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Pathophysiology of urinary incontinence
BASIC SCIENCE
Pathophysiology of urinary incontinence
‘normal’, UI is associated with low rates of presentation for care, which may lead to an underestimation of its true prevalence. Of the UI subtypes, stress urinary incontinence (SUI) is the most common type of UI in women (49%). Thirty-four per cent of women with UI suffer from mixed urinary incontinence (MUI) and 15% from urgency urinary incontinence (UUI).2 The other forms of UI, such as continuous UI or unconscious UI, are much less common. Men may also suffer from UI, typically after prostate surgery, or as a consequence of longstanding subclinical bladder outlet obstruction or chronic urinary retention (overflow UI). The prevalence of UI in men ranges from 1% to 39%, and, in contrast to women, UUI is the most predominant subtype (40 e80%), followed by MUI (10e30%) and SUI (<10%).2 The presence of UI can lead to significant deterioration of a person’s health, both physical and mental, and can thereby compromise an individual’s ability to work and can even induce social isolation. However, the severity of UI is a poor predictor of UI-specific quality of life impairment. Therefore, both the severity of symptoms and the perceived bother and impact on activities of the symptoms have to be assessed in patients presenting with UI. Specific questionnaires have been designed to measure these factors simultaneously and prevalence estimates should take the degree of bother into account to allow measuring the true impact of this debilitating condition. UI also puts an enormous burden on healthcare cost, which, combined with its detrimental effect on the ability of some patients to work, leads to a huge economic impact on society, comparable to other chronic conditions such as ischemic heart disease or diabetes mellitus. A wide variety of conservative (e.g. pelvic floor muscle therapy), medical (e.g. bladder relaxants), minimally invasive procedures (e.g. sacral neuromodulation) or surgical interventions (e.g. mid-urethral slings) are available to treat most types of UI, with efficacy rates exceeding 80%. However, the bladder has been called ‘an unreliable witness’3 and treatment efficacy relies heavily on identifying the correct underlying mechanism causing UI as soon as possible. Baseline tests in the workup of UI are validated questionnaires, urine dipstick, bladder diaries and uroflowmetry. Urinary incontinence may also be a manifestation of another underlying urological condition such as a urinary tract infection, stone disease or a tumour, and the presence of these should be excluded as a part of the diagnostic workup. Should the cause remain unclear and should first-line treatment options fail, then more invasive pressure-flow studies (urodynamics) may be indicated. Understanding the pathophysiological mechanisms of the different types of UI is key to successful treatment and to reducing the condition’s significant impact on the individual patient and on society as a whole.
Michel Wyndaele Hashim Hashim
Abstract Urinary incontinence, or the complaint of involuntary loss of urine, is a debilitating condition of the lower urinary tract with a potentially significant impact on a patient’s physical and mental wellbeing and on their functioning and place in society. Due to the high prevalence of this disorder, the economic burden on healthcare systems worldwide is enormous. Urinary incontinence has a high prevalence in women, but men can be affected as well after a radical prostatectomy or when suffering from chronic urinary retention. Stress, urgency and mixed urinary incontinence are the most common types of urinary incontinence, but other types exist as well. The pathophysiological mechanisms behind these different types of urinary incontinence have been studied extensively. New insights allow for the development of improved diagnostic and therapeutic strategies and ultimately in the reduction of the potentially devastating impact of urinary incontinence on an individual patients’ quality of life. In this review, we explore the current theories on the mechanisms behind urinary incontinence.
Keywords Intrinsic sphincter deficiency; lower urinary tract; mixed urinary incontinence; overactive bladder syndrome; pathophysiology; stress urinary incontinence; urethral hypermobility; urgency urinary incontinence; urinary incontinence
Introduction The lower urinary tract (LUT), consisting of bladder, urethra and urethral sphincter, has a dual function: storage and elimination of urine. Loss of the ability of the LUT to exert these functions can lead to debilitating functional disorders. Urinary incontinence (UI) is defined as ‘the complaint of involuntary loss of urine’.1 This devastating and often stigmatizing condition affects millions of people worldwide, the vast majority of whom are women (at least 2:1 ratio to men).2 Prevalence estimates range from 5% to 69% in community-dwelling women, with most studies reporting a prevalence in the range of 25e45%.2 Approximately 10% of all adult women report urine leakage at least weekly, with 25e45% reporting occasional leakage.2 However, perhaps because of the associated stigma in some communities, or because it is still very often considered to be
Lower urinary tract function Michel Wyndaele MD PhD FEBU is the Senior Clinical Fellow in Female and Functional Urology at Bristol Urological Institute, Southmead Hospital, Bristol, UK. Conflict of interest: none declared.
The LUT consists of the urinary bladder, the urethra and the internal and external urethral sphincters (IUS and EUS). For the majority of time (>99%) the LUT exerts its main function: storage of the urine incessantly produced by the kidneys (the filling phase), allowing us to live our daily lives without continuously passing urine or becoming ‘incontinent’. To permit this storage function of the LUT, a few conditions must be met. First, it is imperative that the urinary bladder can accommodate an
Hashim Hashim MBBS MRCS (Eng) MD FEBU FRCS(Urol) is Consultant Urological Surgeon and Director of the Urodynamic Unit at Bristol Urological Institute, Southmead Hospital, Bristol, UK. Conflict of interest: Dr Hashim Hashim is or has been an investigator, lecturer and consultant for pharmaceutical companies producing or developing drugs for lower urinary tract symptoms.
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BASIC SCIENCE
nerve. Finally, the somatic nervous system innervates the pelvic floor, EUS and distal urethra from Onuf’s nucleus in spinal segments S2eS4 through the pudendal nerve. Due to its anatomy, it is very susceptible to damage during labour or by sustained or repeated straining. The somatic nervous system provides the voluntary control of the EUS. Damage to the pudendal nerve may therefore directly lead to UI due to loss of control of the EUS. Women are more susceptible to this form of UI, as they have a weaker bladder neck and the EUS is their main sphincteric mechanism. To coordinate the activity of the smooth muscles of the LUT with the sphincteric striated muscles, integration of the autonomic and somatic efferent mechanisms within the lumbosacral spinal cord is necessary.
increase in volume without a significant pressure rise. This factor is called ‘compliance’, and is in normal conditions made possible by the elastic properties of the bladder wall. The urinary bladder consists of smooth muscle, the detrusor, which has the property to maintain a constant low tension over a wide range of stretch induced by the increase in volume during filling. The second necessary condition is an intact central and peripheral nervous system that suppresses the bladder smooth muscle during filling, prohibiting premature or unwanted bladder contractions. The final requirement is a closed outlet of the bladder: the IUS or bladder neck needs to maintain a high pressure and the EUS exerts a tonic tension with the ability to voluntarily contract in times of need (e.g. when there is an urge to void). The combination of a relaxed, compliant bladder with low pressure during filling and a high outlet pressure in bladder neck and EUS results in a pressure gradient which permits the storage of urine without leakage, or incontinence. Information about the filling status is continuously sent to the central nervous system and at certain thresholds this information is passed on to the cerebrum to make us aware of the amount of urine in the bladder, eliciting either a first sensation of filling, a desire to void or a strong desire to void. This allows us to control and choose when the LUT exerts its second function: elimination of the stored urine (voiding phase). In normal circumstances, and in cognitively able persons, this will be done at a socially and emotionally appropriate time and location. Should voiding be wanted and appropriate, the central inhibition of the micturition reflex is lifted, inducing a detrusor contraction, and the pressure in the bladder neck and the tonic contraction of the EUS cease, resulting in a decrease in outlet pressure, initiating a reversal of the pressure gradient and evacuation of urine.
Central innervation Coordination of reflexes and normal functioning of the urinary bladder not only occur through complex mechanisms in the spinal cord, but also involve supraspinal neural pathways, as conscious control of when to hold and when to evacuate is necessary in maintaining urinary continence. Axons of the neurons in the spinal cord receiving afferent input from the pelvis project to the brainstem, to the hypothalamus and, through relay neurons, to the cerebral cortex. Lower urinary tract reflexes Storage reflexes: during the storage of urine, distension of the bladder produces low-level vesical afferent firing in the pelvic nerve, which in turn stimulates sympathetic outflow to the bladder and the bladder outlet (bladder neck and urethra) through the hypogastric nerve. This inhibitory sympathetic reflex allows the bladder to accommodate larger volumes by inhibiting the detrusor muscle (through the effect of noradrenaline on b3receptors), by increasing muscle tone in the bladder neck and urethra (through the effect of noradrenaline on a1-adrenoeptors) and by modulating transmission in the bladder ganglia. Vesical afferent firing also stimulates the pudendal outflow to the EUS. These responses occur through spinal reflex pathways and represent ‘guarding reflexes’, which promote continence. A region in the rostral pons (the pontine storage centre or L-region) further increases EUS activity.
Lower urinary tract innervation The normal function of the LUT is controlled by complex neural circuits in the spinal cord and brain that coordinate the activity of autonomic visceral smooth muscles in the urinary bladder and urethra with the activity of voluntary striated muscles in the EUS. These circuits act as oneoff switches to shift the LUT between its two modes of operation, storage and voiding. This is unlike the more tonic patterns of activity of the autonomic pathways that regulate cardiovascular organs. Unlike many other visceral functions, micturition is under voluntary control and depends upon learned behaviour that develops during maturation of the nervous system. Disruption of (one of) these complex neuronal networks, or of (the actions of) their neurotransmitters, may lead to UI. A good knowledge of the innervation of the LUT may also dictate therapeutic choices for certain types of UI or development thereof.
Voiding reflexes: The micturition reflex is triggered when a bladder threshold volume and pressure is exceeded. The increase in bladder volume and pressure elicits intense bladder afferent firing by the stretch receptors within the bladder wall. This activates the dorsal and spinothalamic pathways in the spinal cord, which pass through relay neurons in the periaqueductal grey (PAG) in the midbrain, where they are processed before being sent to the pontine micturition center (PMC) in the brainstem and to suprapontine areas in the brain. When a critical level is reached, and when the timing is appropriate, a bulbospinal reflex, functioning like an ‘on-switch’ coordinated by the PMC, is activated. This reflex stimulates the parasympathetic outflow to the bladder (spinal level S2eS4), initiating a detrusor contraction (through the effect of acetylcholine on the muscarinic M3receptor). The sympathetic and pudendal outflow to the urethral outlet are inhibited, causing a relaxation of the bladder neck and urethra, and of the EUS. Both processes cause a reversal of the pressure gradient, leading to expulsion of urine (voiding
Spinal and peripheral innervation (Table 1) The LUT is peripherally innervated by three different nervous systems, which all contain both afferent sensory (both unmyelinated C-fibres and myelinated A-d fibres) and efferent motor (mostly myelinated) nerves. The sympathetic autonomous nervous system innervates the bladder and bladder neck from spinal segments T10eL2 through the hypogastric nerve. The parasympathetic autonomous nervous system innervates the bladder and bladder neck from spinal segments S2eS4 through the pelvic
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BASIC SCIENCE
Spinal and peripheral innervation of the lower urinary tract and its function Nervous system
Spinal innervation
Peripheral innervation
Targets
Motor function Filling
Sympathetic autonomic nervous system
T10 e L2
Hypogastric nerve
Parasympathetic autonomic nervous system
S2 e S4
Pelvic nerve
Somatic nervous system
S2 e S4
Pudendal nerve
Bladder neck Detrusor Bladder neck Detrusor EUS
Voiding
Contraction Relaxation
Tone þ contraction
Relaxation Contraction Relaxation
EUS, external urethral sphincter.
Table 1
phase). Secondary reflexes in the urethra, which are activated by flow of urine, further stimulate bladder emptying. The entire pathway can be modulated by the suprapontine areas in the brain and the cerebral cortex, allowing postponement of micturition and suppression of premature detrusor contractions by the PMC (‘off-switch’), until a socially accepted time and place is reached to evacuate urine. The PMC would in these circumstances send inhibiting signals to the parasympathetic pelvic nerve to suppress detrusor contractions and exciting signals to the sympathetic hypogastric nerve and to the somatic pudendal nerve to increase outflow resistance by activation of the sphincteric mechanisms in the bladder neck and EUS.
after radical prostatectomy, the preferred treatment for organconfined prostate cancer, and is reported in 4e8% (rates may vary depending on definitions and can be as high as 80%). Urethral hypermobility: In normal physiological circumstances, when the pelvic floor is adequately strong, a transient rise in intraabdominal pressure will result in an equal transmission of this pressure onto the bladder and the urethra. The pelvic floor will reflexively or voluntarily close and contraction of the levator ani will elevate the proximal urethra and bladder neck. The connective tissue supports are tightened and the perineal body elevated which may serve as a urethral backstop. In addition, an intact pubocervicovesical fascia will provide a hammock-like support for the bladder neck upon which the proximal urethra is downwardly compressed when the intra-abdominal pressure suddenly rises.4 Weakening of the pelvic floor leads to a descent and a rotation out of the pelvis of the bladder neck and proximal urethra during an intra-abdominal pressure increase. Due to this descent and outward rotation, the intra-abdominal pressure is no longer equally transmitted and the bladder will absorb the bigger portion as it cannot pass through the pelvic floor and out of the pelvis. This leads to a reversal in the pressure gradient between the bladder and the urethra and a consequent leakage of urine. Furthermore, weakening of the pelvic floor will result in a loss of the hammock-like support provided by the pubocervicovesical fascia, leading to a reduction of the urethral compression during an intra-abdominal pressure rise, and therefore making involuntary loss of urine more likely. This is the commonest cause for stress urinary incontinence.
Pathophysiology of urinary incontinence When one of the previously described mechanisms to contain urine during the storage phase of the bladder fails, UI occurs. Different types of UI can be distinguished and each has its own pathophysiology which will be described in this section. An overview is presented in Table 2. Stress urinary incontinence In SUI, a sudden rise in intra-abdominal pressure, evoked by effort, physical exertion, sneezing or coughing, is not followed by a sufficiently strong increase in urethral pressure, leading to a reversal of the pressure gradient between the bladder and its outlet with leakage of urine as the result. SUI is essentially caused by a urethral deficiency. Women are more susceptible to this type of UI due to the urethral anatomy (shorter urethra) and due to their weaker bladder neck compared to men, which makes them entirely reliant on the EUS for urinary continence. Four factors are essential for the female urethra to remain closed during a rise in intra-abdominal pressure: (i) a healthy functional striated EUS under control of intact somatic (pudendal) innervation; (ii) a well-vascularized mucosa and sub-mucosa, causing passive urethral closure or coaptation; (iii) a properly aligned and functioning IUS or bladder neck; and (iv) an intact vaginal wall to support the urethra. Two pathophysiological mechanisms have been defined in women: urethral hypermobility and intrinsic sphincter deficiency. In contrast to what has long been assumed, both mechanisms are inter-related elements on a spectrum of change rather than being two entirely separate entities. SUI is not only present in women, it is also common in men
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Intrinsic sphincter deficiency (ISD) causes leakage due to a failure of the urethral tonic and sphincteric mechanisms during a rise in intra-abdominal pressure. In normal physiological circumstances, the urethral sphincter has a continuous tone and reflexly contracts before a transient episode of intra-abdominal pressure increase. A loss of the urethral sphincter tone or the inability to initiate a sufficiently strong contraction leads to a reversal of the pressure gradient and therefore to UI. The leakage can typically be severe in ISD even with a minimal rise in intraabdominal pressure. Urethral pressures can be evaluated by a urethral pressure profile, documenting urethral tone (urethral closure pressure) as well as its augmentation during an active contraction. On cystoscopy, the urethra has a ‘hose-pipe’ appearance.
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Definitions and pathophysiological mechanisms of the different types of urinary incontinence Definitions Urinary incontinence (UI) Stress urinary incontinence (SUI)
Urgency urinary incontinence (UUI)
Mixed urinary incontinence (MUI)
Overflow urinary incontinence
Insensible urinary incontinence
Pathophysiology
The complaint of involuntary loss of urine UI during effort or physical exertion (e.g. sporting activities), or due to sneezing or coughing Urgency: the complaint of a sudden compelling desire to pass urine, which is difficult to defer Overactive bladder: the complaint of urgency, with or without UUI, but usually with increased daytime frequency and nocturia, in the absence of infection or other obvious pathology UUI: UI preceded by/associated with urgency UI associated with urgency, but also with effort or physical exertion or on sneezing or coughing (i.e. SUI þ UUI) UI due to a sudden increase in pressure [intraabdominal or bladder (detrusor overactivity)] in an over-distended bladder UI which is not clearly accompanied by either urgency or stress incontinence (i.e. increase in intra-abdominal pressure) provocative factors
Situational urinary incontinence
Coital UI: UI with coitus
Continuous urinary incontinence
Postural UI: UI associated with change of body position (e.g. rising from a seated or lying position) Giggle UI, or enuresis risoria: UI in response to giggling or laughter Complaint of continuous loss of urine
Functional urinary incontinence
Patients have intact storage functions but suffer from the physical inability to reach the toilet in time to pass urine
Urethral hypermobility Intrinsic sphincter deficiency Increase in afferent activity from the bladder: Neurogenic theory C Myogenic theory C Instrinsic theory Abnormal handling of afferent signals in the brain C
Combination of the mechanisms in SUI and UUI Incomplete bladder emptying, e.g. due to detrusor underactivity or bladder outlet obstruction Overflow UI Intrinsic sphincter deficiency Detrusor overactivity with impaired bladder sensation Urethral hypermobility Intrinsic sphincter deficiency Detrusor overactivity Insufficient urethral closure pressure
Insufficient urethral closure pressure Bypassing storage mechanisms: - Vesicovaginal or vesico-uterine fistulas - Ectopic implantation of ureter in urethra Extreme intrinsic sphincter deficiency Temporary or permanent decreased mobility or dexterity
UI, Urinary incontinence; SUI, stress urinary incontinence; UUI, urgency urinary incontinence; MUI, mixed urinary incontinence; OAB, overactive bladder.
Table 2
Cause and treatment: Urethral hypermobility or ISD can be caused by damage to the nerves in the pelvis, or to the muscles and connective tissue of the pelvic floor. Aging and activities (e.g. straining to void or defecate) or medical conditions (e.g. chronic cough or obesity) resulting in long-term repetitive increase in intra-abdominal pressure are all important mechanisms compromising the pelvic floor. The most important cause however is childbirth (and parity), as traumatic or prolonged vaginal deliveries can lead to loss of pelvic support and hence to urethral hypermobility, but also to damage to the urethral sphincter mechanism or its innervation and hence to ISD. ISD can also arise secondary to pelvic surgery (e.g. abdominoperineal
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resection or hysterectomy) or to radiation therapy, due to neuromuscular damage or devascularization of the urethral sphincter mechanism. Neurological disorders may for the same reason also affect urethral sphincter functioning (e.g. multiple sclerosis (MS) or diabetes). Hypoestrogenism, on the other hand, can lead to atrophy and replacement of the submucosal vascular plexus by fibrous tissue, reducing the urethral turgor. Local oestrogen administration can reverse this effect and therefore improve symptoms of SUI. The treatment of urethral hypermobility is aimed at improving the support of the urethra, by transvaginal mid-urethral placement of a supporting synthetic or autologous sling or colposuspension. Autologous slings also
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Urgency (and OAB) is defined as a pathological increase in sensation and from that point of view, two possible pathways have been proposed: (i) an abnormal increase in afferent (sensory) signals sent from the bladder to the brain; or (ii) a decreased capacity of the brain to manage the afferent signals coming from the bladder.
have a role in the treatment of ISD if they are placed close enough to the bladder neck (proximal urethra). Alternatively, bulking agents or artificial sphincters may be indicated for ISD. Post-prostatectomy urinary incontinence: The pathophysiology of post-prostatectomy UI is most likely multifactorial. Radical prostatectomy removes a number of the control mechanisms for urinary continence and can potentially damage other mechanisms. The prostate, which plays a role in continence as part of the proximal sphincteric unit, is removed during this operation, as is the bladder neck, an important first barrier to contain urine in men (as opposed to in women). Therefore, postoperative continence in men after radical prostatectomy relies entirely on the EUS. Furthermore, the neurovascular supply of the EUS lies in close proximity (0.3e1.3 cm) of the apex of the prostate and is therefore susceptible to injury during the procedure. Sphincter deficiency is found in 40e60% of men with post-prostatectomy UI, but recovery is possible due to nerve regeneration during the months following surgery. Urethral strictures, which are a typical late complication of radical prostatectomy, may also lead to sphincter deficiency and impaired urethral closure, as the EUS has been shown to become more fibrotic in this case. Finally, the bladder is also affected by radical prostatectomy with effects on detrusor innervation and function leading to detrusor hypo- and hypercontractility and reduction in bladder compliance.
Increase of afferent activity from the bladder: Two theories about the mechanisms underlying the increase in afferent activity of the bladder have been proposed: a urothelium-based hypothesis and a myogenic hypothesis.6 It has been established that the urothelium is more than just a barrier: urothelial cells also have a sensory function. The urothelium is in close interaction with the suburothelium, which contains afferent nerve endings and myofibroblasts or interstitial cells. The sensory molecules of the urothelium react to mechanical and chemical stimuli by releasing neurotransmitters into the suburothelium, which in turn trigger afferent nerve activity. Muscarinic and b-adrenoceptors have been shown to play a role in the generation of afferent impulses from the bladder, which may explain the effect of antimuscarinics and of b3-agonists on bladder sensation, as an addition to their bladder smooth muscle relaxant effect. The urothelium-based hypothesis states that changes in urothelial receptor function, such as upregulation, and in neurotransmitter release (increase), as well as changes in the sensitivity of the suburothelial cell network may lead to an increase of afferent activity triggered by the bladder and hence to an enhancement of involuntary detrusor contractions. The myogenic hypothesis, on the other hand, states that changes to the excitability of the bladder smooth muscle cells and of their coupling with other mycocytes or interstitial cells can lead to the generation of uninhibited contractions. In the normal detrusor, the smooth muscle cells are poorly coupled, preventing the spread of localized contractions or micromotions during the storage phase. A dense neuronal network allows a coordinated contraction of the entire bladder during voluntary voiding. Partial denervation of the detrusor, due to inflammation or ischaemia, may change the properties of smooth muscle cells, which may hence become more excitable and develop an increased degree of coupling. In such circumstances, a local contraction of bladder smooth muscle may easily spread and lead to a coordinated contraction of (a large part of) the bladder. This local contraction may also elicit afferent activity thereby inducing a sensation of urgency to go along with DO.
Urgency urinary incontinence Unlike urge, which is a physiologic desire to void upon bladder filling, urgency is a pathological sensation and it is the central symptom of the overactive bladder (OAB). Approximately onethird of patients with OAB suffer from UUI, and to understand its pathophysiology, one needs to understand the mechanisms behind the sensation of urgency and behind OAB. The definition of urgency reveals that it is a sensation (subjective), and therefore needs to be clearly distinguished from detrusor overactivity (DO), which is the urodynamic finding of an involuntary detrusor contraction during bladder filling (objective) (Table 2). The detrusor should in normal conditions only contract during voiding. It is important to note that urgency and DO are not interchangeable terms in women: only half of the female patients with urgency demonstrate DO on cystometric studies. The opposite relation is stronger, as 85% of women with DO had OAB.5 In men, both terms are more closely related: 82% of men with OAB showed DO on cystometric studies and 82% of men with DO complained of OAB.5 It is the DO that leads to the involuntary loss of urine associated with the sensation of urgency in UUI, when the intravesical pressure during the contraction outweighs the urethral pressure. Neurological disorders (e.g. MS or spinal injuries) may reduce or annihilate the central inhibition of the micturition reflex during bladder filling, evoking involuntary detrusor contractions triggered from a purely spinal reflex and no longer controlled by a spinobulbospinal pathway. This is called neurogenic DO. Other factors, such as infection, non-bacterial inflammatory conditions of the bladder (e.g. bladder pain syndrome/interstitial cystitis), foreign bodies (e.g. sutures or meshes), bladder stones and neoplasms, may also induce an increased sensation in the bladder and/or DO. These causes need to be eliminated in the diagnostic process. If no clear cause is present, the term idiopathic DO is used.
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Abnormal handling of afferent signals in the brain: Damage to the central inhibitory pathways or sensitization of the afferent signals leads to the loss of control of the primitive voiding reflexes, triggering DO. Suprapontine areas (e.g. medial frontal lobes of the cerebral cortex and the basal ganglia) have been shown to exert a tonic inhibition on the pontine micturition centre. Suprapontine lesions, such as caused by stroke or by Parkinson’s disease, may therefore cause a loss of voluntary inhibition of micturition. A spinal cord lesion above the lumbosacral level interrupts the descending supraspinal pathway through which the micturition is voluntarily controlled. This leads to DO mediated solely by spinal reflex pathways. These unsustained and uncontrolled detrusor contractions are often associated with uncoordinated sphincter overactivity, a phenomenon known as sphincter-detrusor dyssynergia.
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Treatment: the true cause of OAB and UUI is probably a combination of (a part of) these theories and the full pathophysiological mechanism has yet to be unravelled. This makes curative treatment of OAB/UUI very difficult and patient management is therefore mainly aimed at improving quality of life. As mentioned above, the sympathetic nervous system is more dominant during the filling phase and the parasympathetic nervous system becomes more dominant during the voiding phase. Therefore, either antimuscarinics (M3-antagonists) or adrenergic agonists (b3-agonists) are used to inhibit involuntary bladder contractions and to reduce bladder sensitivity. Should these medications render an insufficient result, or should the sideeffects become unbearable, minimally invasive therapies can be initiated such as botulinum toxin injections into the detrusor, which blocks neuromuscular transmission by inhibition of acetylcholine release, or sacral nerve neuromodulation (level S3).
external urethral compression by, for example, fibroids, excessive pelvic organ prolapse, after pelvic floor surgery (overly tight tapes or autologous slings supporting the urethra), due to dysfunctional voiding or in Fowler’s syndrome. Unconscious (insensible) urinary incontinence: The first and only awareness of the incontinence episode is the actual feeling of wetness due to the leaked urine. This type of UI usually presents a severe or final-stage bladder dysfunction such as overflow UI or significant ISD. Another pathophysiological mechanism for unconscious UI is the coexistence of DO and impaired or absent bladder sensation which can be present in patients with neurogenic bladder dysfunction in whom the micturition reflex arc is intact or hyperreflexic, but the central (pontine) control is impaired or absent. Examples are patients with spinal cord injury, MS or during a seizure.
Conclusion Other types of urinary incontinence Mixed urinary incontinence represents a combination of both UUI and SUI present in one single patient. The pathophysiological mechanisms are considered to be a combination of the dysfunctions causing either SUI or UUI as described above. An alternative theory is that urine leakage into the proximal urethra (SUI) triggers a sensory urgency and/or bladder contractions leading to UUI. The disorder is difficult to treat. Usually the most bothersome type of UI is approached first and, if desired, the other type is treated after that.
Insight and understanding of the pathophysiological processes behind the different types of UI are essential for an adequate diagnostic and therapeutic approach to this debilitating condition, and may lead to a reduction of its enormous impact on the individual patient’s quality of life and on society as a whole. Knowledge on the possible mechanisms, and their interactions, is continually evolving, allowing new treatments to be developed to improve the care for patients with UI. An overview of the currently accepted theories on the pathophysiology of UI has been provided in this review.
Overflow urinary incontinence: Overdistension of the bladder, secondary to inefficient bladder emptying, may also lead to involuntary loss of urine. As the volume in the bladder increases to high levels, so does the pressure in the bladder, until at a certain point this pressure exceeds the urethral closure pressure (i.e. a reversal of the pressure gradient) and a leak occurs. The loss of urine is usually limited, just enough to reverse the pressure gradient between bladder and urethra again. Patients therefore often present with continuous urinary leakage or dribbling. An increase in intra-abdominal pressure or a low amplitude bladder contraction may also evoke a leak, masking the overflow UI as either SUI or UUI. The volume required to initiate a leak may be extremely high (multiple litres) as the bladder is a very compliant organ, storing large amounts of urine with a limited increase in pressure, especially if the volume increase builds up slowly over time. Eventually, overstretching of the bladder may lead to peripheral denervation of the bladder and as a result the bladder becomes atonic and is no longer able to contract. If possible, the patient is then taught to intermittently catheterize himself to empty the bladder at a natural rhythm of 4 e5 times a day. This type of UI is often a result of bladder outlet obstruction (BOO) and is therefore more often seen in men, typically elderly men with a prostatic enlargement and chronic urinary retention, although younger men with a urethral stricture or a vesical neck contracture may also present with this symptom. BOO may first lead to OAB, through both urothelial and myogenic mechanisms. Women can also develop BOO, due to
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Funding Michel Wyndaele was partially funded by the Sirate 32 foundation during his work on this review. A REFERENCES 1 Haylen BT, de RD, Freeman RM, et al. An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Neurourol Urodyn 2010; 29: 4e20. 2 Milsom E, Altman D, Cartwright R, et al. Epidemiology of urinary incontinence (UI) and other lower urinary tract symptoms (LUTS), pelvic organ prolapse (POP) and anal incontinence (AI). In: Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence. 5 ed. ICUD-EAU, 2013; 15e108. 3 Blaivas JG. The bladder is an unreliable witness. Neurourol Urodyn 1996; 15: 443e5. 4 DeLancey JO. Structural support of the urethra as it relates to stress urinary incontinence: the hammock hypothesis. Am J Obstet Gynecol 1994 Jun; 170: 1713e20. 5 Hashim H, Abrams P. Is the bladder a reliable witness for predicting detrusor overactivity? J Urol 2006 Jan; 175: 191e4. 6 Koelbl H, Igawa Y, Salvatore S, et al. Pathophysiology of urinary incontinence, faecal incontinence and pelvic organ prolapse. In: Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence. 5 ed. ICUD-EAU, 2013; 261e360.
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Pathophysiology of urinary incontinence
‘normal’, UI is associated with low rates of presentation for care, which may lead to an underestimation of its true prevalence. Of the UI subtypes, stress urinary incontinence (SUI) is the most common type of UI in women (49%). Thirty-four per cent of women with UI suffer from mixed urinary incontinence (MUI) and 15% from urgency urinary incontinence (UUI).2 The other forms of UI, such as continuous UI or unconscious UI, are much less common. Men may also suffer from UI, typically after prostate surgery, or as a consequence of longstanding subclinical bladder outlet obstruction or chronic urinary retention (overflow UI). The prevalence of UI in men ranges from 1% to 39%, and, in contrast to women, UUI is the most predominant subtype (40 e80%), followed by MUI (10e30%) and SUI (<10%).2 The presence of UI can lead to significant deterioration of a person’s health, both physical and mental, and can thereby compromise an individual’s ability to work and can even induce social isolation. However, the severity of UI is a poor predictor of UI-specific quality of life impairment. Therefore, both the severity of symptoms and the perceived bother and impact on activities of the symptoms have to be assessed in patients presenting with UI. Specific questionnaires have been designed to measure these factors simultaneously and prevalence estimates should take the degree of bother into account to allow measuring the true impact of this debilitating condition. UI also puts an enormous burden on healthcare cost, which, combined with its detrimental effect on the ability of some patients to work, leads to a huge economic impact on society, comparable to other chronic conditions such as ischemic heart disease or diabetes mellitus. A wide variety of conservative (e.g. pelvic floor muscle therapy), medical (e.g. bladder relaxants), minimally invasive procedures (e.g. sacral neuromodulation) or surgical interventions (e.g. mid-urethral slings) are available to treat most types of UI, with efficacy rates exceeding 80%. However, the bladder has been called ‘an unreliable witness’3 and treatment efficacy relies heavily on identifying the correct underlying mechanism causing UI as soon as possible. Baseline tests in the workup of UI are validated questionnaires, urine dipstick, bladder diaries and uroflowmetry. Urinary incontinence may also be a manifestation of another underlying urological condition such as a urinary tract infection, stone disease or a tumour, and the presence of these should be excluded as a part of the diagnostic workup. Should the cause remain unclear and should first-line treatment options fail, then more invasive pressure-flow studies (urodynamics) may be indicated. Understanding the pathophysiological mechanisms of the different types of UI is key to successful treatment and to reducing the condition’s significant impact on the individual patient and on society as a whole.
Michel Wyndaele Hashim Hashim
Abstract Urinary incontinence, or the complaint of involuntary loss of urine, is a debilitating condition of the lower urinary tract with a potentially significant impact on a patient’s physical and mental wellbeing and on their functioning and place in society. Due to the high prevalence of this disorder, the economic burden on healthcare systems worldwide is enormous. Urinary incontinence has a high prevalence in women, but men can be affected as well after a radical prostatectomy or when suffering from chronic urinary retention. Stress, urgency and mixed urinary incontinence are the most common types of urinary incontinence, but other types exist as well. The pathophysiological mechanisms behind these different types of urinary incontinence have been studied extensively. New insights allow for the development of improved diagnostic and therapeutic strategies and ultimately in the reduction of the potentially devastating impact of urinary incontinence on an individual patients’ quality of life. In this review, we explore the current theories on the mechanisms behind urinary incontinence.
Keywords Intrinsic sphincter deficiency; lower urinary tract; mixed urinary incontinence; overactive bladder syndrome; pathophysiology; stress urinary incontinence; urethral hypermobility; urgency urinary incontinence; urinary incontinence
Introduction The lower urinary tract (LUT), consisting of bladder, urethra and urethral sphincter, has a dual function: storage and elimination of urine. Loss of the ability of the LUT to exert these functions can lead to debilitating functional disorders. Urinary incontinence (UI) is defined as ‘the complaint of involuntary loss of urine’.1 This devastating and often stigmatizing condition affects millions of people worldwide, the vast majority of whom are women (at least 2:1 ratio to men).2 Prevalence estimates range from 5% to 69% in community-dwelling women, with most studies reporting a prevalence in the range of 25e45%.2 Approximately 10% of all adult women report urine leakage at least weekly, with 25e45% reporting occasional leakage.2 However, perhaps because of the associated stigma in some communities, or because it is still very often considered to be
Lower urinary tract function Michel Wyndaele MD PhD FEBU is the Senior Clinical Fellow in Female and Functional Urology at Bristol Urological Institute, Southmead Hospital, Bristol, UK. Conflict of interest: none declared.
The LUT consists of the urinary bladder, the urethra and the internal and external urethral sphincters (IUS and EUS). For the majority of time (>99%) the LUT exerts its main function: storage of the urine incessantly produced by the kidneys (the filling phase), allowing us to live our daily lives without continuously passing urine or becoming ‘incontinent’. To permit this storage function of the LUT, a few conditions must be met. First, it is imperative that the urinary bladder can accommodate an
Hashim Hashim MBBS MRCS (Eng) MD FEBU FRCS(Urol) is Consultant Urological Surgeon and Director of the Urodynamic Unit at Bristol Urological Institute, Southmead Hospital, Bristol, UK. Conflict of interest: Dr Hashim Hashim is or has been an investigator, lecturer and consultant for pharmaceutical companies producing or developing drugs for lower urinary tract symptoms.
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BASIC SCIENCE
nerve. Finally, the somatic nervous system innervates the pelvic floor, EUS and distal urethra from Onuf’s nucleus in spinal segments S2eS4 through the pudendal nerve. Due to its anatomy, it is very susceptible to damage during labour or by sustained or repeated straining. The somatic nervous system provides the voluntary control of the EUS. Damage to the pudendal nerve may therefore directly lead to UI due to loss of control of the EUS. Women are more susceptible to this form of UI, as they have a weaker bladder neck and the EUS is their main sphincteric mechanism. To coordinate the activity of the smooth muscles of the LUT with the sphincteric striated muscles, integration of the autonomic and somatic efferent mechanisms within the lumbosacral spinal cord is necessary.
increase in volume without a significant pressure rise. This factor is called ‘compliance’, and is in normal conditions made possible by the elastic properties of the bladder wall. The urinary bladder consists of smooth muscle, the detrusor, which has the property to maintain a constant low tension over a wide range of stretch induced by the increase in volume during filling. The second necessary condition is an intact central and peripheral nervous system that suppresses the bladder smooth muscle during filling, prohibiting premature or unwanted bladder contractions. The final requirement is a closed outlet of the bladder: the IUS or bladder neck needs to maintain a high pressure and the EUS exerts a tonic tension with the ability to voluntarily contract in times of need (e.g. when there is an urge to void). The combination of a relaxed, compliant bladder with low pressure during filling and a high outlet pressure in bladder neck and EUS results in a pressure gradient which permits the storage of urine without leakage, or incontinence. Information about the filling status is continuously sent to the central nervous system and at certain thresholds this information is passed on to the cerebrum to make us aware of the amount of urine in the bladder, eliciting either a first sensation of filling, a desire to void or a strong desire to void. This allows us to control and choose when the LUT exerts its second function: elimination of the stored urine (voiding phase). In normal circumstances, and in cognitively able persons, this will be done at a socially and emotionally appropriate time and location. Should voiding be wanted and appropriate, the central inhibition of the micturition reflex is lifted, inducing a detrusor contraction, and the pressure in the bladder neck and the tonic contraction of the EUS cease, resulting in a decrease in outlet pressure, initiating a reversal of the pressure gradient and evacuation of urine.
Central innervation Coordination of reflexes and normal functioning of the urinary bladder not only occur through complex mechanisms in the spinal cord, but also involve supraspinal neural pathways, as conscious control of when to hold and when to evacuate is necessary in maintaining urinary continence. Axons of the neurons in the spinal cord receiving afferent input from the pelvis project to the brainstem, to the hypothalamus and, through relay neurons, to the cerebral cortex. Lower urinary tract reflexes Storage reflexes: during the storage of urine, distension of the bladder produces low-level vesical afferent firing in the pelvic nerve, which in turn stimulates sympathetic outflow to the bladder and the bladder outlet (bladder neck and urethra) through the hypogastric nerve. This inhibitory sympathetic reflex allows the bladder to accommodate larger volumes by inhibiting the detrusor muscle (through the effect of noradrenaline on b3receptors), by increasing muscle tone in the bladder neck and urethra (through the effect of noradrenaline on a1-adrenoeptors) and by modulating transmission in the bladder ganglia. Vesical afferent firing also stimulates the pudendal outflow to the EUS. These responses occur through spinal reflex pathways and represent ‘guarding reflexes’, which promote continence. A region in the rostral pons (the pontine storage centre or L-region) further increases EUS activity.
Lower urinary tract innervation The normal function of the LUT is controlled by complex neural circuits in the spinal cord and brain that coordinate the activity of autonomic visceral smooth muscles in the urinary bladder and urethra with the activity of voluntary striated muscles in the EUS. These circuits act as oneoff switches to shift the LUT between its two modes of operation, storage and voiding. This is unlike the more tonic patterns of activity of the autonomic pathways that regulate cardiovascular organs. Unlike many other visceral functions, micturition is under voluntary control and depends upon learned behaviour that develops during maturation of the nervous system. Disruption of (one of) these complex neuronal networks, or of (the actions of) their neurotransmitters, may lead to UI. A good knowledge of the innervation of the LUT may also dictate therapeutic choices for certain types of UI or development thereof.
Voiding reflexes: The micturition reflex is triggered when a bladder threshold volume and pressure is exceeded. The increase in bladder volume and pressure elicits intense bladder afferent firing by the stretch receptors within the bladder wall. This activates the dorsal and spinothalamic pathways in the spinal cord, which pass through relay neurons in the periaqueductal grey (PAG) in the midbrain, where they are processed before being sent to the pontine micturition center (PMC) in the brainstem and to suprapontine areas in the brain. When a critical level is reached, and when the timing is appropriate, a bulbospinal reflex, functioning like an ‘on-switch’ coordinated by the PMC, is activated. This reflex stimulates the parasympathetic outflow to the bladder (spinal level S2eS4), initiating a detrusor contraction (through the effect of acetylcholine on the muscarinic M3receptor). The sympathetic and pudendal outflow to the urethral outlet are inhibited, causing a relaxation of the bladder neck and urethra, and of the EUS. Both processes cause a reversal of the pressure gradient, leading to expulsion of urine (voiding
Spinal and peripheral innervation (Table 1) The LUT is peripherally innervated by three different nervous systems, which all contain both afferent sensory (both unmyelinated C-fibres and myelinated A-d fibres) and efferent motor (mostly myelinated) nerves. The sympathetic autonomous nervous system innervates the bladder and bladder neck from spinal segments T10eL2 through the hypogastric nerve. The parasympathetic autonomous nervous system innervates the bladder and bladder neck from spinal segments S2eS4 through the pelvic
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BASIC SCIENCE
Spinal and peripheral innervation of the lower urinary tract and its function Nervous system
Spinal innervation
Peripheral innervation
Targets
Motor function Filling
Sympathetic autonomic nervous system
T10 e L2
Hypogastric nerve
Parasympathetic autonomic nervous system
S2 e S4
Pelvic nerve
Somatic nervous system
S2 e S4
Pudendal nerve
Bladder neck Detrusor Bladder neck Detrusor EUS
Voiding
Contraction Relaxation
Tone þ contraction
Relaxation Contraction Relaxation
EUS, external urethral sphincter.
Table 1
phase). Secondary reflexes in the urethra, which are activated by flow of urine, further stimulate bladder emptying. The entire pathway can be modulated by the suprapontine areas in the brain and the cerebral cortex, allowing postponement of micturition and suppression of premature detrusor contractions by the PMC (‘off-switch’), until a socially accepted time and place is reached to evacuate urine. The PMC would in these circumstances send inhibiting signals to the parasympathetic pelvic nerve to suppress detrusor contractions and exciting signals to the sympathetic hypogastric nerve and to the somatic pudendal nerve to increase outflow resistance by activation of the sphincteric mechanisms in the bladder neck and EUS.
after radical prostatectomy, the preferred treatment for organconfined prostate cancer, and is reported in 4e8% (rates may vary depending on definitions and can be as high as 80%). Urethral hypermobility: In normal physiological circumstances, when the pelvic floor is adequately strong, a transient rise in intraabdominal pressure will result in an equal transmission of this pressure onto the bladder and the urethra. The pelvic floor will reflexively or voluntarily close and contraction of the levator ani will elevate the proximal urethra and bladder neck. The connective tissue supports are tightened and the perineal body elevated which may serve as a urethral backstop. In addition, an intact pubocervicovesical fascia will provide a hammock-like support for the bladder neck upon which the proximal urethra is downwardly compressed when the intra-abdominal pressure suddenly rises.4 Weakening of the pelvic floor leads to a descent and a rotation out of the pelvis of the bladder neck and proximal urethra during an intra-abdominal pressure increase. Due to this descent and outward rotation, the intra-abdominal pressure is no longer equally transmitted and the bladder will absorb the bigger portion as it cannot pass through the pelvic floor and out of the pelvis. This leads to a reversal in the pressure gradient between the bladder and the urethra and a consequent leakage of urine. Furthermore, weakening of the pelvic floor will result in a loss of the hammock-like support provided by the pubocervicovesical fascia, leading to a reduction of the urethral compression during an intra-abdominal pressure rise, and therefore making involuntary loss of urine more likely. This is the commonest cause for stress urinary incontinence.
Pathophysiology of urinary incontinence When one of the previously described mechanisms to contain urine during the storage phase of the bladder fails, UI occurs. Different types of UI can be distinguished and each has its own pathophysiology which will be described in this section. An overview is presented in Table 2. Stress urinary incontinence In SUI, a sudden rise in intra-abdominal pressure, evoked by effort, physical exertion, sneezing or coughing, is not followed by a sufficiently strong increase in urethral pressure, leading to a reversal of the pressure gradient between the bladder and its outlet with leakage of urine as the result. SUI is essentially caused by a urethral deficiency. Women are more susceptible to this type of UI due to the urethral anatomy (shorter urethra) and due to their weaker bladder neck compared to men, which makes them entirely reliant on the EUS for urinary continence. Four factors are essential for the female urethra to remain closed during a rise in intra-abdominal pressure: (i) a healthy functional striated EUS under control of intact somatic (pudendal) innervation; (ii) a well-vascularized mucosa and sub-mucosa, causing passive urethral closure or coaptation; (iii) a properly aligned and functioning IUS or bladder neck; and (iv) an intact vaginal wall to support the urethra. Two pathophysiological mechanisms have been defined in women: urethral hypermobility and intrinsic sphincter deficiency. In contrast to what has long been assumed, both mechanisms are inter-related elements on a spectrum of change rather than being two entirely separate entities. SUI is not only present in women, it is also common in men
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Intrinsic sphincter deficiency (ISD) causes leakage due to a failure of the urethral tonic and sphincteric mechanisms during a rise in intra-abdominal pressure. In normal physiological circumstances, the urethral sphincter has a continuous tone and reflexly contracts before a transient episode of intra-abdominal pressure increase. A loss of the urethral sphincter tone or the inability to initiate a sufficiently strong contraction leads to a reversal of the pressure gradient and therefore to UI. The leakage can typically be severe in ISD even with a minimal rise in intraabdominal pressure. Urethral pressures can be evaluated by a urethral pressure profile, documenting urethral tone (urethral closure pressure) as well as its augmentation during an active contraction. On cystoscopy, the urethra has a ‘hose-pipe’ appearance.
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Definitions and pathophysiological mechanisms of the different types of urinary incontinence Definitions Urinary incontinence (UI) Stress urinary incontinence (SUI)
Urgency urinary incontinence (UUI)
Mixed urinary incontinence (MUI)
Overflow urinary incontinence
Insensible urinary incontinence
Pathophysiology
The complaint of involuntary loss of urine UI during effort or physical exertion (e.g. sporting activities), or due to sneezing or coughing Urgency: the complaint of a sudden compelling desire to pass urine, which is difficult to defer Overactive bladder: the complaint of urgency, with or without UUI, but usually with increased daytime frequency and nocturia, in the absence of infection or other obvious pathology UUI: UI preceded by/associated with urgency UI associated with urgency, but also with effort or physical exertion or on sneezing or coughing (i.e. SUI þ UUI) UI due to a sudden increase in pressure [intraabdominal or bladder (detrusor overactivity)] in an over-distended bladder UI which is not clearly accompanied by either urgency or stress incontinence (i.e. increase in intra-abdominal pressure) provocative factors
Situational urinary incontinence
Coital UI: UI with coitus
Continuous urinary incontinence
Postural UI: UI associated with change of body position (e.g. rising from a seated or lying position) Giggle UI, or enuresis risoria: UI in response to giggling or laughter Complaint of continuous loss of urine
Functional urinary incontinence
Patients have intact storage functions but suffer from the physical inability to reach the toilet in time to pass urine
Urethral hypermobility Intrinsic sphincter deficiency Increase in afferent activity from the bladder: Neurogenic theory C Myogenic theory C Instrinsic theory Abnormal handling of afferent signals in the brain C
Combination of the mechanisms in SUI and UUI Incomplete bladder emptying, e.g. due to detrusor underactivity or bladder outlet obstruction Overflow UI Intrinsic sphincter deficiency Detrusor overactivity with impaired bladder sensation Urethral hypermobility Intrinsic sphincter deficiency Detrusor overactivity Insufficient urethral closure pressure
Insufficient urethral closure pressure Bypassing storage mechanisms: - Vesicovaginal or vesico-uterine fistulas - Ectopic implantation of ureter in urethra Extreme intrinsic sphincter deficiency Temporary or permanent decreased mobility or dexterity
UI, Urinary incontinence; SUI, stress urinary incontinence; UUI, urgency urinary incontinence; MUI, mixed urinary incontinence; OAB, overactive bladder.
Table 2
Cause and treatment: Urethral hypermobility or ISD can be caused by damage to the nerves in the pelvis, or to the muscles and connective tissue of the pelvic floor. Aging and activities (e.g. straining to void or defecate) or medical conditions (e.g. chronic cough or obesity) resulting in long-term repetitive increase in intra-abdominal pressure are all important mechanisms compromising the pelvic floor. The most important cause however is childbirth (and parity), as traumatic or prolonged vaginal deliveries can lead to loss of pelvic support and hence to urethral hypermobility, but also to damage to the urethral sphincter mechanism or its innervation and hence to ISD. ISD can also arise secondary to pelvic surgery (e.g. abdominoperineal
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resection or hysterectomy) or to radiation therapy, due to neuromuscular damage or devascularization of the urethral sphincter mechanism. Neurological disorders may for the same reason also affect urethral sphincter functioning (e.g. multiple sclerosis (MS) or diabetes). Hypoestrogenism, on the other hand, can lead to atrophy and replacement of the submucosal vascular plexus by fibrous tissue, reducing the urethral turgor. Local oestrogen administration can reverse this effect and therefore improve symptoms of SUI. The treatment of urethral hypermobility is aimed at improving the support of the urethra, by transvaginal mid-urethral placement of a supporting synthetic or autologous sling or colposuspension. Autologous slings also
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Urgency (and OAB) is defined as a pathological increase in sensation and from that point of view, two possible pathways have been proposed: (i) an abnormal increase in afferent (sensory) signals sent from the bladder to the brain; or (ii) a decreased capacity of the brain to manage the afferent signals coming from the bladder.
have a role in the treatment of ISD if they are placed close enough to the bladder neck (proximal urethra). Alternatively, bulking agents or artificial sphincters may be indicated for ISD. Post-prostatectomy urinary incontinence: The pathophysiology of post-prostatectomy UI is most likely multifactorial. Radical prostatectomy removes a number of the control mechanisms for urinary continence and can potentially damage other mechanisms. The prostate, which plays a role in continence as part of the proximal sphincteric unit, is removed during this operation, as is the bladder neck, an important first barrier to contain urine in men (as opposed to in women). Therefore, postoperative continence in men after radical prostatectomy relies entirely on the EUS. Furthermore, the neurovascular supply of the EUS lies in close proximity (0.3e1.3 cm) of the apex of the prostate and is therefore susceptible to injury during the procedure. Sphincter deficiency is found in 40e60% of men with post-prostatectomy UI, but recovery is possible due to nerve regeneration during the months following surgery. Urethral strictures, which are a typical late complication of radical prostatectomy, may also lead to sphincter deficiency and impaired urethral closure, as the EUS has been shown to become more fibrotic in this case. Finally, the bladder is also affected by radical prostatectomy with effects on detrusor innervation and function leading to detrusor hypo- and hypercontractility and reduction in bladder compliance.
Increase of afferent activity from the bladder: Two theories about the mechanisms underlying the increase in afferent activity of the bladder have been proposed: a urothelium-based hypothesis and a myogenic hypothesis.6 It has been established that the urothelium is more than just a barrier: urothelial cells also have a sensory function. The urothelium is in close interaction with the suburothelium, which contains afferent nerve endings and myofibroblasts or interstitial cells. The sensory molecules of the urothelium react to mechanical and chemical stimuli by releasing neurotransmitters into the suburothelium, which in turn trigger afferent nerve activity. Muscarinic and b-adrenoceptors have been shown to play a role in the generation of afferent impulses from the bladder, which may explain the effect of antimuscarinics and of b3-agonists on bladder sensation, as an addition to their bladder smooth muscle relaxant effect. The urothelium-based hypothesis states that changes in urothelial receptor function, such as upregulation, and in neurotransmitter release (increase), as well as changes in the sensitivity of the suburothelial cell network may lead to an increase of afferent activity triggered by the bladder and hence to an enhancement of involuntary detrusor contractions. The myogenic hypothesis, on the other hand, states that changes to the excitability of the bladder smooth muscle cells and of their coupling with other mycocytes or interstitial cells can lead to the generation of uninhibited contractions. In the normal detrusor, the smooth muscle cells are poorly coupled, preventing the spread of localized contractions or micromotions during the storage phase. A dense neuronal network allows a coordinated contraction of the entire bladder during voluntary voiding. Partial denervation of the detrusor, due to inflammation or ischaemia, may change the properties of smooth muscle cells, which may hence become more excitable and develop an increased degree of coupling. In such circumstances, a local contraction of bladder smooth muscle may easily spread and lead to a coordinated contraction of (a large part of) the bladder. This local contraction may also elicit afferent activity thereby inducing a sensation of urgency to go along with DO.
Urgency urinary incontinence Unlike urge, which is a physiologic desire to void upon bladder filling, urgency is a pathological sensation and it is the central symptom of the overactive bladder (OAB). Approximately onethird of patients with OAB suffer from UUI, and to understand its pathophysiology, one needs to understand the mechanisms behind the sensation of urgency and behind OAB. The definition of urgency reveals that it is a sensation (subjective), and therefore needs to be clearly distinguished from detrusor overactivity (DO), which is the urodynamic finding of an involuntary detrusor contraction during bladder filling (objective) (Table 2). The detrusor should in normal conditions only contract during voiding. It is important to note that urgency and DO are not interchangeable terms in women: only half of the female patients with urgency demonstrate DO on cystometric studies. The opposite relation is stronger, as 85% of women with DO had OAB.5 In men, both terms are more closely related: 82% of men with OAB showed DO on cystometric studies and 82% of men with DO complained of OAB.5 It is the DO that leads to the involuntary loss of urine associated with the sensation of urgency in UUI, when the intravesical pressure during the contraction outweighs the urethral pressure. Neurological disorders (e.g. MS or spinal injuries) may reduce or annihilate the central inhibition of the micturition reflex during bladder filling, evoking involuntary detrusor contractions triggered from a purely spinal reflex and no longer controlled by a spinobulbospinal pathway. This is called neurogenic DO. Other factors, such as infection, non-bacterial inflammatory conditions of the bladder (e.g. bladder pain syndrome/interstitial cystitis), foreign bodies (e.g. sutures or meshes), bladder stones and neoplasms, may also induce an increased sensation in the bladder and/or DO. These causes need to be eliminated in the diagnostic process. If no clear cause is present, the term idiopathic DO is used.
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Abnormal handling of afferent signals in the brain: Damage to the central inhibitory pathways or sensitization of the afferent signals leads to the loss of control of the primitive voiding reflexes, triggering DO. Suprapontine areas (e.g. medial frontal lobes of the cerebral cortex and the basal ganglia) have been shown to exert a tonic inhibition on the pontine micturition centre. Suprapontine lesions, such as caused by stroke or by Parkinson’s disease, may therefore cause a loss of voluntary inhibition of micturition. A spinal cord lesion above the lumbosacral level interrupts the descending supraspinal pathway through which the micturition is voluntarily controlled. This leads to DO mediated solely by spinal reflex pathways. These unsustained and uncontrolled detrusor contractions are often associated with uncoordinated sphincter overactivity, a phenomenon known as sphincter-detrusor dyssynergia.
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Treatment: the true cause of OAB and UUI is probably a combination of (a part of) these theories and the full pathophysiological mechanism has yet to be unravelled. This makes curative treatment of OAB/UUI very difficult and patient management is therefore mainly aimed at improving quality of life. As mentioned above, the sympathetic nervous system is more dominant during the filling phase and the parasympathetic nervous system becomes more dominant during the voiding phase. Therefore, either antimuscarinics (M3-antagonists) or adrenergic agonists (b3-agonists) are used to inhibit involuntary bladder contractions and to reduce bladder sensitivity. Should these medications render an insufficient result, or should the sideeffects become unbearable, minimally invasive therapies can be initiated such as botulinum toxin injections into the detrusor, which blocks neuromuscular transmission by inhibition of acetylcholine release, or sacral nerve neuromodulation (level S3).
external urethral compression by, for example, fibroids, excessive pelvic organ prolapse, after pelvic floor surgery (overly tight tapes or autologous slings supporting the urethra), due to dysfunctional voiding or in Fowler’s syndrome. Unconscious (insensible) urinary incontinence: The first and only awareness of the incontinence episode is the actual feeling of wetness due to the leaked urine. This type of UI usually presents a severe or final-stage bladder dysfunction such as overflow UI or significant ISD. Another pathophysiological mechanism for unconscious UI is the coexistence of DO and impaired or absent bladder sensation which can be present in patients with neurogenic bladder dysfunction in whom the micturition reflex arc is intact or hyperreflexic, but the central (pontine) control is impaired or absent. Examples are patients with spinal cord injury, MS or during a seizure.
Conclusion Other types of urinary incontinence Mixed urinary incontinence represents a combination of both UUI and SUI present in one single patient. The pathophysiological mechanisms are considered to be a combination of the dysfunctions causing either SUI or UUI as described above. An alternative theory is that urine leakage into the proximal urethra (SUI) triggers a sensory urgency and/or bladder contractions leading to UUI. The disorder is difficult to treat. Usually the most bothersome type of UI is approached first and, if desired, the other type is treated after that.
Insight and understanding of the pathophysiological processes behind the different types of UI are essential for an adequate diagnostic and therapeutic approach to this debilitating condition, and may lead to a reduction of its enormous impact on the individual patient’s quality of life and on society as a whole. Knowledge on the possible mechanisms, and their interactions, is continually evolving, allowing new treatments to be developed to improve the care for patients with UI. An overview of the currently accepted theories on the pathophysiology of UI has been provided in this review.
Overflow urinary incontinence: Overdistension of the bladder, secondary to inefficient bladder emptying, may also lead to involuntary loss of urine. As the volume in the bladder increases to high levels, so does the pressure in the bladder, until at a certain point this pressure exceeds the urethral closure pressure (i.e. a reversal of the pressure gradient) and a leak occurs. The loss of urine is usually limited, just enough to reverse the pressure gradient between bladder and urethra again. Patients therefore often present with continuous urinary leakage or dribbling. An increase in intra-abdominal pressure or a low amplitude bladder contraction may also evoke a leak, masking the overflow UI as either SUI or UUI. The volume required to initiate a leak may be extremely high (multiple litres) as the bladder is a very compliant organ, storing large amounts of urine with a limited increase in pressure, especially if the volume increase builds up slowly over time. Eventually, overstretching of the bladder may lead to peripheral denervation of the bladder and as a result the bladder becomes atonic and is no longer able to contract. If possible, the patient is then taught to intermittently catheterize himself to empty the bladder at a natural rhythm of 4 e5 times a day. This type of UI is often a result of bladder outlet obstruction (BOO) and is therefore more often seen in men, typically elderly men with a prostatic enlargement and chronic urinary retention, although younger men with a urethral stricture or a vesical neck contracture may also present with this symptom. BOO may first lead to OAB, through both urothelial and myogenic mechanisms. Women can also develop BOO, due to
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Funding Michel Wyndaele was partially funded by the Sirate 32 foundation during his work on this review. A REFERENCES 1 Haylen BT, de RD, Freeman RM, et al. An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Neurourol Urodyn 2010; 29: 4e20. 2 Milsom E, Altman D, Cartwright R, et al. Epidemiology of urinary incontinence (UI) and other lower urinary tract symptoms (LUTS), pelvic organ prolapse (POP) and anal incontinence (AI). In: Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence. 5 ed. ICUD-EAU, 2013; 15e108. 3 Blaivas JG. The bladder is an unreliable witness. Neurourol Urodyn 1996; 15: 443e5. 4 DeLancey JO. Structural support of the urethra as it relates to stress urinary incontinence: the hammock hypothesis. Am J Obstet Gynecol 1994 Jun; 170: 1713e20. 5 Hashim H, Abrams P. Is the bladder a reliable witness for predicting detrusor overactivity? J Urol 2006 Jan; 175: 191e4. 6 Koelbl H, Igawa Y, Salvatore S, et al. Pathophysiology of urinary incontinence, faecal incontinence and pelvic organ prolapse. In: Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence. 5 ed. ICUD-EAU, 2013; 261e360.
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