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3. Conditions and Syndromes
Keywords
Benign prostate enlargementBladder outlet obstructionUnderactive bladderOveractive bladderNocturnal polyuriaAcute urinary retentionChronic urinary retention3.1 Introduction
In the previous chapter we indicated how important it is to consider the implication of individual LUTS, to distinguish severity and bother and to recognize implications for understanding mechanism and choosing therapy. In this chapter, we describe how symptoms commonly group together. There are two syndromes that are entirely based on the symptom combinations, namely overactive bladder and underactive bladder. There are also settings where an underlying mechanism is likely to give rise to predictable symptom combinations. For example, benign prostate enlargement (BPE) causing obstruction is likely to cause voiding and most micturition LUTS. There are two major considerations healthcare professionals must always bear in mind. Firstly, when a patient describes their symptoms, this does not mean we can assume the underlying cause; additional testing is needed to establish the mechanism and hence direct treatment. Secondly, patients commonly develop more than one issue with age. For example, men may develop BPE and also kidney or heart disease (two possible causes of nocturia). It is a bad mistake to identify only one of the problems present (and urologists are notoriously prostate-focused, and quick to diagnose BPE) and expect that treating it will resolve the symptoms caused by other problems. In this chapter we consider the major situations which can present with LUTS in this way.
3.2 Benign Prostate Enlargement
Although structural anomaly, neurological disease, vesicogenic condition or infection can play a role, benign prostate enlargement/hyperplasia (BPE/BPH) is still by far the most influential factor leading to male LUTS [1]. BPH is a histological diagnosis describing a hyperproliferative process of epithelial and stromal cells in the transition zone of the prostate [2]. This causes outward enlargement of the gland which can readily be felt by digital examination in its anatomical location next to the rectum. Outward enlargement can get substantial, but it is rarely problematic to either rectal or lower urinary tract function. Mainly when a component of the enlargement affects the internal relationship to the urethra, either by compressing or by distorting the bladder outlet, does it begin to acquire clinical significance by causing bladder outlet obstruction (BOO) and thence LUTS [3]. These are principally voiding LUTS, but if there is significant inflammation (see below), storage LUTS may also be experienced.
The prevalence of BPE/BPH and LUTS rises markedly with ageing. It is estimated that nearly 50% of all men at the age of 60 have histological BPH, and by 80 the prevalence approaches 90% [4]. Moderate to severe LUTS was reported by 26% of men aged 40–49 years and almost doubled in those aged 70 or older [5]. There is ethnic difference in the prevalence of LUTS, evident on a global scale [4, 6, 7].
BPE/BPH-related LUTS is rarely life-threatening, yet its impact on quality of life (QoL) can be significant and should not be underestimated in an ageing population. Apart from physical functioning, LUTS may also have a detrimental effect on mental health and social economy. In men with severe LUTS, the annual risk of having at least one fall was increased by 33% compared with men who had mild symptoms [7]. Falls in the elderly is a major concern, which can result in pain, fracture, disability and sometimes mortality [8]. Severity of LUTS is also strongly correlated with anxiety, depression, insomnia and sexual dysfunction [4, 7]. With billions of dollars already spent directly in the treatment of LUTS and urinary obstruction each year, more ancillary healthcare expenditure will be expected, especially in an era of increasing male life expectancy [5, 8].
The aetiology of BPE/BPH is complicated and poorly understood, though several risk factors for the development of BPE/BPH and LUTS have been identified. These include age, genetics, hormones, growth factors, inflammation and lifestyle factors. Age itself is the major risk factor for BPE/BPH and LUTS. The ageing process involves changes in cellular mitogenesis and hormonal homeostasis in the prostate gland, which later proceeds to chromosomal aberration and apoptosis [9]. Ageing is also associated with inflammation and microvascular disease, which provoke ischemia and oxidative stress, providing a favourable environment for BPH [10]. A genetic link for clinical BPH in men younger than 60 years of age has been studied over the past few years. Evidence suggests that it is a heritable disease, which may have an autosomal dominant behaviour. Genetic factors are said to account for 72% increased risk in developing moderate or severe LUTS among elderly men [8].
Sex steroid hormones are linked with the development and maintenance of BPE/BPH. Androgens are particularly relevant. In the prostate, testosterone is converted to dihydrotestosterone (DHT) by type II 5α-reductase, via DHT/androgen receptor signalling, and thereby influences cell proliferation, differentiation, morphogenesis and functional maintenance [11]. The use of 5α-reductase inhibitors in a clinical setting was found to decrease serum concentrations of DHT and slow down the progression of clinical BPH [8]. Although not yet conclusive, oestrogens (both endogenous and exogenous) and selective oestrogen receptor modulators may have a potential role in regulating stromal–epithelial interactions involved in prostatic cellular growth [12]. To date, there is no clear and consistent link identified between hormones and BPE/BPH. Several growth factors and their corresponding receptors were identified on prostatic epithelium and stroma, which can stimulate or inhibit cell division and differentiation processes. To name a few here: epidermal growth factor, fibroblast growth factor, transforming growth factor-β, and the list is by no means exhaustive. Activation of these growth factors, alone or in combination, can induce stromal cells growth, followed by significant tissue remodelling, which is responsible for prostate enlargement [13].
There is a growing body of evidence that suggests that inflammation is closely linked to the development of BPE/BPH and LUTS. Firstly, from a histological point of view, inflammatory infiltrate is the most prevalent feature coexisting with BPH and the degree of inflammation is correlated with prostate volume and weight [14]. Secondly, from an immunological point of view, inflammation may activate cytokine release and raise the concentration of growth factors, resulting in an abnormal proliferation of prostatic cells [15]. Thirdly, an increased level of serum C-reactive protein was observed in men with LUTS, which is likely indicative of systemic inflammation [8].
In a systematic review on metabolic syndrome (MetS) and BPE/BPH, focusing on subsets of MetS and their relationship with total prostate volume (TPV) and LUTS, it was reported that the TPV was significantly larger in men with MetS when compared with those without. Also, the differences in TPV were significantly higher in obese participants and those with low serum high-density lipoprotein cholesterol levels. Interestingly, in contrast to other studies, there were no differences between men with or without MetS for LUTS symptom scores [16]. Heavy smoking, low physical activity and high protein intake can also substantially alter the risks of symptomatic BPH and LUTS [17].
3.2.1 Pathophysiology
The prostate hyperplastic process begins in the periurethral region, namely the transition zone. The increase in cell number and size affects both epithelium and stroma, due to a shift towards proliferation outweighing apoptosis. As enlargement takes place, prostatic intrusion into the urethral lumen or bladder neck can considerably change bladder outlet resistance by causing mechanical obstruction [18]. While the overall size of the prostate does not correlate particularly closely with symptoms, the larger the size, the greater the likelihood that intrusion into the urethral lumen will arise, and hence future clinical deterioration.
The prostatic capsule is relevant to the development of voiding LUTS since it restricts outward transmission of the pressure of tissue expansion, pushing it inward to the urethra and increasing urethral resistance [18]. These anatomical and functional changes may in turn induce significant alterations in the morphology and physiology of urothelium and detrusor muscle, which lead to bothersome LUTS.
3.3 Bladder Outlet Obstruction in Women
3.3.1 Diagnostic Criteria
There are no universally accepted diagnostic criteria for BOO in women. This reflects the varied aetiologies behind the condition, the lack of a reliable treatment to resolve many of them, difficulties in identifying those with obstruction given their diverse symptoms, and in defining a suitable control group [19, 20]. A combination of several urodynamic parameters including detrusor pressure (P det), detrusor pressure at maximal flow rate (P detQ max), maximal flow rate (Q max), urethral resistance and post-void residual urine measures (PVR), combined with clinical and/or radiological findings, are utilized to make a diagnosis. In general, higher than normal voiding pressures, and a slower than normal flow suggests obstruction, and several thresholds have been proposed for this.
In 1998, Chassagne et al. [21] compared clinically obstructed women to those with stress incontinence and found obstruction best predicted by Q max ≤15 mL/s and P detQ max of >20 cmH2O. The same group revised these values twice more—in 2000 to Q max <11 mL/s and P detQ max >21 cmH2O [22], and then Defreitas et al. reprised them in 2004 against normal (not incontinent) controls to Q max <12 and/or P detQ max >25 [23]. Nitti et al. [19] diagnosed obstruction on appearances at voiding cystourethrography, and found significant differences in Q max and P detQ max in obstructed and unobstructed women. Blaivas and Groutz identified 50 women with obstruction (either Q max ≤12 mL/s or P detQ max of ≥20 cmH2O; typical radiographic appearances during a sustained detrusor contraction of ≥20 cmH2O, or an inability to void at similar bladder pressures) and compared them to 50 age-matched controls. They found that maximal detrusor pressure against free flow Q max best discriminated between the cohorts, and proposed a female BOO nomogram that also stratified for severity of obstruction [24].
Akikwala et al. [20] compared five of these diagnostic criteria using the same patient cohort. They found voiding cystourethrography and Chassagne’s criteria tended to agree, while Defreitas’s underestimated and the Blaivas-Groutz nomogram overestimated the presence of obstruction.
Gravina et al. [25] evaluated the BOO index (calculated as P detQ max − 2Q max), which is widely used to diagnose obstruction in men, and found that a result of ≥−8 was predictive for female BOO. Most recently, Solomon et al. [26] reported a new validated nomogram for female BOO using the criterion of P detQ max >2 Q max.
3.3.2 Clinical Aspects
Female BOO is identified in 2.7–29% of women presenting with LUTS [19, 24, 27]. The most frequent aetiology is anti-incontinence surgery, which accounts for up to 40% of cases in some studies, with autologous pubovaginal slings being more implicated than tension-free vaginal tapes [28]. Severe genital prolapse is also a common association [29]. Women with BOO typically present with storage or mixed symptoms, and recurrent urinary tract infection (UTI) [20, 27]. Urinary frequency and urgency are more common features than poor flow, incomplete emptying and straining, with only 40% of women with urodynamic proven BOO reporting obstructive LUTS [27].
When assessing the situation, women with suspected obstruction should be asked about urological, gynaecological and neurological symptoms and relevant past history. Examination should include a perineal, vaginal and neurological examination and a urine dipstick. A serum creatinine and renal tract ultrasound is indicated in those with high residual urine volumes or neurological disease.
Uroflowmetry and PVR may raise suspicion for BOO, but synchronous measurement of detrusor pressure is needed to discriminate between impaired detrusor contractility or obstruction [30], thus urodynamics is essential. Videourodynamics can also demonstrate the location of the obstruction and any vesicoureteric reflux or bladder diverticula, and represents the most appropriate diagnostic test [31].
Once the diagnosis is confirmed, further investigation can establish the cause. In suspected neurological disease, a spine ± brain MRI can be helpful, while a post-void pelvic MRI will demonstrate a urethral diverticulum. Cystoscopy ± urethral calibration under anaesthetic allows the identification of urethral strictures. Further specialist tests are urethral pressure profiles (UPP) and sphincter electromyography (EMG). The pressure exerted along the length of the urethra can be detected by a fine catheter as it is withdrawn. Normal values are calculated from 92—age (in years) [32]. Sphincter EMG allows the activity of the rhabdosphincter to be recorded, with typical findings in Fowler’s syndrome [33], enabling distinction from dysfunctional voiding and detrusor sphincter dyssyn ergia.
3.3.3 Aetiology of Female BOO
Aetiology of female bladder outlet obstruc tion
Category | Causes | Examples |
|---|---|---|
Functional | Dysfunctional voiding | (Non-neurogenic neuropathic bladder) |
Fowler’s syndrome | ||
Primary bladder neck obstruction | ||
Neurological | Detrusor sphincter dyssynergia | Suprasacral spinal cord injury; MS |
Anatomical | Iatrogenic | Anti-incontinence surgery |
Urethral reconstruction | ||
Urethral dilatation | ||
Urethral diverticulectomy | ||
Gynaecological | Ovarian cyst | |
Retroverted uterus | ||
Fibroid disease | ||
Pelvic organ prolapse | Cystocele, rectocele, uterine prolapse | |
Neoplastic | Ovarian, cervical or vaginal tumours | |
Urethral or bladder tumour | ||
Inflammation/infection | Urethral stricture | |
External urethral meatal stenosis | ||
Urethral diverticulum | ||
Skene’s gland cyst or abscess | ||
Urethritis | ||
Urethral caruncle | ||
Atrophic vaginitis | ||
Other | Urethral valves | |
Ectopic ureterocele | ||
Bladder stones |
3.3.3.1 Dysfunctional Voiding
This ‘is defined as an inter mittent and/or fluctuating flow rate due to involuntary intermittent contractions of the periurethral striated muscle during voiding in neurologically normal individuals’ [34]. The incidence is 9–12% of women presenting with LUTS [19, 35]. The disorder was first described in paediatric populations (severe cases being referred to as Hinman’s syndrome or non-neurogenic neurogenic bladder ), but it is also recognized in adults [36]. It is considered a learned response, initiated after episodes of infection or inflammation that cause pain on voiding. The pelvic floor musculature and/or external urethral sphincter demonstrate intermittent contractions during voiding [37]. In severe cases it can lead to raised PVR, urinary retention, reduced bladder compliance and vesicoureteric reflux—due to repeated voiding against a closed external urethral sphincter. It is essential to exclude occult neurological disease, which is reported to be present in 19% of women with this problem [38]. Conservative management with biofeedback and behavioural modification is appropriate. Medical therapies include amitriptyline, anticholinergics and diazepam. Alpha-adrenoceptor antagonists have been utilized, attempting to reduce urethral tone. Terazosin 5 mg daily produced statistically significant improvement in both urodynamic parameters and subjective symptoms in 67% of women [39]. Surgical options include sacral nerve stimulation (SN S).
3.3.3.2 Fowler’s Syndrome
In essence, this is BOO due to a non-relaxing, hypercontractile external urethral sphincter and is associated with painless urinary retention. It differs from dysfunctional voiding in that obstructive symptoms and urinary retention are most prominent, typically associated with urethral spasm and pain. External sphincter EMG patterns during voiding consistently show complex repetitive discharges, with bursts of deceleration [40, 41]. In addition, women have a significantly higher maximal urethral closure pressure (MUCP) and external urethral sphincter volume [42]. Clean intermittent self-catheterization (CISC) or an indwelling catheter may be unavoidable to treat urinary retention (although such devices are often poorly tolerated due to pain). Some patients benefit from using a continent catheterizable channel such as a Mitrofanoff to empty bladder residuals, so avoiding urethral instrumentation. Other surgical options include SNS. The 5-year success rate of SNS used to treat urinary retention and Fowler’s syndrome is reportedly 72%, with a 20% revision rat e [43].
3.3.3.3 Primary Bladder Neck Obstruction
Prevalence rates vary, but it is considered uncommon, affecting <1–8% of women with LUTS [44–46]. Th is is high-pressure, low-flow voiding through a closed bladder neck, with no abnormal activity at the level of the external sphincter. The underlying pathophysiology is thought to be due to increased tone, reduced elasticity, fibrosis and hypertrophy of the bladder neck and proximal urethra. The condition has been treated with CISC, alpha-adrenoceptor antagonists, Otis (blade) urethrotomy, urethral dilatation [47], transurethral incision of the bladder neck (TUIBN) [48] and transurethral resection of the bladder neck (TURBN) [45]. TUIBN is reported to cause potential complications of stress urinary incontinence, vesicovaginal fistula, haemorrhage, recurrent bladder neck obstruction and urethral strict ure [48].
3.3.3.4 Neurological Causes
Detrusor sphincter dyssynergia (DSD) ‘is defined as a detrusor contraction concurrent with an involuntary contraction of the urethral and/or periurethral striated muscle. Occasionally, flow may be prevented altogether’ [34]. It is associated with neurological disorders, including suprasacral spinal cord injury (SCI), multiple sclerosis (MS), transverse myelitis and spinal dysraphism, and manifests as failure of the external urethral sphincter to relax during voiding. Around half of all men with DSD will develop complications, with the risk being lower in women and patients with MS [49, 50]. Adverse consequences of untreated DSD include poor bladder compliance, vesicoureteric reflux, hydronephrosis and renal impairment. Treatment options are limited. Botulinum toxin A reduces muscle contractility and causes atrophy of the injected muscle. 100 IU in total is injected at four sites circumferentially around the female external sphincter [51]. Repeat treatments may be required. Studies report reasonable short-term responses with improvements in voiding pressures, PVR, flow rates and allowing patients to become catheter-free, albeit with the risk of stress or nocturnal incontinence [51–53]. Alternative options include intermittent or indwelling catheters; alpha-adrenoceptor antagonists with baclofen (often combined with anticholinergic drugs) [54]; external sphincterotomy, and ultimately, urinary divers ion.
3.3.3.5 Urethral Stricture Disease in Women
This is responsible for 4–13% of BOO in women [29, 55]. This is a ‘symptomatic, anatomical narrowing of the urethra’ [56], but a minim um calibre for diagnosis has not been set. Urethral calibres of ≤12 Fr–18 Fr have been proposed [57, 58] (compared to the 22 Fr mean calibre of the normal adult female urethra) [59]; however, a urethral calibre of ≤10 F must be present for urodynamic obstruction to be demonstrated [60]. Causes can be idiopathic, iatrogenic (instrumentation, prior urethral surgery, pelvic radiotherapy), infection, inflammation and trauma related. Treatment options include urethral dilatation; under general anaesthetic, the urethra is dilated with metal sounds to 30–40 Fr. Intermittent self-dilatation may be introduced afterwards, although sparse evidence exists to show that this prevents recurrence. In a systematic review, >50% of women undergoing urethral dilatation required further intervention at 43 months follow-up [56]. Success rates are higher with primary surgery (58%) than at repeat procedures (27%). No new incontinence was reported. Augmentation urethroplasty reconstruction involves either dorsal or ventral incision of the urethra and utilizes vaginal or labia minora flaps or vaginal, labial or buccal and lingual oral mucosa free grafts to enlarge the urethral calibre. Martius labial fat pad interpositional grafts can also support the repair. Success rates are high (80–94%) for all techniques with no new stress incontinence reported [56].
3.4 Overactive Bladder
Overactive Bladder (OAB) is defined as a clinical syndrome in which the patient feels ‘urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of urinary tract infection or other obvious pathology’ [61]. The International Consultation on Incontinence Research Society proposed that the terminology be slightly rephrased as: ‘OAB is characterized by urinary urgency, with or without urgency urinary incontinence, usually with increased daytime frequency and nocturia, if there is no proven infection or other obvious pathology’ [62]. As such, its definition is based on patient reported symptoms. In contrast, detrusor overactivity is a urodynamic observation, characterized by involuntary detrusor muscle contractions during the filling phase, which may be spontaneous or provoked [34].
BD showing nocturia caused by OAB . Two days extracted from a 3-day bladder showing nocturia caused by OAB. Times the patient woke for the day are indicated with a red arrow, and bedtime with a purple arrow. Note how the urgency is scored with a 3 (meaning “urgency, but managed to get to the toilet, still with urgency but did not leak urine”) in the daytime and the night-time, showing that this patient’s nocturia is caused by OAB. On a diary where the overnight voids are scored as 1 (normal desire to pass urine and no urgency) and nocturnal polyuria is present, the nocturia should not be classed as OAB-related, regardless of whether there is OAB in the daytime
3.5 Underactive Bladder/Detrusor Underactivity
The underactive bladder (UAB) is a symptom complex, characterized by a slow urinary stream, hesitancy and straining to void, with or without a feeling of incomplete bladder emptying and dribbling, often with storage symptoms [65]. This is a situation that occurs in association with diverse pathologies and does not have a single distinguishing symptom—unlike OAB, where the symptom syndrome is defined by the cardinal symptom of urgency. Even though UAB is principally identified by weakness of the bladder contraction needed for voiding, the symptoms associated cover the storage phase as well. Thus, some confusion may arise from the reporting by these patients of urgency, increased daytime frequency and nocturia. Of course, that could be taken to indicate OAB, but in the UAB patient there will be a slow stream when voiding. In OAB, when urgency drives the toilet visit the urinary stream tends to be good, provided the bladder volume is sufficient. Sometimes the mechanism causing the storage symptoms in UAB may be a significant post-void residual [66] so that the functional storage capacity is reduced, contributing to the increased frequency.
Notoriously, symptoms are unreliable for deciding on urodynamic mechanism. Thus, slow stream evaluated with pressure flow studies (PFS) potentially reflects bladder outlet obstruction (BOO) or detrusor underactivity (DUA) , or both together. The 2002 International Continence Society (ICS) standardization report defines DUA as ‘a contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or failure to achieve complete bladder emptying within a normal time span’ [34]. Frustratingly, PFS interpretation of DUA is hindered by the subjective nature of describing reduced strength, contraction length and prolonged bladder emptying, so the diagnostic parameters are vague and non-quantitative. There is also a lack of consensus on what constitutes a clinically significant post-void residual (PVR).
Pressure flow study for a man with an acontractile detrusor. He was unable to generate any detrusor pressure at all, indicated by the flat green line. All he could do was use Valsalva manoeuvres to raise his abdominal pressure (red line), and thereby raise his bladder pressure indirectly (blue line). These did not generate any urine flow (bottom plot)
The prevalence of DUA in men referred for pressure flow studies (PFS) with non-neurogenic LUTS is reported as 9–28% under the age of 50 years and 48% in those over 70 years; conversely, it is diagnosed in 12–45% of women, particularly those who are elderly and institutionalized [69]. It may be found concomitantly with detrusor overactivity (DO), a combination referred to as ‘detrusor hyperactivity impaired contractility’ in old terminology [70].
3.5.1 Aetiology
Some studies on aetiology have been done for DUA, but less for UAB due to the comparatively recent consensus on terminology for the clinical symptom complex. DUA occurs in a diverse patient population and as such, the aetiology is likely to be multifactorial. Although some conditions like diabetes mellitus (DM) and cauda equina syndrome are recognized, advancing age appears to an important association—though causality is difficult to establish. Ageing is thought to influence the detrusor structure and/or function. The mechanism by which this works is not well understood. Data from animal models using muscle strips, although suggestive of contractility declining with ageing, cannot be extrapolated to the human intact innervated bladder.
Broadly speaking the causative mechanisms can be classified into (1) myogenic, alteration of normal structure of detrusor extracellular matrix causing diminished myocyte contraction; or (2) neurogenic, affecting the micturition reflex, afferent or efferent pathways. BOO is likely to lead to a change in detrusor function due to increased work requirements in overcoming the obstruction. In animal models, the sequence of events comprises three stages: (1) bladder distension, (2) compensatory detrusor hypertrophy and hyperplasia over a few weeks (compensatory stage) and (3) decline in contractile response over a period of time (decompensated stage). Interestingly, in man this has not been proven to be the case; a longitudinal study by Thomas et al. demonstrated that prolonged BOO did not in the majority of patients lead to significant clinical decompensation [71].
Diabetes mellitus (DM) is another major aetiological factor. Diabetic cystopathy is the older term for the bladder dysfunction related to DM, whilst the more recent literature has referred to the problem as ‘diabetic induced bladder dysfunction’ (DBD) . The pathophysiology of DBD is poorly understood; it is traditionally considered to result from autonomic nerve injury due to hyperglycaemia, resulting in axonal degeneration and segmental demyelination and thence to reduced bladder sensation [72]. Clinically there is a reduction of emptying efficiency in a time-dependant fashion during the disease course.
Neurological disease or injury is a common cause of DUA; it is noted in 20% of patients with Parkinson’s disease [73] and multiple sclerosis [74]. Antiparkinsonian drugs may be contributory due to their anticholinergic effects. Patients with cerebrovascular accident tend to develop DO, but during the acute phase it may cause urinary retention (50%), with two-thirds having acontractile bladders. Trauma, prolapsed intervertebral disc in the region of the lumbo-sacral cord or the cauda equina can all cause DUA, as can iatrogenic injury to the pelvic plexus during colorectal, gynaecological or urological sur gery.
3.5.2 Urodynamics and DUA
Invasive PFS is the only recognized modality for estimating detrusor contractile function. There are, however, no universally agreed diagnostic criteria. The current methods are centred on measurement of detrusor contraction strength (not speed or sustainability) based on the maximal urinary flow (Q max) and detrusor pressure at maximal flow (P detQ max), interpreted with data on men undergoing bladder outlet surgery to give a bladder contractility index (BCI) [75]. BCI accordingly can only be used in men in the age group compatible with such a derivation. This parameter is unlikely, therefore, to be applicable for the highly varied patient group overall. The Watts factor is another measure of isometric detrusor pressure with similar limitations. Occlusion testing allows for real-time isovolumetric measurement but is painful and impractical.
A recent development uses the rate of isovolumetric subtracted detrusor pressure increase (t20–80). This shows a significant association with indices of bladder contractility as derived from a derived force–velocity curve, so has been proposed as a detrusor contractility parameter (DCP) which could apply to both sexes and any age group [76]. It is undergoing onward development and validation [77].
3.5.3 Clinical Aspects
The principles of management are to control symptoms, improve quality of life and reduce the risks associated with incomplete bladder emptying, including urinary tract infections, bladder stones, injury to the upper tracts and skin compromise from incontinence. There are no treatments to improve detrusor contraction. The mainstay of treatment is facilitation of bladder emptying, ideally with ISC if no impairment of cognition or dexterity exists. Behavioural interventions, pelvic floor exercises and biofeedback can be implemented with some success. Long-term indwelling catheters should be avoided, but if necessary then a supra-pubic catheter is recommended. There are no effective pharmacotherapies available. Parasympathomimetic agents to increase bladder contractility are not efficacious and are associated with significant side effects. Alpha-adrenoreceptor antagonists to reduce bladder outlet resistance and exogenous prostanoids to augment detrusor contraction have both been studied, but have not shown significant promise. Intravesical electrotherapy involves passing current from a catheter tip within a saline-filled bladder, with the aim of upregulating mechanosensitive bladder afferents. This treatment has shown some positive results in the paediatric population. However, randomized studies are lacking and the treatment is time- and resource-consuming, as multiple sessions are required. Sacral neuromodulation is a well-recognized treatment for patients with non-obstructive urinary retention. Improvement may be achieved in men with DUA [78]. Bladder outlet surgery has a higher risk of failure in men with DUA [79], though men with chronic urinary retention reliant on catheterization may be able to void spontaneously following surgery, albeit with a slow flow. Such patients may be satisfied with the lack of reliance on catheterization. Overall these patients still have poorer outcomes than men with normal detrusor function. Detrusor myoplasty (‘bladder wrap’) using the latissimus dorsi muscle has been described in a small study [80], but it is associated with a high risk of complications and has not become adopted in routine clinical practice.
Ultimate confirmation of BOO or DUA can only be reached with urodynamics, but conservative clinical management potentially could be initiated without that being necessary, and this is where the symptom-based use of UAB is important in providing a basis for developing new approaches to treatment which might be used in a wider co ntext.
3.6 Nocturnal Polyuria
Physiologically, urine production is regulated by several renal mechanisms. Particularly important is arginine vasopressin (AVP) , commonly referred to as anti-diuretic hormone (ADH) , which changes renal excretion of water and regulates plasma osmolality and sodium concentration. This hormone is formed in the paraventricular and supraoptic nuclei of the hypothalamus and is released from the pituitary gland, in response to increased plasma osmolality or low blood pressure and blood volume. The vasopressin-2 (V2) receptor subtype is most important for antidiuresis and is located in the renal collecting duct epithelial cells. V1 receptors (V1a and V1b) are located in the vascular and central nervous systems. When AVP is absent, the thin epithelial membrane between urine and blood in the renal collecting duct is almost impermeable to water. In the presence of AVP, this binds to the V2-receptor, activating aquaporin channels in the membrane, resulting in high permeability and reabsorption of most water from the filtered urine. By this process, small changes in AVP can have a powerful effect retaining water which otherwise would be excreted by the kidneys [81].
In normal physiological conditions, AVP secretion and consequently urine production express a circadian rhythm—both in human [82, 83] and in other species [84]. Consequently, increased secretion of AVP and a decreased urine production are a normal feature during sleeping hours. This circadian rhythm is generated by a molecular genetic feedback mechanism, present in most organs and cells, which is centrally regulated by the suprachiasmatic nucleus of the brain [85]. Genetic defects in the circadian clock system result in adjusted rhythms in both urine production and bladder storage function in mice [84]. Similarly, both in nocturia and in enuresis, this circadian rhythm of AVP secretion and the production of urine seem to be disturbed [82, 83], resulting in increased nocturnal urine production. AVP secretion is influenced not only by diurnal patterns but also by aging and gender. Changes in water metabolism due to age are multifold: the composition of body fluid alters and body fat increases, plasma volume lowers, thirst perception lessens and renal function decreases. This results in a higher susceptibility for mismatches like dehydration or overhydration and hyperosmolality and hypo-osmolality—notably hyponatremia [81].
In brief, nocturnal polyuria can manifest itself when the circadian pattern of AVP secretion is disturbed. Other causes of nocturnal polyuria can result from high evening fluid intake, a defect in AVP action or solute diuresis caused by congestive heart failure, sleep apnoea and renal insufficiency. Nocturnal polyuria often is idiopathic, due to changes according to age [86]. Presented like this, presence or absence of nocturnal polyuria seems quite straightforward. Unfortunately, however, quantifying the presence of nocturnal polyuria is more difficult than it seems, as many different definitions for nocturnal polyuria are available [87]. Which one of these definitions is best is not clear yet [87]. The most intriguing is probably to identify the definition which expresses the actual mechanism of nocturnal polyuria best and is therefore most efficacious.
3.6.1 Definitions of Nocturnal Polyuria
The most widespread definition is the International Continence Society (ICS) definition: an age-dependent nocturnal urine output exceeding 20–33% of 24 h urine output, the nocturnal polyuria index [88]. It is therefore a ratio between night-time and 24 h urine production, in which the first morning void is regarded as night-time urine production for the preceding night. Quite recently, a meta-analysis showed that the clinical and discriminative value of this ICS definition is limited, as the difference in nocturnal voiding frequency between people with and without NP, as defined by the ICS definition, is only 0.6 [89].
In contrast to the ICS definition, the International Children’s Continence Society (ICCS) defines nocturnal polyuria as a nocturnal urine production exceeding 130% of the expected bladder capacity for age, which itself is defined as (age + 1) × 30 [90]. This definition thus uses the relation between night-time urine production (including the first morning void) and the bladder capacity, a completely different strategy from the ratio of the ICS definition.
Several authors have attempted to state more appropriate definitions than those proposed by the continence societies [91–94]. A few definitions are based on nocturnal urine volume or nocturnal urine production, like a nocturnal urine volume >0.9 mL/min [95, 96] or a nocturnal urine production >90 mL/h. [97]. The first one is based on a small sample of young men. The second is based on a large sample of middle-aged and elderly men, and more rigorously tested, showing a better discriminative value than the ICS definition. Nevertheless, it has not been validated in other (clinical) populations yet.
Other nocturnal polyuria definitions are the nocturia index [94] and the nocturia bladder capacity index (NBCi) [98]. The nocturia index is a ratio, representing the nocturnal urine volume divided by the maximum voided volume. It uses, like the ICCS definition, the relation between urine production and bladder capacity and is therefore more like a measure of this association than a definition for nocturnal polyuria. The NBCi is defined as the nocturia index—1, and it represents the actual number minus the predicted number of nocturnal voids. Like many of the other definitions, the first morning void is included in the night-time volume, but it is excluded in the night-time frequency. This can be regarded as a problem because people with a large first morning void, but without nocturia, potentially could be diagnosed as having nocturnal polyuria. Although the NCBi does describe the mechanism of nocturia and nocturnal polyuria most accurately, it is impossible to do statistical analyses related to the nocturnal voiding frequency because nocturnal voiding frequency and NCBi are mathematically associated.
In a further development, both the ICS and the ICCS definitions have been proposed as requiring adjustment according to statistical reasoning. For the ICS definition, the cut-off value was proposed to be changed to 0.53, the upper limit of the 95% confidence interval in a normal population [94]. For the ICCS definition, a 97.5 percentile line for nocturnal urine volume in healthy children was found at 20 × (age + 9), and it was therefore suggested to base the definition on nocturnal urine volume alone instead of on the relation between night-time urine production and bladder capacity [91].
Summarized, all these definitions use different strategies to calculate nocturnal polyuria. More important still, all these definitions lack validation procedures [87]. Therefore, there is no valid nocturnal polyuria definition that can be wholeheartedly recommended. A recent report by the nocturia think tank of the International Consultation on Incontinence-Research Society stated that more practical and clinically meaningful definitions of nocturnal polyuria are needed [99]. This raised the question how to determine the best nocturnal polyuria definition. Conditions currently advocated are that the definition should be based on urine production per time unit instead of on a ratio or a diurnal urine pattern, especially when the first morning void is included [87, 99].
3.6.2 Epidemiology
Clearly, due to the problems described considering all the different nocturnal polyuria definitions used, data on incidence and prevalence of nocturnal polyuria is also widespread. Overall, nocturnal polyuria has been shown to be highly prevalent. A recent meta-analysis estimated a pooled prevalence of 63.8%. Most of the studies included used the Frequency Volume Chart for the assessment of nocturnal polyuria [89]. This is also the recommended method to derive information on the presence of nocturnal polyuria. Ideally, it describes not only voided volumes and timing of these, but also sleeping times [86, 100].
Additionally, the relative risk of nocturnal polyuria was 1.41 for people with nocturia of two or more nocturnal voids compared to people with fewer nocturnal voids [89]. In people with enuresis, nocturnal polyuria is believed to be frequently encountered as well, although data regarding exact prevalence is missing [91]. A plausible reason for this is the fact that nocturnal urine production measurement is difficult due to enuresis episodes. Nevertheless, it was found that enuresis patients excrete less AVP at night than during the day, in contrast to children without enuresis [82].
In conclusion, nocturnal polyuria is an important pathophysiologic factor both in nocturia and nocturnal enuresis. Other factors are bladder storage problems and sleeping problems, and, in nocturia, 24 h polyuria [90, 101, 102]. A thorough assessment of the conditions is appropriate [86, 99]. Therefore, valid definitions for the different causes are needed [99].
3.7 Retention of Urine
Retention of urine is the inability to empty the bladder to completion [103]. Retention of urine could be classified based on the duration of onset into acute, chronic and acute-on-chronic. The International Continence Society (ICS) defines acute urinary retention (AUR) as “a painful, palpable or percussable bladder, when the patient is unable to pass any urine” [34]. Chronic urinary retention (CUR) is defined as “a non-painful bladder, which remains palpable or percussable after the patient has passed urine. Such patients may be incontinent of urine”. The ICS no longer recommends the term ‘overflow incontinence’, although it is still commonly used in clinical practice. Voiding difficulty that happens after surgery, for example after an operation to treat stress incontinence, cannot be included under the term chronic retention—in large part because it is painful. CUR usually implies a persistent, significant post-void residual volume of urine of ≥300 mL [34].
The reported incidence of AUR in large population-based studies varies from 2.2 to 6.8 per 1000 men per year [104–108]. Retention is far more common in men than in women, and AUR is rare in younger men; men in their 70s are at five times more risk of AUR than men in their 40s. Most of the epidemiologic data referred to in the literature are for AUR; data for chronic urinary retention (CUR) are sparse [103]. The Department of Health of England Hospital Episode Statistics (HES) database in 2002–2003 stated that 0.25% [32] of hospital consultant episodes were for retention of urine. The one-year mortality after AUR was reported as 4.1% in men aged 45–54 years, and 32.8% in those aged 85 years and over. In the most prevalent group of men with spontaneous AUR aged 75–84 years, the 1-year mortality was 12.5% in men without co-morbidity and 28.8% in men with co-morbidity [109].
3.7.1 Aetiology of Retention of Urine
Factors leading to acute urinary retention in men
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