(Adapted with permission from Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol 2003;20[6]:327–336.)

Recently, the terms OAB dry and OAB wet have been introduced. About two thirds of patients with OAB have symptoms of urgency and frequency without urinary incontinence, which represent OAB dry. One third of patients have symptoms with urinary incontinence, known as OAB wet (Fig. 28-2). This becomes very important when reviewing industry-sponsored trials, because inclusion criteria and severity of disease are significantly different in these two conditions.

Figure 28-2 Prevalence of OAB wet and OAB dry.

(Adapted with permission from Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol 2003;20[6]:327.)

In 1995, the total economic cost of urinary incontinence for both men and women in the United States, including OAB and stress incontinence, was estimated at $26.3 billion or $3565 per individual of age 65 or older. This included more than $1 billion spent annually on adult disposable products. Forty-eight percent or $12.53 billion of these resources were used to diagnose, treat, care for, and rehabilitate patients with incontinence. The total economic cost of OAB in the United States in 2000 was estimated to be $18.2 billion. The most rapidly growing segment of the U.S. population is women between ages 60 and 80. Up to 50% of women in this age group complain of OAB syndrome. The prevalence of OAB syndrome, as currently defined, is much higher than stress incontinence in the aging female population.

NEUROPHYSIOLOGY OF THE LOWER URINARY TRACT

Autonomic Pathways

Sympathetic nerves exit between spinal cord levels T1 and L2 and synapse in the paravertebral ganglions. The sympathetic system uses noradrenaline as its neurotransmitter, and the receptors are α- and β-adrenergic. Sympathetic input to the bladder is via the hypogastric nerve (Fig. 28-3). When noradrenaline binds to β-receptors on the bladder, it activates adenylate cyclase, which increases levels of cyclic adenosine monophosphate (AMP), thereby relaxing the detrusor muscle of the bladder (Fig. 28-4).

Figure 28-3 Neurourology of bladder storage and elimination: (1) Sympathetic nerves exit the spinal cord between levels T1 and L2. They synapse in the paravertebral ganglion, and postganglionic fibers travel to the bladder via the hypogastric nerve. (2) Parasympathetic nerves exit the spinal cord via S2–S4. Preganglionic fibers travel to the bladder via the pelvic nerve and synapse close to the bladder, then send short postganglionic fibers to the bladder. (3) The external urethral sphincter is innervated by motor neurons that originate in Onuf’s nucleus and travel via the pudendal nerve.

Figure 28-4 Schematic representation of parasympathetic and sympathetic postjunctional receptors.

The parasympathetic system originates at spinal cord levels S2, S3, and S4. Parasympathetic input to the bladder is via the pelvic nerve (see Fig. 28-3). The parasympathetic system uses acetylcholine as its neurotransmitter and muscarinic receptors at target organs. Five subtypes of muscarinic receptors are known, with a predominance of M2 and M3 receptor subtypes in the bladder. Release of acetylcholine by postganglionic parasympathetic nerves activates both M2 and M3 receptor subtypes (see Fig. 28-3). M2 receptors make up approximately 80% of the muscarinic receptors in the bladder. Activation of M2 receptors negatively affects adenylate cyclase, thereby decreasing cyclic AMP, and ultimately inhibiting relaxation caused by the sympathetic system (Fig. 28-4). M3 subtypes, which make up the remaining 20% of muscarinic bladder receptors, activates phospholipase C, increases inositol triphosphate, and subsequently causes detrusor muscle contraction (see Fig. 28-4).

Somatic Pathways

The neurotransmitter for the somatic nervous system is acetylcholine, and its receptors are nicotinic. The striated muscle of the external urethral sphincter is innervated by motor neurons that originate in Onuf’s nucleus in the sacral spinal cord and their axons traveling via the pudendal nerve (see Fig. 28-3).

Central Regulation

Neurotransmitters involved in the central control of micturition include acetylcholine, γ-aminobutyric acid (GABA), glycine, serotonin, dopamine, and noradrenaline. Two regions of the pons are involved in regulating voiding and continence. The pontine micturition center (Barrington nucleus or M region) projects directly to bladder motor neurons and indirectly to urethral motor neurons. The bladder motor neurons are preganglionic and parasympathetic (S2, S3, S4) and located in the intramediolateral cell column of the sacral spinal cord. The urethral motor neurons are located in the sacral ventral horn (Onuf’s nucleus). With stimulation of the pontine micturition center, urethral pressure decreases via inhibition of the urethral motor neurons and intravesical pressure increases by stimulation of the bladder motor neurons (Fig. 28-5).

Figure 28-5 Schematic representation of storage and voiding reflexes. A. During bladder storage distension of the bladder causes afferent signals that, in turn, cause efferent signals via the hypogastric nerve (sympathetic system, relaxation) and the pudendal nerve (increased tone of the striated sphincter). B. During bladder elimination, increased afferent activity via the pudendal nerve travels through the periaqueductal gray matter (PAG) through the pontine micturition center and, ultimately, sympathetic outflow (relaxation) and pudendal outflow (urethral tone) while increasing parasympathetic outflow (contraction).

The pontine continence center, or L region, projects to urethral sphincter motor neurons. With stimulation of the pontine continence center, urethral sphincter tone increases. During the filling phase, the pontine continence center continuously stimulates the urethral sphincter motor neurons to maintain urethral closure (see Fig. 28-5).

Afferent Information

Bladder information is sent from the bladder via the pelvic nerve to the sacral dorsal root ganglia located within the spinal cord. These nerves are primarily made up of myelinated A through D fibers and unmyelinated C fibers. A through D fibers respond to distension and active contraction, whereas C fibers respond to chemical irritation and pain. Several receptors have been identified on these nerves, such as vanilloid, tachykinin, purinergic, and prostanoid receptors (Fig. 28-6). These receptors may have a role in the development of OAB syndrome and may be potential pharmacotherapy targets.

Figure 28-6 Schematic representation of bladder innervation.

ETIOLOGY OF OVERACTIVE BLADDER

Although the cause of OAB is not understood, the problem is most likely multifactorial. The process of bladder storage and evacuation can be visualized as complex neurocircuits in the brain and spinal cord that coordinate the activity of smooth and striated muscle in the bladder and urethra. These circuits act as “on/off switches” to alternate the lower urinary tract between its two modes of operation: storage and elimination. Conditions associated with detrusor overactivity are listed in Box 28-1.

Neurologic Disease

Detrusor overactivity is associated with neurologic lesions of the suprasacral spinal cord and higher centers. These lesions block the sacral reflex arc from the cerebral cortex and other higher centers that are crucial to both voluntary and involuntary inhibition of the bladder. In this group of patients, involuntary detrusor contractions are usually associated with appropriate relaxation of the urethral sphincter because there is preservation of long tracts from the pontine region. Neurologic conditions resulting in detrusor overactivity include multiple sclerosis, dementia, cerebrovascular disorders, and Parkinson’s disease.

Urogynecologic Conditions

Various conditions that may present with symptoms of urgency and frequency are listed in Box 28-2. Idiopathic detrusor overactivity is reserved for symptoms of urgency and frequency, with or without incontinence, that cannot be explained by the presence of other conditions.

URINARY TRACT INFECTION

Inflammation of the bladder epithelium, with or without associated bacteriuria, has been suggested as a cause of bladder overactivity. Bhatia and Bergman (1986) performed urodynamic studies on women with acute urinary tract infections before treatment. Half of those with urodynamic evidence of detrusor overactivity before treatment had stable cystometrograms after the infection was treated. However, Bates et al. (1970) reported on more than 2000 patients examined by videocystography on whom culture and sensitivity studies of midstream urine specimens were performed. They found that of 35 patients infected at the time of the study, only 3 had nonneuropathic detrusor overactivity.

HYPERSENSITIVE BLADDER DISORDERS

Pain is not a common symptom of women with OAB. Pain with a full bladder in conjunction with urgency and frequency suggests a hypersensitive bladder condition, such as interstitial cystitis. Women who have had previous pelvic radiation and those with significant urogenital atrophy may also complain of overactive bladder symptoms.

URODYNAMIC CONDITIONS

Urethral instability is defined as a spontaneous fall in maximum urethral pressure exceeding one third of the resting maximum urethral pressure in the absence of detrusor activity. If simultaneous urethrocystometry is performed during filling, the diagnosis of urethral instability or uninhibited urethral relaxation can be made. Resnick and Yalla (1987) noted a subgroup of elderly women with detrusor overactivity resulting in incontinence, who cannot effectively empty their bladders when attempting to void. Urodynamic testing revealed that impaired contractility caused impaired emptying. They named the condition detrusor overactivity with impaired contractility and hypothesized that this may represent the last stage of detrusor overactivity, in which detrusor function deteriorates.

STRUCTURAL OR ANATOMIC CONDITIONS

At the level of the urethra, urge incontinence can occur with outlet obstruction. This is a well-known problem in men with benign prostatic hyperplasia, and in younger men and women with spinal cord injuries or multiple sclerosis. In women, bladder outlet resistance from previous anti-incontinence surgery can result in irritative symptoms and urge incontinence. Idiopathic bladder outlet obstruction is rare in women. Abnormal voiding is usually caused by poor detrusor function rather than physical obstruction. However, obstructive voiding sometimes occurs with advanced pelvic organ prolapse and after operations for stress incontinence.

The correlation between detrusor overactivity and pelvic surgery is confusing and, at times, unexplainable. Studies on patients operated on for stress incontinence who had stable preoperative cystometrograms note that 7% to 27% develop postoperative detrusor overactivity. Women with mixed symptoms of stress incontinence and OAB will have a resolution of their OAB symptoms in approximately 50% of cases after an anti-incontinence procedure. The remaining 50% may have a persistence or worsening of their symptoms. Postoperative detrusor overactivity or a persistence or worsening of symptoms seems to be more common in patients with previous bladder neck surgery and in those with coexistent detrusor overactivity and preoperative sphincteric incompetence.

Radical pelvic surgery can result in an unstable bladder. Partial denervation of the bladder during the operative process with subsequent development of detrusor dysfunction is currently the most accepted theory.

Other conditions that can impact the lower urinary tract and result in overactive bladder symptoms include pregnancy, pelvic mass, urethral diverticulum, and intravesical lesions.

ORGASM

Orgasm may cause detrusor overactivity. The pathogenesis is unknown, but women sometimes experience urgency or urge incontinence with a gush of urine during climax. Treatment is the same as for detrusor overactivity; sexual counseling and education are often helpful.

MIXED INCONTINENCE

Detrusor overactivity can coexist with stress incontinence in up to 30% of patients. Whether this is a coincidental finding or some underlying relationship between these two conditions is unknown. In women with mixed stress and urge incontinence, a deficient urethral sphincter may result in urge incontinence, if leakage of urine into the proximal urethra stimulates urethral afferents that induce involuntary voiding reflexes. Interestingly, after anti-incontinence surgery, detrusor overactivity may disappear, remain the same, or worsen.

In a matched control study, Colombo et al. (1996) noted that 95% of their patients were cured of stress incontinence after a Burch urethropexy was performed if they had a stable preoperative cystometrogram. On the other hand, only 75% were cured if, preoperatively, they had low compliance or uninhibited bladder contractions.

Women may condition themselves to have urgency and frequency by becoming habitual frequent voiders. This can be seen in women with long-standing stress incontinence because these women will consciously or subconsciously void more frequently to avoid or reduce leakage. Over time, it has been proposed that functional bladder capacity is reduced, and the bladder becomes more sensitive at lower volumes of urine, thus resulting in frequency and urgency (OAB dry). This same phenomenon can occur in women with urge incontinence, resulting in more severe frequency. This can be viewed as a cycle in which symptoms continue to worsen unless intervention is undertaken (Fig. 28-7).

Figure 28-7 Cycle of bladder dysfunction.

Psychological or Psychosomatic Causes

The psychological status of women with detrusor overactivity has been investigated by several authors with conflicting results. Norton et al. (1990) performed psychiatric evaluations on 117 women and found no more psychiatric morbidity in women with detrusor overactivity than in women with stress incontinence. Interestingly, women in whom no urodynamic abnormality could be detected had the highest scores for anxiety and neuroticism. Moore and Sutherst (1990) analyzed the response to treatment of idiopathic detrusor overactivity, relative to “psychoneurotic” status in 53 women. Women who responded poorly to treatment had higher psychoneurotic mean scores than those who responded, although one third of poor responders had a normal psychoneurotic score. Patients who responded well to therapy had scores similar to those of normal urban women.

These studies emphasize the need for future research in this area.

Idiopathic Detrusor Overactivity

With our current diagnostic capabilities, more than 90% of women with detrusor overactivity have no other recognizable disorder. Various theories have been proposed to explain detrusor overactivity, such as detrusor hypersensitivity or deficient inhibitory activity, but no one theory has been identified that adequately explains all or most detrusor overactivity, so it remains idiopathic at this time.

Kinder and Mundy (1987) studied detrusor muscle strips in vitro from patients with detrusor overactivity and from normal continent subjects. The unstable muscle strips showed an increased response to direct electrical stimulation and increased sensitivity to stimulation with acetylcholine. In vivo, this response would correspond to a higher sensitivity of efferent neurologic activity or to a lower level of acetylcholine release necessary to initiate a detrusor contraction. However, it is not clear whether this detrusor supersensitivity is caused by a relative cholinergic denervation or by reduced inhibitory or modulatory neurologic activity, possibly mediated by vasoactive intestinal polypeptide (VIP). VIP is a 28-amino-acid neuropeptide with powerful relaxant effects on smooth muscle. VIP is abundant in normal human bladders and markedly decreased in the bladders of patients with detrusor overactivity. Elbadawi et al. (1993) suggested that spontaneous trigger and subsequent spread of contractile signals via increased cell-to-cell coupling were the likely mechanisms for the development of idiopathic detrusor overactivity.