International Consultation On Incontinence-Research Society Research Articles

Does COVID-19 cause or worsen LUT dysfunction, what are the mechanisms and possible treatments? ICI-RS 2023.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and produced a worldwide pandemic in 2020. There have been 770,875,433 confirmed cases and 6,959,316 attributed deaths worldwide until September 19, 2023. The virus can also affect the lower urinary tract (LUT) leading to bladder inflammation and producing lower urinary tract symptoms (LUTS) in both the acute and chronic phases of disease. At the 2023 meeting of the International Consultation on Incontinence-Research Society (ICI-RS), the literature relating to COVID-19 and bladder dysfunction was reviewed. The LUTSreported, as well as the pathophysiology of these bladder symptoms, were the subject of considerable discussion. A number of different topics were discussed including lower LUTS reported in COVID-19, how SARS-CoV-2 may infect and affect the urinary tract, and proposed mechanisms for how viral infection result in new, worsened, and in some persisting LUTS. The workshop discussed the interaction between the virus and the immune system, covering current evidence supporting theories underlying the causes of acute and chronic LUTS related to COVID-19 infection. Research questions for further investigation were suggested and identified.

Can we define the optimal postvoid residual volume at which intermittent catheterization should be recommended, and are there other measures that could guide an intermittent catheterization protocol: ICI-RS 2023.

The postvoid residual (PVR) volume of urine in the bladder is widely used in clinical practice as a guide to initiate treatment, including clean-intermittent self-catheterization (CISC). It is often believed that an elevated PVR causes complications such as recurrent urinary tract infections (UTI) and renal failure. However, evidence for this is limited and identifying alternative measures to guide treatment decisions may optimize patient care. At the International Consultation on Incontinence Research Society (ICI-RS) meeting in 2023 a Think Tank addressed the question of whether we can define the optimal PVR at which CISC should be recommended, and whether there are other measures that could guide a CISC protocol. The Think Tank conducted a literature review and expert consensus meeting focusing on current limitations in defining and measuring PVR, and highlighting other measures that may optimize selection for, and persistence with, CISC. There is no consensus on the threshold value of PVR that is considered "elevated"or "significant." There is a lack of standardization on terminology, and the normal range of PVR in different populations of different ages remains to be well-studied. The measurement of PVR is influenced by several factors, including intraindividual variation, timing and method of measurement. Furthermore, the evidence linking an elevated PVR with complications such as UTI and renal failure is mixed. Other measures, such as bladder voiding efficiency or urodynamic parameters, may be better at predicting such complications, and therefore may be more relevant at guiding a CISC protocol. There is a lack of high quality evidence to support PVR as a predictor for complications of UTI or renal failure. Threshold values for normal PVR in different populations are unknow, and so threshold values for "elevated"or "significant"PVR cannot be determined. Other factors, such as urodynamic findings, may be better at predicting complications and therefore guiding management decisions, and this remains to be studied. Areas for further research are proposed.

Beyond the urothelium: Interplay between autonomic nervous system and bladder inflammation in urinary tract infection, bladder pain syndrome with interstitial cystitis and neurogenic lower urinary tract dysfunction in spinal cord injury-ICI-RS 2023.

Inflammation and neuronal hypersensitivity are reactive protective mechanisms after urothelial injury. In lower urinary tract dysfunctions (LUTD), such as urinary tract infection (UTI), bladder pain syndrome with interstitial cystitis (BPS/IC) and neurogenic LUTD after spinal cord injury (SCI), chronic inflammation can develop. It is unclear how the protective reactionary inflammation escalates into chronic disease in some patients. During its 2023 meeting in Bristol, the International Consultation on Incontinence-Research Society (ICI-RS) reviewed the urothelial and inflammatory changes after UTI, BPS/IC and SCI. Potential factors contributing to the evolution into chronic disease were explored in a think-tank. Five topics were discussed. (1) Visceral fat metabolism participates in the systemic pro-inflammatory effect of noradrenalin in BPS/IC and SCI. Sympathetic nervous system-adipocyte-bladder crosstalk needs further investigation. (2) Sympathetic hyperactivity also potentiates immune depression in SCI and needs to be investigated in BPS/IC. Gabapentin and tumor necrosis factor-α are promising research targets. (3) The exact peripheral neurons involved in the integrative protective unit formed by nervous and immune systems need to be further identified. (4) Neurotransmitter changes in SCI and BPS/IC: Neurotransmitter crosstalk needs to be considered in identifying new therapeutic targets. (5) The change from eubiosis to dysbiosis in SCI can contribute to UTI susceptibility and needs to be unraveled. The think-tank discussed whether visceral fat metabolism, immune depression through sympathetic hyperactivity, peripheral nerves and neurotransmitter crosstalk, and the change in microbiome could provide explanations in the heterogenic development of chronic inflammation in LUTD. High-priority research questions were identified.

Can we harness the placebo effect to improve care in lower urinary tract dysfunction? ICI-RS 2019.

The proposal "Can we harness the placebo effect to improve care in lower urinary tract dysfunction?" was discussed at the International Consultation on Incontinence-Research Society (ICI-RS) 2019 meeting. The placebo effect can change the treatment outcome whether the treatment is an active treatment or placebo. The total active treatment outcome is a combination of the placebo and the active treatment effect which is seen in placebo-controlled trials. The placebo effect plays an important role in the treatment of lower urinary tract dysfunction in overactive bladder, bladder pain syndrome, and stress urinary incontinence. In clinical practice, a number of factors can be employed to use the placebo effect to maximize its effect on patients receiving an active treatment, such as having the same environment for review such as the same appointment time, same room, and same clinician. Clinicians should also be aware of the nocebo effect which is increased with an overemphasis on side effects or negative outcomes.

Are oxidative stress and ischemia significant causes of bladder damage leading to lower urinary tract dysfunction? Report from the ICI-RS 2019.

Several studies indicate that pelvic ischemia and oxidative stress may play a significant role in lower urinary tract dysfunction (LUTD), including detrusor overactivity (DO)/overactive bladder (OAB) and detrusor underactivity (DU)/underactive bladder (UAB). The present article addresses proposal 1: "Are oxidative stress and ischemia significant causes of bladder damage leading to LUTD?" from the 2019 International Consultation on Incontinence-Research Society (ICI-RS) meeting. Bladder ischemia in animals and humans is briefly described, along with the proposed progression from ischemia to LUTD. Bladder ischemia is compared with ischemia of other organs, and the ongoing development of pelvic ischemia animal models is discussed. In addition, the distribution of blood within the bladder during filling and voiding and the challenges of quantification of blood flow in vivo are described. Furthermore, oxidative stress, including potential biomarkers and treatments, and challenges regarding antioxidant therapy for the treatment of LUTD are discussed. Finally, seven critical research questions and proposed studies to answer those questions were identified as priorities that would lead to major advances in the understanding and treatment of lower urinary tract symptoms (LUTS)/LUTD associated with pelvic ischemia and oxidative stress.

Is polypropylene mesh material fundamentally safe for use as a reconstructive material in vaginal surgery: ICI-RS 2019?

Polypropylene (PP) mesh has been used as a primary or adjuvant material for vaginal reconstruction for both stress urinary incontinence (SUI) and pelvic organ prolapse (POP) for decades. Whether polypropylene is the optimal material for such indications has been called into question by clinicians, regulatory agencies and the public in several countries around the world. This paper is a report of presentations and subsequent discussion at the annual International Consultation on Incontinence Research Society (ICI-RS) Meeting in June 2019 in Bristol, UK on the proposal "Is polypropylene mesh material fundamentally safe for use as a reconstructive material in vaginal surgery?" in which several of the salient issues were presented and discussed.

Can multicentre urodynamic studies provide high quality evidence for the clinical effectiveness of urodynamics? ICI-RS 2019.

AimsLower urinary tract (LUT) function can be investigated by urodynamic studies (UDS) to establish underlying functional abnormalities in the LUT. A multicentre registry could present an opportunity to improve the scientific evidence base for UDS. During the International Consultation on Incontinence Research Society (ICI‐RS) meeting in Bristol, United Kingdom 2019, an expert panel discussed the potential of a multicentre urodynamic registry to improve the quality of urodynamic output.Methodsthe potential importance of a multicentre urodynamic registry, parameter inclusion, quality control, and pitfalls during a registry roll‐out were reviewed and discussed.Results and ConclusionsThe clinical utility, evaluation, and effectiveness of UDS remain poorly defined due to a lack of high quality evidence and large study populations. Therefore, the ICI‐RS proposes formation of a urodynamic panel for future roll‐out of a registry. The inclusion of basic parameters was discussed and the essential parameters were defined as well as the potential pitfalls of a registry roll‐out. The discussion and recommendations in this paper form the base for future urodynamic registry development.

How can we prevent postprostatectomy urinary incontinence by patient selection, and by preoperative, peroperative, and postoperative measures? International Consultation on Incontinence-Research Society 2018.

To review current prevention strategies for urinary incontinence among patients undergoing radical prostatectomy (RP). This is a consensus report of the proceedings of a research proposal from the annual International Consultation on Incontinence-Research Society (ICI-RS), 14 to 16 June 2018(Bristol, UK): "How can we prevent postprostatectomy incontinence by patient selection, and by preoperative, peroperative, and postoperative measures?" Several baseline parameters were proposed as predicting factors for postprostatectomy urinary incontinence (PPUI), including age, tumor stage, prostate volume, preoperative lower urinary tract symptoms, maximum urethral closure pressure, and previous transurethral resection of the prostate. More recently, magnetic resonance imaging has been used to measure the membranous urethral length and sphincter volume. Peroperative techniques include preservative and reconstructive approaches. Bladder neck preservation improved early (6 months), as well as long-term (>12 months) continence rates. Several prospective studies have reported earlier return of continence following preservation of puboprostatic ligaments, although no long-term data are available. Preservation of the urethral length yielded controversial outcomes. Concerning postoperative strategies, it is probably optimal to remove the catheter in a window between 4 and 7 days if clinically appropriate; however, more research in this regard is still required. Postoperative PFME (preoperative pelvic floor muscle exercise) appears to speed up the recovery of continence after RP. Conservative strategies to prevent PPUI include proper patient selection and PFME. Peroperative techniques have largely shown benefit in the short term. Postoperative complications and timing of trial without catheter can influence continence status. Future research initiatives must assess peroperative and postoperative measures, with longer-term follow-up.

How can we improve the diagnosis and management of bladder pain syndrome? Part 2:ICI-RS 2018.

This paper summarises the discussion in a think tank at the International Consultation on Incontinence-Research Society (ICI-RS) 2018 about the treatment of bladder pain syndrome. To review the treatments of bladder pain syndrome from behavioural treatments to surgical interventions. Review the literature in the light of the think tank discussions. All guidelines recommend different levels of treatment starting with conservative behavioral treatments then introducing oral treatments followed by intravesical instillations. If these treatments fail then more invasive treatments such as botulinum toxin injections, neuromodulation, or surgery could be suggested. Unfortunately for all treatments, the numbers are limited and, therefore, the evidence base is not strong. Further suggestions for research are suggested.

Is our current understanding and management of nocturia allowing improved care? International Consultation on Incontinence-Research Society 2018.

Nocturia or waking at night, to urinate is a common cause of awakenings and may lead to sleep disturbance, impaired somatic health, impaired quality of life, and increased mortality. The aim of this report is to point out and discuss the aspects and issues that need to be addressed to improve the care of nocturia. This paper is a report of the presentations and subsequent discussion of a Think Tank session at the annual International Consultation on Incontinence-Research Society (ICI-RS) in June 2018 in Bristol. Nocturia is a known risk factor for in-hospital falls. Unfortunately, its assessment in acutely hospitalized (older) people is not the current practice and ward-based care plans are not tailored to this symptom. A new care pathway for hospitalized patients who have nocturia should be considered. More research into the relation of cardiovascular disorders and nocturnal polyuria (NP) is warranted and management of NP patients may be improved by involving a cardiologist in their management. There is definitely a need for phenotyping nocturia in relation to bladder capacity, filling phase, and emptying phase symptoms and how to treat the different phenotypes. In the near future, smart automated monitoring devices and applications might help us to diagnose and treat nocturia with less efforts.

Are there different patterns of detrusor overactivity which are clinically relevant? ICI-RS 2018.

Different patterns of detrusor overactivity (DO) have been described and included in several standardization terminology documents. However, it is unclear if these different patterns have any clinical significance. This is a report of the proceedings of Proposal 3: "Are there different patterns of detrusor overactivity which are clinically relevant?" from the annual International Consultation on Incontinence-Research Society (ICIRS) meeting, which took place from 14 to 16 June 2018, in Bristol, UK. We have collected and discussed, as a committee, the evidence about different urodynamic (UD) patterns of detrusor overactivity and their potential clinical significance. We reviewed the important previous basic research and clinical studies and compiled summaries. The discussion focused on clinical relevance of different UD patterns of DO and what further research is required. There are several UD definitions of patterns of detrusor overactivity, however the clinical relevance of these definitions remains unclear. Future research should concentrate on defining the pattern of DO in relation to clinical diagnosis, gender, age, and treatment outcomes.

Do we need better information to advise women with stress incontinence on their choice of surgery? Report from the ICI-RS 2018.

The regulatory warnings about thesafety of thesynthetic midurethral slings (MUS) had a significant effect on how patients and physicians approach surgical management of stress urinary incontinence (SUI). In this changing landscape, the purpose of this research Think Tank (TT) was to provide an update of the current knowledge about the safety and efficacy of SUI surgery, to review patient goals and expectations and to identify factors affecting the decision making for surgery. This is a consensus report of the proceedings of TT3: "Do we need better information to advise women with stress incontinence on their choice of surgery?" from the annual International Consultation on Incontinence-Research Society (ICI-RS), June 2018. Despite the body of evidence supporting the continued use of MUS, the short follow-up of most of the studies and the lack of "real life" data regarding pain and sexual dysfunction make the development of recommendations challenging. Women with SUI are often happy to "trade" efficacy for a procedure with less associated morbidity and therefore it is not always the procedure with the highest success rate that is ultimately chosen. However, a number of factors influence treatment decision and there is limited evidence about what level of all these factors women are willing to tolerate for a given success rate, or how much success they are willing to trade for a lower complication rate. The ICI-RS proposed research questions which may be able to assist in improving the counseling and management of women with SUI.

Bladder-bowel interactions: Do we understand pelvic organ cross-sensitization? International Consultation on Incontinence Research Society (ICI-RS) 2018.

Mounting evidence from experimental animal and human studies suggests that cross-sensitization exists between different organs. Lower urinary tract (LUT) and bowel dysfunction commonly overlap, and the role of cross-sensitization between pelvic visceral organs is uncertain. At the International Consultation on Incontinence Research Society (ICI-RS) meeting in 2018, a panel of clinicians participated in a discussion on bladder and bowel interactions in the context of pelvic organ cross-sensitization. Bladder and bowel problems commonly co-occur in adults and children across different disorders, and the mechanism responsible for overlapping dysfunction is uncertain in most instances. At a neuronal level, cross-sensitization occurs as a result of afferent signaling from the LUT and lower bowel through different central and peripheral mechanisms. Studies in animals and humans have demonstrated evidence for cross-organ sensitization following experimental inflammation or distension of the lower bowel, affecting the LUT. Nerve stimulation is an effective treatment for different functional LUT and bowel disorders, and whether this treatment may influence cross-organ sensitization remains uncertain. The role of physiologically dormant C-fibers, the bladder-gut-brain axis, and gut microbiome in cross-sensitization are speculative. Recommendations for research were made to explore the role of cross-organ sensitization in the pathogenesis of co-occurring LUT and bowel dysfunction in humans.

Psychological comorbidities and functional neurological disorders in women with idiopathic urinary retention: International Consultation on Incontinence Research Society (ICI-RS) 2019.

Chronic urinary retention occurring in young women is poorly understood and a cause may not be found in a majority of cases. Different psychological comorbidities and functional neurological symptom disorders (FNDs) have been reported; however, these have been poorly explored. At the International Consultation on Incontinence Research Society meeting in 2019, a panel of clinicians generated a proposal to explore the relationship between psychological comorbidities, FNDs, and urinary retention in women with chronic idiopathic urinary retention. Psychological comorbidities such as depression and anxiety, and FNDs such as leg weakness and loss of consciousness, have been reported in women with idiopathic urinary retention. Individuals react differently to physical and emotional stressors, and experimental models have demonstrated a relationship between the stress response and developing urinary retention. Trauma, particularly sexual trauma, may be a shared risk factor for developing psychological comorbidities and urinary retention. Children with voiding postponement often suffer from psychological comorbidities and behavioral disturbances; however, there is no evidence to suggest that this progresses to urinary retention in adulthood. "Psychogenic urinary retention" has been described in the urology and psychiatry literature in the past, and anecdotal cases of successful voiding following psychotherapy have been reported, though the true pathophysiology of this entity is uncertain. Psychological and functional disorder comorbidities are reported in women with chronic urinary retention. The nature of the association between urinary retention and functional neurological disorder comorbidities needs to be further explored in terms of a disorder of bladder-brain interaction.

Botulinum toxin A for refractory OAB and idiopathic urinary retention: Can phenotyping improve outcome for patients: ICI‐RS 2019?

Botulinum toxin A (BTX-A) is a well-established treatment for refractory idiopathic overactive bladder (OAB). It has also been used with short-term success in treating idiopathic urinary retention. However, efficacy and complication rates are variable and predicting those likely to benefit most from treatment would enable personalization of therapy and optimization of outcomes. At the International Consultation on Incontinence-Research Society (ICI-RS) meeting in 2019 a Think Tank addressed the question of how we can improve the way we phenotype patients undergoing BTX-A treatment. The Think Tank conducted a literature review and expert consensus meeting focussing on how advances in basic science research of the mechanism of action of BTX-A, as well as assessment of psychological comorbidity, can be translated into clinical practice to improve patient selection for therapy. Idiopathic OAB and idiopathic urinary retention are heterogenous conditions encompassing several phenotypes with multiple potential pathophysiological mechanisms. Animal models have demonstrated a central nervous system mechanism of action of intravesically injected BTX-A and this has been confirmed in human functional MRI studies, but whether this tool can be used to predict outcome from treatment remains to be determined. Phenotyping based on psychological comorbidity using validated screening tools should be studied as a way to potentially optimize patient selection for therapy. Advances in basic science research into the mechanism of action of BTX-A have improved our understanding of the pathophysiology of OAB and may lead to novel ways to phenotype patients. Psychological assessment is another way in which phenotyping may be improved. Areas for further research are proposed.

International Continence Society consensus on the diagnosis and treatment of nocturia.

Patients with nocturia have to face many hurdles before being diagnosed and treated properly. The aim of this paper is to: summarize the nocturia patient pathway, explore how nocturia is diagnosed and treated in the real world and use the Delphi method to develop a practical algorithm with a focus on what steps need to be taken before prescribing desmopressin. Evidence comes from existing guidelines (Google, PubMed), International Consultation on Incontinence-Research Society (ICI-RS) 2017, prescribing information and a Delphi panel (3 rounds). The International Continence Society initiated this study, the authors represent the ICI-RS, European Association of Urology, and Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU). Diagnostic packages: consensus on, history taking for all causalities, intake diary (fluid, food) and bladder diary, not for its duration. Pelvic (women) or rectal (men) examination, prostate-specific antigen, serum sodium check (SSC), renal function, endocrine screening: when judged necessary. Timing or empty stomach when SSC is not important. Therapeutic packages: the safe candidates for desmopressin can be phenotyped as no polydipsia, heart/kidney failure, severe leg edema or obstructive sleep apnea syndrome. Lifestyle interventions may be useful. Initiating desmopressin: risk management consensus on three clinical pictures. Follow-up of desmopressin therapy: there was consensus on SSC day 3 to 7, and at 1 month. Stop therapy if SSC is <130 mmol/L regardless of symptoms. Stop if SSC is 130 to 135 mmol/L with symptoms of hyponatremia. A summary of the nocturia patient pathway across different medical specialists is useful in the visualization and phenotyping of patients for diagnosis and therapy. By summarizing basic knowledge of desmopressin, we aim to ease its initiation and shorten the patient journey for nocturia.

What is the utility of urodynamics, including ambulatory, and 24 h monitoring, in predicting upper urinary tract damage in neuro-urological patients and other lower urinary tract dysfunction? ICI-RS 2017.

This article focuses on how, and if, urodynamics can help to identify which kidneys are in danger of deteriorating in function and also gives recommendations for future research. At the International Consultation on Incontinence-Research Society (ICI-RS) in 2017, a multi-disciplinary group presented a literature search of what is known about the utility of Urodynamics, including ambulatory, and 24 h monitoring, in predicting upper urinary tract damage in neuro-urological patients and other lower urinary tract dysfunctions. Wider discussions regarding knowledge gaps, and ideas for future research ensued and are presented in this paper along with a review of the evidence. The current treatment strategy both in congenital and acquired neurogenic bladder is rather aggressive and successful when addressing hazards to kidney function. This article has highlighted uncertainties concerning the use of 40 cmH2O DLPP and even the lower value of 20. The current literature suggests that patients with spina bifida and those with spinal cord injury have a higher risk of developing upper urinary tract damage and kidney function impairment than those with multiple sclerosis. Future research should focus on less invasive methods to assess the risk to the upper and lower urinary tract such as urine and serum measurements of cytokines that are involved in the pathophysiology of urinary tract impairment.

Current controversies in urinary tract infections: ICI-RS 2017.

The current definition of urinary tract infection (UTI) relies on laboratory and clinical findings, which may or may not be relevant, depending upon the patient group under consideration. This report considers the utility of current definitions for UTI in adults with and without underlying neurological conditions in order to identify gaps in current understanding and to recommend directions for research. This is a consensus report of the proceedings of Think Tank TT3: "How do we define and when do we treat UTI in neurological and non-neurological adult patients?" from the annual International Consultation on Incontinence-Research Society (ICI-RS), June 8-10, 2017 (Bristol, UK). Evidence considering the definitions of UTI in patients with and without neurological diseases was reviewed and synthesized. We examined research on laboratory methods and clinical definitions, focusing on specific cut-off values for the quantification of significant bacteriuria, and leucocyturia. Several areas were identified, mostly related to the lack of evidence-based definitions of significant bacteriuria for different patient groups, as well as uncertainties about the role of inflammatory biomarkers, and non-specific symptoms and signs. One of the biggest challenges in clinical practice is to discriminate between asymptomatic bacteriuria and symptomatic UTI. Future research should concentrate on risk factors for developing symptomatic UTI in different patient groups. Targeted investigations for specific populations, such as the frail elderly, and patients with neurogenic bladder dysfunction, are still needed.

How can we develop a more clinically useful and robust algorithm for diagnosing and treating nocturia? ICI-RS 2017.

Nocturia, or waking up at night to void, is a highly prevalent and bothersome symptom. Currently, there is a lack of clear and consistent recommendations regarding evaluation and management of nocturia. The aim of this report is to discuss how to fill the gaps in our knowledge in order to develop a practical patient-oriented diagnostic and therapeutic algorithm for nocturia. This paper is a report of the presentations and subsequent discussion of a Think Tank session at the annual International Consultation on Incontinence Research Society (ICI-RS) in June 2017 in Bristol. Further investigations are needed to better understand the pathophysiology of nocturia, to allow improvement in diagnosis, and to optimize treatment by increasing efficacy and reducing adverse events. Patient-oriented practical guidelines on nocturia are needed to help clinicians from different disciplines diagnose and treat nocturia.

Do the definitions of the underactive bladder and detrusor underactivity help in managing patients: International Consultation on Incontinence Research Society (ICI-RS) Think Tank 2017?

The Think Tank aimed to discuss the pitfalls and advantages of current definitions in terms of research and management of underactive bladder (UAB). UAB broadly defines a symptom complex of bladder emptying problems and does not indicate a specific pathology. Detrusor underactivity (DU) is a urodynamic diagnosis from pressure-flow studies. The correlation of UAB with DU remains to be precisely determined. The presentations and subsequent discussion, leading to research recommendations during the Think Tank of the International Consultation on Incontinence Research Society in Bristol, 2017, are summarized. To develop more specific individualized management strategies, the Think Tank panel proposed (i) that, since defining a single type of index patient to represent all UAB will not fulfill all clinical research needs, several index patients should be defined by phenotyping of patients with UAB, including, children, young men and women, elderly male and female patients with co-existing DU and detrusor overactivity, and neurological patients with UAB; (ii) prospective longitudinal studies to assess the natural history of UAB, in the different target populations, based on different UAB phenotypes, should be initiated; (iii) DU should be precisely defined by urodynamic parameters; and (iv) work to develop validated specific questionnaires combined with non-invasive tests for screening, diagnosis and follow up, needs to be continued. The precise relationship of UAB to DU remains to be defined. Phenotyping patients with UAB/DU, performing prospective trials of natural history, and developing symptom questionnaires and diagnostic investigations will improve our ability to identify and treat UAB/DU.