REVIEWS Voiding dysfunction due to detrusor underactivity: an overview Marcus J. Drake, Jonathan Williams and Dominika A. Bijos Abstract | Detrusor underactivity (DUA) is defined as a voiding contraction of reduced strength and/or duration, which prolongs urination and/or prevents complete emptying of the bladder within a ‘normal’ period of time. This issue is associated with voiding and postmicturition urinary symptoms, and can predispose to urinary infections and acute urinary retention. The aetiology of DUA is influenced by multiple factors, including ageing, bladder outlet obstruction, neurological disease, and autonomic denervation. The true prevalence of this condition remains unknown, as most data come from referral populations. Urodynamic testing is used to diagnose the condition, either by assessing the relationship between bladder pressures and urinary flow, or by interrupting voiding to measure detrusor pressure change under isovolumetric conditions. Current treatments for DUA have poor efficacy and tolerability, and often fail to improve quality of life; muscarinic receptor agonists, in particular, have limited efficacy and frequent adverse effects. Bladder emptying might be achieved through Valsalva straining, and intermittent or indwelling catheterization, although sacral nerve stimulation can reduce dependency on catheterization. Novel stem-cell-based therapies have been attempted; however, new drugs that increase contractility are currently largely conceptual, and the complex pathophysiology of DUA, difficulty achieving organ specificity of treatment, the limited availability of animal models, and the subjective nature of current outcome measures must be addressed to facilitate the development of such agents. Drake, M. J. et al. Nat. Rev. Urol. 11, 454–464 (2014); published online 8 July 2014; doi:10.1038/nrurol.2014.156

Introduction

Urology Department, University of Bristol and Bristol Urological Institute, Southmead Hospital, Bristol, Avon BS10 5NB, UK (M.J.D., J.W., D.A.B.). Correspondence to: M.J.D. [email protected]

Normal bladder voiding involves a sequence of behavi­ oural and physiological steps, including coordinated bladder contraction and outlet-sphincter relaxation, which are integrated to expel urine when socially appro­ priate. In situations in which bladder contraction is defi­ cient, the individual affected might report lower urinary tract symptoms (LUTS), particularly during voiding and immediately postmicturition (Box 1). The urodynamic findings associated with LUTS can include poor urinary flow rates in conjunction with low detrusor pressures and incomplete emptying of the bladder. Voiding LUTS are bothersome for patients, and voiding dysfunction is an important health issue owing to the consequences of complications linked to this condition, such as UTI and e­mergency clinical admissions for acute urinary retention. Scientifically, partial bladder-outlet obstruction (BOO) in men is probably the best-understood form of voiding dysfunction, mostly as a result of the high prevalence of benign prostatic obstruction. Nevertheless, men without BOO can also experience clinically relevant voiding problems; indeed, detrusor underactivity (DUA) is present in 9–48% of men under­going urodynamic evalu­ ation for non-­neurogenic LUTS.1 Furthermore, BOO is rare in women who present with issues related to voiding Competing interests M.J.D. declares that he is advisory board member for Apogepha. M.J.D. is an advisory board member and has received speaker bureau and research support from Allergan, Astellas, Ferring, and Pfizer. J.W. and D.A.B. declare no competing interests.

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dysfunction. In the absence of BOO, voiding symptoms are usually explained by the concept that bladder con­ traction can become intrinsically too weak, or ‘under­ active’. This situation, termed DUA, has been identified by the International Consultations on Incontinence as a key symptomatic problem, with limited understanding of the aetiological mechanisms and uncertain profes­ sional consensus.2 The impact of DUA on quality of life is potentially considerable, and therapies for this condition generally lack efficacy and are associated with consider­ able adverse effects. Furthermore, key clinical issues rel­ evant to DUA have been described as ambiguous and confusing, owing to a deficiency of accepted termino­ logy, definitions, and diagnostic methods and cri­teria.1 Accordingly, this Review describes the state of our knowledge of the underlying pathophysiological mecha­ nisms, current management approaches, and possible future therapies, as well as the limitations and c­hallenges relating to these aspects of DUA.

Terminology The International Continence Society (ICS) Standard­ ization Committee has proposed consensus defini­ tions for lower urinary tract function and dysfunction.3 These definitions state that normal voiding is achieved by a voluntarily initiated, continuous detrusor contrac­ tion that leads to complete bladder emptying within a normal timespan, and in the absence of obstruction.3 Accordingly, DUA is described as a detrusor contraction



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REVIEWS Key points ■■ By default, the lower urinary tract is maintained in storage mode; voiding involves a sequence of behavioural and physiological steps, which permit passage of urine when safe and socially appropriate ■■ Detrusor underactivity (DUA) represents a contraction of reduced strength and/or duration during voiding, resulting in prolonged bladder emptying and/or failure to completely empty the bladder within a normal timespan ■■ Aetiological factors relevant to DUA include ageing, bladder outlet obstruction, denervation, and neurological disease ■■ Urodynamic diagnostic approaches assess bladder pressures and urinary flow, or detrusor pressure changes upon interruption of voiding; generally, fluctuating, poorly sustained detrusor contraction and a low flow rate characterize DUA ■■ Therapy is based on the presenting symptoms, with catheterization (usually intermittent) representing the mainstay treatment in symptomatic patients; pharmacological therapies are limited by low efficacy, adverse effects, and marginal quality-of-life improvements ■■ Potential therapeutic strategies include attempts to increase detrusor contractility or modulate afferent nerve activity, but the development of new therapeutic options for DUA faces substantial challenges

Box 1 | Definitions of voiding and postmicturition urinary symptoms The standardized definitions of voiding and postmicturition LUTS that are associated with DUA have been proposed by the ICS,3 as follows:

Voiding LUTS ■■ Slow stream: reported by the individual as his or her perception of reduced urine flow, usually compared with previous performance or in comparison with other individuals ■■ Intermittent stream (intermittency): the term used when the individual describes urine flow that stops and starts, on one or more occasions, during micturition ■■ Hesitancy: describes patient self-reported difficulty in initiating micturition, which results in a delay in the onset of voiding after the individual is ready to pass urine ■■ Straining to void: term that describes the muscular effort used to either initiate, maintain, or improve the urinary stream; suprapubic pressure might be used to initiate or maintain flow ■■ Terminal dribble: the term applied when an individual describes a prolonged final part of micturition, when the urine flow has slowed to a trickle or dribble Postmicturition LUTS ■■ Feeling of incomplete emptying: a self-explanatory term for a feeling of urine retention in the bladder experienced by the individual after passing urine ■■ Postmicturition dribble: the involuntary loss of urine immediately after completion of urination, usually after leaving the toilet in men, or after rising from the toilet in women Abbreviations: DUA, detrusor underactivity; ICS, International Continence Society; LUTS, lower urinary tract symptoms.

of reduced strength and/or duration during voiding, causing bladder emptying to be prolonged and/or failure to achieve complete bladder emptying within a normal period of time;3 insufficient evidence was available to specify ‘normal’ durations for voiding, and this remains the case. The most extreme form of DUA results from an acontractile detrusor, which cannot be demonstrated to contract during urodynamic studies. However, DUA is usually associated with reduced, fluctuating, and poorly sustained detrusor pressure, and a reduced urinary flow rate (Figure 1), unlike BOO (the generic term for partial obstruction of urinary flow during voiding), which is characterized by reduced urinary flow rate but increased detrusor pressure. Thus, voiding abnormali­ ties, DUA and BOO, are usually diagnosed by studying the synchronous values of urinary flow rate and detru­ sor pressure.4 Clinical entities similar to DUA defined

according to the ICS criteria3 have been described under slightly different terms; for example underactive bladder or impaired detrusor contractility,1 as well as hypotonic bladder,5 and detrusor or bladder failure.6 Both DUA and BOO can result in voiding LUTS and postmicturition LUTS (Box 1).3 Both conditions can also be associated with failure to achieve complete empty­ing of the bladder, with a variable postvoid residual (PVR) urine volume remaining within the bladder after the patient has finished voiding. 3 In this regard, chronic retention of urine is characterized by a nonpainful bladder that remains palpable or percussible after the patient has passed urine.3 Incomplete voiding can also take the form of acute urinary retention (AUR), which is defined as a painful, palpable, or percussible bladder in patients who are unable to pass any urine despite having a full bladder, in whom the retention volume is markedly larger than the expected normal bladder capacity.3 DUA is explicitly a problem of the voiding phase of the micturition cycle, in contrast to detrusor overactivity and overactive bladder that cause problems with storage of urine. An individual can potentially suffer from both detrusor overactivity during the storage phase of micturition and DUA during voiding; the authors who first reported this issue referred to the combination as ‘d­etrusor hyperactivity with impaired contractility’.7

Mechanisms of voiding Normal control of micturition The lower urinary tract is configured by default for col­ lection and storage of urine within the bladder. The switch to voiding of the bladder involves a sequence of integrated behavioural and physiological steps, which permit passage of urine out of the body when safe and socially appropriate (Table 1). 8 In men, the linkage between the genital and urinary tracts necessitates addi­ tional reflex changes from the default storage settings in the context of ejaculation. The voiding process begins with a decision that bladder emptying is necessary and timely, based on a strong desire to void, or anticipated circumstances (for example, if access to a toilet is pre­ dicted to become unavailable; Table 1). The person then moves to a suitable environment, typically by proceeding to the toilet and adjusting clothing. The physiological process of urine expulsion is then initiated, in the form of coordinated detrusor contraction and outlet relaxation (opening of the urinary sphincter and bladder neck),9 which constitutes the transition from the storage phase of the micturition cycle to the voiding stage (Table 1). Several central nervous system (CNS) centres are invol­ved in the process of environmental assessment, decision-­m aking, and physiological coordination, notably, the prefrontal cortex, the periaqueductal grey and the pontine micturition centre (PMC).10 The rele­ vant spinal nuclei that mediate the muscular responses in the lower urinary tract are the parasympathetic nucleus for detrusor contraction, the Onuf ’s nucleus for contrac­ tion of urinary sphincter, and the sympathetic nucleus for bladder-neck contraction (Table 1); the balance of activity in these nuclei is regulated by the PMC so

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REVIEWS Pves (cmH20)

100

0

Pabd (cmH20)

100

0

Pdet (cmH20)

100

0

Flow (ml/s)

25

0 8:10

8:20

8:30

8:40

8:50

9:00

9:10

9:20

9:30

9:40

9:50 10:00 10:10 10:20 10:30 10:40 10:50 11:00

Time (m:s)

Figure 1 | Results of an invasive urodynamic assessment in a patient with DUA. This example captures the voiding phase of micturition assessed by invasive urodynamics pressure-flow studies in a man with detrusor underactivity. Plots of the vesical (bladder) pressure (Pves), the abdominal pressure (Pabd; recorded from within the rectum), and the calculated detrusor pressure (Pdet) are shown over time. Pves is the pressure exerted on the contents of the urinary bladder, and is the sum of Pabd and Pdet. In addition, bottom trace shows the dynamic urine flow rate in ml/s. Before voiding, the bladder contained 215 ml of urine. At 8.50 min (indicated by the scale along the bottom of the plots), the man started to attempt voiding, as indicated by increases in the urodynamic pressures (between the first two vertical dashed lines from the left), but experienced a substantial delay in the onset of urine flow (hesitancy), with flow only starting at 9.50 min. Peak flow (Qmax) was reached at 10.08 min (third vertical dashed line), at which point the flow rate was 10 ml/s and Pdet was 46 cmH2O; thus, the man had low bladder contractility index—calculated as Pdet@Qmax + 5Qmax—of 96 (a normal value is ≥100). Bladder contraction (Pdet) and the urinary flow rate were fluctuating and poorly sustained, a profile characteristic of detrusor underactivity. Voiding ended and pressures returned to normal at around 10.41 min (fourth vertical dashed line). Abbreviations: cmH2O, centimetres of water (unit of pressure); DUA, detrusor underactivity.

that detrusor contraction results in voiding due to an orchestrated synergic relaxation of the bladder neck and urinary sphincter. Once bladder emptying is complete, voiding terminates and the storage mode is restored. The neuromuscular processes that control micturition enable voiding to be terminated prematurely, if desired—for example if another person intrudes into the toilet area.

Impaired control of voiding Fully functional voiding requires intact motor and sensory systems for initiation, maintenance, adjustment, and termination of micturition, which coordinate appro­ priate activities of the bladder and outlet. This system is complex, and at risk of attrition in many locations. Motor (efferent) innervation is needed to generate the required detrusor contraction, and efferent inhibitory nerves actively elicit simultaneous outlet relaxation.11 The effer­ ent actuator must be able to cope with normal environ­ mental perturbations, for example, variations in outlet resistance.12 Thus, any factor affecting the motor func­ tion of the bladder, or the ability of the bladder to adapt to environmental perturbations, might lead to a contrac­ tion of insufficient strength for normal voiding. Loss of excitatory motor innervation is a normal feature of the 456  |  AUGUST 2014  |  VOLUME 11

ageing human bladder,13 and is also seen in BOO,14 as well as in acontractile bladders of patients with spinal-cord injury.15 Ischaemia in bladder tissues can be a contribu­ tory factor in functional impairment of the destrusor.16,17 Inhibitory influences on peripheral bladder innervation are recognized (inhibition of parasympathetic ganglia by sympathetic inputs, for example),11 and inappropri­ ate suppression of this process could, in theory, impair efferent function driving the voiding contraction. Loss of detrusor muscle mass has also been described as a poten­ tial contributory factor in voiding dysfunction in clini­ cal studies that used ultrasonography to estimate bladder weight.18 Furthermore, structural disruptions of detru­ sor cells, a decrease in the muscle-to-collagen ratio, and widened spaces between muscle cells have been reported in patients with impaired bladder contractility and no obstruction on urodynamics.19,20 In aged rats, decreased M3-muscarinic-receptor densities have been observed,21 and changes in a range of genes that could potentially regulate muscle function have been described.22 In addi­ tion, the transition from the storage to the voiding phase requires the volitional initiation of the micturition reflex; should this mechanism be impaired, inability to initiate voiding will result in complete urinary retention.



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REVIEWS Table 1 | Behavioural and physiological processes underpinning the micturition cycle Biological and physiological component

Storage mode

Storage mode during sex in men*

Voiding mode

Behavioural and/or physiological circumstance

Default

Ejaculation

Strong desire to urinate or anticipation of a situation in which voiding would be difficult (before travelling, for example) Movement to a toilet area and adjustment of clothing

Physiological function coordinated by activity of the PMC‡

Storage of urine in the bladder

Storage of urine in the bladder while permitting the passage of semen out of the urethra

Voiding of urine from the bladder

Bladder neck status (under the control of the SNS)

Contracted

Contracted

Relaxed

Urinary sphincter status (controlled by the Onuf’s nucleus)

Contracted

Relaxed

Relaxed

Detrusor status (under the control of the SNS)

Relaxed

Relaxed

Contracted

*In men, the linkage between the urinary tract and genital function results in an additional storage mode permutation of the lower urinary tract musculature for ejaculation. ‡The PMC within the brainstem coordinates autonomic PNS and SNS as well as somatic signalling to control the urinary system and acts akin to a switch, enabling the activation of voiding. Abbreviations: PMC, pontine micturition centre; PNS, parasympathetic nervous system; SNS, sympathetic nervous system.

Together with the efferent neuromuscular signal­ ling controlling voiding, sensory (afferent) innervation is needed throughout the dynamic process of bladder emptying to signal whether urine remains present in the lower urinary tract. In theory, this feedback could con­ stitute contributions from bladder receptors—effectively signalling ‘fullness’—and urethral receptors (reporting flow), although the relative importance of different afferent populations is not known. Absence of stored urine is the intended culmination of voiding—at least, generally-speaking, in humans. Deficiency in the sensory innervation, peripherally or in central reporting or signal processing, means the CNS might wrongly consider that complete emptying has been achieved, leading to prema­ture termination of the voiding reflex; consequent return to the storage phase before complete emptying of the bladder will result in a PVR of urine in the bladder. Indeed, afferent dysfunction is increasingly recognized as a potential contributory factor in DUA.23 In reality, the probable cumulative nature of multiple influences contri­ buting to DUA has been recognized.24 Overall, DUA might best be viewed as the symptomatic manifestation of various pathophysiological factors, which are likely to vary between individuals, and depending on the context (clinical or preclinical). Importantly, studies must con­ sider this variability to enable better understanding and improved management of DUA.

The aetiology of DUA As alluded to in the previous paragraphs, the aetiology of DUA is probably multifactorial. Ageing is a relevant factor; however, not all individuals develop clinically relevant DUA as they age,25 and DUA is not merely a com­p onent of the natural progression of ageing. 23 Further­more, data from animal studies suggest that the contractile potential of the bladder does not diminish with increasing age.21,22,26 BOO needs to be considered as a potential contri­ butory factor in the development of DUA, but the relationship between these conditions is incompletely

understood. BOO is a common finding in older men due to the high prevalence of BPH. Nonetheless, clearly not all men with BOO develop DUA and, conversely, men with DUA do not necessarily have BOO.27 Evidence suggests that detrusor contractility does not decline in patients with long-term BOO.28 Furthermore, BOO is uncommon in elderly women and, correspondingly, voiding dysfunction in women is associated with a high prevalence of DUA upon urodynamic investigation.29 DUA is common in the setting of neurogenic bladder dysfunction, for example, in patients with multiple sclero­sis (MS), Parkinson disease, or cerebrovascular accident.25 In patients with MS, urodynamic findings reflect the location of demyelinating lesions, with lesions in the pontine brainstem recognized as being particu­ larly important to DUA.30 Cerebrovascular accident can affect both voiding and storage function; stroke in the dominant hemisphere is associated with DUA and detru­ sor overactivity in 36% and 64% of cases, respectively, and a slightly higher prevalence of DUA (40%) has been reported in patients with bilateral stroke.31 Neurogenic DUA could suitably be considered a specific category of the condition, with distinct aetiological underpinnings.25 Clearly, voiding function will be affected by loss of peripheral autonomic innervation, either in the motor (efferent) branch or the sensory (afferent) branch of the micturition reflex. Radical exenterative pelvic surgery and abdominal surgery represent events that can impair either one or both of these peripheral innerva­ tion pathways. For example, radical hysterectomy can result in bladder denervation,32 although modern surgi­ cal approaches seem to be associated with a decreased p­ostoperative risk of this outcome.33 Hirschsprung disease (particularly the most severe forms of this condition), which is caused by an absence of nerves controlling all or part of the large intestine, can be associated with bladder dysfunction.34 Peripheral neuropathies, such as Guillain–Barré syndrome, can also affect the bladder and the urinary outlet.35 Indeed, the high prevalence of DUA among patients with

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REVIEWS Table 2 | Prevalence estimates for DUA from urodynamic study populations Study

Maximum flow rate (Qmax)

Detrusor pressure at maximum flow (Pdet@Qmax)

Other parameters used to define DUA

Prevalence of DUA (age range of study population)

Kaplan et al. (1996)90

Voiding dysfunction due to detrusor underactivity: an overview.

Detrusor underactivity (DUA) is defined as a voiding contraction of reduced strength and/or duration, which prolongs urination and/or prevents complet...
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