symptom over a certain period of time or rate its impact on life activities. When administered in a clinical setting, questionnaires can complement physical exams to help arrive at a diagnosis and treatment plan. For example, the American Urological Association’s Symptoms Score Questionnaire is used by clinicians when evaluating benign prostatic hyperplasia in men. Some questionnaires, such as the Genitourinary Pain Index, were developed and/or are used at this time mostly in clinical research settings. What many of these questionnaires have in common, however, is that when deployed in isolation, the result can be like the story of the five blind men and the elephant: each one may yield a partial description of a person’s symptoms, but may not provide the complete picture needed to identify and/or better understand and manage the underlying cause(s). New research approaches incorporating multiple questionnaires to study people with LUTS, evaluation of “standard” uses of questionnaires, and the careful development of comprehensive tools for assessing LUTS have now yielded information critical both for identifying subtypes of LUTS and/or LUTS-predominant conditions, and for conducting research and clinical assessments going forward.
NEW UNDERSTANDING OF UROLOGIC CHRONIC PELVIC PAIN SYNDROME
Chronic, often debilitating pain in the pelvic or genital areas with or without a frequent or urgent need to urinate are hallmark LUTS for a cluster of disorders referred to as urologic chronic pelvic pain syndrome (UCPPS). UCPPS serves as an umbrella term for the two most common forms of chronic pelvic pain, interstitial cystitis/bladder pain syndrome (IC/BPS, also called IC/painful bladder syndrome [PBS]), which predominantly affects women, and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), which affects men. These conditions reduce quality of life and productivity and incur significant health care costs for millions of Americans. Despite many years of committed basic and clinical research efforts supported by the NIDDK and other research-funding agencies, the cause(s) of UCPPS has long remained elusive, as have widely or fully effective treatments. Moreover, diagnostic tests specific for UCPPS are not currently available, and many UCPPS symptoms are similar to symptoms of other conditions, such as invasive bladder cancer or endometriosis. Thus, those diseases need to be ruled out first—making IC/BPS or CP/CPPS a “diagnosis of exclusion.” Historically, attempts at clinical diagnosis have included questionnaires focused on bladder and prostate symptoms and pelvic pain, along with exclusionary medical tests.
Embracing Novel Approaches: MAPP Research Network
By the mid-2000s, new perspectives from a diversity of research and clinical expertise and insights from other fields led to changes in the research approach for UCPPS. A comprehensive strategy was developed to take into account not only urologic contributors but also the influence of comorbid conditions and non-urologic factors on the onset or development of UCPPS and its symptoms—and how differences in LUTS and other symptoms among individuals diagnosed with UCPPS might be important to identifying clinically significant subgroups of patients. In 2008, the NIDDK established the multi-center Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network to conduct innovative, collaborative studies of UCPPS. Since its inception, the Network’s unique approach to IC/BPS and CP/CPPS has entailed approaches that “look beyond” the bladder and prostate—the traditional focal points for study of these syndromes— to uncover meaningful new insights into the clinical and biological features of UCPPS and its relationships with other chronic pain conditions, all to set the stage for future interventions and improved clinical management.
In its first phase, the MAPP Research Network recruited 424 individuals with UCPPS—233 women with IC/BPS and 191 men with either IC/BPS or CP/CPPS—in a central, Trans-MAPP Epidemiology and Phenotyping study to better understand how these conditions progress over time and to learn if patients might fall into different, distinguishable subgroups based on differing symptoms that may arise from different causes—and, thus, may require different treatments. To achieve its many goals, the Network also recruited large numbers of “control” participants—both healthy persons without any pain syndromes, and those without UCPPS but with one or more chronic pain conditions often found in people with UCPPS, such as irritable bowel syndrome, fibromyalgia, and chronic fatigue syndrome.
Distinguishing Characteristics: LUTS and Non-LUTS in People with UCPPS
A large part of the Trans-MAPP study consisted of participants completing a variety of questionnaires to describe not only the key symptoms of pain and bladder dysfunction, but also commonly co- occurring chronic pain conditions such as irritable bowel syndrome; stress; and issues such as depression, sleep quality, and general quality of life. While the majority have already been employed in health care settings and in clinical research to assess the impact of UCPPS on individuals and the outcomes of clinical trials, respectively, a few of these questionnaires were developed or modified specifically for use in the MAPP Research Network.
By combining outcomes of the questionnaires assessing urologic, non-urologic, and psychosocial symptoms and quality of life with “body pain mapping,” MAPP researchers uncovered important new information about pain patterns and other symptoms in people with IC/BPS and CP/CPPS. Along with completing the questionnaires, the women and men participants with UCPPS were also asked to look at a “body map”—2 drawings representing the front and back of the body, partitioned into 45 numbered sites comprising 8 body regions—and to check off any site in which they had experienced pain in the past week. From the resulting data, MAPP investigators found that, whereas a quarter of participants reported pain only in the pelvic region, 75 percent reported pain in both pelvic and nonpelvic regions. Following this observation, the investigators created three subgroups for comparison: people with pelvic pain only; people who had pelvic pain along with pain in one to two nonpelvic regions, or “intermediate pain”; and people with pelvic pain and pain in three to seven nonpelvic regions, or “widespread pain.”
Intriguingly, there were no differences in pelvic pain severity or urinary symptoms across these three groups. In contrast, nonpelvic pain severity, prevalence of chronic overlapping pain conditions, worsening psychosocial health, and poor quality of life increased as the number of pain regions a person had increased. Notably, more women than men experienced widespread pain, and women were more likely to report a greater burden of nonpelvic and nonurinary symptoms and conditions as their pain locations increased. MAPP investigators also compared just the intermediate and widespread pain groups to see if there were any significant differences among study participants with UCPPS who reported nonpelvic pain. This comparison yielded similar results to those for the three-group comparison regarding pelvic pain and urinary symptoms, nonpelvic pain, and several other health measures, but also revealed more gender-specific differences. For example, compared to individuals whose pain was categorized as intermediate, men with widespread pain were more likely to have migraines and anxiety, while women were more likely to have irritable bowel syndrome and sleep disturbance.
Changing Approaches to Symptom Evaluation in People with UCPPS
The differences—and similarities—found in the Trans-MAPP body mapping study among people diagnosed with UCPPS have significant implications for better understanding the cause(s) and/or development of these syndromes and associated LUTS, for research studies on potential treatment approaches, and for clinical diagnosis and personalized care. At the same time, the Network uncovered potentially “game-changing” information about how standard questionnaire data are collected and used for people with UCPPS. In the past, many questionnaires were used to generate a composite “score” for UCPPS that combined pain (pelvic and/or genitourinary) and bladder symptoms. However, an analysis of data from a subset of questionnaires administered in the trans-MAPP study allowed Network scientists to determine that such a composite score can actually mask independent changes in each symptom area. Their analysis suggests that improvement or worsening can occur in pain independently of bladder symptoms such as urgency and frequency, and vice versa, and that a composite score limits the ability of researchers and clinicians to detect such changes. In addition, they found a differential impact of these key symptoms on an important comorbidity, depression: only pain symptoms were associated with depression. These MAPP Research Network findings indicate that, going forward, pain and urinary symptoms should be scored independently in UCPPS to enable more accurate research analyses and improved patient care.
TOOL DEVELOPMENT FOR UNDERSTANDING LUTS
As the MAPP Research Network was developed and conducted its studies focused on syndromes associated with a subset of LUTS, a broader challenge remained: for the wide range of LUTS, we still need to learn more about differing etiologies and potential patient subgroups to improve management and treatment of symptoms. This is true even when a person’s LUTS have been linked to a problem in a structure or function in the lower urinary tract, as there still may be other factors influencing the symptoms he or she is experiencing.
Symptoms of Lower Urinary Tract Dysfunction Research Network
To address the gaps in understanding and treating LUTS, the NIDDK established the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) in 2012. LURN is an interdisciplinary, cooperative research network with several long-term goals: to identify and explain the important subtypes of LUTS in women and men; to improve the measurement of patient experiences of LUTS; to disseminate novel findings to researchers, clinicians, and patients; and to generate data, research tools and biological samples for future studies.
To help attain these intertwined goals, LURN enrolled nearly 2,000 women and men from among individuals presenting with LUTS to a health care provider at a LURN research site. To limit duplication with the work of the MAPP Research Network, persons with pain as a dominant LUTS were not included. Working with these participants, LURN collected clinical data, health-related quality of life assessments, and self-reported symptom measurements at “baseline,” and characterized these and changes in LUTS over a 12-month period, yielding a wealth of data and enabling numerous informative studies.
Measuring Patient Experiences of LUTS
A critical goal for LURN has been to develop improved means for finding clinically important subgroups, or subtypes, among people with LUTS. Their approach was to pursue an intensive questionnaire development process, casting a wide net over LUTS in both women and men to develop the most comprehensive and nuanced instrument they could that would: (1) be able to elicit granular and precise information about symptom experience from individuals; and (2) serve as a “pool” of questions from which more targeted questionnaires could be developed and validated for clinical and research purposes. Through the development process, they also wished to explore the boundaries of what was “measurable” for LUTS—i.e., to what degree unique or abnormal experiences with LUTS could be captured through a person’s self-reported responses on a questionnaire.
The resulting questionnaire, called the Comprehensive Assessment of Self-reported Urinary Symptoms, or CASUS, was developed through an iterative process involving health care providers and women and men with LUTS who were not part of the LURN cohort. Vigorous steps were undertaken to ensure that the CASUS would be widely understandable, potentially translatable, and acceptable to women and men from different educational and racial/ethnic backgrounds. Emphasis was placed on including new types of questions that could get at data gaps such as specific physical sensations accompanying LUTS, particularly sensations accompanying bladder leakage (incontinence). Over 90 LUTS-related items are included in the CASUS, covering multiple symptom categories, such as frequency (day and night), sensations (including pain), urgency, urine flow, incontinence, and incomplete emptying—as well as a person’s recall of any lifetime experience suggestive of LUTS. The CASUS was then put through its paces with over 1,000 participants from the LURN Observational Cohort Study. Their responses not only demonstrated that CASUS could be used in symptomatic persons to obtain a wide range of information about LUTS, but also revealed intriguing sex/gender differences in sensations associated with urinary incontinence that can be explored to look for potential causes.
Adapting CASUS for Practical Application
The CASUS is an extensive menu of items that can be used in concert with other data from the LURN Observational Cohort Study to delve deeply and pursue extensive subgrouping of LUTS. However, it might not be easily administered in all situations, either research or clinical. At the same time, LURN investigators wanted to ensure that the aspects of CASUS that were missing from other assessment tools for LUTS were still retained as much as possible.
Starting from the CASUS, LURN investigators proceeded to develop, through a multi-step process, two scaled-down questionnaires—one for research use, and one for clinical use. These became the LURN Symptom Index-29 (LURN SI-29) and the LURN SI-10. The LURN SI-29 is intended to be a representative outcome assessment for use in research; it includes 29 items covering urgency, incontinence, voiding difficulty, nighttime voiding (nocturia), and pain. The briefer LURN SI-10 for clinical use is intended to elicit responses that would indicate whether there is a need for further clinical investigation and/or intervention; it includes 10 items assessing frequency, nocturia, urgency, incontinence, bladder pain, and post-voiding symptoms, and an additional item on symptom bother. Both have been validated against other questionnaires representing different aspects of LUTS. Both are also meant to be used with either women or men, rather than needing separate instruments.
Another aspect important to the application of CASUS, its derivatives, and other LUTS questionnaires is the accuracy of recall in self-report—i.e., most questionnaires ask individuals to provide assessments of their symptoms within a specified time, such as the past 7 days. Because this could affect the robustness of LUTS data obtained via CASUS, etc., LURN investigators performed another study, in which they obtained daily responses to 18 CASUS items over 7- and 30-day periods, averaged them, and compared them to the corresponding 7- or 30-day recall versions of responses to the items. This study demonstrated good tracking of recall responses with averaged daily responses, with minimal bias—i.e., over- or underreporting of symptoms—supporting the continued use of both 7- and 30-day recall questionnaires in the assessment of LUTS.
LOOKING TO THE FUTURE
Much remains to be learned about LUTS—their causes, development, and how best to manage and treat people experiencing these symptoms. Through multiple activities—including the use and development of improved questionnaires— in MAPP, LURN, and other investigations such as the NIDDK’s Prevention of Lower Urinary Tract Research Consortium (PLUS), more comprehensive subgrouping of people with LUTS and LUTS-predominant conditions is now possible, with important implications for future trial design and clinical management.