Benoit Peyronnet
email: peyronnetbenoit@hotmail.fr

Emma Mironska

Christopher Chapple

Linda Cardozo

Matthias Oelke

Roger Dmochowski

Gérard Amarenco

Xavier Gamé

Roger Kirby

Frank Van Der Aa

Jean-Nicolas Cornu

A Comprehensive Review of Overactive Bladder Pathophysiology: On the Way to Tailored Treatment

Keywords: Detrusor overactivity, Overactive bladder, Urinary incontinence, Urodynamics

Context: Current literature suggests that several pathophysiological factors and mechanisms might be responsible for the nonspecific symptom complex of overactive bladder (OAB).

Objective: To provide a comprehensive analysis of the potential pathophysiology underlying detrusor overactivity (DO) and OAB.

Evidence acquisition: A PubMed-based literature search was conducted in April 2018, to identify randomised controlled trials, prospective and retrospective series, animal model studies, and reviews.

Evidence synthesis: OAB is a nonspecific storage symptom complex with poorly defined pathophysiology. OAB was historically thought to be caused by DO, which was either "myogenic" (urgency initiated from autonomous contraction of the detrusor muscle) or "neurogenic" (urgency signalled from the central nervous system, which initiates a detrusor contraction). Patients with OAB are often found to not have objective evidence of DO on urodynamic studies; therefore, alternative mechanisms for the development of OAB have been postulated. Increasing evidence on the role of urothelium/suburothelium and bladder afferent signalling arose in the early 2000s, emphasising an afferent "urotheliogenic" hypothesis, namely, that urgency is initiated from the urothelium/suburothelium. The urethra has also recently been regarded as a possible afferent origin of OAB-the "urethrogenic" hypothesis. Several other pathophysiological factors have been implicated, including metabolic syndrome, affective disorders, sex hormone deficiency, urinary microbiota, gastrointestinal functional disorders, and subclinical autonomic nervous system dysfunctions. These various possible mechanisms should be considered as contributing to diagnostic and treatment algorithms.

Conclusions:

There is a temptation to label OAB as "idiopathic" without obvious causation, given the poorly understood nature of its pathophysiology. OAB should be seen as a complex, -3-multifactorial symptom syndrome, resulting from multiple potential pathophysiological mechanisms. Identification of the underlying causes on an individual basis may lead to the definition of OAB phenotypes, paving the way for personalised medical care. Patient summary: Overactive bladder (OAB) is a storage symptom syndrome with multiple possible causes. Identification of the mechanisms causing a patient to experience OAB symptoms may help tailor treatment to individual patients and improve outcomes.

Introduction

Overactive bladder (OAB) was defined in 2002 by the International Continence Society (ICS) as a storage symptom syndrome characterised by "urgency, with or without urgency urinary incontinence (UUI), usually with increased daytime frequency and nocturia" [START_REF] Abrams | The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society[END_REF]. The ICS also acknowledged within this definition that these symptoms are usually "suggestive of urodynamically demonstrable detrusor overactivity but can be due to other forms of urethravesical dysfunction" [START_REF] Abrams | The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society[END_REF]. This definition helped increase the awareness within the medical community regarding storage lower urinary tract symptoms (LUTS) and facilitated clinical research initiatives. Current guidelines propose a linear pathway, based purely on treatment invasiveness (conservative therapies and then drugs, minimally invasive surgery, and invasive surgery). However, the high rate of discontinuation of OAB medications [START_REF] Chapple | Persistence and adherence with mirabegron versus antimuscarinic agents in patients with overactive bladder: a retrospective observational study in UK clinical practice[END_REF] and the unclear results of recent randomised controlled trials (RCTs) comparing surgical options [START_REF] Amundsen | Onabotulinumtoxin A vs sacral neuromodulation on refractory urgency urinary incontinence in women: a randomized clinical trial[END_REF] highlight the limitation of this "one size fits all" approach.

Owing to the difficulty in identifying the underlying pathology for the development of OAB in most patients, it is often labelled as "idiopathic". Recently, it has been suggested that there are several subtypes of OAB [START_REF] Roosen | A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature[END_REF][START_REF] Apostolidis | Can we create a valid treatment algorithm for patients with drug resistant overactive bladder (OAB) syndrome or detrusor overactivity (DO)? Results from a think tank (ICI-RS 2015)[END_REF]. The aim of the present review is to provide an updated and comprehensive overview of the potential pathophysiology underlying OAB, with the hope that describing clinical phenotypes may lead to a personalised approach to therapy.

Evidence acquisition

A PubMed-based literature search was conducted in April 2018, screening for RCTs, prospective and retrospective series, animal model studies, and reviews about OAB pathophysiology and management. The search strategy included the following terms: "overactive bladder", "urgency", "bladder overactivity", "storage symptoms", "pathophysiology", "aetiogenesis", and "mechanism", used alone or in combination. After removal of duplicates, two authors (B.P. and J.N.C.) independently screened the titles and abstracts of 5197 records for eligibility. The inclusion criteria were studies directly addressing the pathophysiology and mechanisms of OAB, and their possible therapeutic implications.

Studies addressing male benign prostatic obstruction and/or enlargement as well as bladder pain syndrome/interstitial cystitis were excluded. The full texts of 294 potentially eligible studies were retrieved and screened. A flowchart of the selection process is shown in Figure 1. Reference lists of articles selected in our initial search were also screened in order to identify other relevant manuscripts.

Evidence synthesis

Multiple contributory factors to OAB phenotypes have been proposed, and several potential OAB subtypes have been identified (Supplementary Fig. 1) [START_REF] Roosen | A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature[END_REF][START_REF] Apostolidis | Can we create a valid treatment algorithm for patients with drug resistant overactive bladder (OAB) syndrome or detrusor overactivity (DO)? Results from a think tank (ICI-RS 2015)[END_REF] based on the underlying mechanism or pathophysiology, as summarised in Table 1.

Phenotyping according to urodynamic demonstration of detrusor overactivity

involuntary detrusor contractions during the filling phase which may be spontaneous or provoked" [START_REF] Abrams | The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society[END_REF]. DO has often been assumed to be synonymous with OAB [START_REF] Roosen | A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature[END_REF]; however, the presence of DO in only 50% of female OAB patients has prompted further research to consider the existence of alternative mechanisms relating to the role of the urothelium, suburothelium, urethra, and central nervous system (CNS) in the pathogenesis of OAB [START_REF] Roosen | A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature[END_REF].

This suggests that a "bladder afferent signalling" mechanism contributes to the OAB symptom complex. Each one of these mechanisms exerts their effect at different levels of the bladder afferent pathway, and we outline these various hypotheses below.

Myogenic hypothesis: urgency originating from the detrusor

The pioneering works of Brading suggest that DO-driven urgency is mostly related to myogenic dysfunction inherent to denervation-related supersensitivity. Drake et al [START_REF] Drake | Model of peripheral autonomous modules and a myovesical plexus in normal and overactive bladder function[END_REF] later proposed that DO may result from histological changes of the detrusor, leading to abnormal electrical coupling of smooth muscle cells so that physiological micromotions become synchronised into active involuntary detrusor contraction [START_REF] Hulls | Spatiotemporal analysis of spontaneous myogenic contractions in the urinary bladder of the rabbit: timing and patterns reflect reported electrophysiology[END_REF]. However, other data suggest that increased afferent signalling resulting from urothelial/suburothelial dysfunction may contribute to uninhibited detrusor contractions [START_REF] Chapple | Chapter 2: Pathophysiology of neurogenic detrusor overactivity and the symptom complex of "overactive bladder[END_REF] or that DO could be initiated from changes in central neural control of the micturition reflex (see section 3.1.4). As the definition and diagnosis of DO are well standardised [START_REF] Abrams | The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society[END_REF], this criterion has been regarded as a good candidate to profile OAB patients and has been investigated accordingly, but the results have been poor with regard to its impact on treatment outcomes [START_REF] Roosen | A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature[END_REF][START_REF] Rachaneni | Effectiveness of BTX-A and neuromodulation in treating OAB with or without detrusor overactivity: a systematic review[END_REF]. Among the current treatment armamentarium, only the use of conservative management and vaginal application of oestradiol, antimuscarinics, sacral neuromodulation (SNM), or intradetrusor botulinum toxin injections are supported by level 1 evidence in patients with urodynamically proven DO [START_REF] Roosen | A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature[END_REF].

Urotheliogenic hypothesis: urgency originating from the bladder urothelium/suburothelium

In the late 1980s, studies demonstrated that either DO or an abnormal perception of bladder filling could provoke the sensation of urgency [START_REF] Creighton | Sensory urgency: how full is your bladder?[END_REF]. Since then, several studies have shown abnormal detrusor sensory function in patients with OAB [START_REF] Yamaguchi | Defining overactive bladder as hypersensitivity[END_REF][START_REF] Lee | Overactive bladder is not only overactive but also hypersensitive[END_REF][START_REF] Blyweert | Interstitial cells of the bladder: the missing link?[END_REF]. The growing body of evidence on the role of increased activity of bladder afferents [START_REF] Chapple | Chapter 2: Pathophysiology of neurogenic detrusor overactivity and the symptom complex of "overactive bladder[END_REF][START_REF] Roosen | A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature[END_REF] supports the idea [START_REF] Roosen | A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature[END_REF][START_REF] Apostolidis | Can we create a valid treatment algorithm for patients with drug resistant overactive bladder (OAB) syndrome or detrusor overactivity (DO)? Results from a think tank (ICI-RS 2015)[END_REF] of urgency resulting from urothelial/suburothelial dysfunction in some patients, which may not manifest as DO. UUI may indeed be less frequent in this subgroup of patients, but urinary frequency may be more common [START_REF] Lee | Overactive bladder is not only overactive but also hypersensitive[END_REF][START_REF] Chen | Are patients with bladder oversensitivity different from those with urodynamically proven detrusor overactivity in female overactive bladder syndrome?[END_REF], and this is thought to be mediated by abnormal sensory and signalling properties of the urothelium and suburothelial fibroblasts [START_REF] Chapple | Chapter 2: Pathophysiology of neurogenic detrusor overactivity and the symptom complex of "overactive bladder[END_REF][START_REF] Roosen | A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature[END_REF] as well as possibly sympathetic dysfunction (see section 3.2.6). Beyond the sensory function of the urothelium/suburothelium, spontaneous contractions of the mucosa itself, originating from the muscularis mucosae, have been suggested as a possible origin of urgency [START_REF] Kushida | On the origin of spontaneous activity in the bladder[END_REF]. Drugs modulating the sensory pathways, bladder afferent firing, and release of neurotransmitters, such as botulinum toxin, ß3-adrenergic receptor agonists, or phosphodiesterase inhibitors, from the urothelium may be regarded as valuable options in these patients [START_REF] Kanai | Mechanisms of action of botulinum neurotoxins, ß3-adrenergic receptor agonists and IPDE5 inhibitors in modulating detrusor function in overactive bladder: ICI-RS 2011[END_REF]. Although the mechanisms of action have not been fully elucidated, biofeedback [START_REF] Wyndaele | Bladder biofeedback for the treatment of refractory sensory urgency in adults[END_REF], antimuscarinics [START_REF] Vijaya | Antimuscarinic effects on current perception threshold: a prospective placebo control study[END_REF],

and SNM [START_REF] Oliver | Measuring the sensations of urge and bladder filling during cystometry in urge incontinence and the effects of neuromodulation[END_REF] have been shown to reduce bladder oversensitivity and may also be considered as interesting options to tackle these urothelial/suburothelial dysfunctions.

Urethrogenic hypothesis: urgency originating from the urethra

In the early 20th century, Barrington [START_REF] Barrington | The component reflexes of micturition in the cats, parts 1 and 2[END_REF] described various component reflexes of micturition in cats. The second of theses reflexes was evoked by running water through the urethra, and -7-resulted in a strong bladder contraction mediated through pudendal and pelvic afferent and efferent signals [START_REF] Barrington | The component reflexes of micturition in the cats, parts 1 and 2[END_REF]. Using an animal model, Jung et al [START_REF] Jung | Urethral afferent nerve activity affects the micturition reflex; implication for the relationship between stress incontinence and detrusor instability[END_REF] found that activation of urethral afferents by urethral perfusion could modulate the micturition reflex and thus hypothesised that entry of urine into the proximal urethra in patients with stress urinary incontinence (SUI) may stimulate urethral afferents, inducing and/or increasing DO. Their findings were confirmed a few years later in healthy human volunteers with the hypothesis of an urethrovesical reflex [START_REF] Shafik | Role of positive urethrovesical feedback in vesical evacuation. The concept of a second micturition reflex: the urethrovesical reflex[END_REF]. Many patients experience urgency when moving from a sitting or lying position to a standing position. This sign has been postulated to be a clinical feature of OAB originated from the urethra [START_REF] Hubeaux | Stand up urgency: is this symptom related to a urethral mechanism?[END_REF]. These patients may not display DO on urodynamics, as the investigation is usually performed only in the sitting position and the catheter might partially seal the bladder neck. It could also be hypothesised that patient positioning during filling cystometry may influence involuntary detrusor contractions. Valsalva-induced involuntary detrusor contractions have been proposed as a way to unmask DO in these patients [START_REF] Serels | Surgical treatment for stress urinary incontinence associated with Valsalva induced detrusor instability[END_REF]. It is fairly well established that surgical repair of SUI improves storage LUTS in some patients with mixed incontinence [START_REF] Jain | Effectiveness of midurethral slings in mixed urinary incontinence: a systematic review and meta-analysis[END_REF], but the role of SUI surgery for isolated OAB (notably dry OAB) in selected patients with "urethral urgency" has not been evaluated to date. Indeed, there is unlikely to be an appetite for such a trial, particularly if patients are already dry. Conversely, de novo urgency is reported to occur in over 10% of patients undergoing any form of surgery for SUI. In patients with pelvic organ prolapse, it has been postulated, as part of the integral theory, that urgency may result from a prematurely activated micturition reflex caused by a lax vagina's inability to support bladder neck/proximal urethra stretch receptors, which could explain the high rates of OAB symptom resolution after surgical correction of pelvic organ prolapse [START_REF] Petros | The integral theory of continence[END_REF].

While primary deterioration of urethral tone has been advocated as a possible cause of OAB, the concept of urethral sphincter instability (ie, urethral pressure variation during bladder filling) has been proposed as another mechanism of urethra-driven urgency, which may be due to a lack of pudendal or central neurological control [START_REF] Kirschner-Hermanns | Fundamentals and clinical perspective of urethral sphincter instability as a contributing factor in patients with lower urinary tract dysfunction-ICI-RS 2014[END_REF]. Some evidence supports the role of SUI surgery in patients with urethral pressure variation [START_REF] Koonings | Combined detrusor instability and stress urinary incontinence: where is the primary pathology?[END_REF]. By reporting that patients with refractory OAB successfully treated with SNM had an immediate recurrence of both DO and urethral pressure variation after bilateral modulation of the pudendal nerves (which stimulates urethral function), Groenendijk et al [START_REF] Groenendijk | Urethral instability and sacral nerve stimulation-a better parameter to predict efficacy?[END_REF] suggested that SNM might be a valuable option in patients with urethra-driven OAB. Duloxetine may hypothetically be an interesting option in patients with "urethral urgency" by increasing urethral tone and has been shown to be an effective treatment for OAB in an RCT [START_REF] Steers | Duloxetine compared with placebo for treating women with symptoms of overactive bladder[END_REF].

Two other mechanisms of OAB symptoms due to severe SUI might be encompassed in this urethrogenic hypothesis. First, constant leakage in patients with severe SUI may result in a chronically underfilled, "defunctionalised" bladder. Such patients may develop artifactual DO or impaired compliance generating urgency [START_REF] Afraa | Urodynamic parameters evolution after artificial urinary sphincter implantation for post-radical prostatectomy incontinence with concomitant bladder dysfunction[END_REF]. Those bladder dysfunctions have been shown to resolve in many cases after surgical correction of SUI by restoring the physiological cycles of bladder storage and voiding [START_REF] Afraa | Urodynamic parameters evolution after artificial urinary sphincter implantation for post-radical prostatectomy incontinence with concomitant bladder dysfunction[END_REF]. The second mechanism would be pre-emptive urinary frequency to prevent incontinence episodes in patients with severe SUI.

Supraspinal hypothesis: urgency originating from the brain and brainstem

Central neural control of micturition has been studied extensively over the past few decades [START_REF] Holstege | Anatomical and physiological observations on supraspinal control of bladder and urethral sphincter muscles in the cat[END_REF], and the decreased capacity to functionally integrate afferent information or reduced supraspinal inhibitory control on the micturition reflex has been suggested since the late 1990s as a possible pathophysiological mechanism of OAB with the emergence of functional brain imaging [START_REF] Griffiths | Brain control of normal and overactive bladder[END_REF]. Increasing evidence supports the idea of two distinct subtypes of "brain OAB": one with and one without DO [START_REF] Griffiths | Bladder control, urgency, and urge incontinence: evidence from functional brain imaging[END_REF]. The insula (lower bladder volumes) and anterior cingulate gyrus/supplementary motor area (higher volumes) may be neural characteristics of urgency without DO, while the neural signature of DO seems to be deactivation in the prefrontal cortex [START_REF] Griffiths | Bladder control, urgency, and urge incontinence: evidence from functional brain imaging[END_REF]. The difference in supraspinal activity between OAB patients with or without DO was confirmed by Tadic et al [START_REF] Tadic | Brain activity underlying impaired continence control in older women with overactive bladder[END_REF], demonstrating that older age and a greater burden of white matter damage in patients with DO are associated with more severe functional urinary impairment. Several reports support the hypothesis that this "white matter disease" could be the anatomical substrate for the brain aetiology of OAB associated with DO, maybe through frontal hypoperfusion [START_REF] Apostolidis | Is there "brain OAB" and how can we recognize it? International Consultation on Incontinence-Research Society (ICI-RS) 2017[END_REF].

Behavioural therapies seem appropriate to treat "brain OAB" by offering the possibility of retraining the supraspinal network to function normally, as recently evidenced by Griffiths et al [START_REF] Griffiths | Brain mechanisms underlying urge incontinence and its response to pelvic floor muscle training[END_REF]. Interestingly, these authors observed two patterns of brain reactions to bladder filling and were able to predict a response or nonresponse to biofeedback [START_REF] Griffiths | Brain mechanisms underlying urge incontinence and its response to pelvic floor muscle training[END_REF]. SNM has been shown to influence activity in several brain areas involved in micturition control and to promote neuroplastic reorganisation of cortical activity [START_REF] Blok | Different brain effects during chronic and acute sacral neuromodulation in urge incontinent patients with implanted neurostimulators[END_REF]. Some evidence suggests that posterior tibial nerve stimulation (PTNS) could also trigger plastic reorganisation of the cortical network involved in micturition control [START_REF] Finazzi-Agrò | Percutaneous tibial nerve stimulation produces effects on brain activity: study on the modifications of the long latency somatosensory evoked potentials[END_REF].

Detrusor underactivity

Significant efforts have been made by the urological community over the past few years to define underactive bladder symptom complex as a new clinical entity [START_REF] Chapple | The underactive bladder: a new clinical concept?[END_REF]. While underactive bladder is considered to be the clinical correlate of urodynamically defined detrusor underactivity, the voiding symptomatology of detrusor underactivity has been shown to overlap with OAB and urgency was reported to be the most common symptom in patients with urodynamically proven detrusor underactivity (seen in over 50% of patients) [START_REF] Uren | Qualitative exploration of the patient experience of underactive bladder[END_REF]. Not surprisingly, underactive bladder symptoms are associated with an increased prevalence of urgency, UUI, and nocturia in a survey-based epidemiological study including 977 patients [START_REF] Faraj | A cross-sectional study in the USA of the epidemiology and quality of life of underactive bladder symptoms[END_REF]. The occurrence of urinary urgency in patients with DO can also be attributed to the wellknown DO/impaired contractility entity [START_REF] Rademakers | Prediction of sacral neuromodulation treatment success in men with impaired bladder emptying-time for a new diagnostic approach[END_REF], which, in this context, is no doubt related to increased postvoid residuals and the subsequent reduced functional bladder capacity. In addition, urgency in detrusor underactivity can be attributed to urinary tract infections (UTIs) secondary to chronic urinary retention [START_REF] Kim | Origin of urgency symptom in underactive bladder: commentary on "underactive bladder: clinical features, urodynamic parameters, and treatment[END_REF] or the impact of such retention on the urinary microbiota (see section 3.2.5). Current data suggest that detrusor underactivity may result from urothelial/suburothelial dysfunction (urotheliogenic hypothesis) and/or from detrusor muscle dysfunction (myogenic hypothesis) [START_REF] Kerdraon | Pathophysiology of detrusor underactivity in the elderly[END_REF]. Despite encouraging preliminary data on cholinesterase inhibitors, no treatment has yet been proved clinically effective in restoring detrusor contractility [START_REF] Smith | Advanced therapeutic directions to treat the underactive bladder[END_REF], and therefore, clean intermittent self-catheterisation is still regarded as the standard of care for these patients despite the fact that the effectiveness of catheterisation alone in relieving storage LUTS in such patients has not been assessed clearly [START_REF] Gani | The underactive bladder: diagnosis and surgical treatment options[END_REF]. Potential future treatments such as procontractile drugs or stem cell therapy are currently under investigation but remain hypothetical [START_REF] Gani | The underactive bladder: diagnosis and surgical treatment options[END_REF], and SNM has been shown to be helpful in patients with detrusor underactivity and OAB symptoms, especially in those with some residual detrusor contractility and DO [START_REF] Kim | Origin of urgency symptom in underactive bladder: commentary on "underactive bladder: clinical features, urodynamic parameters, and treatment[END_REF].

Phenotyping according to pathophysiological cofactors

Metabolic syndrome

A link between metabolic syndrome and OAB has been demonstrated in many studies, especially between obesity and OAB [START_REF] Bunn | Is there a link between overactive bladder and the metabolic syndrome in women? A systematic review of observational studies[END_REF][START_REF] He | Metabolic syndrome, inflammation and lower urinary tract symptoms: possible translational links[END_REF]. While this association was initially thought to be driven through benign prostatic hyperplasia/chronic prostatic inflammation [START_REF] He | Metabolic syndrome, inflammation and lower urinary tract symptoms: possible translational links[END_REF], increasing evidence has shown that OAB occurs equally in both men and women with metabolic syndrome [START_REF] Bunn | Is there a link between overactive bladder and the metabolic syndrome in women? A systematic review of observational studies[END_REF][START_REF] He | Metabolic syndrome, inflammation and lower urinary tract symptoms: possible translational links[END_REF]. OAB may have its own pathophysiology in patients with metabolic syndrome, relying on increased mechanical load stimulating sensory afferents of the trigone and bladder neck, but also on oxidative stress, systemic inflammation, and insulin resistance that promote chronic pelvic ischaemia and urothelial dysfunction [START_REF] Bunn | Is there a link between overactive bladder and the metabolic syndrome in women? A systematic review of observational studies[END_REF][START_REF] He | Metabolic syndrome, inflammation and lower urinary tract symptoms: possible translational links[END_REF].

Most of the current established treatment options for OAB, such as antimuscarinics, SNM, and botulinum toxin, have been reported to be less effective in patients with metabolic syndrome, or at least less effective than in other patient populations [START_REF] Richter | Characteristics associated with treatment response and satisfaction in women undergoing onabotulinumtoxin A and sacral neuromodulation for refractory urgency urinary incontinence[END_REF][START_REF] Lua | Comparing anticholinergic persistence and adherence profiles in overactive bladder patients based on gender, obesity, and major anticholinergic agents[END_REF][START_REF] Schneider | Do gender, age or lifestyle factors affect responses to antimuscarinic treatment in overactive bladder patients?[END_REF]. In contrast, the β3-adrenoreceptor agonist mirabegron, which was designed initially as an antiobesity drug [START_REF] Hainer | Beta3-adrenoreceptor agonist mirabegron-a potential antiobesity drug?[END_REF], was found to be equally effective in both obese and nonobese OAB patients [START_REF] Krhut | Impact of body mass index on treatment efficacy of mirabegron for overactive bladder in females[END_REF], and might be well suited for this patient population although dose adjustment may be needed [START_REF] Mossa | Beta-3 adrenoreceptor signaling pathways in urothelial and smooth muscle cells in the presence of succinate[END_REF].

In the first RCT to date assessing the role of phosphodiesterase inhibitors in female patients, daily low-dose tadalafil was reported to be an effective and well-tolerated treatment for OAB [START_REF] Chen | Efficacy of daily low-dose tadalafil for treating overactive -29-bladder: results of a randomized, double-blind, placebo-controlled trial[END_REF]. Considering the pathophysiological role of the inflammatory and oxidative stress pathways in patients with metabolic syndrome and OAB, phosphodiesterase inhibitors might become a noteworthy therapeutic option in such patients, as supported by a growing number of animal model studies and preliminary clinical trials [START_REF] Ding | Treatment of obesity-associated overactive bladder by the phosphodiesterase type-4 inhibitor roflumilast[END_REF]. However, based on the available literature, treatments targeting obesity, such as weight loss programmes and bariatric surgery, may be regarded as the most effective therapeutic options by acting on the multiple mechanisms listed above, with cure rates for UUI being as high as 19% and 79%, respectively [START_REF] Subak | Weight loss to treat urinary incontinence in overweight and obese women[END_REF][START_REF] Said | Effect of bariatric surgery on urinary and fecal incontinence: prospective analysis with 1-year follow-up[END_REF][START_REF] Luke | Effects of bariatric surgery on untreated lower urinary tract symptoms: a prospective multicentre cohort study[END_REF].

Affective disorders

While the impact of OAB may predispose affected individuals to anxiety and depressions, some evidence suggests that emotional stress and a history of anxiety/depression may be risk factors for the development of OAB in women [START_REF] Vrijens | Affective symptoms and the overactive bladder-a systematic review[END_REF]. This is not surprising in view of the central processing of afferent impulses in the limbic region of the brain. Recent data provided a detailed assessment of the temporal relationship between these symptoms, and demonstrated the influence of emotional stress and affective disorders on the natural history of OAB [START_REF] Vrijens | Affective symptoms and the overactive bladder-a systematic review[END_REF].

Hence, there may be a bidirectional association between affective disorders and OAB, with common underlying biological mechanisms resulting in co-occurrence of both disorders.

Corticotrophin-releasing factor (CRF) has been investigated as a possible common pathophysiological contributor to OAB and anxiety/depression [START_REF] Klausner | Corticotropin releasing factor: a mediator of emotional influences on bladder function[END_REF]. The concomitant decrease in serum CRF levels and improvement of depression-induced OAB observed using a CRF receptor type 1 antagonist in a recent animal model study confirm this possible mechanism, while highlighting a possible therapeutic pathway for social stress-induced OAB [START_REF] Wróbel | SN003, a CRF1 receptor antagonist, attenuates depressive-like behavior and detrusor overactivity symptoms induced by 13-cis-retinoic acid in rats[END_REF]. Serotonin depletion has been postulated as another shared pathophysiological candidate for both anxiety/depression and OAB, as its role in affective disorders is well established and several experimental studies have demonstrated that lowering of serotonin levels in the CNS was accompanied by urinary frequency and DO [START_REF] De Groat | Influence of central serotonergic mechanisms on lower urinary tract function[END_REF][START_REF] Chiba | The role of serotonergic mechanism in the rat prefrontal cortex for controlling the micturition reflex: an in vivo microdialysis study[END_REF]. Duloxetine, a noradrenalineserotonin reuptake inhibitor, has been reported to improve significantly frequency and urgency in an RCT of female OAB patients [START_REF] Steers | Duloxetine compared with placebo for treating women with symptoms of overactive bladder[END_REF] and may be a valuable candidate for the treatment of stress-induced OAB, as shown in animal studies [START_REF] Wróbel | The influence of duloxetine on detrusor overactivity in rats with depression induced by 13-cis-retinoic acid[END_REF]. Indeed, it is licensed for the treatment of depression at a lower dose than that studied for the treatment of SUI.

Transient receptor potential (TRP) channel dysfunctions might also play a key role in the cooccurrence of affective disorders and OAB [START_REF] Kaneko | Transient receptor potential (TRP) channels: a clinical perspective[END_REF]. Central sensitisation, defined as increased responsiveness of nociceptive neurons in the CNS to normal or subthreshold afferent input, has recently been suggested as a last common pathophysiological cofactor of anxiety/depression and OAB [START_REF] Reynolds | Does central sensitization help explain overactive bladder[END_REF]. Many of the pathophysiological mechanisms mentioned above may be common to social stress-induced OAB and functional gastrointestinal disorders/pelvic organ cross-talk OAB phenotypes (see section 3.2.5) [START_REF] Leue | Functional urological disorders: a sensitized defence response in the bladder-gut-brain axis[END_REF]. Duloxetine, TRP vanilloid (TRPV) antagonists, or CRF antagonists may target shared biological underpinning of anxiety/depression and OAB, and thus, might become treatment options for emotional -13-stress-induced OAB. SNM is the most widely studied and properly assessed treatment in our current armamentarium in this population [START_REF] Killinger | Coexisting depressive symptoms do not limit the benefits of chronic neuromodulation: a study of over 200 patients[END_REF].

Sex hormone deficiency

The impact of sex hormone deficiency on the lower urinary tract in female patients has been clearly established with oestrogen and progesterone receptors demonstrated in the urethra, bladder, and pelvic floor muscles [START_REF] Hanna-Mitchell | Do we need to know more about the effects of hormones on lower urinary tract dysfunction? ICI-RS 2014[END_REF]. Epidemiological studies have supported the role of sex hormone deficiency in the aetiogenesis of LUTS, with up to 70% of women relating the onset of urinary incontinence to their final menstruations [START_REF] Hanna-Mitchell | Do we need to know more about the effects of hormones on lower urinary tract dysfunction? ICI-RS 2014[END_REF]. Several mechanisms could explain the role of oestrogen deprivation in the onset of urinary urgency such as increased detrusor contractility through Rho-kinase pathway activation, increased acetylcholine release, changes in urothelial afferent signalling, or increased connexin-43 expression [START_REF] Hanna-Mitchell | Do we need to know more about the effects of hormones on lower urinary tract dysfunction? ICI-RS 2014[END_REF][START_REF] Lee | Changes of muscarinic receptors and connexin-43 expression as a mechanism of overactive bladder in ovariectomized rats[END_REF]. OAB in these patients is commonly associated with UTIs and vulvovaginal symptoms such as vaginal dryness, itching, and dyspareunia, which have recently been defined as a symptom complex known as genitourinary syndrome of menopause [START_REF] Portman | Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society[END_REF]. According to the latest Cochrane metaanalysis, the use of vaginal oestrogen may improve urinary incontinence, especially UUI [START_REF] Cody | Oestrogen therapy for urinary incontinence in post-menopausal women[END_REF],

although the relevance of this option might be questioned in women without vaginal atrophy.

In an RCT, Nelken et al [START_REF] Nelken | Randomized trial of estradiol vaginal ring versus oral oxybutynin for the treatment of overactive bladder[END_REF] reported similar effects when using a vaginal oestradiol ring or oral oxybutynin in postmenopausal women with OAB but with more side effects for oxybutynin, which reinforces the putative role of local oestrogen in these patients. The impact of menopausal status on the outcome of standard OAB treatments has not been evaluated except for mirabegron, with a recent prospective study reporting no influence of sex hormone levels on the clinical efficacy of the β3 agonist [START_REF] Kallner | Hormonal influence on the effect of mirabegron treatment for overactive bladder[END_REF].

In contrast to women, evidence regarding sex hormone deficiency as a causative factor of OAB in men is scarce, but experimental studies suggest that testosterone may decrease detrusor excitability [START_REF] Hristov | Testosterone decreases urinary bladder smooth muscle excitability via novel signaling mechanism involving direct activation of the BK channels[END_REF], improve bladder wall fibrosis [START_REF] De Barros | Testosterone supplementation's effects on age-related bladder remodeling-experimental study in rats[END_REF], and may impact urothelial mediator release [START_REF] Bravo | Effect of short-term androgen deficiency on bladder contractility and urothelial mediator release[END_REF], providing a rationale for a causative role of androgen deficiency in the aetiogenesis of OAB. Testosterone replacement has been shown to improve LUTS in male patients, unfortunately without detailed analysis of storage symptoms [START_REF] Haider | Long-term testosterone therapy improves urinary -31-and sexual function, and quality of life in men with hypogonadism: results from a propensity matched subgroup of a controlled registry study[END_REF].

Urinary microbiota

Following advances in culture methods, recent data suggested that the human urinary tract contains microbial communities referred to as the urinary microbiota, challenging the old dogma that urine is usually sterile [START_REF] Drake | The urinary microbiome and its contribution to lower urinary tract symptoms; ICI-RS 2015[END_REF][START_REF] Aragón | The urinary tract microbiome in health and disease[END_REF]. According to recent preliminary studies, the urinary microbiota may play a role in the pathogenesis of OAB, although the mechanisms underlying the causative relationship, as well as its possible therapeutic implications, are still unclear [START_REF] Aragón | The urinary tract microbiome in health and disease[END_REF]. Bacterial DNA [START_REF] Pearce | The female urinary microbiome: a comparison of women with and without urgency urinary incontinence[END_REF][START_REF] Brubaker | Urinary bacteria in adult women with urgency urinary incontinence[END_REF] and a higher load of bacteria [START_REF] Kj | Incontinence medication response relates to the female urinary microbiota[END_REF] are more frequently detected in patients with UUI, with possibly decreased urinary microbiome diversity [START_REF] Pearce | The female urinary microbiome: a comparison of women with and without urgency urinary incontinence[END_REF][START_REF] Kj | Incontinence medication response relates to the female urinary microbiota[END_REF][START_REF] Karstens | Does the urinary microbiome play a role in urgency urinary incontinence and its severity?[END_REF][START_REF] Wu | Urinary microbiome and psychological factors in women with overactive bladder[END_REF]. Some Lactobacillus spp. (eg, Lactobacillus crispatus) may be markers of a healthy female bladder with a possibly lower Lactobacillus load in patients with UUI [START_REF] Pearce | The female urinary microbiome: a comparison of women with and without urgency urinary incontinence[END_REF][START_REF] Kj | Incontinence medication response relates to the female urinary microbiota[END_REF]. Owing to their acid-producing qualities, Lactobacillus spp. may protect the lower urinary tract by controlling the growth of more virulent bacteria unable to survive in an acidic environment.

While intravaginally administered Lactobacillus has shown promise in preventing recurrent

UTIs, no studies to date have investigated the role of Lactobacillus probiotics in OAB [START_REF] Pearce | The female urinary microbiome: a comparison of women with and without urgency urinary incontinence[END_REF].

Several preliminary studies have suggested a significant impact of the urinary microbiome on the outcomes of various OAB treatments such as antimuscarinics or intradetrusor botulinum toxin injection [START_REF] Brubaker | Urinary bacteria in adult women with urgency urinary incontinence[END_REF][START_REF] Kj | Incontinence medication response relates to the female urinary microbiota[END_REF][START_REF] Pearce | The female urinary microbiome in urgency urinary incontinence[END_REF], with responders more likely to have fewer bacteria and a less diverse community at baseline in some of these studies [START_REF] Kj | Incontinence medication response relates to the female urinary microbiota[END_REF]. This supports the idea that urinary microbiota-related OAB may not be treated effectively by conventional OAB treatments, although data from the three available studies are contradictory [START_REF] Pearce | The female urinary microbiome in urgency urinary incontinence[END_REF]. In a recent -15-study, an aberrant urinary microbiome with less diversity was found to be positively correlated with higher levels of depression and anxiety [START_REF] Wu | Urinary microbiome and psychological factors in women with overactive bladder[END_REF], which suggests that urinary microbiota may have the same potential as the gut microbiota to communicate with the brain, notably eliciting central sensitisation. Hence, like the well-established brain-gut-microbiota axis, a brain-bladder-microbiota axis might also exist. Whether this axis could involve the same mechanisms of bidirectional communication (neurotransmitter release, immune system stimulation, etc.) and be integrated as part of a more global brain-gut-bladder microbiota axis through central sensitisation warrants further investigation, but could provide a better understanding of OAB syndrome (see section 3.2.5). In addition it is clear that in clinical practice UTIs are usually characterised by significant bladder storage symptoms.

Functional gastrointestinal disorders

The bladder and colorectum have the same embryological origin, both developing from the cloaca, and thus share spinally derived neural pathways with dichotomised afferents innervating both organs and converging at a single dorsal ganglion root, which allows mechanisms of communication between the bladder and the colon known as cross-talk [START_REF] Malykhina | Do the urinary bladder and large bowel interact, in sickness or in health? ICI-RS 2011[END_REF].

These common neural pathways may also be the drivers of cross-sensitisation defined as sensitisation of afferent nerves of one of the pelvic organs due to an acute insult in the other [START_REF] Malykhina | Do the urinary bladder and large bowel interact, in sickness or in health? ICI-RS 2011[END_REF]. The co-occurrence of urological and gastrointestinal functional disorders reported in numerous studies is thought to be underpinned at least partly by the pelvic organ cross-talk and cross-sensitisation mechanisms [START_REF] Malykhina | Do the urinary bladder and large bowel interact, in sickness or in health? ICI-RS 2011[END_REF][START_REF] Kaplan | Systematic review of the relationship between bladder and bowel function: implications for patient management[END_REF].

Several reports have suggested bidirectional relationships between OAB and faecal incontinence or constipation [START_REF] Malykhina | Do the urinary bladder and large bowel interact, in sickness or in health? ICI-RS 2011[END_REF][START_REF] Kaplan | Systematic review of the relationship between bladder and bowel function: implications for patient management[END_REF]. However, the gastrointestinal condition that has most frequently been inter-related to OAB is irritable bowel syndrome (IBS) [START_REF] Malykhina | Do the urinary bladder and large bowel interact, in sickness or in health? ICI-RS 2011[END_REF][START_REF] Kaplan | Systematic review of the relationship between bladder and bowel function: implications for patient management[END_REF][START_REF] Persson | The relationship between irritable bowel syndrome, functional dyspepsia, chronic fatigue and overactive bladder syndrome: a controlled study 6 years after acute gastrointestinal infection[END_REF], with a prevalence of IBS as high as 33.3% in patients with OAB [START_REF] Matsumoto | Relationship between overactive bladder and irritable bowel syndrome: a large-scale internet survey in Japan using the overactive bladder symptom score and Rome III criteria[END_REF], both disorders being characterised by increased frequency of visceral emptying due to increased sensation (urgency for OAB; pain and discomfort for IBS) [START_REF] Thompson | Rome III diagnostic questionnaire for the adult functional GI disorders (including alarm questions) and scoring algorithm[END_REF].

There has been growing interest over the past few years on the possible role of central sensitisation in the co-occurrence of functional urological and gastrointestinal disorders [START_REF] Reynolds | Does central sensitization help explain overactive bladder[END_REF].

This central sensitisation might be triggered by pelvic organ cross-sensitisation, with activation of peripheral neural pathways leading to an amplification of signalling in the spinal cord and brain [START_REF] Kaplan | Systematic review of the relationship between bladder and bowel function: implications for patient management[END_REF]. However, some authors have recently suggested that central sensitisation could be a primary dysfunction affecting the co-occurrence of both gastrointestinal and urological functional disorders alongside affective disorders (ie, anxiety and depression) as part of a brain-gut-bladder axis [START_REF] Reynolds | Does central sensitization help explain overactive bladder[END_REF][START_REF] Leue | Functional urological disorders: a sensitized defence response in the bladder-gut-brain axis[END_REF]. This possible brain-gut-bladder axis-OAB phenotype might be induced by stress due to either psychological factors (eg, a previous traumatic event)

or physical factors (ie, internal/external physical threat). While infection is a well-established internal physical threat that could cause stress, hypothetically the gut and bladder microbiota could be involved as causative factors through peripheral and central sensitisation, which would support the idea of a brain-gut-bladder-microbiota axis [START_REF] Reynolds | Does central sensitization help explain overactive bladder[END_REF][START_REF] Leue | Functional urological disorders: a sensitized defence response in the bladder-gut-brain axis[END_REF].

Treatments targeting the bladder or colorectum have been reported to improve or worsen functional disorders in the other organ [START_REF] Malykhina | Do the urinary bladder and large bowel interact, in sickness or in health? ICI-RS 2011[END_REF][START_REF] Kaplan | Systematic review of the relationship between bladder and bowel function: implications for patient management[END_REF], which may support the use of treatments that have been proved to target both the bladder and the bowel in this OAB phenotype, such as SNM or PTNS [START_REF] Caremel | Can sacral neuromodulation improve minor incontinence symptoms in doubly incontinent patients successfully treated for major incontinence symptoms?[END_REF][START_REF] Booth | A feasibility study of transcutaneous posterior tibial nerve stimulation for bladder and bowel dysfunction in elderly adults in residential care[END_REF]. Recent studies have indicated the potential role of SNM/PTNS in treating IBS in patients with affective disorders [START_REF] Lewis-Fernández | An open-label pilot study of duloxetine in patients with irritable bowel syndrome and comorbid major depressive disorder[END_REF], and selected data also support the role of SNM/PTNS in treating social stress-induced OAB [START_REF] Steers | Duloxetine compared with placebo for treating women with symptoms of overactive bladder[END_REF][START_REF] Steers | Duloxetine compared with placebo for treating women with symptoms of overactive bladder[END_REF][START_REF] Wróbel | The influence of duloxetine on detrusor overactivity in rats with depression induced by 13-cis-retinoic acid[END_REF]. Through this logic, duloxetine may also be a future therapeutic option in the management of patients with "brain-gut-bladder axis-OAB" by targeting central sensitisation. Treatments aimed at interfering with neurogenic inflammation underlying pelvic organ cross-sensitisation such as TRPV1 receptor antagonists -17-or α1-adrenoreceptor antagonists might also be interesting therapeutic approaches to evaluate in this population.

Autonomic nervous system dysfunction

Sympathetic, parasympathetic, and somatic nerves are well-known determinants of lower urinary tract physiological functioning [START_REF] Chapple | Chapter 2: Pathophysiology of neurogenic detrusor overactivity and the symptom complex of "overactive bladder[END_REF][START_REF] Chen | Are patients with bladder oversensitivity different from those with urodynamically proven detrusor overactivity in female overactive bladder syndrome?[END_REF] and are altered in several neurological conditions proven to be associated with lower urinary tract dysfunction (eg, Parkinsonism, multiple sclerosis) [START_REF] Mcleod | Disorders of the autonomic nervous system: Part 1. Pathophysiology and clinical features[END_REF]. Blanc et al [START_REF] Blanc | Activity of the autonomous nervous system measured based on the variability of heart rate in female urinary incontinence[END_REF] were the first authors to hypothesise that subclinical autonomic nervous system dysfunction may be a causative factor of "idiopathic" OAB. A few years later, Choi et al [START_REF] Choi | Analysis of heart rate variability in female patients with overactive bladder[END_REF] confirmed the hypothesis of an autonomic imbalance associated with OAB. More comprehensive insights into this autonomic balance dysfunction were emphasised by Hubeaux et al [START_REF] Hubeaux | Autonomic nervous system activity during bladder filling assessed by heart rate variability analysis in women with idiopathic overactive bladder syndrome or stress urinary incontinence[END_REF] by assessing heart rate variability during filling cystometry. They reported the predominance of parasympathetic activity when the bladder was empty and a preponderance of sympathetic activity at the end of bladder filling in women with OAB [START_REF] Hubeaux | Autonomic nervous system activity during bladder filling assessed by heart rate variability analysis in women with idiopathic overactive bladder syndrome or stress urinary incontinence[END_REF], which could suggest that bladder filling induces a global sympathetic response in women with OAB. Interestingly, the same research group initiated another study, which demonstrated that sympathetic dysfunction might be predominant over parasympathetic dysfunction in OAB patients and that OAB patients with autonomic dysfunction may be less likely to exhibit DO on urodynamics [START_REF] Hubeaux | Evidence for autonomic nervous system dysfunction in females with idiopathic overactive bladder syndrome[END_REF]. While other studies demonstrated similar alterations of sympathetic activity in OAB patients [START_REF] Ben-Dror | Alterations of heart rate variability in women with overactive bladder syndrome[END_REF], an association between OAB and increased parasympathetic activation has also been reported [START_REF] Aydogmus | Is overactive bladder a nervous or bladder disorder? Autonomic imaging in patients with overactive bladder via dynamic pupillometry[END_REF].

Interestingly, in a recent study, it was reported that antimuscarinics may decrease parasympathetic dysfunction while improving OAB symptoms in these patients [START_REF] Aydogmus | Is overactive bladder a nervous or bladder disorder? Autonomic imaging in patients with overactive bladder via dynamic pupillometry[END_REF]. In contrast, a recent report suggested that sympathetic dysfunction in OAB patients could predict a poor response to antimuscarinics and suggested a possible role of ß3 agonists to restore impaired sympathetic efferent pathway activation eliciting detrusor muscle inhibition [START_REF] Ates | Impact of sympathetic dysfunction -33-in the etiology of overactive bladder in women: a preliminary study[END_REF].

The various autonomic testing tools available may then help tailor first-line treatment in OAB patients.

How to identify the phenotypes

Currently, the various OAB subtypes are mostly identified through an exjuvantibus management, failure of first-line treatments narrowing down the search towards the actual mechanisms/aetiologies, and proper treatment [START_REF] Apostolidis | Can we create a valid treatment algorithm for patients with drug resistant overactive bladder (OAB) syndrome or detrusor overactivity (DO)? Results from a think tank (ICI-RS 2015)[END_REF]. Hypothetical approaches to distinguish the different OAB patterns are outlined below, supporting a "prism" approach (Fig. 1). These assumptions regarding the diagnostic approach to these multiple OAB subtypes as well as their speculative therapeutic implications are displayed in Figure 2. Hypotheses on the diagnostic approach are put forward below, but are not meant to replace the European Association of Urology, American Urological Association, and International Consultation on Incontinence evidence-based guidelines in daily practice for now [START_REF] Gormley | Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline[END_REF][START_REF] Nambiar | EAU guidelines on assessment and nonsurgical management of urinary incontinence[END_REF][START_REF] Abrams | 6th International Consultation on Incontinence[END_REF].

Clinical examination and medical history

It is likely that most of the profiling of OAB patients could be achieved through a thorough medical history and clinical examination. Indeed, a patient's medical history could specifically identify several of the pathophysiological cofactors mentioned above (metabolic syndrome, menopause, affective disorders, and gastrointestinal functional disorders). The use of dedicated questionnaires and scores might help in detecting and quantifying these important concomitant disorders (eg, Hospital Anxiety and Depression Score for affective disorders [START_REF] Drossaerts | Screening for depression and anxiety in patients with storage or voiding dysfunction: a retrospective cohort study predicting outcome of sacral neuromodulation[END_REF]). Thorough clinical interview and physical examination to identify pertinent signs and symptoms will aid in highlighting any underlying pathological mechanisms contributing to OAB. For example, one may identify specific components of metabolic -19-syndrome (obesity, hypertension, etc.) and symptoms suggestive of andropause (erectile dysfunction, decreased libido, etc.) or menopause (especially vulvovaginal atrophy). It is also important to elucidate specifics regarding the nature of a patient's LUTS. The coexistence of voiding LUTS may suggest detrusor underactivity, while urgency on standing may suggest a urethral origin of urgency. The existence of urgency with or without incontinence (OAB wet vs OAB dry) could help in differentiating DO-versus hypersensitivity-driven urgency (and then hypothetically myogenic vs urotheliogenic dysfunction) [START_REF] Giarenis | Can we predict detrusor overactivity in women with lower urinary tract symptoms? The King's Detrusor Overactivity Score (KiDOS)[END_REF] with possible therapeutic implications (eg, scant evidence to support the use of botulinum toxin in OAB dry patients) [START_REF] Gormley | Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline[END_REF][START_REF] Apostolidis | Can we create a valid treatment algorithm for patients with drug resistant overactive bladder (OAB) syndrome or detrusor overactivity (DO)? Results from a think tank (ICI-RS 2015)[END_REF]. Uroflowmetry and measurement of postvoid residual would be of interest to help in the screening for detrusor underactivity.

Simple clinical autonomic nervous system testing (eg, heart rate variability, blood pressure response to standing, hand grip exercise, cold pressor test, etc.) may help identify subclinical autonomic nervous system dysfunction in OAB patients [START_REF] Blanc | Activity of the autonomous nervous system measured based on the variability of heart rate in female urinary incontinence[END_REF][START_REF] Choi | Analysis of heart rate variability in female patients with overactive bladder[END_REF][START_REF] Hubeaux | Autonomic nervous system activity during bladder filling assessed by heart rate variability analysis in women with idiopathic overactive bladder syndrome or stress urinary incontinence[END_REF][START_REF] Hubeaux | Evidence for autonomic nervous system dysfunction in females with idiopathic overactive bladder syndrome[END_REF][START_REF] Ben-Dror | Alterations of heart rate variability in women with overactive bladder syndrome[END_REF][START_REF] Aydogmus | Is overactive bladder a nervous or bladder disorder? Autonomic imaging in patients with overactive bladder via dynamic pupillometry[END_REF][START_REF] Ates | Impact of sympathetic dysfunction -33-in the etiology of overactive bladder in women: a preliminary study[END_REF].

Clinical manifestations of central sensitisation could also be detected during clinical examination using a group of psychophysical laboratory techniques known as quantitative sensory testing [START_REF] Ates | Impact of sympathetic dysfunction -33-in the etiology of overactive bladder in women: a preliminary study[END_REF].

Urodynamics

Computer-urodynamic multichannel investigation might be helpful in identifying the origin of urgency by assessing the presence of DO suggestive of detrusor or supraspinal cause (see sections 3.1.1 and 3.1.4). In contrast, bladder oversensitivity without DO may be the urodynamic feature of urothelial origin [START_REF] Creighton | Sensory urgency: how full is your bladder?[END_REF][START_REF] Yamaguchi | Defining overactive bladder as hypersensitivity[END_REF][START_REF] Lee | Overactive bladder is not only overactive but also hypersensitive[END_REF][START_REF] Blyweert | Interstitial cells of the bladder: the missing link?[END_REF][START_REF] Roosen | A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature[END_REF]. Standing DO, Valsalva-induced DO, or urethral pressure variations during filling cystometry may suggest urgency originating from the urethra [START_REF] Jung | Urethral afferent nerve activity affects the micturition reflex; implication for the relationship between stress incontinence and detrusor instability[END_REF][START_REF] Shafik | Role of positive urethrovesical feedback in vesical evacuation. The concept of a second micturition reflex: the urethrovesical reflex[END_REF][START_REF] Hubeaux | Stand up urgency: is this symptom related to a urethral mechanism?[END_REF][START_REF] Serels | Surgical treatment for stress urinary incontinence associated with Valsalva induced detrusor instability[END_REF][START_REF] Jain | Effectiveness of midurethral slings in mixed urinary incontinence: a systematic review and meta-analysis[END_REF][START_REF] Petros | The integral theory of continence[END_REF][START_REF] Kirschner-Hermanns | Fundamentals and clinical perspective of urethral sphincter instability as a contributing factor in patients with lower urinary tract dysfunction-ICI-RS 2014[END_REF]. The diagnosis of detrusor underactivity as a contributing factor of storage symptoms could be made from the urodynamic study [START_REF] Chapple | The underactive bladder: a new clinical concept?[END_REF][START_REF] Uren | Qualitative exploration of the patient experience of underactive bladder[END_REF][START_REF] Faraj | A cross-sectional study in the USA of the epidemiology and quality of life of underactive bladder symptoms[END_REF][START_REF] Rademakers | Prediction of sacral neuromodulation treatment success in men with impaired bladder emptying-time for a new diagnostic approach[END_REF]. However, the clinical relevance of such urodynamic phenotyping of OAB is questionable, as several series have reported similar efficacy of various OAB treatments in patients with or without DO [START_REF] Rachaneni | Effectiveness of BTX-A and neuromodulation in treating OAB with or without detrusor overactivity: a systematic review[END_REF].

Given the possible lack of statistical power and poor design of most of these studies, as well as the absence of data regarding the impact of more complex urodynamic features on treatment outcomes, the role of urodynamics in the diagnosis of OAB phenotypes would require further evaluation.

Is further "futuristic" diagnostic testing needed?

Hypothetically, some more complex testing might be of interest to identify OAB phenotypes; measurement of serum and urine concentrations of stress-related hormones such as CRF or cortisol may be used in the future to diagnose stress-induced OAB [START_REF] Roosen | A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature[END_REF][START_REF] Klausner | Corticotropin releasing factor: a mediator of emotional influences on bladder function[END_REF]. Measuring serum testosterone may help detect androgen deficiency as a contributor of OAB in elderly men [START_REF] Hanna-Mitchell | Do we need to know more about the effects of hormones on lower urinary tract dysfunction? ICI-RS 2014[END_REF]. Inflammatory markers such as serum C-reactive protein may be of interest to identify whether inflammation is involved in the pathophysiology of OAB [START_REF] Bunn | Is there a link between overactive bladder and the metabolic syndrome in women? A systematic review of observational studies[END_REF][START_REF] He | Metabolic syndrome, inflammation and lower urinary tract symptoms: possible translational links[END_REF][START_REF] Malykhina | Do the urinary bladder and large bowel interact, in sickness or in health? ICI-RS 2011[END_REF][START_REF] Hsiao | The role of serum C-reactive protein in women with lower urinary tract symptoms[END_REF].

Functional brain imaging eventually coupled with urodynamics may provide supraspinal markers of the different "brain" OAB subtypes [START_REF] Griffiths | Brain control of normal and overactive bladder[END_REF][START_REF] Griffiths | Bladder control, urgency, and urge incontinence: evidence from functional brain imaging[END_REF][START_REF] Tadic | Brain activity underlying impaired continence control in older women with overactive bladder[END_REF][START_REF] Weissbart | Specific changes in brain activity during urgency in women with overactive bladder after successful sacral neuromodulation: an fMRI study[END_REF][START_REF] Nardos | Abnormal functional connectivity in women with urgency urinary incontinence: can we predict disease presence and severity in individual women using Rs-fcMRI[END_REF]. Urinary markers involved in LUTS pathophysiology have widely been studied over the past 10 yr [START_REF] Peyronnet | The role of urinary markers in the assessment and follow-up of lower urinary tract disorders: a literature review[END_REF] and could theoretically point towards some OAB subtypes (eg, increased urinary levels of nerve growth factor and brain-derived neurotrophic factor may indicate urothelial/suburothelial "sensory" dysfunction or central sensitisation) [START_REF] Lee | Overactive bladder is not only overactive but also hypersensitive[END_REF][START_REF] Blyweert | Interstitial cells of the bladder: the missing link?[END_REF][START_REF] Roosen | A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature[END_REF][START_REF] Chen | Are patients with bladder oversensitivity different from those with urodynamically proven detrusor overactivity in female overactive bladder syndrome?[END_REF][START_REF] Kushida | On the origin of spontaneous activity in the bladder[END_REF][START_REF] Reynolds | Does central sensitization help explain overactive bladder[END_REF][START_REF] Peyronnet | The role of urinary markers in the assessment and follow-up of lower urinary tract disorders: a literature review[END_REF][START_REF] Birder | How does the urothelium affect bladder function in health and disease? ICI-RS 2011[END_REF].

Finally, 16S RNA sequencing and expanded quantitative urine culture could help in identifying the urinary microbiota [START_REF] Aragón | The urinary tract microbiome in health and disease[END_REF].

While the interest of this elaborated testing in clinical research is obvious to enhance the understanding of the multiple pathophysiological contributors of OAB, their role in daily practice in the future is unlikely due to practical and cost-effectiveness issues.

-21-

Discussion

This report provides a comprehensive overview of OAB pathophysiology in an attempt to clarify the complexity underlying the concept of "idiopathic" OAB and to plead for a shift towards the more accurate nomenclature of multifactorial OAB. Clearly different mechanisms could provoke the sensation of urinary urgency. Increasingly, the evidence over the past few years has shown that metabolic syndrome [START_REF] Bunn | Is there a link between overactive bladder and the metabolic syndrome in women? A systematic review of observational studies[END_REF], affective disorders [START_REF] Klausner | Corticotropin releasing factor: a mediator of emotional influences on bladder function[END_REF], sex hormone deficiency [START_REF] Hanna-Mitchell | Do we need to know more about the effects of hormones on lower urinary tract dysfunction? ICI-RS 2014[END_REF], urinary microbiota [START_REF] Aragón | The urinary tract microbiome in health and disease[END_REF], gastrointestinal functional disorders [START_REF] Malykhina | Do the urinary bladder and large bowel interact, in sickness or in health? ICI-RS 2011[END_REF], and subclinical autonomic nervous system dysfunction [START_REF] Hubeaux | Autonomic nervous system activity during bladder filling assessed by heart rate variability analysis in women with idiopathic overactive bladder syndrome or stress urinary incontinence[END_REF] may all be associated with OAB, and that OAB could have its own specific pathophysiology within all these frameworks. We feel that a "prism" spectrum approach could help identify these various OAB pathophysiological features. Numerous clues in the literature indicate that such phenotyping of OAB may translate into improved treatment decision making and outcomes despite data being too scarce currently to assert that each phenotype would need a specific treatment algorithm. It is important to stress that these OAB subtypes are clearly not mutually exclusive and that they likely commonly overlap. This may provide a robust rationale for combination therapy, as it could tackle several mechanisms increasing the chance of therapeutic success.

Our report has several limitations. Although the ideas presented here have arisen from peerreviewed publications and reached consensus among a panel of recognised international experts in the field, the new concept is not based on high-level evidence studies. Nevertheless, we believe that the data presented here could be strong enough to challenge the relevance of the treatment algorithm described in current international guidelines [START_REF] Gormley | Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline[END_REF][START_REF] Nambiar | EAU guidelines on assessment and nonsurgical management of urinary incontinence[END_REF]. Another drawback is that translating these concepts into daily clinical practice will require additional investigations that may be hampered by the lack of a standardised definition of the various OAB pathophysiological features as well as the lack of consensual techniques to diagnose these key contributing factors. Some exploratory therapeutic strategies of OAB such as antidiuresis with desmopressin could not be addressed in the way the present manuscript was designed, which could be regarded as a shortcoming [START_REF] Hashim | Desmopressin, as a "designer drug," in the treatment of overactive bladder syndrome[END_REF]. Although we decided to exclude the role of bladder outlet obstruction and bladder pain syndrome in our hypotheses, this could be regarded as a significant limitation to the present review. This decision was made because the pathophysiological mechanisms underlying OAB symptoms in these clinical scenarios were deemed to largely overlap those of some phenotypes presented herein (myogenic, urotheliogenic, and detrusor underactivity for bladder outlet obstruction; affective disorders, urinary microbiota, and functional gastrointestinal disorders for bladder pain syndrome).

However, one could consider that bladder outlet obstruction and bladder pain syndrome would fulfil the criteria to be considered as two additional OAB subtypes, especially with regard to their distinct therapeutic algorithms. Finally, the decision to consider equally OAB subtypes based on well-established pathophysiological mechanisms and those defined by the existence of pathophysiological cofactors could be a matter of debate, as in the latter case, one could question the link between each of these comorbidities and OAB symptoms in a given patient.

Conclusions

There is not one single form of OAB syndrome but rather several OAB phenotypes based on the underlying mechanisms and pathophysiological cofactors, supporting a paradigm shift in OAB towards treatment strategies that could be tailored to individual patient characteristics (Fig. 3). We believe that new studies should assess the outcomes of the current OAB treatments for each different OAB subpopulation, leading to more personalised medical approaches, particularly as we progress into the era of combination pharmacotherapy. The urological community, research organisations, health insurances, and governmental health

Fig. 1 -Fig. 2 -Fig. 3 -

 123 Fig. 1 -PRISMA flowchart. PRISMA = Preferred Reporting Items for Systematic

Figure 1 Figure 2 OAB

 12 Figure 1

Table 1 -Possible OAB phenotypes

 1

	Phenotyping according to pathophysiological	Phenotyping according to urodynamic
	factors	demonstration of detrusor overactivity
	Metabolic syndrome	Myogenic
	Affective disorders	Urotheliogenic
	Sex hormone deficiency	Urethrogenic
	Urinary microbiota	Supraspinal
	Functional gastrointestinal disorders	Urotheliomyogenic: detrusor underactivity
	Autonomic nervous system dysfunction
	OAB = overactive bladder.

nonfinancial support from Astellas. Linda Cardozo has received funding for research or lecturing from Astellas and Pfizer, and for research consultancy and/or advisory work from Allergan, Astellas, BMR, Ferring, Pfizer, and Syner-Med. Matthias Oelke reports personal fees from Allergan, Bayer Healthcare, Biocompatibles, Ferring, and Mundipharma; personal fees and other from Apogepha; grants, personal fees, and nonfinancial support from Astellas and Pfizer; personal fees, nonfinancial support, and other from GlaxoSmithKline; personal fees and nonfinancial support from Lilly and Recordati, all outside the submitted work. Roger Dmochowski is a consultant/advisor for Medtronic and Allergan. Gérard Amarenco is a consultant and speaker for Astellas, Pfizer, Allergan, Laborie, and Wellspect. Xavier Gamé is a consultant for Astellas, Pierre Fabre, Allergan, Medtronic, and Ipsen. Frank Van Der Aa has spoken on behalf of and received honorarium from Astellas, Pfizer, and GlaxoSmithKline; and is a consultant for Medtronic, Allergan, and Astellas. Roger Kirby has been reimbursed by Astellas, GSK, Pfizer, and MSD for attending conferences, lecturing, and expenses of research studies. Jean-Nicolas Cornu is a consultant/speaker for Astellas, Pfizer, Boston Scientific, Medtronic, and Bouchara Recordati. Emma Mironska has nothing to disclose.

Funding/Support and role of the sponsor: None.

authorities should promote studies looking at a personalised approach to OAB patients.

Clearly from a public health standpoint, the cost effectiveness of a tailored versus a "one size fits all" treatment approach is evident, particularly based on the poor long-term compliance with existing pharmacotherapy.

Author contributions: Benoit Peyronnet had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Peyronnet, Cornu, Amarenco, Gamé. Financial disclosures: Benoit Peyronnet certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Benoit Peyronnet is a consultant for Astellas, Allergan, Medtronic, and Boston Scientific. Christopher Chapple is a consultant, researcher, and speaker for Astellas, Allergan, Pfizer, and Medtronic; has received personal fees and nonfinancial support from Allergan and Pfizer; and has received grants, personal fees, and

Acquisition of data