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6. Symptoms Complexes in Urology
Keywords
Symptom complexOveractive bladderDetrusor overactivityUnderactive bladderDetrusor underactivityBladder pain syndromePainful bladder syndromeInterstitial cystitisIntroduction
Traditionally, the terminology that was used in functional urology was based on the likely underlying pathophysiological cause. Terms like ‘prostatism’ and ‘detrusor instability’ were used to describe the group of symptoms associated with what we now recognize as benign prostatic obstruction and detrusor overactivity (DO) respectively. The development and widespread acceptance of urodynamic studies as a clinical diagnostic tool led to the recognition that symptoms do not reliably predict the underlying pathophysiological problem. This was neatly summarized by Patrick Bates who, whilst working with Richard Turner-Warwick at the Middlesex Hospital, coined the term “the bladder is an unreliable witness” [1]. The term lower urinary tract symptom (LUTS) was introduced by Paul Abrams in 1994, which largely replaced the terms in usage at the time such as prostatism and BPH when describing urinary symptoms [2].
Consequently contemporary urological practice has moved away from using definitions tied to pathophysiology, favoring a symptoms-based approach instead [3, 4]. In addition to not presuming cause, this approach provides a clear set of symptoms on which to base a clinical diagnosis and initiate basic treatment without the need for expensive and invasive tests. This approach has not been without its critics who have suggested this approach has led to the medicalisation of normal voiding patterns and may favour commercial interests.
It is helpful to frame any discussion on symptom complexes in the context of how lower urinary tract symptoms (LUTS) are classified in contemporary practice. Wein was the first to classify lower urinary tract dysfunction on the basis of the phases of the micturition cycle: storage and voiding [5]. This approach has been adopted by the International Continence Society which now classifies LUTS into three groups: storage, voiding and, in addition, post-micturition. Typical storage symptoms include frequency, urgency, nocturia and incontinence. Hesitancy, intermittency, slow stream and straining are representative of typical voiding symptoms. Post-micturition symptoms include a ‘feeling of incomplete emptying’ and ‘post-micturition dribble’ [6]. In this chapter we discuss and critique the principal symptom-complexes encountered in modern urological practice: the overactive bladder, the underactive bladder and bladder pain syndrome.
From a semantic point of view, it is important to distinguish the term syndrome from symptom complex. A syndrome refers to a grouping of symptoms and clinical signs which relate to the deviation of the function of an organ or a lesion in the organ. A symptom complex is a grouping of symptoms or clinical signs without any consideration for a lesion or functional disturbance of particular organ. As OAB and, in theory, UAB describe a grouping of symptoms which may or may not occur in association without a demonstrable urodynamic abnormality they are considered to be symptom complexes.
The Overactive Bladder
Definitions and Terminology
The overactive bladder (OAB) is the oldest recognized symptom complex in functional urology. It is defined by the ICS as “urgency, with or without urge incontinence, usually with frequency and nocturia” [6]. The sine qua non of OAB is urinary urgency, “a sudden and compelling desire to void that is difficult to defer”. The term OAB-wet is used when patients are incontinent whereas OAB-dry is used when patients remain continent. The term OAB was introduced by Paul Abrams and Alan Wein in 1996 who proposed that a symptom-based definition should be used, based upon the fact that many patients who were bothered by symptoms did not exhibit DO on filling cystometry [3]. In addition, it did not seem necessary that all patients with symptoms should have to undergo invasive testing before commencing readily available and relatively safe drug treatment [2, 3]. The simplicity of the term OAB compared to the previous urodynamic terms renders it easier for patients to understand, which has contributed to the growing profile of OAB and arguably led to increased research in the field and a subsequent rise in the number of agents available to manage the condition. The term “detrusor overactivity” (DO) continues to be used as a descriptor in urodynamic studies [7].
The ICS definition has received some criticisms. It does not differentiate different causes of the symptom complex, which some have argued is necessary in order to provide the most appropriate management. Similarly, it does not quantify how many voids per day or night constitute frequency or nocturia, respectively, which could result in over-medicalisation of the extremes of normal [7]. Similarly, the inclusion of terms such as “usually” and “with or without” makes aspects of the definition vague. A further criticism was highlighted by Wein, who notes that the inclusion of the word urgency, fails to include those with unaware urinary incontinence and demonstrable DO [4]. Urgency, which is a sensory symptom, is also often difficult to interpret and differentiate from the normal urge to pass urine when the bladder is full. Some have suggested a “fear of leakage” is necessary to separate pathological urgency from a normal urge to pass urine [8], though this is not part of the current definition. Another important issue is that that urgency and urge cannot be differentiated in many languages which limits the application of the definition in some countries.
Epidemiology
Studies assessing the relationship between OAB and DO
Study | OAB definition | No. of subjects | OAB-dry patients with DO (%) | OAB-wet patients with DO (%) | Overall OAB patients with DO (%) |
|---|---|---|---|---|---|
Al Ghazo et al. [9] | ICS 2002 [5] | Male: 92 | 63 | 93 | 76 |
Female: 117 | 61 | 70 | 59 | ||
Digesu et al. [10] | ICS 1988 [16] | Female: 843 | – | – | 54.2 |
Giarenis et al. [11] | ICS 2002 | Female: 556 | – | – | 43 |
Hashim and Abrams [12] | ICS 2002 | Male:a | 69 | 90 | – |
Female:a | 44 | 58 | – | ||
Hyman et al. [13] | Urge incontinence | Male: 28 | – | – | 75 |
Jeong et al. [14] | ICS 2002 | Female: 513 | – | – | 32.6 |
Sekido et al. [15] | ICS 2002 | Male: 12 | – | – | 75 |
Female: 38 | – | – | 37 |
Several major epidemiological studies have been undertaken to attempt to quantify the prevalence of OAB and the incidence of the specific symptoms, as well as their effect on quality of life [17–21]. Together these studies have shown that OAB is common in both women and men, with a prevalence as high as 24.7% in the EpiLUTS survey of 20,000 adults aged >40 years [20]. OAB has also been shown to increase in prevalence with increasing age in both sexes, with the EPIC study (>19,000 respondents) showing a rise from 10.8% of men and 12.2% of women in the general population, to 13.1% and 14.8% in respectively in those >40 years [17, 18]. These studies have been criticized as overestimating the scale of the problem, in view of the rather subjective methods, such as telephonic interviews and online questionnaires, that were used to assess symptoms. In addition to its significant prevalence in the population, several studies have demonstrated that OAB may have detrimental impact on mental health and sexual function, as well as on employment and productivity [21]. The economic impact of OAB is perhaps best demonstrated in the EPIC study’s cost analysis of OAB which estimated the cost-per-country at USD 13 billion per year, comprising investigation and treatment, treatment of depression secondary to OAB, nursing costs and lost productivity [17].
Pathophysiology
No single aetiology has been identified as causative of OAB. The mechanisms can be broadly categorised into two main groups: increased afferent activity and dysregulated afferent signal management. The first involves abnormal afferent signalling and may be related to either urothelial receptor dysfunction and neurotransmitter release or to detrusor myocyte hyperexcitability. In the latter there may be increased activation of voiding pathways or a defect in normal centrally-mediated inhibition. In reality the cause in any given individual is likely to be complex and multifactorial, encompassing components from each of the hypotheses.
The Myogenic Hypothesis
An early myogenic theory of bladder overactivity suggested a ‘denervation hypersensitivity’ whereby bladder outlet obstruction (BOO) caused denervation of the detrusor with subsequent increased myocyte electronic coupling and widespread excitation throughout the detrusor [22]. Later work suggests that this electronic coupling occurs through gap junction channels, composed primarily of connexin proteins. Increased Cx43 expression has been demonstrated in patients with urgency symptoms [23]. The role of connexin proteins remains a subject for further study. Furthermore, it has been suggested that the arrangement of the detrusor muscle into modules allows for a coordinated response to detrusor excitability mediated by a peripheral myovesical plexus [24].
The Urothelial Hypothesis
The urothelium and associated suburothelium, comprising nerves, vessels and connective tissue contributes to bladder modulation [25]. Responses to mechanical and chemical stimuli are mediated through an array of receptors which have been identified in urothelial cells, triggering neurohormonal stimulation of closely-related afferent nerve fibres. It is proposed that abnormalities in urothelial cell signalling could cause increased afferent signalling, with resultant increases in efferent signalling and detrusor activity [26]. As urgency itself is a sensory symptom it is possible that the afferent signalling alone is sufficient to cause symptoms.
The Neurogenic Hypothesis
During the storage phase of the voiding cycle, aberrant central signalling may result in inappropriate detrusor contractions. Central nervous system (CNS) damage may result in reduced inhibitory signalling and inappropriate activation of primitive voiding reflexes [27]. The former have been linked to suprapontine cortical lesions affecting the central inhibitory centres. Observations of patients with Parkinson’s and multiple sclerosis have led to the suggestion that disruption of the basal ganglia and lesions of the cervical spinal cord, especially the posterior and lateral columns, may lead to the development of neurogenic detrusor overactivity (NDO). Similarly, it has been observed that inappropriate activation of unmyelinated C fibres involved in the mediation of the sacral spinal reflex may result in NDO [28].
Conclusions
OAB is perhaps the best understood of the symptom complexes in urology. Despite this it continues to provide significant challenges to the research community. Further research is required to tie together the current hypotheses on the pathophysiological basis of the condition,. Epidemiological analysis reveals just how significant a problem OAB continues to be, with the least conservative estimates suggesting almost one quarter of the population > 40 years are affected. The high economic cost of the problem, emphasises the importance public and academic attention to the symptom complex.
The Underactive Bladder
Definitions and Terminology
Recently there has been growing interest in the problem of impaired bladder emptying not related to bladder obstruction. As with OAB, a urodynamic concept and terms became established before the development of symptom complex. The term Detrusor underactivity (DUA) was adopted by the ICS in the 2002 standardization of terminology document, where DUA is defined as ‘a contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal time frame’ [4]. This definition, while succeeding in its provision of a clear conceptual outline, fails to provide defined parameters for what constitutes ‘prolonged bladder emptying’ or ‘a normal timeframe’, neither does it detail how these parameters might change according to patient demographics. Nevertheless, this definition is the one most commonly cited in the literature and in practice [29]. It must also be noted that, despite attempts at standardisation, a plethora of terms are still used in the literature to refer to DUA, including detrusor failure, atonic bladder and chronic retention.
Recently a symptom-based counterpart of DUA has been proposed. An ICS working group have proposed that UAB is a ‘symptom complex suggestive of detrusor underactivity and is usually characterised by prolonged urination time with or without a sensation of incomplete bladder emptying, usually with hesitancy, reduced sensation on filling, and a slow stream’ [30]. Whether this definition is sufficiently specific to exclude those with similar symptoms arising as a result of other pathologies, such as BOO or OAB remains to be established. The apparent absence of a pathognomic symptom (c.f. urgency in OAB) is a key issue which may hamper practical application [29]. While it is unlikely that this definition of UAB is sufficiently robust for diagnostic purposes in current clinical practice, it may be helpful for promoting further clinical research [31]. Further studies are needed to validate this definition and establish its specificity, before further refinement, if possible, can be made.
Epidemiology
Understanding the epidemiology of UAB has been limited by the lack of a concrete definition, or a simple and accurate proxy measure such as urinary retention or post void residual. Thus, researchers have initially had to look at the group of patients with LUTS who have undergone urodynamic studies to first understand the prevalence of DUA, albeit this is a highly selected population. A review of the literature found that DUA was common in this group, being present in 9–45% of men and 12–45% of older women (>55 years) being investigated for non-neurogenic LUTS [32].
Recently some questionnaire-based populations studies have attempted to clarify the prevalence of voiding LUTS, with ‘difficulty in bladder emptying’ reported by 23% of individuals from the general population (age range 33–92 years, mean 74.3 years) [33]. In addition, investigators have attempted to identify the prevalence of individual symptoms associated with DUA in order to differentiate UAB from the normally functioning bladder and the symptoms associated with BOO. A group from Bristol (UK) found that men with DUA are more likely to have decreased and/or interrupted urinary stream, hesitancy, feeling of incomplete bladder emptying, palpable bladder, feeling of incomplete bowel emptying, absent and/or decreased sensation, and always straining to void compared with controls with urodynamics studies. The symptoms of decreased stream, hesitancy and urgency were more common in BOO than DUA, with DUA being further distinguished by the increased prevalence of abnormal sexual function, stress incontinence, enuresis, palpable bladder, absent and/or decreased sensation, always straining to void, bowel straining, feeling of incomplete bowel emptying, and poor bowel control. Women with DUA were distinguished from controls with normal urodynamics by decreased and/or interrupted urinary stream, hesitancy, feeling of incomplete bladder emptying, palpable bladder, absent and/or decreased sensation, enuresis, and impaired mobility in the same study [34]. This work informed the initial attempts at refining the definition of UAB.
Pathophysiology
DUA is traditionally considered to be the result of impaired detrusor activity through impaired parasympathetic efferent signalling or through structural changes in the muscle itself, neurogenic and myogenic hypotheses, respectively [29]. Recent work has suggested that other aetiological factors are also at play the pathogenesis of DUA, and indeed its symptom-based counterpart [31]. It is important to recognise that UAB, as a symptom complex, does not necessarily correlate with DUA and that afferent signalling may a play a more significant role in the pathophysiology of UAB.
Urothelial Dysfunction
Recent work to establish the role of the urothelium in normal and abnormal bladder functioning has provided some interesting insights into the potential aetiology of UAB/DUA. Bladder biopsies taken from men with DUA (defined as bladder contractility index (BCI) <100) compared to those of controls (BCI >100) showed that those with DUA have significantly lower levels of adenosine triphosphate (ATP), with a significant correlation between ATP level and detrusor pressure at maximum flow [35]. Jiang and Kuo established deficiencies in E-cadherin expression, muscarinic receptors (M2 and M3), P2X3 receptors and endothelial nitric oxide synthase when comparing urodynamically-confirmed DUA to urodynamically-confirmed stress urinary incontinence. Conversely, DUA patients had elevated levels of mast cells, apoptotic cells and increased expression of the β3-adrenoreceptor [36]. While it remains to be seen if these changes are causative or representative of DUA, these studies do succeed in demonstrating a link between DUA and urothelial dysfunction, suburothelial inflammation and altered sensory transduction.
Neurogenic Dysfunction
The role of afferent signals from the bladder and urethra in monitoring bladder filling during storage and voiding is recognised and it has been suggested that failure of this signalling could result in premature termination of the micturition reflex in DUA [37]. Similarly, afferent signals from the urethra have been shown to play a significant role in bladder functioning, with urethral anaesthesia having been shown to impair bladder emptying and urethral electrical stimulation succeeding in stimulating bladder contraction [38, 39]. The identification of serotonin receptors on urethral sensory fibres led Coelho et al. to infuse serotonin into the urethras and bladders of anaesthetised rats. Urethral infusion caused bladder contraction, whereas bladder infusion did not. The effect of urethral infusion was mitigated by urethral anaesthesia and serotonin-receptor blockade [40]. This work may prove particularly important as it represents a potential pharmacological target.
Pelvic Ischaemia
Work on rabbits suggests that bladder ischaemia secondary to pelvic arterial insufficiency can lead to ultrastructural damage and denervation, secondary to oxidative stress [41]. More recent work looking at the syndromes induced by this ischaemia found that rats with pelvic arterial insufficiency developed DO at 8 weeks and DUA at 16 weeks, with associated changes in muscarinic receptor expression and neural damage. This could support the hypothesis that ischaemia underpins both pathologies and that DUA is positioned as the end-stage of a spectrum of ischaemia [42].
Conclusions
UAB remains poorly understood. The difficulty of defining a symptom complex without a pathognomic symptom has led to epidemiological estimates that may not accurately reflect the scale of the problem. The utility of UAB as a symptom complex separate to its urodynamic counterpart, DUA, is that it facilitates discussions at an academic level until such a time as a definition sufficiently specific to differentiate UAB from alternative diagnoses is reached and, more importantly, it facilitates discussions with patients, for whom the term is much easier to understand.
Bladder Pain Syndrome
Definitions and Terminology
It could be said that Interstitial cystitis (IC) is to the bladder pain syndrome (BPS) as DO is to OAB or DUA is to UAB. While the defining characteristics of IC are not observed during urodynamics, it has previously been defined by the National Institute of Diabetes and Digestive and Kidney Diseases (USA) using strict and directly observable features such as glomerulations and Hunner ulcers observed during cystoscopy [43]. Later work suggested the requirement for a move towards a symptom-based definition, with the strict criteria failing to diagnose over 60% of patients in whom experienced clinicians felt that a diagnosis of IC was at least likely [44].
BPS is the most poorly understood and difficult to manage of all the symptom complexes in urology, it is defined as “suprapubic pain related to bladder filling, accompanied by other symptoms such as increased daytime and night-time frequency, in the absence of proven urinary infection or any other obvious pathology” [6]. The American Urological Association includes in its similar definition a required time-frame of at least 6 weeks [45, 46]. It should be noted that while this text summarises the current knowledge relating to BPS, several urological pain syndromes have been defined by the ICS, including pain syndromes of the urethra, vulva, vagina, scrotum, perineum and pelvis [6]. They are connected insomuch as they are all chronic pain syndromes with poorly understood aetiology associated with symptoms of a urogynaecological nature and/or sexual dysfunction.
Epidemiology
The prevalence of IC/BPS appears to be rising, though whether this is a genuine phenomenon or related to the varying definitions of IC/BPS over time is difficult to distinguish [47]. It is likely that the combination of a symptom-based definition and greater public and clinician awareness is responsible. This increased awareness was demonstrated by Davis et al. who used Google Trends data to show that the number of searches for IC/BPS has increased annually since 2005 [48].
A large study of census data from the United States evaluated the prevalence of symptoms that could result in a diagnosis of BPS using two definitions, one with high sensitivity and one with high specificity. This work estimated the prevalence as somewhere between 2.7% and 6.5% among adult females. Interestingly, of these patients less than 10% had a formal diagnosis of IC/BPS, suggesting that under diagnosis is a major problem [49]. A separate study evaluated a managed-care population in the Pacific Northwest of the United States and showed the prevalence of physician-made diagnoses to be 197 and 41 per 100,000 in women and men, respectively, with a female:male ratio of 5:1, much lower than previously thought [50]. Nevertheless, female sex remains the only clear risk factor for developing IC/BPS [48].
Pathophysiology
Several theories on the aetiopathogenesis of BPS have been offered, though to date no definitive process by which the pathology develops has been agreed upon. Some of the major recent theories are outlined below.
The Glycosaminoglycan Layer Hypothesis
The glycosaminoglycan (GAG) layer is formed from an extracellular matrix of polysaccharide molecules, collagen, elastin, fibronectin and laminin and covers the bladder urothelium [51]. It has been proposed that its role is to protect the urothelium from the effects of electrolytes, microorganisms and other solutes [52]. Infectious and inflammatory processes may damage the GAG layer, allowing passage of harmful substances into the bladder wall, with resultant pain, frequency and urgency [53].
The Epithelial Permeability Hypothesis
The role of urothelium is bladder modulation is just beginning to be fully appreciated [25]. Neuromodulation following signals from ATP and acetylcholine (ACh) receptors are thought to provide information to the central nervous system on bladder filling, in addition to a role in the regulation of blood flow and detrusor contractions [53]. It has been suggested that a loss in urothelial permeability can result in BPS, as well as OAB [54]. The effect of nitric oxide (NO) on the urothelium has also been implicated in the bladder functioning [55]. Differences in levels of ATP and NO in the bladder mucosa of rat models was positively and negatively correlated with bladder activity, respectively [56]. This demonstrated the importance of a normally functioning urothelium. Importantly, permeability changes may result in increased anti-proliferative factor (APF) activity, associated with increased apoptosis and decreased cellular proliferation [57].
The Inflammation Hypothesis
It has been postulated that dysfunctional urothelium is a major activator of mast cells, which release several active molecules including histamine and serotonin, as well as inflammatory cytokines, potentially resulting in inflammation, pain, fibrosis and detrusor contraction in IC/BPS [53]. Histamine and its metabolites have been detected in greater quantities in patients with IC/BPS than healthy controls [53]. The urine of patients with IC/BPS has also been shown to contain neutrophils and eosinophils [48]. Though these findings suggest an inflammatory component, understanding the processes by which mast cells are activated and which underpin the inflammatory response in IC/BPS remains a topic for future research.
The Neural Up-Regulation Hypothesis
The inflammatory response is regulated by neuroendocrine pathways, including the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis [53].
Neuroendocrine changes have been reported in the SNS of cats with Feline Idiopathic Cystitis (FIC), widely regarded as a cat model for IC/BPS [58, 59]. FIC cats have been shown to have elevated levels of thyroxin hydroxylase in the nucleus coreolus, an enzyme responsible for increased catecholamine production [60]. Similarly, elevated levels of noradrenaline (NE) have been demonstrated in the urine of FIC cats and in humans [58, 59].
An altered stress function in IC patients was demonstrated by Dimitrakov et al. who used interleukin-6 (IL-6) to stimulate corticotropin-releasing hormone (CRH) from the hypothalami of IC patients and age-matched controls. Following administration of IL-6, IC patients had a delayed adrenocorticotrophic hormone (ACTH) release. They were also noted to have higher baseline levels of NE and an exaggerated NE response. Decrease in NE levels was greater in IC patients following the administration of amitriptyline, known to inhibit SNS activity [61]. Taken together these results may represent a defect in hypothalamic CRH neuronal function and support a theory of altered stress response in IC/BPS. HPA-axis abnormalities were further suggested by a study of FIC cats that demonstrated significantly smaller adrenal glands and suggested a mild primary adrenal insufficiency [62]. Further research is required to confirm this in humans.
Further to the above, Liu et al. demonstrated increased expression of transient receptor potential vallinoid receptor subtype 1 (TRPV1) nerve fibres in the suburothelium of IC patients. TRPV1 nerve fibre density correlated well with the severity of symptoms such as pain, urgency and frequency [63].
Presently it is not clear whether these neuroendocrine alterations occur as a result of previously described pathological processes, or whether they directly contribute to the pathogenesis of IC/BPS.
Conclusions
With some estimating as many as 60% of patients with likely IC/BPS being missed following the strict criteria of the 1990s the need for a symptom complex became clear. However, despite increasing prevalence and increasing public awareness (as demonstrated by the Google Trends data for Internet searches of IC/BPS) relatively little is known about the condition. Current prevalence estimates vary wildly, and while there are several accepted hypotheses regarding the pathogenesis, clear relationships of cause and effect remain to be elucidated. That being said, recent work has uncovered some exciting new avenues for future research, offering hope in the future to those presently suffering with this often debilitating and troublesome condition.
Summary
The genesis of the OAB symptom complex has arguably raised the profile of the most bothersome LUTS, namely the storage symptoms. This has facilitated the conduct of epidemiological research which has highlighted the scale of the problem and the impact upon quality of life of patients. Along with this there has been a rise in investment in basic and clinical research and the development of several new pharmacological agents. The symptom complex approach has been criticised in that it may medicalise individuals who may be normal and consequently may serve commercial rather than patient interests. The counter point to this argument is that the symptom complex has allowed patients to be treated initially by the non-specialist practitioner without the need for invasive testing. The UAB and BPS symptom complexes are at much earlier stage in their development, and it remains to be seen whether a definition with sufficient specificity is possible so as to exclude patients with BOO in the case of UAB, and whether new simple effective treatments can be developed for both.
