Mechanisms of Disease: central nervous system involvement in overactive bladder syndrome

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1 Mechanisms of Disease: central nervous system involvement in overactive bladder syndrome Karl-Erik Andersson SUMMARY The pathophysiology of overactive bladder syndrome (OABS) and detrusor overactivity (DO) is complex and involves both peripheral and central nervous system (CNS) factors. Central in OABS is urgency, the pathophysiology of which is unknown. Increased afferent activity, decreased capacity to process afferent information, decreased suprapontine inhibition, and increased sensitivity to contractionmediating transmitters are all potential causes of DO and OABS. Because both urgency and initiation of the micturition reflex depend on afferent input from the lower urinary tract, it seems logical that in the search for new therapies for DO/OABS, afferent functions and central control of afferent functions are targets of interest. Voiding and storage reflexes involve several transmitters and transmitter systems that could be targets for the development of drugs that control DO/OABS. Perturbations of these systems are found in CNS disorders associated with DO/OAB, such as stroke, Parkinson s disease, spinal cord injury and multiple sclerosis. This short overview focuses on the afferent pathways and on how the transmitter systems that control micturition can be perturbed by disease to give rise to DO/OABS. KEYWORDS afferent function, detrusor overactivity, periaqueductal gray matter, pontine micturition center, urgency REVIEW CRITERIA Data for this review were identified by searches of PubMed and references from relevant articles. Relevant articles were also identified through searches of the author s files. The search terms overactive bladder, CNS mechanisms and bladder, afferent functions and bladder, and urgency were used. Only papers published in English were reviewed. K-E Andersson is Professor of Clinical Pharmacology at the University of Lund, Sweden. Correspondence Department of Clinical and Experimental Pharmacology, Lund University Hospital, S Lund, Sweden Karl-Erik.Andersson@klinfarm.lu.se Received 20 August 2004 Accepted 18 September doi: /ncpuro0021 INTRODUCTION The International Continence Society defines OABS as urgency, with or without incontinence, usually with frequency and nocturia. 1 Urgency, defined as the complaint of a sudden compelling desire to pass urine, which is difficult to defer, 1 is a central symptom of OABS. It can also be associated with involuntary detrusor contractions, urodynamically demonstrated as DO. It should be noted that urgency is difficult to measure, and no validated tool for its assessment is currently available. Furthermore, there are no animal models of urgency. Because the sensation of desire to void, urgency, and initiation of the micturition reflex depend on afferent input from the lower urinary tract, afferent functions and their central control have been of interest as targets for new therapies. Micturition in the adult is a spinobulbospinal reflex, which is under suprapontine tonic inhibitory control. 2 Voluntary control is dependent on how effectively suprapontine pathways influence (enhance or inhibit) this inhibitory input. Adequate sensory input is the prerequisite for conscious bladder control; changes in sensory mechanisms could disturb bladder function. Thus, it has been proposed that urge incontinence is a disease of bladder sensors. 3 Because of the complexity of CNS control of the lower urinary tract, DO/OABS occurs as a result of a variety of neurological disorders, as well as in response to changes in peripheral innervation and in the smooth and skeletal muscle components of the lower urinary tract and pelvic floor. 4,5 Theoretically, the pathophysiology of DO/OABS might be dependent on increased afferent activity, decreased capacity of the CNS to process afferent information, decreased suprapontine inhibition or increased sensitivity to contraction-mediating transmitters in the target organ (Figure 1). SENSORY AFFERENT PATHWAYS From the dorsal root ganglia, sensory nerve cell bodies project to the bladder, where information is received, and to the spinal cord. Retrograde DECEMBER 2004 VOL 1 NO 2 NATURE CLINICAL PRACTICE UROLOGY 103

2 Decreased capacity to process afferent information Decreased suprapontine inhibition in the urethral sphincter and pelvic floor. They are believed to act as on/off switches to shift the lower urinary tract between two modes of operation: storage and voiding. 2 In adults, urine storage and voiding are subject to voluntary control mediated by the cerebral cortex. In infants, however, these switching mechanisms function in a reflex manner to produce involuntary voiding. 2 Injuries or diseases of the nervous system in adults can disrupt voluntary control of micturition, and cause re-emergence of reflex micturition, resulting in DO/OABS and incontinence. Increased afferent activity Increased sensitivity to released contraction-mediating transmitter Figure 1 Pathophysiology of detrusor overactivity and overactive bladder syndrome could involve various factors. tracing studies show that most of the sensory innervation of the bladder and urethra originates in the thoracolumbar region and travels via the pelvic nerve. 6 In addition, some of the afferents originating in ganglia at the thoracolumbar level of the sympathetic outflow project via the hypogastric nerve. The sensory nerves of the striated muscle in the rhabdosphincter travel in the pudendal nerve to the sacral region of the spinal cord. Sacral sensory nerve terminals uniformly project to all areas of the detrusor and urethra, whereas lumbar sensory nerve endings are numerous in the trigone and scarce in the bladder body. The hypogastric and pelvic pathways are involved in generating the sensations associated with normal bladder filling, and with bladder pain. The pelvic and pudendal pathways are also involved in generating thermal sensations from the urethra and the sensation that micturition is imminent. The incoming information eventually controls activity in the parasympathetic, sympathetic, and somatic efferent nerves that project to the lower urinary tract. MICTURITION AND STORAGE REFLEXES Normal micturition in both humans and animals occurs in response to afferent signals from the lower urinary tract, and is controlled by neural circuits in the brain and spinal cord. These circuits coordinate the activity of smooth muscle in the detrusor and urethra with that of striated muscle Sensations during cystometry At gradual bladder filling during cystometry, three distinct sensations have been described: an initial sensation of filling, a first desire to void, and a subsequent strong desire to void. 7 The first sensation of bladder filling is probably perceived only during artificial filling. The sensation is weak and not constant; it is probably dependent on cortical fluctuations in perception and interpretation of sensory information. Impulses related to the desire to void are transmitted through the pelvic nerves, and those relaying the sensation of a full bladder travel via the pudendal nerves. The sense of imminent micturition probably resides in the urethra, and the desire to void comes from stretching the bladder wall. 8 The volumes at which these sensations occur are very reproducible in an individual, but can differ greatly among individuals. 7 Even if the relation between a strong desire to void recorded during cysto metry 7,9 and the symptom of urgency experienced by OABS patients has not been established, it is generally assumed that changes in these afferent mechanisms are associated with lower urinary tract symptoms, including DO/OABS. Cucchi et al. 10 examined whether the contractility of overactive bladders was affected by voiding urgency in women. They found that patients with idiopathic DO had more powerful bladder contractions than unaffected controls, and that the most powerful bladder contractions were associated with the greatest urge severity. The authors speculated that in DO there is a facilitated voiding contraction, and that this facilitation might be centrally amplified by severe urgency. Micturition pathways Distension of the bladder wall is the primary stimulus for initiation of the micturition reflex (Figure 2). In addition, mechanisms related to the urothelium and adjacent afferent nerves 104 NATURE CLINICAL PRACTICE UROLOGY ANDERSSON DECEMBER 2004 VOL 1 NO 2

3 could act as volume sensors. 11 At least two types of afferent neurons innervate the urinary bladder: Aδ and C-fibers. Aδ afferent neurons have myelinated axons and are mechanosensitive; they are activated by both low (non-nociceptive) and high (nociceptive) intravesical pressure. C-fiber afferents possess unmyelinated axons and do not respond to bladder distension; they are activated by cold, heat, or chemical irritation of the bladder mucosa. C-fiber afferents are believed to have primarily nociceptive functions, 12 but also to contribute to micturition in the fetus and neonatally, and when the bladder and/or the micturition reflex is damaged in adults. Once threshold tension is achieved during bladder filling, afferent impulses that are conveyed mainly by the pelvic nerve reach centers in the CNS. In cats, the afferent neurons send information to the periaqueductal gray (PAG) matter in the brain, which in turn communicates with the pontine tegmentum, 13 where two different regions involved in micturition control have been described. 14 One is a dorsomedially located M region, corresponding to Barrington s nucleus or the pontine micturition center. A more-lateral L region could serve as a pontine urine storage center. It has been suggested that this storage center suppresses bladder contraction and regulates the activity of striated urethral sphincter muscle during urine storage. The M and L regions could represent separate functional systems that act independently. 15 Suprapontine control of the pontine micturition center (inhibitory modulation) has not been described in detail, although several positron emission tomography studies in humans indicate involvement of a number of brain areas, including the medial frontal cortex and the diencephalon The important role of forebrain structures in the control of micturition is evident from observations in patients with anterior cortical lesions. In these patients, bladder control is disrupted by symptoms of unsuppressed initiation of micturition, while voiding itself can be coordinated normally. 19 Athwal et al. 17 observed increased activity in the PAG with increasing bladder volume, and also in the midline pons, mid-cingulate cortex, and bilaterally in the frontal lobe area. They interpreted their findings as support for the hypothesis that PAG receives information about bladder fullness and relays it to areas involved Urothelium IC 1 Smooth muscle C-fiber C-fiber in the control of bladder storage. These authors also suggested that the network of brain regions involved in modulating perception of the urge to void are distinct from those associated with perception of bladder fullness. To assess urge sensation, Athwal and colleagues used a perceptual scale ranging from 0 4, where 0 = no sensation, 1 = initial sensation, 2 = first urge to void, 3 = strong urge, and 4 = uncomfortable urge. It is questionable whether uncomfortable urge equates to urgency as defined by the International Continence Society or as experienced by patients suffering from OABS. Descending pathways connect with preganglionic neurons originating in the lumbar sympathetic nuclei, the sacral parasympathetic nuclei, and somatic motoneurons innervating the striated urethral sphincter (Onuf s nucleus). Coordination between detrusor and sphincter is controlled within the pontine region. TRANSMITTERS AND TRANSMITTER SYSTEMS Micturition reflexes involve several transmitters and transmitter systems that are potential targets for DO/OABS therapies. Glutamate is probably involved as an excitatory transmitter in supraspinal control circuitry, and also in the efferent limb of the pathway between the pontine micturition center and preganglionic neurons. 20,21 Several other transmitters can modulate the glutamatergic mechanisms that control micturition. Receptors for these transmitters give us insight into the mechanisms of 3 Aδ fiber Figure 2 Different mechanisms can initiate the micturition reflex. Distension of the bladder (1) initiates activity in the Aδ fibers. Myogenic activity (contraction, 2) can generate afferent activity (possibly though C-fibers), creating afferent background noise. Signaling via the urothelium (3), possibly involving the suburothelial interstitial cells (IC), may initiate afferent activity. 2 GLOSSARY PERIAQUEDUCTAL GRAY (PAG) Gray matter within the brain, located around the cerebral aqueduct, associated with responses including bladder tone, pain and feeding DECEMBER 2004 VOL 1 NO 2 ANDERSSON NATURE CLINICAL PRACTICE UROLOGY 105

4 PAG Suprapontine mechanisms PMC Spinal control mechanisms Bladder Urethra Smooth muscle Urethra Striated muscle Pelvic floor Parasympathetic activity Sympathetic activity Ganglia Somatic activity Figure 3 Spinal cord injury can evoke activity in silent C-fibers, initiating a spinal voiding reflex. At the same time, the outflow region contracts (normal coordination of relaxation of the outflow region and detrusor contraction is at the pontine level) leading to detrusor sphincter dyssynergia. PAG, periaqueductal gray matter; PMC, pontine micturition center. the pathogenesis of DO/OABS, as well as providing potential drug targets. These transmitters include dopamine, γ-aminobutyric acid (GABA), serotonin, and the enkephalins. 21,22 BLADDER DYSFUNCTION AND CNS DISORDERS Stroke Animal models used to investigate stroke have yielded some insights into the pathophysiologic mechanisms involved in development of strokeassociated DO/OABS. Experimental cerebral infarction after occlusion of the middle cerebral artery in rats produces ischemia within the putamen and cortex, 23 areas that are important for micturition. DO, characterized by increased frequency of micturition and decreased bladder capacity, is evident in these rats as little as 30 min after infarction. 24,25 This supports the notion of tonic cortical inhibition of bladder function. Yokoyama et al. 26 proposed that the decrease in bladder capacity associated with cerebral infarction was due to upregulation of an excitatory pathway from the forebrain and downregulation of a tonic inhibitory pathway from the same region. This overactivity might involve N-methyl-d-aspartate (NMDA) receptor glutamatergic mechanisms, because it was reversed by an NMDA antagonist. Also, dopamine D 2 receptor excitatory mechanisms are implicated because sulpiride, which selectively blocks D 2 -like dopamine receptors, increased bladder capacity in cerebrally infarcted rats. 27 Other factors could include altered dopaminergic glutamatergic interactions in the brain, 28 a central mechanism that is sensitive to nitric oxide, 29 and decreased GABAmediated inhibition of micturition. 30 Spinal cord injury In spinal cord injury, the degree of dysfunction is related to the disease process itself, the area of the spinal cord affected by the disease, and the severity of neurological impairment. 31,32 Neurological injury, which can involve parasympathetic, sympathetic and somatic nerve fibers, can cause a complex combination of signs and symptoms. Overactive voiding can develop days or weeks after acute spinal cord injury. Damage to the spinal cord above the sacral level results in DO. This type of neurogenic DO is mediated by the emergence of a capsaicin-sensitive, C-fiber-mediated spinal micturition reflex due to reorganization of synaptic connections in the spinal cord (Figure 3). In addition, bladder afferents that are normally unresponsive to low intravesical pressures become more mechanosensitive, leading to the development of DO. 4 Capsaicin-sensitive C-fibers have also been implicated in DO in patients with upper motoneuron diseases such as multiple sclerosis and Parkinson s disease. The mechanism that underlies the increased mechanosensitivity of C-fibers after spinal cord injury might be plasticity of the dorsal root ganglion cells that project to the bladder. Plasticity might take the form of cell enlargement and increased electrical excitability. A shift in expression of sodium channels from a high-threshold, tetrodotoxin-resistant type to a low-threshold, tetrodotoxin-sensitive type can occur after spinal cord injury NATURE CLINICAL PRACTICE UROLOGY ANDERSSON DECEMBER 2004 VOL 1 NO 2

5 Parkinson s disease Parkinson s disease is one of the most common neurological causes of voiding dysfunction, often resulting in DO/OABS and impairment of relaxation of the striated urethral sphincter. 33 Urinary symptoms are primarily related to storage and include frequency, urgency and urge incontinence. These symptoms correlate with the urodynamic finding of involuntary detrusor contractions at early stages of bladder filling. DO becomes more severe as Parkinson s disease progresses, and affects up to 90% of patients. 31,34,35 Central dopaminergic pathways have both excitatory and inhibitory effects on rat bladder function. 21 Activation of D 1 - or D 2 -like dopamine receptors inhibits or stimulates micturition, respectively, in the normal rat, and blockade of D 1 - and D 2 -like receptors stimulates or does not affect micturition, respectively, in the normal rat. 27,36,37 Thus, D 1 -like receptors might tonically inhibit the micturition reflex and the D 2 - like receptors that are involved in its facilitation. Idiopathic Parkinson s disease is characterized by selective destruction of striatal (nucleus caudatus and putamen) dopaminergic neurons that pass from the substantia nigra pars compacta to the putamen It has been suggested that loss of inhibitory D 1 -like receptors causes DO in parkinsonian monkeys, 41 allowing D 2 receptors to facilitate micturition. Multiple sclerosis In multiple sclerosis, voiding dysfunction is mainly caused by spinal lesions, although cerebral lesions might contribute. Impairment of neurological function results from demyelinating plaques of the white matter of the brain and spinal cord, especially the posterior and lateral columns of the cervical cord. The pathophysiological mechanisms of OABS in these patients might vary depending on the site of lesions. 42,43 Up to 90% of patients who have had multiple sclerosis for more than 10 years have symptoms of voiding dysfunction. These symptoms include frequency, urgency and urge incontinence, in addition to urinary hesitancy, intermittency and poor urinary flow. 43 Urodynamically, the most common pattern is neurogenic DO (affecting about 70% of patients with multiple sclerosis), accompanied by detrusor external sphincter dyssynergia (in 50% of patients). 44 Animal models of multiple sclerosis are available, 45 but experimental therapeutic targets have not yet been identified. CONCLUSIONS Impaired capacity to process afferent information owing to damage to the systems that exert inhibitory control on micturition at different levels of the CNS is an important factor in the pathogenesis of DO/OABS. Drugs that enhance inhibitory control mechanisms may be used to treat DO/OABS. References 1 Abrams P et al. (2002) The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 21: de Groat WC et al. 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