Alan J. Wein, MD, PhD (Hon), FACS
For the purposes of description and teaching, the micturition cycle is best divided into two relatively discrete phases: bladder filling/urine storage and bladder emptying/voiding. The micturition cycle normally displays these two modes of operation in a simple on-off fashion. The cycle involves switching from inhibition of the voiding reflex and activation of storage reflexes to inhibition of the storage reflexes and activation of the voiding reflex—and back again. This chapter begins with a functional, physiologic, and pharmacologic overview of normal and abnormal lower urinary tract function. A simple way of looking at the pathophysiology of all types of voiding dysfunction is then presented, followed by a discussion of various systems of classification and categorization. Consistent with the author’s philosophy and prior attempts to make the understanding, evaluation, and management of voiding dysfunction as logical and simple as possible (Wein and Barrett, 1988; Wein, 2002), a functional and practical approach is favored.
Normal Lower Urinary Tract Function: Overview
Two-Phase Concept of Function: Filling/Storage and Emptying/Voiding
Whatever disagreements exist regarding the anatomic, morphologic, physiologic, pharmacologic, and mechanical details involved in both the storage and the expulsion of urine by the lower urinary tract, the author has always taken the rather simple-minded view that the “experts” would agree on certain general points (Wein, 1981; Wein and Barrett, 1988; Wein, 2007; Wein and Moy, 2007). The first is that the micturition cycle involves two relatively discrete processes: (1) bladder filling and urine storage and (2) bladder emptying or voiding. The second is that, whatever the details involved, one can succinctly summarize these processes from a conceptual point of view as follows:
Bladder filling and urine storage require:
Bladder emptying/voiding requires:
The smooth sphincter refers to the smooth musculature of the bladder neck and proximal urethra. This is a physiologic but not an anatomic sphincter and one that is not under voluntary control. The striated sphincter refers to the striated musculature that is a part of the outer wall of the proximal urethra in both the male and the female (this portion is often referred to as the intrinsic or intramural striated sphincter or rhabdosphincter) and the bulky skeletal muscle group that closely surrounds the urethra at the level of the membranous portion in the male and primarily the middle segment in the female (often referred to as the extrinsic or extramural striated sphincter). The extramural portion is the classically described external urethral sphincter and is under voluntary control (for a detailed discussion see Chapter 60; DeLancey et al, 2002; Zderic et al, 2002).
Mechanisms Underlying the Two Phases of Function: Overview
This section briefly summarizes pertinent points regarding the physiology and pharmacology of the various mechanisms underlying normal bladder filling/storage and emptying/voiding abnormalities, which constitute the pathophysiologic mechanisms seen in the various types of dysfunction of the lower urinary tract. The general information is consistent with that detailed in Chapter 60 and in previous source materials and their supporting references: Wein and Barrett, 1988; deGroat et al, 1993, 1999, 2001; Zderic et al, 2002; Andersson and Arner, 2004; Andersson and Wein, 2004; Morrison et al, 2005; Mostwin et al, 2005; Yoshimura and Chancellor, 2007; Fowler et al, 2008; Birder et al, 2009; and Koelbl et al, 2009. Other specific references are provided only when particularly unique or applicable.
Bladder Response during Filling
The normal adult bladder response to filling at a physiologic rate is an almost imperceptible change in intravesical and detrusor pressure. During at least the initial stages of bladder filling, after unfolding of the bladder wall from its collapsed state, this high compliance (Δ volume/Δ pressure) of the bladder is due primarily to its elastic and viscoelastic properties. Elasticity allows the constituents of the bladder wall to stretch to a certain degree without any increase in tension. Viscoelasticity allows stretch to induce a rise in tension followed by a decay (“stress relaxation”) when the filling (stretch stimulus) slows or stops. The viscoelastic properties are considered to be primarily due to the characteristics of the extracellular matrix in the bladder wall. Andersson and Arner (2004) cite references demonstrating that the main extracellular components are elastic fibers and collagen fibrils present in the serosa, between muscle bundles, and between the smooth muscle cells in the muscle bundles. Brading and colleagues (1999) add that they believe that there is continuous contractile activity in the smooth muscle cells to adjust their length during filling but without the type of synchronous activity that would increase intravesical pressure, impede filling, and could cause urinary leakage. Clinically and urodynamically, therefore, the bladder seems “relaxed.” The urothelium also expands but must preserve its barrier function while doing so.
There may also be a non-neurogenic active component to the storage properties of the bladder. Hawthorn and colleagues (2000) have suggested that an as yet unidentifiable relaxing factor is released from the urothelium during filling and storage, and Andersson and Wein (2004) have suggested that urothelium-released nitric oxide may have an inhibitory effect on afferent mechanisms as well.
The viscoelastic properties of the stroma (bladder wall less smooth muscle and epithelium) and the urodynamically relaxed detrusor muscle thus account for the passive mechanical properties and normal bladder compliance seen during filling. The main components of the stroma are collagen and elastin. In the usual clinical setting, filling cystometry seems to show a slight increase in intravesical pressure, but Klevmark (1974, 1999) elegantly showed that this pressure rise is a function of the fact that cystometric filling is carried out at a greater than physiologic rate and that, at physiologic filling rates, there is essentially no rise in bladder pressure until bladder capacity is reached.
When the collagen component of the bladder wall increases, compliance decreases. This can occur with chronic inflammation, bladder outlet obstruction, neurologic decentralization, and various other types of injury. Bladder muscle hypertrophy, which can result from outlet obstruction, can also result in decreased compliance because it is said to be less elastic than normal detrusor; it also can synthesize increased amounts of collagen (Mostwin, 2006). Once decreased compliance has occurred because of a replacement by collagen of other components of the stroma, it is generally unresponsive to pharmacologic manipulation, hydraulic distention, or nerve section. Most often, under those circumstances, augmentation cystoplasty is required to achieve satisfactory reservoir function.
Does the nervous system affect the normal bladder response to filling? At a certain level of bladder filling, spinal sympathetic reflexes facilitatory to bladder filling/storage are clearly evoked in animals, a concept developed over the years by deGroat and others (deGroat et al, 1993; deGroat and Yoshimura, 2001; Chancellor and Yoshimura, 2002; Zderic et al, 2002; Yoshimura and Chancellor, 2007; see Chapter 60), who have also cited indirect evidence to support such a role in humans. This inhibitory effect is thought to be mediated primarily by sympathetic modulation of cholinergic ganglionic transmission. Through this reflex mechanism, two other possibilities exist for promoting filling/storage. One is neurally mediated stimulation of the predominantly α-adrenergic receptors (α1) in the area of the smooth sphincter, the net result of which would be to cause an increase in resistance in that area. The second is neurally mediated stimulation of the predominantly β-adrenergic receptors (β3 inhibitory) in the bladder body smooth musculature, which would cause a decrease in bladder wall tension. McGuire and colleagues (1983) have also proposed a direct inhibition of detrusor motor neurons in the sacral spinal cord during bladder filling related to increased afferent pudendal nerve activity generated by receptors in the striated sphincter. Good evidence also seems to exist to support an inhibitory effect of other neurotransmitters (e.g., glycine, gamma amino butyric acid [GABA], opioids, purines, the noradrenergic system) on the micturition reflex at various levels of the neural axis. Bladder filling and consequent wall distention may also result in the release of factors from the urothelium that may influence contractility (e.g., acetylcholine [Ach], adenosine triphosphate [ATP], nitric oxide, prostaglandins, other peptides, as yet unidentified inhibitory factors).
Outlet Response during Filling
There is a gradual increase in urethral pressure during bladder filling, contributed to at least by the striated sphincteric element and perhaps by the smooth sphincteric element as well. The rise in urethral pressure seen during the filling/storage phase of micturition can be correlated with an increase in efferent pudendal nerve impulse frequency and in electromyographic activity of the striated sphincter. This constitutes the efferent limb of a spinal somatic reflex, the so-called guarding reflex, which results in a gradual increase in striated sphincter activity during normal bladder filling and storage. Although it seems logical and certainly compatible with neuropharmacologic, neurophysiologic, and neuromorphologic data to assume that the muscular component of the smooth sphincter also contributes to the change in urethral response during bladder filling, probably through sympathetically induced contraction, it is extremely difficult to prove this either experimentally or clinically. The direct and circumstantial evidence in favor of such a hypothesis has been summarized by Wein and Barrett (1988), Brading (1999), and Andersson and Wein (2004).
The passive properties of the urethral wall certainly deserve mention because these undoubtedly play a role in the maintenance of continence (Zinner et al, 1983; Brading, 1999). Urethral wall tension develops within the outer layers of the urethra; however, urethral pressure is a product not only of the active characteristics of smooth and striated muscle but also of the passive characteristics of the elastic, collagenous, and vascular components of the urethral wall because this tension must be exerted on a soft or plastic inner layer capable of being compressed to a closed configuration—the “filler material” representing the submucosal portion of the urethra. The softer and more pliable this area is, the less pressure required by the tension-producing area to produce continence. Finally, whatever the compressive forces, the lumen of the urethra must be capable of being obliterated by a watertight seal. This “mucosal seal mechanism” explains why a thin-walled rubber tube requires less pressure to close an open end when the inner layer is coated with a fine layer of grease than when it is not, the latter case being much like scarred or atrophic urethral mucosa.
Voiding with a Normal Bladder Contraction
A decrease in outlet resistance occurs with adaptive shaping or funneling of the relaxed bladder outlet. Besides the inhibition of any continence-promoting reflexes that have occurred during bladder filling, the change in outlet resistance may also involve an active relaxation of the smooth sphincter area through a noradrenergic noncholinergic (NANC) mechanism, proposed to be mediated by nitric oxide (Andersson and Arner, 2004; Andersson and Wein, 2004). The adaptive changes that occur in the outlet are probably also due at least in part to the anatomic interrelationships of the smooth muscle of the bladder base and proximal urethra. Longitudinal smooth muscle continuity (Mostwin, 2006; see Chapter 60) would promote shortening and widening of the proximal urethra during a coordinated emptying bladder contraction. Other reflexes that are elicited by bladder contraction and by the passage of urine through the urethra may reinforce and facilitate complete bladder emptying. Superimposed on these autonomic and somatic reflexes are complex, modifying supraspinal inputs from other central neuronal networks. These facilitatory and inhibitory impulses, which originate from several areas of the nervous system, allow the full conscious control of micturition in the adult.
Urinary Continence during Abdominal Pressure Increases
Assuming that the bladder outlet is competent at rest, a major factor required for the prevention of urinary leakage during increases in intra-abdominal pressure is that there is at least equal pressure transmission to the proximal urethra (the midurethra, as well as in the female) during such activity. This phenomenon was first described by Enhorning (1961) and has been confirmed in virtually every urodynamic laboratory since that time. Failure of this mechanism is an invariable correlate of effort-related urinary incontinence in the female and male. The urethral closure pressure increases with increments in intra-abdominal pressure, indicating that active muscular function related to a reflex increase in striated sphincter activity or other factors that increase urethral resistance is also involved in preventing such leakage. Tanagho (1978) was the first to provide direct evidence of this. A more complete description of the factors involved in sphincteric incontinence can be found later in this chapter and in Chapters 60 and 63.
Sensory Aspects
Afferent input from the striated muscle of the sphincter and pelvic floor travels in the pudendal nerve. The most important afferents for initiating and maintaining normal micturition are those in the pelvic nerve, relaying to the sacral spinal cord. These convey impulses from tension, volume, and nociceptive receptors located in the serosal, muscle, and urothelial and suburothelial layers of the bladder and urethra. In a neurologically normal adult the sensation of filling and distention, but not urgency or pain, is what develops during normal filling/storage and initiates the reflexes responsible for emptying/voiding (deGroat and Yoshimura, 2001; Chancellor and Yoshimura, 2002; Morrison et al, 2005; Birder et al, 2009; see Chapter 60). Alterations in this finely tuned pathway can be responsible for significant alterations in lower urinary tract function.
Abnormalities of Filling/Storage and Emptying/Voiding: Overview of Pathophysiology
Excluding psychologic reasons, the pathophysiology of failure of the lower urinary tract in the adult to fill with or store urine adequately or to empty adequately must logically be secondary to reasons related to the bladder, the outlet, or a combination (Wein, 1981; Wein and Barrett, 1988).
Filling/Storage Failure
Bladder Overactivity
The possible pathophysiologies of the symptom syndrome “overactive bladder” (defined by the ICS as urgency with or without urge incontinence, usually with frequency and nocturia) can be summarized as (1) reduced suprapontine inhibition, (2) damaged axonal paths in the spinal cord, (3) damaged axonal paths in the periphery, (4) loss of peripheral inhibition, (5) enhancement of excitatory neurotransmission in the micturition reflex pathway, (6) increased lower urinary tract afferent input, and (7) idiopathic. Staskin (2001) and Mostwin and colleagues (2005) also hypothesized that decreased stimulation from the pelvic floor can contribute to phasic bladder overactivity. Decreased compliance during filling/storage may be secondary to neurologic injury or disease, usually at a sacral or infrasacral level, but may result from any process that impairs or destroys the viscoelastic or elastic properties of the bladder wall.
Filling/Storage Failure due to Altered Sensation
Bladder-related storage failure may also occur in the absence of overactivity because of increased afferent input from inflammation, irritation, other causes of hypersensitivity, and pain. The causes may be chemical, psychologic, or idiopathic. One classic example is painful bladder syndrome, a term that is replacing interstitial cystitis (see Chapter 12). Increased afferent activity can then be responsible for true detrusor overactivity (an involuntary contraction), true urgency without DO, a premature feeling of fullness or distention without urgency or DO, or the sensation of pain during filling.
Outlet Underactivity
Decreased outlet resistance may result from any process that damages the innervation of structural elements of the smooth or striated sphincter, or both, or damages or impairs the support of the bladder outlet in the female. This may occur with neurologic disease or injury, surgical or other mechanical trauma, or aging. Classically, sphincteric incontinence in the female was categorized into relatively discrete entities: (1) so-called genuine stress incontinence and (2) intrinsic sphincter deficiency, originally described as type III stress incontinence (DeLancey et al, 1994; Mostwin et al, 2005; Koelbl et al, 2009; see Chapters 60, 63, 71, and 73). Genuine stress incontinence in the female was described as associated with hypermobility of the bladder outlet because of poor pelvic support and with an outlet that was competent at rest but lost its competence only during increases in intra-abdominal pressure. Intrinsic sphincter deficiency (ISD) described a nonfunctional or poorly functional bladder neck and proximal urethra at rest. The implication of classic ISD was that a surgical procedure designed to correct only urethral hypermobility would have a relatively high failure rate, as opposed to one designed to improve urethral coaptation and compression. The contemporary view is that the majority of cases of effort-related incontinence in the female involve varying proportions of support-related factors and ISD. It is possible to have outlet-related incontinence that is due only to ISD but not due solely to hypermobility or poor support—some ISD must exist.
Stress or effort-related urinary incontinence is a symptom that arises primarily from damage to muscles, nerves, or connective tissue, or a combination, within the pelvic floor (DeLancey et al, 2002; Mostwin et al, 2005; Koelbl et al, 2009). Urethral support is important in the female, the urethra normally being supported by the action of the levator ani muscles through their connection to the endopelvic fascia of the anterior vaginal wall. Damage to the connection between this fascia and this muscle, damage to the nerve supply, or direct muscle damage can therefore influence continence. Bladder neck function is likewise important, and loss of normal bladder neck closure can result in incontinence despite normal urethral support. In older writings, the urethra was sometimes ignored as a factor contributing to continence in the female, and the site of continence was thought to be exclusively the bladder neck. However, in approximately 50% of continent women, urine enters the urethra during increases in abdominal pressure. The continence point in these women (highest point of pressure transmission) is at the midurethra.
Urethral hypermobility implies weakness of the pelvic floor support structures. During increases in intra-abdominal pressure, there is descent of the bladder neck and proximal urethra. If the outlet opens concomitantly, stress urinary incontinence ensues. In the classic form of urethral hypermobility, there is rotational descent of the bladder neck and urethra. However, the urethra may also descend without rotation (it shortens and widens), or the posterior wall of the urethra may be pulled (sheared) open while the anterior wall remains fixed. However, urethral hypermobility is often present in women who are not incontinent, and thus the mere presence of urethral hypermobility is not sufficient to make a diagnosis of a sphincter abnormality unless urinary incontinence is also demonstrated. The “hammock hypothesis” of John DeLancey (1994) proposes that for stress incontinence to occur within hypermobility, there must be a lack of stability of the suburethral supportive layer. This theory proposes that the effect of abdominal pressure increases on the normal bladder outlet, if the suburethral supportive layer is firm, is to compress the urethra rapidly and effectively. If the supportive suburethral layer is lax or movable, or both, compression is not as effective. Intrinsic sphincter dysfunction denotes an intrinsic malfunction of the urethral sphincter mechanism itself. In its most overt form, it is characterized by a bladder neck that is open at rest and a low abdominal leak point pressure and urethral closure pressure (see Chapter 62) and is usually the result of prior surgery, trauma with scarring, or a neurologic lesion.
