Non-neurogenic Female LUTS

3. DIAGNOSIS

3.1 History and physical examination

Taking a thorough clinical history and carrying out a focused physical examination are fundamental to the process of clinical evaluation. Despite the lack of supportive high-level evidence, there is universal agreement that they should be the first step in the assessment of anyone with LUTS.

The history should include a full evaluation of LUTS, as well as sexual, gastrointestinal, and neurological symptoms. The history should categorise LUTS as storage, voiding and post-micturition symptoms, and broadly classify UI as SUI, UUI or MUI whilst acknowledging that there may be other causes of UI such as uro-genital fistulae, overflow incontinence or anatomical abnormalities [14].

The history should also identify patients who need onward referral to an appropriate clinic/specialist. These may include patients with associated pain, haematuria, history of recurrent urinary tract infection (UTI), pelvic surgery or radiotherapy, continuous incontinence suggesting a fistula (see Section 4.8), new-onset enuresis or suspected neurological disease. A neurological, obstetric, and gynaecological history may help to understand the underlying cause and identify factors that may affect treatment decisions. Guidance on history-taking and diagnosis in relation to UTIs, neuro-urological conditions and chronic pelvic pain (CPP) can be found in the relevant EAU Guidelines [11,15,16]. Patients should also be asked about other comorbidities as well as smoking status, previous surgical procedures, and current medications, as these may affect LUTS.

Examination should include abdominal examination, to detect an enlarged urinary bladder or other abdominal masses, and digital examination of the vagina and rectum. Pelvic examination in women includes assessment of oestrogen status, pelvic floor muscle (PFM) function and careful assessment of any associated pelvic organ prolapse (POP). A cough stress test is necessary to look for SUI. A focused neuro-urological examination should also be routinely undertaken.

3.1.1. Summary of evidence and recommendation for history taking and physical examination

3.2. Patient questionnaires

This includes symptom scores, symptom questionnaires/scales/indices, patient-reported outcome measures (PROMs) and health-related quality of life (HRQoL) measures. Questionnaires should have been validated for the language in which they are being used, and, if used for outcome evaluation, should have been shown to be sensitive to change. The US Food and Drug Administration (FDA) published guidance for industry on PROM instruments (questionnaires) in 2009 [17].

Although many studies have investigated the validity and reliability of urinary symptom questionnaires and PROMs, most of these studies included mixed populations (men and women). This limits the extent to which results and conclusions from these studies can be applied to particular LUT syndromes in women. A SR included 22 studies that assessed eleven case-finding tools for OAB. All tools were found to have good sensitivity and specificity for OAB or incontinence symptoms [18]. Some questionnaires are responsive to change and may be used to measure outcomes, although evidence for this is inconsistent [19,20].

Another SR including 73 studies assessed 27 specific and six generic instruments that measure quality of life (QoL) in women with UI. In this review, the incontinence QoL (IQoL) questionnaire was found to be the most psychometrically robust disease-specific tool for use in English-speaking women with UI. Evidence on the performance of generic QoL tools for this population is limited [21]. There is no evidence to indicate whether use of QoL or condition-specific questionnaires has an impact on outcome of treatment.

Detailed description of the different urinary symptoms questionnaires and PROMs is beyond the scope of these guidelines. For more information, we recommend the 7th ICI review on PROM assessment [22]. Clinicians must evaluate the tools that exist, for use alone or in combination, for assessment and monitoring of treatment outcome [23]. The questionnaires can be found on the following websites: 
www.iciq.net, eprovide.mapi-trust.org, www.ncbi.nlm.nih.gov.

3.2.1. Summary of evidence and recommendation for patient questionnaires

3.3. Bladder diaries

Measurement of the frequency and severity of LUTS is an important step in the evaluation and management of LUT dysfunction. Bladder diaries are a semi-objective method of quantifying symptoms, such as frequency of UI events, number of nocturia episodes, etc. They also quantify urodynamic variables, such as voided volume, 24-hour urine volume or nocturnal total urine volume.

Fluid intake and voided volume measurement can be used to support diagnoses and management planning and for identifying polyuria. Diaries can also be used to monitor treatment response but in patients with severe UI, a bladder diary is unlikely to accurately report 24-hour urine output.

Consensus terminology is now well-defined and widely accepted [1,24]. However, the terms micturition diary, frequency/volume chart, bladder diary and voiding diary, have been used interchangeably for many years, but only bladder diaries include information on fluid intake, times of voiding, voided volumes, UI episodes, pad usage, degree of urgency and severity of UI recorded for at least 24 hours. When reviewing the evidence, all synonymous search terms have been included.

Two studies have demonstrated the reproducibility of diaries in both men and women [25,26]. Another two studies have shown the feasibility, reliability, and validity of the bladder diary [27,28]. Further studies have demonstrated variability of diary data within a 24-hour period and compared voided volumes recorded in diaries with those recorded by uroflowmetry [29,30]. Another study found that keeping a bladder diary had a therapeutic benefit [31].

A number of observational studies have demonstrated a close correlation between data obtained from bladder diaries and standard symptom evaluation [32-35]. The optimum number of days required for bladder diaries appears to be based on a balance between accuracy and compliance [36,37].

3.3.1. Summary of evidence and recommendations for bladder diaries

3.4. Urinalysis and urinary tract infection

Reagent strip (dipstick) urinalysis may indicate proteinuria, haematuria or glycosuria, or suggest UTI requiring further assessment. Please refer to the Urological Infections Guidelines for diagnosis and treatment of UTI [15].

Urine dipstick testing is a useful adjunct to clinical evaluation in patients in whom urinary symptoms are suspected to be due to UTI. Urinalysis negative for nitrite and leukocyte esterase may exclude bacteriuria in women with LUTS [38], and should be included, with urine culture when necessary, in the evaluation of all patients with LUTS. Urinary incontinence or worsening of LUTS may occur during UTI [39] and existing UI may worsen [40]. The rate and severity of UI were unchanged after eradication of asymptomatic bacteriuria in nursing home residents [41].

3.4.1. Summary of evidence and recommendations for urinalysis

3.5. Post-void residual volume

Post-void residual (PVR) volume is the amount of urine that remains in the bladder after voiding. It is a measure of voiding efficiency, and results from a number of contributing factors. The detection of significant PVR volume is important because it may worsen symptoms and, more rarely, may be associated with UTI, upper urinary tract (UUT) dilatation and renal insufficiency. Both bladder outlet obstruction (BOO) and/or detrusor underactivity (DU) can potentially contribute to the development of significant PVR volume. Post-void residual volume can be measured by catheterisation or ultrasound (US).

Most studies investigating PVR volume have assessed mixed populations including those with neurogenic UI, so results should be applied with caution to women with non-neurogenic LUTS. Studies investigating the best method of measuring PVR volume [41-46] conclude that US measurement of PVR volume is preferable to catheterisation due to its favourable risk-benefit profile.

There is no consensus on what constitutes a significant PVR volume in women [47-52], therefore the Panel prefers the use of bladder voiding efficiency (BVE) - the proportion of the total bladder volume that is voided by the patient. Bladder voiding efficiency can be calculated as a percentage: BVE = voided volume (VV)/(VV+PVR) × 100. This may be a more reliable parameter to evaluate poor voiding [53].

3.5.1. Summary of evidence and recommendations for post-void residual volume

3.6. Urodynamics

Urodynamic testing is widely used as an adjunct to clinical diagnosis, in the belief that it may help to provide or confirm a diagnosis, predict treatment outcome, or facilitate discussion during counselling. The simplest form of urodynamic evaluation is uroflowmetry. The maximum flow rate (Q_max), the volume voided and the shape of the curve in addition to the PVR volume (see above) are the most important aspects to be assessed [54]. The bladder should be sufficiently full because of the volume dependency of Q_max [55,56]. A minimum voided volume of 150 mL is advised in men, but there is little evidence to suggest a volume threshold in women. It is relevant to ask the patient whether or not the voiding is representative.

Invasive urodynamic tests include multichannel cystometry and pressure-flow studies, ambulatory monitoring and video-urodynamics, and different tests of urethral function, such as urethral pressure profilometry. The International Continence Society (ICS) and the United Kingdom Continence Society (UKCS) provide standards to optimise urodynamic test performance and reporting [57,58]. A characteristic of a good urodynamic study is that the patient’s symptoms are replicated, recordings are checked for quality control, and results interpreted in the context of the clinical problem, remembering that there may be physiological variability within the same individual [57]. Non-invasive alternatives for measurement of detrusor pressure and BOO include transabdominal wall near-infrared spectroscopy and US detrusor wall thickness analysis, but as yet, these techniques have not been adopted into routine clinical practice [54].

Further condition-specific information regarding the role of urodynamic testing in OAB, SUI, BOO and UAB can be found in respective sections of these guidelines.

3.6.1. Variability

In common with most physiological tests there is variability in urodynamic results. This has consequences for the reproducibility, diagnostic accuracy, and predictive value of urodynamic testing. The ICS Good Urodynamic Practice Guidelines state [57] that, at least in the case of cystometry and pressure-flow studies, one set of measurements suffices, but only if the patient’s symptoms have been replicated; however, some studies contradict this [59,60]. There is also conflicting evidence about the reproducibility of maximum urethral closure pressure (MUCP) measurement [59,60]. Valsalva leak point pressure (VLPP) measurement is not standardised and there is also minimal evidence about its reproducibility.

3.6.2. Diagnostic accuracy

Clinical diagnosis and cystometric findings sometimes do not correlate [61,62] and asymptomatic women may have abnormalities on urodynamic testing. The diagnostic accuracy of urethral pressure profilometry [63] and urethral retro-resistance pressure measurement in SUI is poor [54]. Valsalva leak point pressure did not reliably assess UI severity in a cohort of women selected for surgical management of SUI [64]. Urethral pressure reflectometry may have greater diagnostic accuracy but its clinical role remains unclear [65]. Ambulatory urodynamics may detect unexpected physiological variance from normal more often than conventional cystometry does, but the clinical relevance of this is also uncertain [66,67].

A pressure-flow study, that is, the simultaneous measurement of flow rate and detrusor pressure during voiding, can reveal whether a poor flow rate and PVR volume are due to BOO, DU, or a combination of both. Also, it may provide information on the degree of pelvic floor relaxation and thus diagnose dysfunctional voiding. Several proposals to define BOO in women have been made. These definitions are based on detrusor pressure, either P_detQ_max or the maximum value P_det._max, and in combination with the Q_max value. These measures are sometimes combined with the findings during fluoroscopic imaging as part of a video urodynamic study (see Section 4.5.4.8) [68,69]. Unlike the situation in men, there is no universally accepted threshold for BOO diagnosis in women. Bladder contraction strength parameters are derived from detrusor pressure and flow rate during a pressure-flow study or from stop tests [69], but again, validation is poor. Although these parameters estimate the strength of the contraction, they ignore its speed and duration (see Section 4.4.3.2) [70]. A video-urodynamic study can be useful to detect the site of obstructed voiding, which may be anatomical or functional [71]. Also, video-urodynamics may detect urethral diverticula, bladder diverticula or gross reflux as a pressure-absorbing reservoir.

3.6.3. Predictive value

Performing urodynamic evaluation is only useful if it leads to more effective clinical care and better outcomes. A Cochrane review of eight randomised controlled trials (RCTs) showed that use of urodynamic tests in women with UI increased the likelihood of prescribing drugs but reduced the likelihood of undergoing surgery. However, there was no evidence that this altered the clinical outcome [72]. A recent SR and meta-analysis of eight trials (six with exclusively female SUI patients) concluded that urodynamic studies did not improve outcomes from the treatment of SUI [73]. A meta-analysis including four RCTs comparing surgical outcomes in women with self-reported SUI (or stress-predominant MUI) who were investigated via urodynamics with women who had symptom review and physical examination only, found that there was no difference in cure and complication rates [74]. Furthermore, a large retrospective multicentre study found that only 36% of patients were defined as uncomplicated according to the definitions used in large RCTs [75]. The urodynamic observations were not consistent with the pre-urodynamic diagnosis in 1,276 out of 2,053 patients (62.2%). Voiding dysfunctions were urodynamically diagnosed in 394 patients (19.2%) and planned surgery was cancelled or modified due to the urodynamic findings in 304 of 1,582 patients (19.2%) in whom data were available [76]. A large UK multi-centre RCT is underway designed to evaluate the effectiveness and cost-effectiveness of invasive urodynamic investigations in management of women with refractory OAB symptoms [77].

The predictive value of urethral function tests remains unclear. In observational studies, there was no consistent correlation between the results of these tests and subsequent success or failure of SUI surgery [33-35,78]. The same was true in a secondary analysis of an RCT [79].

The presence of pre-operative detrusor overactivity (DO) in women with stress-predominant MUI has been associated with post-operative UUI but did not predict overall treatment failure following mid-urethral sling (MUS) surgery or colposuspension [79]. The urodynamic diagnosis of DO has no predictive value for treatment response in studies on antimuscarinics, onabotulinumtoxinA (onabotA) and sacral nerve stimulation (SNS) in patients with OAB symptoms [80,81]. Augmentation cystoplasty aims to abolish DO, improve bladder compliance, and increase functional bladder capacity but there is no evidence to guide whether or not pre-operative urodynamics are predictive of outcome. Most clinicians would, however, consider pre-operative urodynamics as essential prior to contemplating augmentation cystoplasty.

A pressure-flow study is capable of discriminating BOO from DU as a cause of voiding dysfunction. A low pre-operative flow rate and a low detrusor voiding pressure have been shown to correlate with voiding dysfunction after both tension-free vaginal tape (TVT) and autologous fascial sling procedures [82-84]. Bladder contraction strength parameters combining flow rate and detrusor pressure only poorly predicted voiding dysfunction after autologous fascial sling [85]. Post-hoc analysis of two high-quality surgical trials of TVT, Burch colposuspension and autologous fascial sling showed that no pre-operative urodynamic parameter predicted post-operative voiding dysfunction in a selected population of women with low pre-operative PVR volume [86,87].

The Panel recognises that it is often valuable to use urodynamic test results to select the optimum management strategy; however, there is inconsistent evidence regarding the predictive value of such tests. When urodynamics and clinical assessment (i.e., by history and examination) are in disagreement, there needs to be a careful re-evaluation of the clinical symptoms and investigation results to ensure that the diagnosis is correct before invasive treatments are contemplated.

3.6.4. Summary of evidence and recommendations for urodynamics

3.7. Pad testing

Measurement of urine loss using an absorbent pad worn over a set period of time or during a protocol of physical exercise can be used to quantify the presence and severity of UI, as well as provide objective evidence of response to treatment.

The clinical utility of pad tests in woman with UI has been assessed in three SR’s [88-90]. One SR included eighteen studies and concluded that one hour pad test was more accurate but less reproducible when compared to the longer duration pad tests. A recent crossover trial showed that twenty minute pad testing was acceptable to patients and comparable to a 60 minute pad test for assessing the severity of SUI [91]. A one hour pad test using a standardised exercise protocol, and a diagnostic threshold of 1.4 g shows good specificity but low sensitivity for symptoms of SUI and MUI. A 24-hour pad test using a threshold of 4.4 g is more sensitive but is difficult to standardise, with variation according to activity level [92].

The usefulness of pad tests in quantifying severity and predicting outcome of treatment is uncertain [88,93,94]. Pad tests are responsive to change following successful treatment [95]. Pad testing using a standardised bladder volume (50% of cystometric capacity) was suggested to allow for a more reliable assessment of UI in a small study of 25 women [96]. There is no evidence that one type of pad test is superior to another.

3.7.1. Summary of evidence and recommendations for pad testing

3.8. Imaging

In clinical practice, imaging is used to understand the relationship between anatomy and function. This can be assessed simultaneously using video urodynamic studies. For further details please see the condition specific sections. Ultrasound and magnetic resonance imaging (MRI) have largely replaced X-ray imaging in the evaluation of the pelvic floor. Ultrasound is sometimes preferred to MRI because of its ability to produce three-dimensional (3D) and 4D (dynamic) images at lower cost and wider availability.

There is no need for UUT imaging unless a high-pressure bladder, severe POP or chronic urinary retention is suspected or diagnosed, or abnormal renal function tests are observed. In cases of suspected UI caused by an UUT anomaly or uretero-vaginal fistula, UUT imaging (urography, computed tomography [CT]) may be indicated [97].

3.8.1. Ultrasound

Ultrasonography of the LUT plays a role in the evaluation of women with LUTS.

Ultrasonography using different imaging approaches, such as abdominal, transvaginal, transrectal, perineal and transurethral are described. The bladder neck and urethra are easily visible, and measurements can be done at rest and during straining, coughing and pelvic floor contraction. The parameters assessed may include bladder neck mobility or descent, urethro-vesical angle, and urethral rotation and can be useful particularly in the evaluation of SUI [98,99]. Ultrasonography can be used to assess PFMs and their function. Contraction of PFM results in displacement of pelvic structures that can easily be imaged on US. Integrity of the levator ani muscle can be determined by 3D transperineal US. Ultrasound may also provide information on the anatomical changes of the LUT, and pelvic floor associated with persistence of symptoms post-treatment [100].

Ultrasound is also used to measure detrusor wall thickness which has been studied for its diagnostic utility in OAB and BOO. The details are presented in the relevant sections of this guideline. In summary no consensus exists as to the relationship between OAB/BOO and/or increased bladder wall thickness (BWT)/detrusor wall thickness (DWT) [101], and there is no evidence that BWT/DWT imaging improves management of OAB. There is no widely accepted standardised bladder volume for BWT measurement.

A retrospective study including 227 women with voiding symptoms (hesitancy, intermittency, and poor stream) revealed that DWT was not associated with any urodynamic parameters that may indicate BOO [102].

3.8.2. Magnetic resonance imaging

There is a general consensus that MRI provides good global pelvic floor assessment, including POP, defecatory function and integrity of the pelvic floor support [103]. However, there is a large variation in MRI interpretation between observers [104] and little evidence to support its clinical usefulness in the management of LUTS/UI. There is no conclusive evidence that MRI evaluation of POP is more clinically useful than vaginal examination. Studies have assessed the use of imaging to assess the mechanism of MUS insertion for SUI. One study suggested that MUS placement decreased mobility of the mid-urethra but not of the bladder neck [105]. Following MUS, a wider gap between pubic symphysis and sling (assessed by imaging) has been shown to correlate with a lower chance of cure of SUI [106].

3.8.2.1. Summary of evidence and recommendation for imaging

3.9. Urinary Biomarkers and Microbiota

Interest in the role of urinary biomarkers for the diagnosis of LUT dysfunction has increased in recent years. Nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), prostaglandin E2, adenosin triphosphate (ATP) and purinergic receptors (P2X) in bladder tissue have been studied as biomarkers for OAB. Serum beta natriuretic peptide (BNP), urinary 6-sulfaoxymelatonin and C-reactive protein (CRP), melatonin, vasopressin levels have been studied in relation to nocturia. Regarding BOO, currently, there are no validated biomarkers for female BOO available but one SR has suggested that NGF levels are elevated in women with BOO when compared with normal controls [107].

For SUI, urinary IL 12-70, urinary (uNGF) and N-telopeptide of type I collagen (NTx) have been studied. Currently, studies investigating urinary biomarkers are methodologically limited often due to failing to control for confounding variables and consequently results are conflicting [108].

Another area of discovery is the role of urinary microbiota in identifying and differentiating various types of UI and other LUT disease in women. A SR described studies showing differences in the types and relative proportions of bacteria such as Lactobacillus, Gardnerella, and Atopobium vaginae, among women with different types of UI compared with healthy controls. Urinary microbiota has also been shown to differ depending on women’s response to anticholinergic treatment response [109]. Further research is needed before the place of urine microbiota assessment in the clinical pathway for women with LUTS is fully defined.

Further information on the diagnostic efficacy of biomarkers in OAB can be found in Section 4.1.3.4.

3.9.1. Summary of evidence and recommendation for urinary biomarkers