REVIEWS Contemporary concepts in the aetiopathogenesis of detrusor underactivity Nadir I. Osman and Christopher R. Chapple Abstract | Detrusor underactivity (DUA) is a poorly understood, yet common, bladder dysfunction, referred to as underactive bladder, which is observed in both men and women undergoing urodynamic studies. Despite its prevalence, no effective therapeutic approaches exist for DUA. Exactly how the contractile function of the detrusor muscle changes with ageing is unclear. Data from physiological studies in animal and human bladders are contradictory, as are the results of the limited number of clinical studies assessing changes in urodynamic parameters with ageing. The prevalence of DUA in different patient groups suggests that multiple aetiologies are involved in DUA pathogenesis. Traditional concepts focused on either efferent innervation or myogenic dysfunction. By contrast, contemporary views emphasize the importance of the neural control mechanisms, particularly the afferent system, which can fail to potentiate detrusor contraction, leading to premature termination of the voiding reflex. In conclusion, the contemporary understanding of the aetiology and pathophysiology of DUA is limited. Further elucidation of the underlying mechanisms is needed to enable the development of new and effective treatment approaches. Osman, N. I. & Chapple, C. R. Nat. Rev. Urol. advance online publication 21 October 2014; doi:10.1038/nrurol.2014.286

Introduction

Department of Urology, Royal Hallamshire Hospital, Glossop Road, Sheffield, South Yorkshire S10 2JF, UK (N.I.O., C.R.C.).

Detrusor underactivity (DUA) is a common diagnosis reported in 9–48% of men and 12–45% of women who receive urodynamic evaluation for non-neurogenic lower urinary tract symptoms (LUTS).1–3 In 2002, DUA was defined by the International Continence Society as “a contraction of reduced [sic] strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal time span”.4 However, the specificity of this definition is limited by the absence of normative data and numeric definitions of normal contraction strength and duration. Despite being commonly identified in u­rological patients, the aetiological factors and pathophysiological mechanisms resulting in DUA are poorly understood, and research into this area is lacking, in contrast to detru­ sor overactivity (DOA) and its associated symptoms that comprise overactive bladder. Defining DUA in symptom-based terms is a complex problem, as DUA is associated with a spectrum of both voiding and storage LUTS. Examples of such symptoms include urinary frequency, nocturia, incontinence, weak flow and intermittency. In particular, DUA is symptomatically indistinguishable from the LUTS associated with bladder outlet obstruction (BOO) and uro­dynamic studies, the only accepted method of determining detru­ sor pressure and hence contractile function, are the only way to differentiate DUA from BOO. This ambiguity complicates the acquisition of epidemiological

Correspondence to: C.R.C. c.r.chapple@ sheffield.ac.uk

Competing interests C.R.C. is a consultant and researcher for Allergan, Astellas, Pfizer and Recordati. N.I.O. declares no competing interests.

data—hampering the determination of the prevalence of DUA and the evaluation of possible underlying aetiological factors. Currently, no effective treatments are available for DUA other than bladder drainage, for example by intermittent self-catheterization, which, unfortunately, has led many researchers to believe that DUA is i­ncurable, resulting in a lack of enthusiasm for further research. Owing to editorials,5,6 reviews,7–9 as well as thema­ tic sessions at clinical conferences, interest has been renewed in DUA and its associated symptoms, which have been referred to as the underactive bladder. In this Review, we summarize and discuss the available evidence relating to the aetiology and pathophysiology of this common, but poorly understood, bladder dysfunction.

Aetiological factors

DUA can be a sign and/or a result of a variety of pathological processes: its origin can be idiopathic, neurogenic or myogenic, iatrogenic or functional (Box 1). In addition, some patients experience DUA owing to pharmaco­ therapy, and in many its development is multifactorial. This Review focuses on the aetiology of altered detrusor function due to normal ageing and neurogenic or m­yogenic causes.

Ageing Several investigators have sought to answer the question of whether DUA is a consequence of age-related changes in detrusor structure and function. For exam­ ple, in ex vivo ‘organ bath’ studies, bladder contrac­ tility was measured using both animal and human

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REVIEWS Key points ■■ The aetiology and pathophysiology of detrusor underactivity (DUA) are poorly understood—multiple aetiological factors and pathogenic mechanisms are likely to be involved ■■ Definite aetiologies include injuries or diseases of the nervous system and diabetes mellitus. Bladder outlet obstruction and normal ageing can, at present, only be considered likely causes of DUA ■■ Aetiological factors probably cause DUA by interrupting processes that are essential for the generation of an efficient voiding contraction ■■ Pathophysiological mechanisms can be classified as myogenic (affecting detrusor myocytes or their surrounding matrix) or neurogenic (affecting central neural control mechanisms governing the voiding reflex or afferent and/or efferent nerves) ■■ To develop new effective treatments, a better understanding of the mechanism underlying the generation of a normal voiding contraction and which abnormalities cause DUA is required

Box 1 | Aetiological factors in detrusor underactivity Idiopathic Normal ageing Unknown factors in younger people Neurogenic injury and/or disease Vascular ■■ Stroke (early phase) Degenerative ■■ Parkinson disease ■■ Multisystem atrophy Demyelinating neuropathies ■■ Multiple sclerosis Peripheral neuropathies ■■ Guillain–Barré syndrome ■■ Neurosyphilis (tabes dorsalis) ■■ Herpes zoster and herpes simplex ■■ Diabetes mellitus ■■ AIDS Spinal cord and cauda equina ■■ Intravertebral disc prolapse ■■ Cauda equina lesions ■■ Spinal cord tumours ■■ Spinal canal stenosis ■■ Spinal cord injury ■■ Sacral fracture Pelvic fracture Pudendal nerve injury (bilateral) Myogenic Bladder outlet obstruction Diabetes Iatrogenic Radical pelvic surgery ■■ Radical prostatectomy ■■ Radical hysterectomy ■■ Anterior resection, abdomino-perineal resection Radiation therapy Functional ■■ Fowler’s syndrome ■■ Dysfunctional voiding Pharmacotherapy Drugs with anticholinergic effects ■■ Antimuscarinics ■■ Antihistamines ■■ Antipsychotics ■■ Antiparkinson medications ■■ Antispasmodics ■■ Tricyclic antidepressants Opioids

bladder-muscle strips. In clinical studies, urodynamic evaluations of symptomatic individuals were performed and, in some cases, correlated to morphological changes of b­ladder‑muscle tissue that were observed on microscopy. Studies on animal tissues Ex vivo studies investigating the effect of ageing on bladder contractility are numerous. Mainly, such studies use muscle tissue from rats and assess fibre contraction mediated by electrical, potassium, cholinergic or purinergic signalling, comparing ‘young’ with ‘old’ animals. Experiments typically involve the suspension of muscle strips in an organ bath, where they are connected to a force-displacement transducer, through which the isometric tension that develops in response to stimuli can be recorded. Often, contractile responses to electricalfield stimulation are measured: one study showed greater responses in young (aged 4–6 months) than in old (aged 28–30 months) animals,10 whereas other studies found no age-related difference.11,12 Interestingly, in one report, muscle strips from the bladder base, but not those from the bladder body, showed an age-related reduction in contractile response.13 Another study found that trigonal muscle from old rats (aged 27 months) showed reduced contractile responses compared with muscle from young rats (aged 6 months), whereas muscle from the circular layer showed the reverse; muscle from the longitudina­l layer did not show age-related differences.14 The same findings were observed with chemically induced contraction using potassium chloride solution.14 Some other studies assessing responses to potassium chloride also found an age-related reduction in contractility,12,15 but the majority of such studies did not report differences between young and old animals.11,16–22 Cholinergic stimulation can be induced using pharmacological agents, such as muscarinic agonists (for example, bethanechol), or acetylcholine. As with other induction methods, contrasting results have been reported for choli­n ergic stimulation of muscle contraction: some studies demonstrated no difference,12,17,20,21,23,24 whereas others demonstrated an age-related increase13 or decrease11,15,19 in contractile responses. Purinergic stimu­l ation using ATP induced greater responses in tissues from old animals than in tissues from young animals in most studies,13,15,24,25 but some studies found no age‑related differences in contractile responses.12,13,17 Using whole bladder specimens from rats aged 3 months and 24 months, one team of researchers measured the amplitude and rate of generated pressure, as well as emptying efficiency under repeat electrical stimulation in organ baths.26 They found that bladders from old animals fatigued faster than bladders from young animals. Tissue analysis using high-performance liquid chromatography revealed that phosphocreatine and ATP concentrations were significantly lower in old bladders compared with young bladders, supporting the hypothesis that a reduced capacity for energy production could be the cause of the accelerated fatigue of old bladders.

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REVIEWS Although the advantage of laboratory bench studies is that fibre contractility can be directly measured, it is difficult to extrapolate such ex vivo data to an intact, innervated bladder. Furthermore, the findings from the use of a variety of physiological and nonphysiological stimuli in these experiments are contradictory. Discrepancies of results could be attributable to differences between examined animal strains and species10 or variations in biopsied regions.14 Alternatively, a decline in contractility seen in vivo might be explained by age-related changes in the afferent and/or efferent functions or central control mechanisms of detrusor contraction.23 Data such as those discussed above make it difficult to draw definitive conclusions and to evaluate their relevance to the situation in humans—the functional innervation in rats has a high noncholinergic, nonadrenergic component, in contrast to the predominantly cholinergic innervation in humans. Moreover, the marked difference in the duration of the ageing process in animals compared to humans must be borne in mind. In summary, given these limitations and hetero­ geneous results, the data from animal tissues cannot be used to support the theory of an age-related decline in d­etrusor contractile function in humans. Studies on human tissues Few ex vivo studies on human tissue samples have been performed. One team of researchers studied 227 bladder biopsy specimens from patients with normal bladders, BOO, idiopathic DOA or neurogenic DOA using multiple stimuli, such as nerve-mediated and direct electrical stimulation, as well as agonists, including carbachol, ATP and potassium. 27 No evidence was found of an age-related decrease in muscle contractitility elicited by direct muscle activation using carbachol or direct electrical muscle stimulation in any of the groups. However, an age-related decrease was observed in nerve-mediated, electrically stimulated contractility in the BOO and DOA groups, suggesting a decline in functional innervation with increasing age in these groups; no decline was observed in the control group. Similarly, another study found no significant differences in the contractile responses to electrical-field stimulation, potassium, ATP and carbachol in biopsy specimens from patients in three age groups (70 years).28 Moreover, asymptomatic men do not seem to experience a decline in contractility with age.29 An alternative approach is to study whether any changes occur in composition and ultrastructure of bladder muscle tissue during normal ageing. In a quanti­ tative morphometric study of 86 bladder specimens from autopsies of young (aged 35–45 years) and old (aged 65–75 years) patients of both sexes, an age-related decline in the ratio of smooth muscle to connective tissue was found, with no difference between the sexes.30 Similar findings were observed in a semi-quantitative study, with the conclusion that ageing was associated with detru­sor fibrosis, independent of the presence of BOO.31 In nonobstructed, aged bladders, smooth-muscle cell morpho­ logy was normal, but a reduction in innervation was

observed.32 Although detru­sor contractile function was not measured directly, these studies suggest a tendency toward increased bladder wall fibrosis with ageing, which could explain a decrease in contractility. One group of researchers studied bladder muscle speci­mens from patients with a variety of bladder dysfunctions using electron microscopy, and proposed that the normally contractile, ageing detrusor has a distinct ultrastructural pattern.33 Termed the ‘dense band pattern’, its features are sarcolemma with depleted caveo­l ae (plasma membrane invaginations) and long dense bands, which are cell adhesion complexes that are associated with several structural proteins, including α‑actinin, actin, filamin, calponin, vinculin, tensin and integrins.34 A subsequent clinicopathological validation study suggested that this pattern was dominant in all individuals aged >65 years with ‘stable’, unobstructed, normally contractile bladders on urodynamic evaluation.33 An age-related depletion in caveolae was also observed in the detrusor muscle of rats.35 Caveolae are an abundant feature in animal cells, and are thought to have predomi­ nantly signalling functions. Caveolae could have an important role in bladder smooth muscle function, and alterations in caveolae expression might lead to DUA.36–38 In summary, accepting the limitations when extrapolating results from ex vivo studies to the intact bladder, it seems clear that the available evidence does not support an age-related myogenic pathological change in humans. By contrast, distinct changes in the morpho­ logy of bladder muscle tissue could plausibly account for reduced contractile function. Clinical studies Arguably, clinical urodynamic data collection is a pragmatic method to determine age-related trends in detrusor function (Table 1). As part of a cross-sectional study of DOA and ageing, detrusor contractility was studied in 85 ambulatory, community-dwelling women of three age groups (20–39 years, 40–59 years and >60 years) using video-urodynamics.39 Detrusor contraction strength was determined using projected isovolumetric detrusor pressure (Pdet). 40 Both flow rate and contraction strength declined significantly with age, regardless of DOA presence. The maximum urethral closure pressure and bladder sensation also showed a significant age-related decline. A comparison of urodynamic data from women aged >75 years with women aged 40 years with LUTS.44 A further study in men with BPH also

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REVIEWS Table 1 | Studies assessing the relationship between contractility and ageing Study

Patient sex

Age groups

n

Findings

Pfisterer et al. (2006)39

Female

20–39 40–59 >60

85

flow rate (P = 0.006) projected isovolumetric Pdet (P 40

253

Qmax (P = 0.014) PVR (P = 0.02) = Pdet@Qmax

Madersbacher et al. (1996)45

Male

45–90 (mean 67.3)

222

Qmax (P = 0.045) PVR (P = 0.0013) = Pdet@Qmax

Qmax (P not reported) Pdet@Qmax (P not reported) = maximum Pdet

*Values are ± 1 SD. Abbreviations: =, no change; , increase; , decrease; cmH2O, centimetres of water (unit of pressure); Pdet, detrusor pressure; Pdet@Qmax, Pdet at Qmax; PVR, postvoid residual; Qmax, peak flow.

found no change in maximum Pdet or Pdet@Qmax with increasing patient age.45 These data are limited by the fact that studies were mainly conducted in symptomatic individuals who probably had other underlying pathophysiological abnormalities, in addition to the relatively small groups studied and the variation in age cut-offs. Furthermore, it is unclear whether age-related changes of detrusor function depend on patient sex. Perhaps a more pronounced decline in contractile function of the bladder could be expected in males owing to bladder wall fibrosis consequent to benign prostatic obstruction. Overall, these clinical urodynamic data do not provide strong evidence to support the assertion that detrusor contractile function declines with normal ageing.

Bladder outlet obstruction A common assumption among clinicians is that a decline in detrusor function is a terminal event in the pathological progression of BOO. Certainly, this supposition is supported by studies in animals, in which the sequelae of surgically induced BOO are well described and have been separated into three stages: in the beginning, after BOO is induced (for example, through a ring or ligature), resistance at the bladder outlet rises and the bladder becomes distended. Then, the muscle compensates and becomes hypertrophic and hyperplastic. Consequently, the weight of the bladder increases over several weeks with an associated increase in blood supply. At this point, the contractility of the bladder is normal and remains stable for a variable length of time—the compensated stage. Eventually, the bladder decompensates,46,47 and typically has an impaired response to contractile agonists

(for example, electrical-field stimulation, betha­nechol or potassium). Histologically, the muscle shows evidence of increased connective tissue deposition.48 Permanent c­o ntractile failure can result if the o­b struction is not relieved. The proposed explanation for these changes is based upon cyclic ischaemic and reperfusion injury. The increased pressure that is needed to overcome the outlet resistance causes increased bladder wall tension (according to the law of Laplace). This tension compresses the vessels in the bladder wall, resulting in tissue ischaemia. Using laser Doppler flowmetry, this process has been observed in the bladder walls in a pig model of BOO.49 As the bladder fills and empties during the micturition cycle, alternating cycles of ischaemia and reperfusion occur, which results in the generation of reactive oxygen species50 and the release of free intracellular calcium, causing protease51 and phospholipase activation48 and membrane lipid peroxidation.52 These processes in turn result in damage to cellular and subcellular membranes of myocytes and neuronal cells. The outcome is i­mpairment of cellular contractile function and denervation.53 The findings in animals cannot be easily reconciled to the situation in humans: often, the animals studied are young and female, and the obstruction is acutely imposed, which does not mirror the progressive nature of BOO in humans. In clinical practice, men with BOO seem to experience a spectrum of outcomes, which range from being entirely asymptomatic to experiencing LUTS, acute retention or chronic retention. A prolonged period of BOO often does not result in clinically manifest bladder decompensation: in a cohort of 170 men with BOO who were followed for a mean of 13.9 years, no significant deterioration in urodynamic parameters was observed (no change in Pdet@Qmax and a reduction in Qmax of only 1 ml/s), and only 17% of patients required any form of intervention.54 Moreover, most men who do experience an acute decompensation of bladder function (those who develop acute urinary retention) have preserved detrusor function. In addition, even among men with chronic urinary retention, some have preserved contractility, which is usually associated with poor compliance and upper renal tract changes (referred to as high pressure chronic retention).55,56 Evidently, many aspects of the pathophysiology of DUA that relate to BOO are poorly understood and the clinical picture in any i­ndividual patient is probably multifactorial in nature.

Diabetes mellitus Diabetic bladder dysfunction (DBD, also called diabetic cystopathy) is associated with a time-dependent decline in voiding efficiency over the course of the disease, and a loss of bladder sensation.57,58 These symptoms have been attributed to the autonomic neuropathy associated with diabetes that occurs as result of axonal degeneration and segmental demyelination.59 Hyperglycaemia underlies this nerve injury through mechanisms that include the activation of the polyol pathway, the generation of free radicals, activation of protein kinase C and formation of advanced glycation end-products.60 Nerve growth factor

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REVIEWS Site of dysfunction

Higher brain centres PAG Brain

Major aetiological factors

Mechanisms

Brain circuits Pontine micturition centre Periaqueductal gray Limbus Hypothalamus Prefrontal cortex

Efferent pathways Sacral cord Sacral nerves Pelvic nerves Postganglionic neurons

Failure of integration or processing

Impaired activation of detrusor

Neurological disease or injury Normative ageing*

Afferent pathways Peripheral afferents Anterolateral white column Posterior column

Early termination of voiding reflex

Bladder outlet obstruction* Diabetes mellitus

Bladder

Detrusor muscle Detrusor myocyte Extracellular matrix

Loss of intrinsic contractility

Figure 1 | Major aetiologies, sites of dysfunction and pathogenic mechanisms that result in DUA. The major aetiologies of DUA are likely to cause impairment of detrusor voiding function through four primary mechanisms. These mechanisms can be triggered by pathologies that cause interruption of the normal voiding reflex centrally or peripherally (brain circuits, efferent or afferent nerves), or, alternatively, interfere with normal intrinsic detrusor muscle contraction. *Bladder outlet obstruction and normative ageing are probable rather than definite factors. Abbreviations: DUA, detrusor underactivity; PAG, periaqueductal gray.

(NGF) is important in the maintenance of sympathetic and sensory nerve function and has been implicated in DBD. Rats with streptozotocin-induced diabetes mellitus had decreased levels of NGF in the dorsal root ganglia associated with a raised PVR and bladder capacity.61,62 DBD could also be a direct consequence of detrusor myocyte impairment owing to abnormalities in intercellular connections and excitability, intracellular signalling, receptor density and distribution. These mechanisms are not well understood: both increases and reductions in contractility have been demonstrated,63,64 in keeping with the data from ageing studies in animals. These contradicting observations could be explained by time-dependent changes occurring in the bladder wall (DBD temporal theory).65 This hypothesis postulates that osmotic diuresis resulting from high blood glucose levels could cause bladder distension and a rise in intravesical pressure, leading to compensatory bladder hypertrophy. Clinically, this stage would manifest in storage LUTS. With disease progression, toxic products of oxidative stress accumulate, leading to nerve and myocyte injury, which clinically manifest as poor bladder sensation, voiding symptoms and impaired bladder emptying.

Neurological disease or injury A multitude of nervous system diseases or injuries can lead to DUA. Cerebrovascular accident (stroke) is frequently associated with bladder dysfunction—in the long term most commonly in the form of DOA. In the acute setting, 50% of patients will develop urinary

retention (which is thought to be due to cerebral shock), 75% of whom demonstrate acontractile detrusors.66 In Parkinson disease, DUA occurs in 10 cmH2O in supramembranous urethra in males or distal urethra in females on micturitional urethral pressure profilometry

10 patients with impaired contractility showed degeneration pattern 3 patients with normal contractility did not show degeneration pattern

Elbadawi et al. (1997)33

Prospective case series

30 women 14 men

65–91

Also included patients with DOA and BOO

PVR >50 ml when no BOO according to Abram–Griffiths nomogram PVR >250 ml in patients with BOO

Using PVR criteria: full degeneration pattern observed in 12/16 patients with DUA and 2/6 with borderline DUA (both with BOO) and 0/34 patients without DUA Using Schäfer nomogram: full degeneration pattern observed in 9/18 with weak and/or very weak contractility (2 with BOO) and 5/38 with normal and/or strong contractility

Hindley et al. (2002)80

Controlled prospective case series

2 women 19 men 6 controls (sex not reported)

18–90

No obstruction according to Abrams–Griffiths nomogram

PVR >300 ml, weak or very weak contractility according to Schäfer nomogram

Degeneration pattern observed in 20 patients Degeneration pattern not observed in controls

Brierly et al. (2003)76

Controlled prospective case series

3 women 11 men 17 controls (7 women and 10 men)

19–81

No obstruction according to Abrams–Griffiths nomogram

PVR >300 ml, weak or very weak contractility according to Schäfer nomogram

Significantly greater disruptive cell count in DUA vs matched controls (P = 0.0002)

Holm et al. (1995)31

Controlled prospective case series

14 men (12 with acute retention and 2 with chronic retention) 6 controls (men)

50–94

Acute or chronic urinary retention

Only patients with chronic retention underwent urodynamic studies, one of whom was obstructed

No specific ultrastructural findings accompanied urinary retention

Abbreviations: BOO, bladder outlet obstruction; cmH2O, centimetres of water (unit of pressure); DOA, detrusor overactivity; DUA, detrusor underactivity; PVR, postvoid residual.

urodynamic findings before and after surgery. Ultimately, many patients will recover contractile function by 1 year after surgery. A study in cats, in which the pelvic plexus was extirpated, suggests that there is restitution of intrinsic cholinergic nerves and muscle cell regeneration after the initial injury-related degeneration.75 In patients with infectious diseases of the nervous system, DUA can be entirely reversible, for example in patients with Guillain–Barré syndrome or herpes zoster (shingles), or it can be permanent, owing to progressive neuropathies, which occur in patients with, for example, AIDS or neurosyphilis (tabes dorsalis).

Pathophysiological mechanisms

The generation of normal, volitional bladder voiding contraction requires a functioning detrusor muscle, intact efferent and afferent innervation and integral central neural control mechanisms (Figure 1). An interruption to the normal function of any of these essential components could lead to impairment of the detrusor voiding contraction and the clinical manifestation of DUA. In a large proportion of patients with DUA, probably more than one of these components is affected; particularly elderly patients may have concomitant diabetes, BOO or neurological disease (for example, stroke or Parkinson disease). Furthermore, transient urinary retention can be caused by acute illness (for example, pneumonia or myocardial infarction) or pharmacotherapy (Box 1). It is essential to identify such patients so that they are not subjected to i­nappropriate treatments, such as bladder outlet surgery.

Myogenic pathologies In theory, a pathology that changes the normal structure of the extracellular matrix of the detrusor muscle could result in attenuation of the contraction that the myocytes generate. The myocytes themselves could also be affected by aberrations in key cellular mechanisms (for example, ion storage and/or exchange, excitation–­ contraction c­oupling, calcium storage and energy generation) that could impair their intrinsic ability to generate a contraction.76 In both situations, an inefficient detru­sor contractio­n can occur—even if i­nnervation was intact. In addition to the changes occurring in the detrusor with normal ageing, a set of studies proposed that distinct ultrastructural patterns observed by electron microscopy characterise different bladder dysfunctions, including DUA.77–79 Although the accuracy and reproducibility of the classification system developed on the basis of these observations is disputed, other groups have noted similar findings in patients with DUA (Table 2).76,80 DUA is characterized by a ‘degeneration’ pattern represented by disrupted detrusor myocytes and axo­nal degeneration (Figure 2).77 An unresolved question is whether these changes represent a cause of DUA or occur as a consequence of a separate pathological insult that results in DUA. In addition, several important biomechanical factors can affect detrusor contractile function. In men with BOO, the bladder can increase its ability to generate pressure owing to the ‘detrusor reserve’, which is defined as the difference between the isovolumetric Pdet and the

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REVIEWS a

b

c

Figure 2 | Electron microscopy images of ultrastructural changes in detrusor underactivity. a | Normal detrusor muscle showing two muscle bundles divided by a wide collagen-rich septum. Within the bundles, individual fascicles separated by a thin microseptum can be observed. b | At higher magnification, smooth, intact sarcolemma with a thin interstitium between adjacent muscle cells can be observed. c | The ‘degeneration’ pattern is exemplified by a disruptive cell with a shrivelled appearance and sarcolemma breakdown, as well as deposition of debris and collagen in the interstitium. Reprinted from The Journal of Urology 169, Brierly, R. D. et al. A prospective controlled quantitative study of ultrastructural changes in the underactive detrusor, 1374–1378, © 2003, with permission from Elsevier.

maximum Pdet .81 In men with BOO and minimal PVR, detrusor reserve was elevated 200 ml), the detrusor reserve was significantly lower.81 A loss of detrusor reserve might explain why patients with DUA develop chronic retention despite having apparently normal projected isovolumetric Pdet. Animal models have demonstrated that BOO can result in regional differences in bladder wall thickness and contractility, which are proposed to occur because of variability in tissue remodel­ ling after the obstruction is induced and the bladder enlarges.82 Such regional differences could interfere with the normal propagation of waves of contraction, resulting in less efficient voiding. Similarly, bladder diverti­ cula might also impair propagation of a contraction and diminish the energy generated.

Central control mechanisms The voiding reflex is facilitated by the spinobulbo­spinal pathway that passes through the sacral parasympa­thetic nucleus and the pontine micturition centre (PMC). The PMC receives input from higher centres in the cerebral cortex, particularly the limbic system. In animals, functional neuroimaging has provided interesting insights: populations of PMC neurons, termed direct neurons, become activated just before and during reflex bladder contractions;83–85 many of these neurons pass to the lumbo­ sacral cord. In humans, similar areas of the brain stem and cortex seem to be implicated in the voiding reflex: the insular cortex, the hypothalamus, the peri­aqueductal gray and the PMC.86 In theory, a lesion that affects any of these regions could result in DUA, although a correlation between the site of a lesion and the u­rodynamic finding is not always apparent in c­linical practice.87 Efferent function Any interruption to efferent signalling may manifest as absent or reduced detrusor contraction. Some evidence suggests that a reduction in autonomic bladder innervation occurs during normal ageing.88 A range of diseases and injuries can also result in disturbance of efferent signalling (Box 1).

Afferent function Although most research has focused on the myogenic and efferent contributions to the pathogenesis of DUA, the importance of the afferent system is increasingly being recognized. The afferent system is integral to the function of the efferent system in the neural control of micturition, both during the storage and the voiding phase. The afferent system monitors the volume during the storage phase, and also the magnitude of detrusor contractions during voiding. Urethral afferent nerves respond to flow and are important in potentiating the detrusor contraction.89,90 An age-related increase in the threshold of bladder capacity, which prompts voiding, has been shown in women and it could be that normal ageing is associated with a degree of afferent dysfunction.39,91 This suggestion is supported by functional MRI in asymptomatic elderly patients, showing reduced responses to bladder filling in the insular cortex, which maps visceral sensation.92 The particular dysfunction of the afferent system is also likely to determine the nature of the symptoms experi­ enced by patients with DUA. If the afferent system is intact, patients might experience storage LUTS, whereas, if sensation is impaired, patients typically suffer from i­nfrequent voiding (Figure 3). Given that both tissue changes and a decline in sensory function appear to occur with ageing, both factors probably contribute to DUA in elderly patients. One hypothesis integrates the findings from ultrastructural studies of tissue changes that accompany normal ageing with the altered afferent function seen in ageing and disease,93 proposing that ageing results in tissue changes that alter the biomechanical properties of the bladder, including a reduction in elasticity. This process results in changes in the passive compliance curve, with a greater initial compliance at low volumes followed by an increase in pressure and, hence, wall stress as bladder capacity is reached. Afferent outflow can be considered to be a function of wall stress; therefore, clinically, this scenario results in a delayed desire to void, leading to increased bladder capacity, which in turn is followed by urgency when capacity is reached. Conversely, when a small volume of urine is passed, wall stress declines dramatically, resulting in a reduction in

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REVIEWS Afferent function

Detrusor underactivity Voiding LUTS Slow flow Intermittency Hesitancy Straining

Intact

Impaired

Incomplete bladder emptying

Reduced sensation of bladder emptying

Infrequent voiding

Feeling of incomplete emptying Frequency Nocturia with or without incontinence

Incontinence

Normal intervoid interval

Figure 3 | The role of afferent function in the pathogenesis of the symptoms of DUA. The symptoms associated with DUA include a wide spectrum of voiding, storage and post-micturition LUTS. Patients with impaired afferent function void less frequently and, if bladder emptying is reduced, can suffer from incontinence that is typically more prominent during the night time, owing to urethral relaxation during sleep. Patients with preserved afferent function can have a normal intervoid interval provided bladder emptying is normal. If bladder emptying is poor, patients typically experience a sensation of incomplete emptying after voiding, urinary frequency and/or nocturia with or without incontinence. Abbreviations: DUA, detrusor underactivity; LUTS, lower urinary tract symptoms.

afferent activity, which in turn leads to an early termination of detrusor contraction and reduced voiding efficiency. This theory provides a potential explanation for the finding of detrusor hyperactivity impaired contractility, which has been described to occur with ageing.94 An important group of patients who present with symptomatic DUA or urinary retention are women with Fowler’s syndrome95 and patients with dysfunctional voiding. The aetiopathogenic mechanisms underlying these conditions are poorly understood and the distinction between them is not clear; however, interruption to afferent signalling is thought to be involved in both disorders.96 In Fowler’s syndrome, a poorly relaxing external urethral sphincter might inhibit bladder afferent signalling, leading to poor bladder sensation and DUA.97,98 One theory suggests that this abnormal sphincter activity is caused by destabilisation of membranes of sphincter muscle cells because of hormonal imbalances in affected women.99,100 In dysfunctional voiding, poor pelvic floor relaxation is thought to lead to DUA.101 However, the proposed aetiology is non-organic—commonly thought to be a maladaptive behavioural response to a painful stimulus (for example, urethritis) in childhood or adult life.4,102

Conclusions

DUA is a common but poorly understood lower urinary tract dysfunction, with multiple potential causes. No consensus exists on how to effectively define DUA, how to categorize it based on aetiology and how to treat it with anything more than bladder drainage. Consequently, DUA has received little attention in the scientific literature, 1.

2.

3.

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apart from an assortment of inconsistent clinical, pathological, physiological, urodynamic and ultrasound data, both in animals and humans. DUA occurs in a heterogeneous group of patients. The potential aetiologies are multi­factorial and include disorders of bladder innervation, structure and function, which in some individuals could be a consequence of the ageing process. The pathophysiological mechanisms underlying DUA are not well character­ized, but clearly lower urinary tract dysfunctions, such as BOO, might have a contributory role. Congenital factors are also probably of importance in some patients. Most research has focused on a myogenic pathogenesis, and less attention has been given to the possible role of the efferent and afferent pathways, as well as central control mechanisms. Further elucidation of these mechanisms could aid the development of novel pharmacotherapies. Review criteria The MEDLINE and Embase databases were searched for English-language reports pertaining to detrusor underactivity published between January 1950 and March 2014. Search terms included “bladder contractility”, “detrusor contractility”, “underactive bladder”, “detrusor underactivity”, “bladder underactivity”, “impaired detrusor contractility”, “acontractile detrusor”, “detrusor failure”, “hypotonic bladder”, “detrusor areflexia”, “raised PVR” and “urinary retention”. Abstracts were screened for relevance. Original studies, review articles, commentaries and editorials were included. Selected studies were assessed for content relating to aetiology and pathogenesis of detrusor underactivity.

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