Treatment of Lower Urinary Tract Symptoms and Overactive Bladder Focus on Bladder Sensory Innervation

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1 REVIEW ARTICLE Treatment of LUTS and OAB Treatment of Lower Urinary Tract Symptoms and Overactive Bladder Focus on Bladder Sensory Innervation Ding-Yuan Chen, Hann-Chorng Kuo Department of Urology, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan ABSTRACT Lower urinary tract symptoms (LUTS) are highly prevalent, especially among elderly men and women, with a negative impact on health-related quality of life. LUTS are associated with great emotional costs for individuals and substantial economic costs for society. Recent investigation of LUTS in men noted that bladder dysfunction plays an important role in addition to bladder outlet obstruction. The urothelial release of neurotransmitters such as acetylcholine (ACh), adenosine triphosphate (ATP) and the neuropeptide substance P, and the expression of TRPV1 and P2X3 receptors strongly imply a role for the urothelium in human bladder mechanosensation. An abundance of suburothelial sensory nerves and vesicles containing ACh and ATP in nerve fiber terminals have been found in the human bladder wall, suggesting the lamina propria of the bladder plays an important role in the transmission of a sensation of bladder fullness and in the bladder response to stretch. In addition, nerve growth factor levels have been shown to be elevated in the bladder tissues of men with bladder outlet obstruction, patients with overactive bladders, and women with interstitial cystitis. Based on the results from recent investigations, bladder disorders like neurogenic detrusor overactivity, idiopathic detrusor overactivity, interstitial cystitis, overactive bladder due to bladder outlet obstruction and urothelial dysfunction might have a common pathway in the abnormality of expression of sensory receptors or release of transmitters in the suburothelial nerves or interstitial cells. In this regard, inhibition of receptor expression or transmitter release in the sensory nerve terminals in the suburothelial space might provide good therapeutic effects in the treatment of sensory urgency, interstitial cystitis and detrusor overactivity. (Tzu Chi Med J 2006; 18: ) Key words: sensory innervation, detrusor overactivity, neurotransmitter, interstitial cystitis, overactive bladder INTRODUCTION Lower urinary tract symptoms (LUTS) consist of a complex of bladder storage and emptying symptoms. Previously, treatment of LUTS was focused on bladder emptying symptoms and bladder outlet obstruction (BOO). Recent investigations have discovered that the sensory innervation of the urinary bladder plays an important role in storage as well as emptying LUTS. The treatment strategy for LUTS should be shifted to aim at the sensory innervation rather than the detrusor muscles. LOWER URINARY TRACT SYMPTOMS (LUTS) IN MEN LUTS are highly prevalent, especially among elderly men and women, with a negative impact on healthrelated quality of life. LUTS are associated with great emotional costs for individuals and substantial economic costs for society [1,2]. The prevalence and severity of LUTS increases with age and the progressive increase in the ageing population has increased the social economic burden and severity of LUTS [3]. Received: October 6, 2006, Revised: October 13, 2006, Accepted: October 14, 2006 Address reprint requests and correspondence to: Dr. Hann-Chorng Kuo, Department of Urology, Buddhist Tzu Chi General Hospital, 707, Section 3, Chung Yang Road, Hualien, Taiwan PPP

2 D. Y. Chen, H. C. Kuo LUTS are comprised of storage symptoms (including frequency, urgency, nocturia, and incontinence), voiding symptoms (including hesitancy, intermittency, residual urine sensation, straining to void and poor stream) and postvoid symptoms (incomplete emptying and terminal dribbling). The pathophysiology of LUTS could be bladder dysfunction (bladder hypersensitivity, detrusor overactivity (DO), detrusor underactivity), BOO (bladder neck dysfunction, prostatic obstruction, urethral stricture, poorly relaxed urethral sphincter, urethral sphincter dyssynergia) or a combination of these etiologies [4]. Many men have both storage and voiding symptoms. In men voiding symptoms are more common, but storage symptoms are encountered frequently [5]. The frequent co-morbidity with prostatic diseases in men adds complexity to the diagnosis and management of male LUTS. Recent investigations of male LUTS noted that bladder dysfunction plays an important role, in addition to BOO. LUTS suggestive of an overactive bladder (OAB) have been estimated to be present in 16% of people in Europe and United States [6]. A multinational large scale study revealed that 90% of men aged 50 to 80 years suffer from potentially troublesome LUTS and many men have both storage and voiding symptoms [3]. Benign prostatic hyperplasia (BPH) is often associated with male LUTS, but LUTS cannot be used to make a definite diagnosis of BPH. LUTS can occur in women, children, and also in men with either poor detrusor function or BOO. OAB symptoms comprise the same symptoms as storage LUTS and their prevalence increases with age. Since most men with OAB do not experience incontinence [7], men with storage LUTS are often misdiagnosed with clinical BPH. Storage symptoms correlate poorly with BOO, male OAB symptoms may be caused by bladder dysfunction such as DO or impaired detrusor contractility, or occur in combination with BOO [4]. BOO may cause DO, however, many studies have reported only 45%-50% of men with LUTS have urodynamically confirmed DO and BOO [8,9]. LUTS IN WOMEN LUTS are more prevalent in women than in men. The influence of ageing, menopause and childbirth add complexity to the etiology of female LUTS. OAB symptoms are frequently mixed with stress urinary incontinence. The ageing process results in intrinsic urethral sphincteric deficiency which increases the prevalence of urinary incontinence and may potentiate DO and OAB symptoms. In Taiwan, about 10% of men and women have symptoms suggestive of OAB [10]. This figure is far less than that in Europe where 16% of women were reported to have storage symptoms suggestive of OAB [6]. In addition to OAB symptoms, women also have voiding symptoms such as dysuria, intermittency, residual sensation and urinary retention suggestive of bladder outlet dysfunction or obstruction. In a large scale videourodynamic study of women with LUTS, BOO was found in about 9% of women with LUTS refractory to medical treatment [11]. OAB symptoms are well correlated with DO, however, voiding symptoms correlate poorly with BOO. A study applying the American Urological Association (AUA) symptom index for LUTS, revealed symptom scores on the storage and voiding subscales did not differ significantly between men and women from years old [12]. In another study from Japan, comparable storage symptom scores on the International Prostate Symptom Score (IPSS) were noted in men and women over 40 years old [13]. In a group of men and women with persistent storage symptoms, 89% of patients whose primary symptoms were frequency and urgency had urodynamic DO [14]. These data suggest that both men and women have storage and voiding symptoms and can be assessed with identical symptom score questionnaires such as the AUA or IPSS symptom indexes. THE UROTHELIUM AND OVERACTIVE BLADDER The urinary bladder urothelium had been viewed as a passive barrier, however, recent evidences demonstrated that the urothelium is a responsive structure which exhibits both sensor (ability to respond to thermal, mechanical and chemical stimuli) and transducer (ability to release chemicals) functions. Studies have also revealed that afferent nerves and urothelial cells in the bladder exhibit a number of common properties, including the expression of certain receptors and ion channels (such as TRPV1). In addition, localization of afferent nerves adjacent to the urothelium suggests that these cells may be targets for transmitter release from bladder nerves or that chemicals released by urothelial cells may alter afferent excitability. The alteration in afferent nerves or urothelial cells in pelvic viscera may contribute to the sensory abnormalities in the urinary bladder [15]. Recent investigations have shown suburothelial innervation expressing the capsaicin receptor TRPV1 [16], the purinergic receptor P2X3 [17], and the sensory neuropeptides substance P and calcitonin gene-related peptide (CGRP) [18] in the pathophysiology of human DO. PPQ

3 Treatment of LUTS and OAB Patients with neurogenic detrusor overactivity (NDO) due to spinal cord lesions were found to have increased TRPV1 and P2X3 immunoreactive suburothelial innervation compared to controls [19]. Women with idiopathic detrusor overactivity (IDO) were found to have increased density of suburothelial substance P and CGRP immunoreactive fibers compared to controls [18]. The urothelial release of neurotransmitters such as acetylcholine (ACh), adenosine triphosphate (ATP) and the neuropeptide substance P, and the expression of TRPV1 and P2X3 receptors strongly imply a role for the urothelium in human bladder mechanosensation [20-22]. Recent investigations also discovered a suburothelial nexus of myofibroblasts or interstitial cells may be the substrate for a stretch-receptor organ. These cells are extensively linked by gap junctions and may respond to ATP in a mode similar to the activation of ATP-gated P2Y receptors [23,24]. The urothelial release of ACh and ATP on bladder filling increases with ageing [20] and in spinal cord NDO [25], implicating an abnormal release of these neurotransmitters in the pathophysiology of DO. In treatment of IDO with intradetrusor injection of botulinum toxin type A (BTX-A) decreased immunoreactivity of P2X3 expression in suburothelial fibers was noted, which correlated with improvement in patients' sensation of urgency [19]. The actual pathophysiology of detrusor overactivity after neurogenic lesions, BOO and ageing has not been well elucidated. Recently, the urothelium and suburothelial space have received renewed interest because of their possible roles not only in mediating solute transport but also in sensing bladder fullness [26]. An abundance of suburothelial sensory nerves and vesicles containing ACh and ATP in nerve fiber terminals have been found in the human bladder wall, suggesting the lamina propria of the bladder plays an important role in the transmission of sensation of bladder fullness and in the bladder response to stretch [27-29]. These stretch-sensing apparatus may transmit sensory signals as well as mediate the detrusor reflex [30]. A change in hydrostatic pressure on the apical face of the urothelium results in ATP generation which is postulated to activate P2X3 receptors on sensory nerves [31]. The P2X3 receptors are colocalized with VR-1 receptors and are believed to be involved in afferent pathways that control urinary bladder volume reflexes [32]. Increased stretch activated ATP release has been reported from human urothelial cells cultured from the bladders of patients with interstitial cystitis and spinal cord injury. In the mammalian bladder, unmyelinated sensory afferent C-fibers become predominant and mediate detrusor reflex after spinal cord transection [33]. Intravesical vanilloid therapy using capsaicin or resiniferatoxin acts on the vanilloid receptor TRPV1 and is an effective therapy in patients with detrusor hyperreflexia due to spinal cord lesions [34]. TRPV1 receptors are found on the afferent nerves in the lamina propria and co-localize with acetylcholine- containing nerve fibers as well as substance P and CGRP in rat bladders [23,26,35]. Under some pathological conditions in the urinary bladder, such as infection or trauma, the production of transmitters such as ATP, substance P, and CGRP can act on nearby tissues and on afferent nerve terminals in an autocrine fashion to increase afferent nerve activity [36]. The production and release of these neurotransmitters increase during conditions of inflammation and pain [37,38]. The suburothelial interstitial cells may be affected and sensory transmission occurs earlier, increasing the sensation of bladder fullness or mediating detrusor contraction through a gap junction extending into the detrusor muscles [39,40]. Moreover, many C fibers in the bladder mucosa contain sensory neuropeptides (such as substance P, neurokinin A, CGRP) which on release, can modulate the micturition reflex and might cause detrusor overactivity [25]. A local inflammatory process might be induced through the afferent and efferent nerves in these interstitial cellular networks which integrate signal transmission from the urothelium to detrusor muscles in the bladder wall [41]. In the urinary tract, nerve growth factor (NGF) is produced by bladder smooth muscle and urothelium. Recent work indicates that NGF is involved in the ongoing regulation of neural function, as well as in inflammation and pain. Clinical and experimental data also link increased levels of NGF in the bladder tissue and urine to painful inflammatory conditions in the lower urinary tract, such as interstitial cystitis and chronic prostatitis [42-44]. Bladder inflammation by intravesical irritants or in chronic interstitial cystitis leads to acute afferent nerve activity [45] and to long-term plasticity that lowers the threshold for nociceptive and mechanoceptive afferent fibers [46]. Chronic sensitization of afferent fibers might involve both peripheral and central mechanisms. Intravesical irritants cause increased expression of the c-fos protein in the lumbosacral spinal cord [47]. A rise in bladder NGF in the muscle or urothelium initiates signals that are transported along bladder afferent nerves to the dorsal root ganglion or spinal cord [48]. NGF levels are elevated in the bladders of men with BOO, patients with OAB and women with interstitial cystitis [48,49]. Intravesical BTX-A reduces levels of NGF in the bladder of IDO as well as NDO [50]. Although the mechanism for the reduced bladder NGF has not been elucidated, prevention of neu- PPR

4 D. Y. Chen, H. C. Kuo ral plasticity by blockade of NGF production has been postulated to cause reduction of urge incontinence and symptoms of OAB [50]. Based on the results from recent investigations, bladder disorders such as NDO, IDO, OAB due to BOO, interstitial cystitis and urothelial dysfunction might have a common pathway in the abnormality of expression of sensory receptors or release of transmitters in the suburothelial nerves or interstitial cells [41]. In this regard, inhibition of receptor expression or transmitter release in the sensory nerve terminals in the suburothelial space might provide good therapeutic effects in the treatment of sensory urgency, interstitial cystitis and DO. If these hypotheses can be proven, patients with DO, bladder hypersensitivity, and interstitial cystitis refractory to conventional treatment can be treated in a totally new way without adverse effects. The underlying pathophysiology mediating detrusor hyperreflexia and urgency frequency as well as bladder pain in DO, OAB, and interstitial cystitis can also be explored. TREATMENT OF OAB BY INTRAVESICAL RESINIFERATOXIN OAB is a symptom syndrome characterized by urgency frequency with or without urge incontinence and it may affect quality of life [51]. OAB is diagnosed by subjective symptoms, of which the core symptom is urgency. Both sensory urgency and DO might be involved in the pathophysiology of this symptom syndrome. This condition may wax and wane and is occasionally associated with symptoms of suprapubic pain with a full bladder. Current treatments are usually unsuccessful in completely eradicating the urgency sensation. Behavioral therapy and pelvic floor muscle training have been tried to relieve this bothersome syndrome [52]. Some patients with OAB and hypersensitive bladder may respond to antimuscarinic agents [53], but this treatment has some adverse effects such as dizziness, dry mouth, blurred vision, and constipation, which are intolerable for some elderly patients [54]. Treatment with intra-detrusor BTX-A injections demonstrated satisfactory results in increasing bladder capacity and decreasing the urgency sensation in patients with NDO or IDO [55,56]. However, increased postvoid residual volumes and urinary retention which sometimes develop in the first post-treatment month may prohibit its wide-spread application in patients with mild to moderate symptoms refractory to antimuscarinic agents [57]. Therefore, it is mandatory to search for an effective alternative therapy without serious adverse effects that can be applied in patients with OAB. There is not yet a conclusion on the pathophysiology of hypersensitive bladder and OAB. Although urothelial dysfunction and changes in the urinary potassium concentration have been proposed to account for this condition, treatments aimed at these pathophysiologies have not been able to improve this condition adequately [58,59]. It is possible that the chronic symptomatology in bladder hypersensitivity is due to central sensitization and persisting abnormality or activation of the afferent sensory system [60]. Intradetrusor injection of BTX-A modulates the release of neurotransmitters from sensory nerve endings, and effectively modulates the inflammatory process mediated by nociceptive afferent nerve dysfunction [61,62]. Previous investigations in intravesical vanilloid therapy were aimed at treating NDO due to spinal cord lesions [34,63,64]. Only a few investigations have used capsaicin or resiniferatoxin to treat DO or bladder hypersensitivity from non-spinal cord lesions [65,66]. As evidenced by positive ice water test results, overexpression and hyperactivity of the vanilloid receptors in the urinary bladder have been identified in patients with DO due to various non-spinal lesions [67]. Therefore, use of intravesical vanilloid agonists such as capsaicin or resiniferatoxin to treat DO refractory to anticholinergic agents might be effective. Intravesical capsaicin therapy exerts an excellent effect in patients with incontinence due to multiple sclerosis or spinal cord injuries [68-70]. However, because of its irritative effect, patients with non-spinal lesions might not be able to tolerate capsaicin therapy. Resiniferatoxin, an ultrapotent capsaicin analog, has been shown to have a clinical effect similar to capsaicin but with less neuronal excitatory effect [71]. Thus, resiniferatoxin treatment is more suitable than capsaicin for patients who have normal bladder sensation and OAB [72]. Resiniferatoxin treatment has been demonstrated to have a therapeutic effect in patients with detrusor hyperreflexia due to spinal cord lesions [73-75]. At a concentration of 100 nm, resiniferatoxin induced full desensitization and successfully treated detrusor hyperreflexia in neurologically impaired patients who did not have improvement after capsaicin treatment [75]. In one study, a 50 nm solution of resiniferatoxin was found to delay or suppress involuntary detrusor contractions during filling cystometry in patients with IDO [65]. These findings indicate that desensitization of capsaicin sensitive primary afferents by intravesical resiniferatoxin can have a therapeutic effect on hyperactive or sensory disorders of the urinary bladder. The clinical effect of intravesical resiniferatoxin at PPS

5 Treatment of LUTS and OAB a concentration of 100 nm was demonstrated in treating DO due to non-spinal cord lesions in patients refractory to anticholinergic treatment [76]. Twenty-one of 41 patients with NDO and urinary incontinence had clinical improvement (51.2%) whereas 18 had stationary results and 2 developed urinary retention with overflow incontinence. The effect of resiniferatoxin treatment in these 21 patients lasted for 2 to 9 months with a median duration of 5 months. After treatment, the cystometric capacity significantly increased, and detrusor pressure showed a significant reduction, but maximal flow rate, and residual urine volume showed no significant difference. Among the 20 patients with failed treatment, only 4 (20%) had an increase in maximal cystometric capacity by 50% and none had a reduction in detrusor pressure. The magnitude of the neurotoxic effect of resiniferatoxin seems to depend on the dose of vanilloids. The dose that we used in a previous study resulted in temporary neurotoxcity but was insufficient to cause any irreversible effects. Nevertheless, a reduction of detrusor pressure might account for the decrease in urgency and urge incontinence in patients with DO. The causes of failed treatment with resiniferatoxin have not been elucidated. If complete desensitization of vanilloid receptors accounts for a successful result, then repeat treatment with resiniferatoxin may be helpful in complete blockage of vanilloid receptors. A high concentration of resiniferatoxin might cause acute desensitization but might also result in neurotoxicity to the A-delta fibers mediating detrusor contractions, whereas a lower concentration might have less neurotoxicity and less desensitization of C-fibers. In order to achieve a better desensitization of C-fibers without neurotoxicity to A-delta fibers, repeat treatment with a lower concentration of resiniferatoxin might be necessary. A recent randomized, double-blind, placebo-controlled study showed that four installations of resiniferatoxin at a concentration of 10 nm were well tolerated and effective in about 50% of patients with refractory detrusor overactivity compared to the control group at 3 months after instillation [77]. Although the adverse effects after multiple 10 nm resiniferatoxin treatments were minimal, the therapeutic effect decayed with time and only 34.6% of the patients exhibited a successful result at 6 months [77]. Thirty four men and 23 women out of a total of 67 patients completed all four treatments (85%). The success rate in the resiniferatoxin group was significantly better than in the control group (78% vs 24%, p<0.001 at one month; 50% vs 14%, p< at 3 months; 28.6% vs 3.5%, p<0.001 at 6 months). At 12 months after treatment only 3 patients (11%) in the study group and none in placebo group had effective relief of symptoms (p<0.001). The results of this phase II study showed that multiple intravesical instillations of 10 nm resiniferatoxin had a significantly superior therapeutic outcome compared with a placebo in patients with refractory DO. The therapeutic results obtained with multiple instillations of 10 nm resiniferatoxin at 3 months in this study were similar to those in a previously reported study [76]. Resiniferatoxin is a capsaicin analog that is specific for the vanilloid receptors in the bladder. Vanilloid receptors are present not only on sensory fibers but also in bladder urothelium and smooth muscle cells [78-80]. The vanilloid receptor TRPV1 participates in normal bladder function, is essential for normal mechanically evoked purinergic signaling by the urothelium and is involved in ATP release [81]. In conditions of NDO and IDO, there is up-regulation of unmyelinated nerve fibers expressing vanilloid receptors [16]. The vanilloid receptors on the sensory fibers in the bladder become overexpressed in DO, and this is the key for the successful treatment with resiniferatoxin. In patients with spinal cord injury, vanilloid-sensitive fibers in the bladder assume a central role in the reflex emptying of the bladder at low volumes [82]. Instillation of resiniferatoxin can desensitize vanilloid receptors on the sensitive fibers resulting in the disappearance of spontaneous detrusor contractions during bladder filling [65]. Purinergic P2X3-immunoreactive nerve fibers in NDO were decreased in patients who responded to intravesical resiniferatoxin [83]. Previous study showed that instillation of 50 nm resiniferatoxin can delay or suppress involuntary detrusor contractions during filling cystometry, hence, explaining the mechanism by which urinary incontinence can disappear or improve after resiniferatoxin treatment [84]. This finding indicates that vanilloid-sensitive fiber input has an important role in the generation of involuntary detrusor contractions in patients with NDO or IDO [75]. Although intravesical resiniferatoxin treatment is theoretically effective in the treatment of DO, successful therapeutic results are not obtained in many patients. The success rate (including continence rate and rate of improvement) in recent studies using a single instillation of resiniferatoxin at concentrations of 50 nm to 100 nm was reported to be about 50% or less [65,85]. The therapeutic effect of multiple low dose resiniferatoxin was significantly superior to a placebo, indicating that desensitization of vanilloid receptors in the bladder can reduce DO and improve urinary incontinence [76,77]. The success rate with multiple intravesical instillations of resiniferatoxin at a concentration of 10 nm is PPT

6 D. Y. Chen, H. C. Kuo higher than that using a single instillation of resiniferatoxin at a concentration of 50 or 100 nm [65,85], suggesting that a single intravesical instillation of 50 or 100 nm resiniferatoxin might not achieve adequate desensitization. In previous double-blind, placebo-controlled trials of intravesical resiniferatoxin for spinal detrusor overactivity, the effect of resiniferatoxin on increasing bladder capacity was controversial [84,86]. The therapeutic effect of a single instillation of resiniferatoxin might be affected by several factors, such as urine dilution during the treatment, or reflexic expulsion of the instilled solution. These factors may result in unknown concentrations actually administered into the bladder and could result in diverse therapeutic results [85]. Repeated instillations might lead to greater desensitization of afferent fibers and can provide a satisfactory therapeutic outcome in the majority of patients [77, 87]. TREATMENT OF OVERACTIVE BLADDER BY BTX-A BTX-A treatment of NDO due to spinal cord lesion was reported to provide satisfactory results [55]. Detrusor underactivity developed after detrusor injection of 300 U of BTX-A and lasted for 9 months [55]. Seventythree percent of patients with neurogenic bladder resumed a continent condition after treatment. Achievement of urinary continence and an increase in bladder capacity seem promising. However, the results for patients with non-neurogenic DO were not as good as NDO [56]. The lamina propria sensory nerves have been implicated in the responses of the bladder to stretch and chemical stimulations, which could be associated with abnormal bladder function such as DO [88,89]. BTX-A can cause muscle paralysis by blocking ACh release at the neuromuscular junction [90]. Recently, BTX-A was used successfully in the treatment of myofascial pain syndrome, migraine, and other types of headache independent of muscular paralysis [60]. In a model of pain associated with formalin induced inflammation, rats pretreated with BTX-A displayed significantly decreased pain behaviors [61]. Reduction of expressions of P2X3 and TRPV1 receptors on suburothelial sensory fibers have been observed in patients receiving detrusor BTX- A injections for DO and have been associated with reduction in the degree of urgency in patients with a successful therapeutic result. An antinociceptive effect through a direct decrease in the amount of neuropeptides such as substance P and CGRP released from activated sensory neurons has been postulated to account for the clinical effectiveness of BTX-A in pain relief [61,62]. Nociceptive sensory fibers and stretch sensing fibers are abundant in the suburothelial space [32,35]. If BTX-A delivered directly to the suburothelial space modulates the release of neurotransmitters from sensory nerve endings, it might effectively inhibit the occurrence of DO mediated by sensory nerve dysfunction [19]. In previous studies using BTX-A for IDO, most investigators used detrusor injections of 200 U or 300 U. The therapeutic results varied greatly. Kessler et al treated 11 patients with IDO with detrusor injections of 300 U BTX-A and the maximal bladder capacity increased from 220 to 340 ml. However, 4 patients needed clean intermittent catheterization (CIC) due to large postvoid residuals [91]. Rajkumar et al treated 15 IDO women with detrusor injections of 300 U BTX-A and 14 had improvements in urgency and frequency. The therapeutic effects lasted for 5-6 months [92]. Popat et al used 200 U BTX-A for 31 IDO patients. Although significant improvement in bladder capacity was noted after treatment, 20% of the patients needed CIC [93]. Schulte-Baukloh et al used 300 U of BTX-A detrusor and urethral injections for 7 women with OAB without DO. The bladder capacity increased by 20% and all patients could void without the need for CIC [94]. In the author's previous study, detrusor injections of 200 U BTX-A provided a 73.3% success rate in 30 IDO patients, with a mean therapeutic duration of 5.3 months [56]. Further study using suburothelial injections of BTX-A at a dose of 200 U revealed therapeutic results (85% success rate) as good as those achieved with 300 U BTX-A in other studies [57]. In another recent study comparing 200 U, 150 U and 100 U of BTX-A, we found that 100 U also had excellent therapeutic effects in IDO (73.3%) when compared with the results of 200 U. However, there was a higher failure rate in NDO [95]. There is no consensus about the optimal dose of BTX-A in treatment of refractory OAB or DO. An injection of 300 U of BTX-A is most commonly used for NDO, whereas U have been applied in treating IDO. The effects of 200 U BTX-A on IDO were similar with suburothelial injections and detrusor injections when compared with previous reports. This is possibly due to the diffusion of the toxin between the detrusor and the suburothelial space, as shown by a decrease in sensory fibers in the suburothelial space after detrusor injection of BTX-A. However, patients receiving suburothelial injections of 200 U of BTX-A had a higher rate of adverse events compared to those receiving detrusor injections of the same dose [95]. Recently, the dose of BTX-A for IDO was further PPU

7 Treatment of LUTS and OAB reduced to 100 U by many investigators and a satisfactory outcome was still achieved. Werner et al treated 26 women with IDO with a 53% success rate [96]. Schmid et al treated 100 IDO patients with an 88% success rate [97]. However, the therapeutic effects of 100 U BTX-A need further clarification. A dose related increase in adverse events has been found with increasing doses of BTX-A [95]. In a recent report by the author, urinary tract infection occurred in 35% of patients, a large postvoid residual requiring CIC in 30%, and difficult urination in 75% [57]. This high incidence might prohibit patients receiving a second injection when their LUTS relapse. A 100 U dose of suburothelial BTX-A reduced the rates of urinary tract infection to 4.3%, a large postvoid residual to 30.4%, and difficult urination to 56.5% [95]. Therefore, adjustment of the dose of BTX- A for IDO patients seems mandatory to minimize de novo adverse events.. One important factor for a successful therapeutic outcome with BTX-A is adequate distribution of toxin into the suburothelial space and detrusor muscles. Desensitization of the mechanoreceptors on suburothelial sensory fibers can result in a decrease in the bladder urgency sensation and a reduction of sensory neuropeptide-mediated detrusor overactivity [19]. Injection of BTX-A into detrusor muscles can cause paralysis of the affected muscle fibers [56,91-93]. Together, these effects can decrease the bladder sensation and increase bladder capacity. However, if the BTX-A is not adequately distributed into the bladder wall, or the toxin is injected outside the bladder wall, the desired effect might not be achieved. This might explain why some investigators used large doses of BTX-A in detrusor injections but the therapeutic effects were similar to those with suburothelial BTX-A injections [57,94]. It is possible that much of the BTX-A solution is injected too deep and outside the bladder wall with detrusor injections. In order to achieve a favorable therapeutic result, suburothelial injection of BTX-A seems to be a better route of injection than direct injection into the detrusor muscle. Although suburothelial injections of BTX-A have effects on sensory fibers, detrusor contractility can also be impaired after treatment [56,57,91-94]. The extent of detrusor underactivity might be even greater than after detrusor injections of BTX-A at the same dose. For patients with detrusor overactivity and impaired contractility (DHIC), this adverse event might cause large postvoid residuals and urinary tract infection. To prevent this undesired adverse event, the dose of BTX-A and injection sites should be carefully adjusted. The trigone and bladder base have been found to have abundant sensory fibers. Injections of BTX-A into these areas have been shown to have therapeutic effects on idiopathic urgency frequency syndrome and interstitial cystitis [98]. Although the trigone of the urinary bladder is rich in sensory fibers, the role of trigonal sensory fibers on bladder urgency sensation and DO has not been explored yet. The embryology and function of the trigone are different from bladder body. The trigone is composed of superficial and deep smooth muscles which are innervated by adrenergic fibers and are believed to relate to the competence of the ureterovesical junctions as well as the internal sphincter, the so-called 'lissosphincter". The sensation from the trigone might be related to bladder emptying rather than storage. Hence, treatment aimed at reducing sensation from the trigone might not improve the urgency sensation occurring during the bladder filling phase. In addition, paralysis of trigonal muscles by BTX-A might decrease the tone of muscles controlling competence of the ureterovesical junction or bladder neck, resulting in vesicoureteral reflux or bladder neck incompetence. Although vesicoureteral reflux might be a potential complication after BTX-A in these areas, there is no evidence of it so far. An advantage of trigonal injections of BTX-A is that detrusor underactivity does not develop after treatment. CHRONIC INTERSTITIAL CYSTITIS AND TREATMENT Interstitial cystitis (IC) is a debilitating chronic disease of unknown etiology characterized by urgency frequency and suprapubic pain with a full bladder. Current treatments are usually unsuccessful in completely eradicating bladder pain and increasing bladder capacity [59]. Urothelial dysfunction, overexpression of suburothelial sensory receptors and central sensitization have all been speculated as the pathogenesis of sensory urgency and bladder pain symptoms [99]. Recent investigations suggest that the lamina propria of the bladder plays an important role in transmitting the sensation of bladder fullness and in the response of the bladder to chemical stimuli and inflammation [23,26,35]. Release of NGF, CGRP, substance P, and ATP increase in IC [21,100, 101]. Overexpression of TRPV1 and P2X3 receptors on sensory nerves are also reduced after BTX-A treatment for OAB as well as IC [19]. In recent decades, treatment of chronic IC has not substantially progressed. Intravesical resiniferatoxin was once considered effective but a large scale multiple center trial did not confirm this [102]. Other intravesical therapies such as hyaluronic acid and BCG, and oral PPV

8 D. Y. Chen, H. C. Kuo medications such as pentosan polysulphate, cyclosporine A, and amitriptyline have not been demonstrated effective in the long-term [103]. Hydrodistention is still the most popular treatment for refractory IC. Since BTX-A has been shown to have effects on both motor and sensory nerve function, it is rational to use BTX-A treatment for this painful bladder syndrome. Currently, there is no satisfactory treatment for bladder hypersensitivity and IC. Although a leaky urothelium has been speculated to cause chronic inflammation of the bladder, intravesical heparin therapy and oral pentosan polysulphate could not eradicate bladder pain and intractable frequency in most patients with chronic IC [58,104], suggesting restoration of epithelial function can only partially repair the pathophysiology but not the inflammatory or possible central sensitization pain process that characterizes IC. Although BTX-A is effective in the treatment of NDO and IDO [55-57,98], there have only been a few studies using BTX-A in treatment of IC [78,105]. In recent basic research, BTX-A inhibited not only the release of ACh and norepinephrine, but also that of ATP, substance P and CGRP from the detrusor muscle and urothelium [16-19]. In clinical experiments, BTX-A reduced DO, impaired bladder sensation, and decreased visceral pain in chronic inflammatory diseases [38,56, 57,98]. These results suggest that BTX-A treatment can modulate sensory transmission as well as reduce detrusor contractility. However, the author's previous trial of 100 U BTX-A in the treatment of chronic IC did not provide satisfactory results, although the measured parameters had significant improvement [105]. It is possible that inadequate distribution of BTX-A to the bladder wall, an inadequate dose of toxin, or a lack of some promoting factors increases bladder wall dysfunction. The suburothelial space immediately below the basal lamina is well supplied with sensory nerves which transmit the sensation of bladder fullness and response to bladder inflammation [9,35]. These afferent functions are believed to be mediated through the capsaicin receptor TRPV-1 and ATP-gated ion channel P2X3 on the sensory neurons of the human urinary bladder [35]. A local inflammatory process might be induced through the afferent and efferent nerves in the suburothelial interstitial cellular network which integrate the transmission of signals from the urothelium to the detrusor muscles in the bladder wall [106]. The release of substance P, CGRP, and NGF from sensory nerves on stimulation were increased during inflammation and reduced after BTX-A treatment. Intravesical NGF administration can sensitize bladder afferent fibers through changes in the conduction of afferent ions. Intravesical instillation of NGF can induce bladder hyperactivity in rats while in a rat chemical cystitis model [45], detrusor injection of BTX-A has been shown to have therapeutic effects in increasing bladder capacity and compliance [107]. In this regard, inhibition of neuroplasticity of the sensory fibers in the suburothelial space by intravesical BTX-A injections might have good therapeutic effects on pain and sensory urgency in patients with chronic IC. BTX-A induced inhibition of rapid afferent firing has been demonstrated by a reduction of fos-positive cells in the dorsal horn of formalin-challenged rat models [108]. Increased central c-fos expression has been demonstrated in animal models of NDO and chronic bladder inflammation [109]. NGF has been demonstrated to activate TRPV1 on small afferent nerves, which can promote release of substance P and induce neurogenic inflammation. Reduction of NGF production could lead to inhibition of neurogenic inflammation and further peripheral desensitization [101]. In treatment of chronic IC, this effect might have an important role in reducing bladder pain. If we can inject BTX-A into the detrusor or suburothelium repeatedly, neurogenic inflammation in the dorsal root ganglia or central nervous system (sacral cords in IC) might be eliminated gradually and the visceral pain can thus be relieved. However, the bladder capacity might not increase if we only inhibit the sensory pathway or desensitize the central nervous system. Previous investigations of BTX-A on IC did not show uniform results. Smith et al noted a 67% success rate with a therapeutic duration of 9 months [38]. Giannantoni et al found 85.7% of patients had improvement but the duration was only 3 months [110]. Kuo reported a significant improvement of measured parameters in 8 patients but only 2 patients declared they were satisfied with treatment outcome [105]. The causes for unsuccessful therapeutic results or short therapeutic duration might be due to inadequate desensitization of the central nervous system Further trials using new treatment modalities such as repeat intravesical injections of BTX-A, possibly combined treatment with hydrodistention might have a higher success rate and a longer therapeutic duration in the patients with severe chronic IC refractory to conventional medical treatment. REFERENCES 1. Engstrom G, Henningsohn L, Steineck G, Leppert J: Self-assessed health, sadness and happiness in relation to the total burden of symptoms from the lower urinary tract. BJU Int 2005; 95: PQM

9 Treatment of LUTS and OAB 2. Hu TW, Wagner TH, Bentkover JD, et al: Estimated economic costs of overactive bladder in the United States. Urology 2003; 61: Rosen R, Altwein J, Boyle P, et al: Lower urinary tract symptoms and male sexual dysfunction: The Multinational Survey of the Ageing Male (MSAM-7). Eur Urol 2003; 44: Kuo HC: Pathophysiology of lower urinary tract symptoms in aged men without bladder outlet obstruction. Urol Int 2000; 64: Peters TJ, Donovan JL, Kay HE, et al: The International Continence Society Benign Prostatic Hyperplasia Study: The bothersomeness of urinary symptoms. J Urol 1997; 157: Milson I, Abrams P, Cardozo L, Roberts RG, Thuroff J, Wein AJ: How widespread are the symptoms of an overactive bladder and how are they managed? A population based prevalence study. BJU Int 2001; 87: Temml C, Heidler S, Ponholzer A, Madersbacher S: Prevalence of the overactive bladder syndrome by applying the International Continence Society definition. Eur Urol 2005; 48: Laniado ME, Ockrim JL, Marronaro A, Tubaro A, Carter SS: Serum prostate-specific antigen to predict the presence of bladder outlet obstruction in men with urinary symptoms. BJU Int 2004; 94: Eckhardt MD, van Venrooij GE, Boon TA: Symptoms, prostate volume, and urodynamic findings in elderly male volunteers without and with LUTS and in patients with LUTS suggestive of benign prostatic hyperplasia. Urology 2001; 58: Chen GD, Lin TL, Hu SW, Chen YC, Lin LY: Prevalence and correlation of urinary incontinence and overactive bladder in Taiwanese women. Neurourol Urodyn 2003; 22: Kuo HC: Lower urinary tract symptoms and videourodynamic characteristics of female bladder outlet obstruction. Urology 2005; 66: Lepor H, Machi G: Comparison of AUA symptom index in unselected males and females between fiftyfive and seventy-nine years of age. Urology 1993; 42: Terai A, Matsu Y, Ichioka K, Ohara H, Terada N, Yoshimura K: Comparative analysis of lower urinary tract symptoms and bother in both sexes. Urology 2004; 63: Romanzi LJ, Groutz A, Heritz DM, Blaivas JG: Involuntary detrusor contractions: Correlation of urodynamic data to clinical categories. Neurourol Urodyn 2001; 20: Birder L: Role of the urothelium in bladder function. Scand J Urol Nephrol Suppl 2004; 215: Brady CM, Apostolidis AN, Harper M, et al: Parallel changes in bladder suburothelial vanilloid receptor TRPV1 (VR1) and pan-neuronal marker PGP9.5 immunoreactivity in patients with neurogenic detrusor overactivity after intravesical resiniferatoxin treatment. BJU Int 2004; 93: Brady C, Apostolidis A, Yiangou Y, et al: P2X3-immunoreactive nerve fibers in neurogenic detrusor overactivity and the effect of intravesical resiniferatoxin (RTX). Eur Urol 2004; 46: Smet PJ, Moore KH, Jonavicius J: Distribution and colocalization of calcitonin gene-related peptide, tachykinins, and vasoactive intestinal peptide in normal and indiopathic unstable human urinary bladder. Lab Invest 1997; 77: Apostolidis A, Popat R, Yiangou Y, et al: Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of Botulinum toxin for human detrusor overactivity. J Urol 2005; 174; Yoshida M, Miyamae K, Iwashida H, Otani M, Inadome A: Management of detrusor dysfunction in the elderly: Changes in acetylcholine and adenosine triphosphate release during ageing. Urology 2004; 63: Sun Y, Chai TC: Up-regulation of P2X3 receptor during stretch of bladder Urothelial cells from patients with interstitial cystitis. J Urol 2004; 171: Apostolidis A, Brady CM, Yiangou Y, Davis J, Fowler CJ, Anand P: Capsaicin receptor TRPV1 in urothelium of neurogenic human bladders and the effect of intravesical resiniferatoxin. Urology 2005; 65: Wiseman OJ, Fowler CJ, Landon DN: The role of the human bladder lamina propria myofibroblasts. BJU Int 2003; 91: Sui GP, Rothery S, Dupont E, Fry CH, Severs NJ: Gap junctions and connexin expression in human suburothelial interstitial cells. BJU Int 2002; 90: Khera M, Somogyi GT, Kiss S, Boone TB, Smith CP: Botulinum toxin A inhibits ATP release from bladder urothelium after chronic spinal cord injury. Neurochem Int 2004; 45: Avelino A, Cruz C, Nagy I, Cruz F: Vanilloid receptor 1 expression in the rat urinary tract. Neuroscience 2002; 109: Smet PJ, Edyvane KA, Jonavicius J, Marshall VR: Distribution of NADPH- diaphorase-positive nerves supplying the human urinary bladder. J Autonom Nerv Syst 1994; 47: Morrison J, Wen J, Kibble A: Activation of pelvic afferent nerves from the rat bladder during filling. Scand J Urol Nephrol 1999; 201: Gabella G: The structural relations between nerve fibers and muscle cells in the urinary bladder of the rat. J Neurocytol 1995; 24: Namasivayam S, Eardley I, Morrison JFB: Purinergic sensory neurotransmission in the urinary bladder: An in vitro study in the rat. BJU Int 1999; 84: Cockayne DA, Hamilton SG, Zhu OM, et al: Urinary bladder hyporeflexia and reduced pain-related behavior in P2X3-deficient mice. Nature 2000; 407: Avelino A, Cruz F: TRPVI (vanilloid receptor) in the urinary tract: Expression, function and clinical applications. Naunyn Schmiedebergs Arch Pharmacol 2006; 373: De Groat WC, Yoshimura N: Mechanisms underlying PQN

10 D. Y. Chen, H. C. Kuo the recovery of lower urinary trart function following spinal cord injury. Prog Brain Res 2006; 152: Fowler CJ, Beck RO, Gerrard S, Betts CD, Fowler CG: Intravesical capsaicin for treatment of detrusor hyperreflexia. J Neurol Neurosurg Psych iatry 1994; 57: Yiangou Y, Facer P, Ford A, et al: Capsaicin receptor VR1 and ATP-gated ion channel P2X3 in human urinary bladder. BJU Int 2001; 87: Maggie CA: The dual sensory and efferent functions of the capsaicin-sensitive primary sensory nerves in the bladder and urethra. In: Maggie CA, ed. The Autonomic Nervous System: Nervous control of the urogenital system, vol 3, London, Harwood Academic Publisher, London 1993, pp Smith CP, Chancellor MB: Emerging role of botulinum toxin in the management of voiding dysfunction. J Urol 2004; 171: Smith CP, Radziszewski P, Borkowski A, Somogyi GT, Boone TB, Chancellor MB: Botulinum toxin A has antinociceptive effects in treating interstitial cystitis. Urology 2004; 64: Powell DW, Mifflin RC, Valentich JD, Crowe SE, Saada JI, West AB: Myofibroblasts. II. Intestinal subepithelial myofibroblasts. Am J Physiol 1999; 277:C Hatton WJ, Mason HS, Carl A, et al: Functional and molecular expression of a voltage-dependent K(+) channel (Kvl.1) in interstitial cells of Cajal. J Physiol 2001; 533: Apostolidis A, Dasgupta P, Fowler CJ: Proposed mechanism for the efficacy of injected botulinum toxin in the treatment of human detrusor overactivity. Eur Urol 2006; 49: Dupont MC, Spitsbergen JM, Kim KB, Tuttle JB, Steers WD: Histological and neurotrophic changes triggered by varying models of bladder inflammation. J Urol 2001; 166: Tuttle JB, Steers WD, Albo M, Nataluk E: Neural input regulates tissue NGF and growth of the adult urinary bladder. J Auton Nerv Syst 1994; 49: Steers WD, Kolbeck S, Creedon D, Tuttle JB: Nerve growth factor in the urinary bladder of the adults regulates neuronal form and function. J Clin Invest 1991; 88: Chuang YC, Fraser MO, Yu Y, et al: The role of bladder afferent pathways in bladder hyperactivity induced by the intravesical administration of nerve growth factor. J Urol 2001; 165: Lamb K, Gebhart GF, Bielefeldt K, et al: Increased nerve growth factor expression triggers bladder overactivity. J Pain 2004; 5: Persson K, Sando JJ, Tuttle JB, Steers WD: Protein kinase C in cyclic stretch- induced nerve growth factor production by urinary tract smooth muscle cells. Am J Physiol 1995; 269:C Lowe EM, Anand P, Terenghi G, Williams-Chestnut RE, Sinicropi DV, Osborne JL: Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis. Br J Urol 1997; 79: Okragly AJ, Niles AL, Saban R, et al: Elevated tryptase, nerve growth factor, neurotrophin-3 and glial cell linederived neurotrophic factor levels in the urine of interstitial cystitis and bladder cancer patients. J Urol 1999; 161: Giannantoni A, Di Stasi SM, Stephen RL, Bini V, Costantini E, Porena M: Intravesical resiniferatoxin versus botulinum-a toxin injections for neurogenic detrusor overactivity: A prospective randomized study. J Urol 2004; 172: Abrams P, Kelleher CJ, Kerr LA, Rogers RG: Overactive bladder significantly affects quality of life. Am J Manag Care 2000; 6(Suppl 11): S Ouslander JG: Management of overactive bladder. N Eng J Med 2004; 350: Chapple CR: Muscarinic receptor antagonist in the treatment of overactive bladder. Urology 2000; 55(5A Suppl): Yarker Y, Goa KL, Fitton A: Oxybutynin: A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in detrusor instability. Drugs Aging 1995; 6: Reitz A, Stohrer M, Kramer G, et al: European experience of 200 cases treated with botulinum-a toxin injections into the detrusor muscle for urinary incontinence due to neurogenic detrusor overactivity. Eur Urol 2004; 45: Kuo HC: Urodynamic evidence of effectiveness of botulinum A toxin injection in treatment of detrusor overactivity refractory to anticholinergic agents. Urology 2004; 63: Kuo HC: Clinical effects of suburothelial injection of botulinum A toxin in patients with non-neurogenic detrusor overactivity refractory to anticholinergics. Urology 2005; 66: Parsons CL, Housley T, Schmidt JD, et al: Treatment of interstitial cystitis with intravesical heparin. Br J Urol 1994; 73: Hanno PM, Sant GR: Clinical highlights of the National Institute of Diabetes and Digestive and Kidney Diseases/Interstitial Cystitis Association scientific conference on interstitial cystitis. Urology 2001; 57(6 Suppl 1): Aoki KR: Evidence for antinociceptive activity of botulinum toxin type A in pain management. Headache 2003; 43(Suppl 1): S Cui M, Aoki KR: Botulinum toxin type A (BTX-A) reduces inflammatory pain in the rat formalin model. Cephalalgia 2000; 20: Durham PL, Cady R, Cady R: Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy. Headache 2004; 44: Cruz F, Guimaraes M, Silva C, Reis M: Suppression of bladder hyperreflexia by intravesical resiniferatoxin. Lancet 1997; 350: Silva C, Rio ME, Cruz F: Desensitization of bladder sensory fibers by intravesical resiniferatoxin, a capsaicin analog: Long-term results for the treatment of detrusor hyperreflexia. Eur Urol 2003; 38: PQO