Hypotheses of Detrusor Overactivity

Until recently, insight into the pathophysiologic basis of DO has generally focused on cellular mechanisms by which unregulated motor activity could arise. The neurogenic hypothesis states that DO arises from generalized, nerve-mediated excitation of the detrusor muscle (de Groat, 1997). There are several interdependent mechanisms by which this may arise. First, damage to the brain can induce DO by reducing suprapontine inhibition. Second, damage to axonal pathways in the spinal cord allows the expression of primitive spinal bladder reflexes. Third, synaptic plasticity leads to reorganization of sacral activity, with the emergence of new reflexes, which may be triggered by C-fiber bladder afferent neurons. Finally, sensitization of peripheral afferent terminals in the bladder can trigger DO.

The myogenic hypothesis suggests that overactive detrusor contractions result from a combination of an increased likelihood of spontaneous excitation within smooth muscle of the bladder and enhanced propagation of this activity to affect an excessive proportion of the bladder wall (Brading and Turner, 1994; Brading, 1997). Patchy denervation is a common observation in DO, regardless of etiology (German et al, 1995; Charlton et al, 1999; Drake et al, 2000; Mills et al, 2000). A smooth muscle cell deprived of its innervation shows an upregulation of surface membrane receptors and may have altered membrane potential, which increases the likelihood of spontaneous contraction in that cell. DO is also associated with characteristic changes in ultrastructure (Elbadawi et al, 1993; Haferkamp et al, 2003a, 2003b), which could facilitate the propagation of the contraction over a wider proportion of the body of the detrusor than normal. However, the observations in different models of DO and from clinical specimens do not uniformly describe these features.

Afferent Mechanisms in Overactive Bladder and Detrusor Overactivity

The afferent nerve endings are widely distributed in the bladder wall and are particularly dense in the connective tissue underneath the urothelium. In this location, they may be influenced by several cell types. Urothelial cells possess sensory and signaling properties that allow them to respond to their chemical and physical environments and to communicate with subjacent structures (Birder, 2001). Suburothelial interstitial cells lie in close physical proximity to nerve fibers, suggesting a role in sensory transduction or regulation (Wiseman et al, 2003). The number of impulses fired by an afferent ending at any level of distention can be varied physiologically; that is, the gain of the sensory nerve endings can be changed to vary the “afferent sensitivity.” Thus the rate of firing in a particular afferent normally associated with a high vesical volume can occur at lower volumes if the afferent ending has been sensitized. Accordingly, the release of substances from the urothelium, as well as the direct interaction between afferent nerve endings and other cell types, may physiologically influence central reporting of the bladder state and could well contribute pathophysiologically. In theory, OAB may arise if the level of sensory activity is inappropriately high for any given degree of bladder distention, resulting from pathologically sensitized or abnormally numerous afferent nerve endings. The interaction among afferents, urothelium, and interstitial cells is thus interesting, in that modulating their interactions may result in amelioration of symptom severity. The expression of various receptors on urothelium and afferents, particularly members of the transient receptor potential (TRP) family, may thus be relevant in the development of future clinical management options. The sensory information is carried to the spinal cord by myelinated Aδ fibers and unmyelinated C fibers. As a general rule, the Aδ fibers are regarded as responding to passive bladder distention and active detrusor contraction (“in series” mechanoreceptors [Iggo, 1955]), thus conveying information about bladder filling (Janig and Morrison, 1986). C fibers are regarded as responding primarily to chemical irritation of the bladder mucosa (Habler et al, 1990) or to thermal stimulus (Fall et al, 1990). Accordingly, they may be less active in the physiologic state than the Aδ fibers. Nonetheless, there is almost certainly considerable overlap in the sensory information carried by the two types of afferent, and the C fibers may take on a more prominent role in the pathologic state.

Integrative Physiology of Overactive Bladder

The afferent, neurogenic, and myogenic mechanisms alluded to earlier are essentially based on physiology of individual cell types. However, the complexity of lower urinary tract function is substantially increased by the potential interactions between differing cell types and their humoral/paracrine environments. The integrative properties determining the interaction between cell types is manifest in the neural circuits of the central nervous system, as well as the periphery (Fig. 66–1)—the latter working through networks (neural, interstitial cells) and by direct cell communication in the urothelium or muscle cell–to–muscle cell. The presence of interstitial cells in the bladder led to the proposal of a regulatory “myovesical plexus” comprising nerves (excitatory and inhibitory, peripheral and central) and interstitial cells loosely, akin to gut myenteric plexuses. The integrative hypothesis of OAB draws on the various contributory factors to understand the normal micturition cycle, OAB, and DO (Drake et al, 2001). Several observations can be understood by focusing on activity within the bladder wall itself:

Figure 66–1 The integrative hypothesis of overactive bladder and detrusor overactivity. Neural circuits in the central nervous system and cellular interactions in the periphery integrate afferent input and modulatory influences, in a hierarchy of regulatory structures underpinning normal bladder function. Storage function is characterized by sensations of filling and desire to void at suitable volumes, whereas voiding function is characterized by volitional control and complete emptying. Lesions at various levels have seemingly similar effects because their effects are mediated by final common pathways of sensation and bladder contraction.

The crucial factors in the integrative hypothesis are the level of excitation and degree of propagation in the myovesical plexus structures of the bladder wall. Both will be at low levels during normal bladder filling. Local excitability is high in OAB, whereas propagation alone is high in asymptomatic DO; both are increased where DO is symptomatic. Propagation is high in normal voiding (driven by efferent commands from the central nervous system [CNS]). Increased local excitation with impaired propagation could explain why patients have OAB and a PVR (detrusor hyperactivity with impaired contractility (Resnick and Yalla, 1987).

Central Nervous System

The development of functional brain imaging technology allows estimation of gross activity in specific brain areas and has been used to study bladder filling in normal and symptomatic individuals. Intriguing insights into contributions from various parts of the cerebral cortex such as the insula and the prefrontal cortex have resulted. Alterations in the regional brain activity of symptomatic individuals with OAB have been reported (Griffiths et al, 2007). Understanding brain responses to lower urinary tract activity through autonomic afferent processing networks, as is already under investigation for the gastrointestinal tract, will be crucial in the endeavor to develop improved clinical management options.

Etiology

Neurologic disease is associated with a high prevalence of LUT dysfunction, and this is to be anticipated given the fundamental regulatory influence of innervations on bladder and bladder outlet. Aging is associated with increased LUTS; this may be through the attritional effects on inhibitory innervation and brain function. Bladder outlet obstruction has long been considered an etiologic factor in generation of DO and OAB, but there is now some doubt as to whether this is correct.