Neuroselective Current PerceptionThreshold Evaluation of Bladder Mucosal Sensory Function

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1 European Urology European Urology 45 (2004) Neuroselective Current PerceptionThreshold Evaluation of Bladder Mucosal Sensory Function Osamu Ukimura *, So Ushijima, Hisashi Honjo, Tsuyoshi Iwata, Kei Suzuki, Naoki Hirahara, Koji Okihara, Yoichi Mizutani, Akihiro Kawauchi, Tsuneharu Miki Department of Urology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto , Japan Accepted 13 August 2003 Published online 4 September 2003 Abstract Objective: To evaluate human bladder mucosal sensory function by neuroselective Current Perception Threshold (CPT) measures from healthy and neuropathic bladders. Methods: Eight healthy volunteers and 38 patients with urinary symptoms underwent conventional urodynamic tests including water-filling cystometry and ice water test. Standardized neuroselective CPT measures were obtained from the left index finger and the mucosa of the posterior bladder wall. Three different CPTs were obtained from each test site using a constant alternating current sinusoid waveform electrical stimulus presented at 2000 Hz, 250 Hz and 5 Hz stimulation frequencies, which could selectively reflect the functions of the large myelinated fibers (A-beta-fiber), the small myelinated fibers (A-delta-fiber), and the unmyelinated fibers (C-fiber), respectively. Results: As the determination of CPT values on the finger skin, the CPT values in the bladder could be determined using the neuroselective measures in all patients but three who had no sensory response (absence of sensation) caused by complete spinal injury. In the 8 patients with detrusor hyperreflexia due to incomplete spinal cord injury (supra-sacral lesion), the bladder CPT value (4:0 1:9) at 5 Hz was significantly lower ( p < 0:01) than that in the controls (26:2 17:7). In the neurogenic bladders determined to be underactive (n ¼ 11, including post pelvic surgery, post infra-sacral level spinal cord injury and diabetes patients), the higher CPT values of bladder mucosal sensory functions were found at 5 Hz ( p < 0:05), 250 Hz ( p ¼ 0:07), and 2000 Hz ( p < 0:05) compared to the controls. Conclusions: Quantitative neuroselective measurement of CPT values in the human bladder mucosal function was feasible. Hypersensitivity or hyposensitivity of the urinary sensory function could be determined using the CPT values in comparison to control. The quantitative neuroselective estimation of the bladder sensory functions in different types of sensory peripheral nerve fibers may contribute to the appropriate selection of therapeutic strategy in patients with urinary sensory dysfunction. # 2003 Elsevier B.V. All rights reserved. Keywords: Bladder; Urinary sensory function; Mucosal sensory function; Afferent nerve; Sensory function test; Electronic stimulation; Current perception threshold (CPT); Sensory Nerve Conduction Threshold (snct) 1. Introduction Dysfunction of capsaicin-sensitive afferent nerve fibers (unmyelinated C-fibers) in the human bladder is associated with detrusor hyperreflexia [1 3]. Diagnosing dysfunction for the specific subpopulations of bladder afferent fibers in the neurogenic bladder could * Corresponding author. Tel. þ ; Fax: þ address: ukimura@koto.kpu-m.ac.jp (O. Ukimura). help guide therapeutic intervention. Neuroselective modulation of bladder afferent activity as a treatment for conditions such as sensory urgency, detrusor instability and hyperreflexia is currently being evaluated. Recently, intravesical instillation therapy using capsaicin as well as resiniferatoxin was reported effective in patients with hypersensitive disorders of the lower urinary tract [1,4,5]. Historically, the diagnostic approach for lower urinary tract dysfunction has mainly concentrated on detrusor and sphincter motor /$ see front matter # 2003 Elsevier B.V. All rights reserved. doi: /j.eururo

2 O. Ukimura et al. / European Urology 45 (2004) function and the non-neuroselective electro diagnostic evaluation of bladder sensory function [6 8]. The painless automated sensory Nerve Conduction Threshold (snct 1 ) evaluation, through the application of a constant current neuroselective electrical stimulus, provides reliable measures of spinal sensory and peripheral sensory nerve function from the large and small myelinated and unmyelinated nerve fibers [9 12]. Additionally, the CPT measures permit the detection of both hyperesthetic (abnormally low) and hypoesthetic (abnormally elevated) sensory thresholds [13]. This easy to conduct electro diagnostic procedure has established normative painless Current Perception Threshold (CPT) values for various cutaneous sites from studies conducted around the world [14 17]. Here we report the first application of the automated neuroselective snct/cpt evaluation of bladder mucosal sensory function using an intravesical electrode. Additionally, we report on the snct/cpt evaluation of a patient with spinal cord injury who underwent intravesical resiniferatoxin instillation therapy for hypersensitive disorders of the lower urinary tract. 2. Materials and methods All of the examination procedures as well as the intravesical resiniferatoxin instillation therapy were permitted by the Committee for Clinical Research on Human Subjects in our institution. A total of 46 subjects, including 8 healthy volunteers (mean age 39 years) and 38 patients (mean age 56 years), were enrolled in this study (Table 1). Patients included the 11 patients who complained of reflux incontinence due to supra-sacral lesion injury (including 8 incomplete and 3 complete spinal injury), 16 patients who complained of slight urinary disturbance with no urgency symptoms, and 11 patients who complained of urinary difficulty with pathological residual urine due to chronic diabetes (n ¼ 5), post pelvic surgery (n ¼ 4), or post infra-sacral incomplete spinal injury (n ¼ 2). Conventional urodynamic studies include water-filling cystometry (10 50 ml/min, filling rate, changed depending on capacity) and the ice water test. The temperature of the water for water-filling cystometry was at or near body temperature. Ice water test was performed in the patients with reflex incontinence. Ice water test volume corresponding to one half of the cystometric capacity was used. First, conventional urodynamic tests were performed, and in the other day, electro diagnostic test was performed Electro diagnostic studies CPT measures from both skin (index finger, median nerve) and the bladder mucosa were performed. The patient was placed in a comfortable reclining position for the CPT measures. CPT values (100 ¼ 1 ma) were measured using the Neurometer 1 CPT/C electro diagnostic neurostimulator (Neurotron Inc., Baltimore, MD, USA), which emits sinusoid waveform constant alternating current stimuli at quartz crystal calibrated frequencies of 2000, 250, and 5 Hz at intensity levels from to 9.99 ma. CPT values (1 ¼ 0:01 ma) at frequencies of 2000, 250, and 5 Hz were determined, at first on the skin of the left index finger distal phalange standardized median nerve test site [18], and secondly on the posterior bladder wall mucosa using an intravesical catheter electrode with placement localized by ultrasonic visualization. The intravesical catheter electrode was 5 French in diameter with an electrode on the top of the catheter, flexible, fixed curve) (Cordis Webster Inc, Baldwin Park, CA, USA) (Fig. 1). The area of intravesicle stimulating electrode stimulating surface had 1.67 mm in diameter. The area of dispersion electrode surface had 18 mm (or larger) in diameter. The measurement of CPT values on skin was performed using a pair of 1 cm. diameter gold plated electrodes, coated with a thin layer of conductive gel and then taped to the medical and lateral sides of the distal phalange of the index finger [18]. The measurement of CPT values on the bladder was performed between the dispersion electrode on the inside of the thigh (or on the lower abdominal skin) and intra-vesical electrode. In attempt to give no distension to the bladder wall, CPT measure was routinely performed with approximately 50 ml or less of urine (trans-abdominal ultrasound estimated volume) remained in the bladder. Remained urine volume was determined to be small enough to avoid increasing of the individual intravesical pressure based on the finding of conventional water cystometry. Contact of the top of intravesical electrode to the bladder mucosa with no apparent pushing to the wall of bladder body by the intravesical electrode was confirmed using a trans-abdominal ultrasonography Table 1 Subjects Volunteers and patients Number Healthy volunteers 8 Patients with reflux incontinence 11 (supra-sacral spinal cord injury) Incomplete injury 8 Complete injury 3 Patients with slight urinary disturbance 16 (without urgency symptom) Patients with urinary difficulty and pathologic residual urine 11 Chronic diabetes (DM) 5 Post-pelvis surgery 4 Spinal cord injury (infra-sacral spinal cord injury) 2 Fig. 1. Intravesical electrode (5 Fr in diameter).

3 72 O. Ukimura et al. / European Urology 45 (2004) of the bladder. The dispersion electrode was of sufficient surface area to reduce the current density so that the evoked sensation is only perceived at the high current density catheter electrode tip. At each frequency, stimulus intensity to increment from zero to a maximum of 9.99 ma until the patient could report detecting a sensation around the site of the electrode, and re-presented at decreasing intensities until it was not detected within a range of 0.10 ma. The patient was then presented with a series of choice tests that consists of randomly generated pairs of real and false (placebo) stimuli along with pairs of false stimuli, with each stimulus separated by a rest period. The threshold is determined after a minimum of seven consecutive consistent forced-choice presentation responses. The CPT value was determined as an average of both the stimulus consistently detected and the stimulus that was consistently not detected. More details regarding the snct/cpt device operation have been reported previously [17,19]. The complete CPT test required approximately 10 minutes for the skin test, and 20 minutes for bladder mucosa test. Computerized statistical analysis was performed using the w 2 -test or Student s t test. A p-value of less than 0.05 is considered to be statistically significant. The analyses were performed with statistical software packages (DA Stats, THINK Pascal 4.02: PAF01644, Japan) Intravesical resiniferatoxin instillation therapy Intravesical resiniferatoxin instillation therapy was performed using 100 ml of 1 mm resiniferatoxin for 30 min in a patient with detrusor hyperreflexia due to spinal cord injury. For monitoring of therapeutic effects following intravesical resiniferatoxin therapy, electro diagnostic CPT and conventional cytometry studies were performed. 3. Results In the sameway as the determination of CPT values on the skin, the CPT values in the bladder could be determined using the device in all patients but three who had no sensory response (absence of sensation) caused by complete spinal injury (Table 2). Catheterization and stimulation were well tolerated by all volunteers and patients. The 8 healthy volunteers median nerve CPT measures were all within previously established normative parameters [14 17]. The mean bladder mucosal CPT values of the 8 volunteers (mean age 39 years) were considered to be a control for normal sensitivity (Table 2). The bladder mucosal CPT values in the 8 controls were approximately half of the CPT values on the skin of the index finger at 5 Hz ( p ¼ 0:11) and 250 Hz ( p ¼ 0:10), and significantly lower at 2000 Hz ( p < 0:01) (Table 2). In the 8 patients with detrusor hyperreflexia due to incomplete injury of cervical or thoracic (supra-sacral lesion) spinal cord, diagnosed by the presence of uninhibited contraction as well as by a positive ice water test, the bladder CPT value (4:0 1:9) at 5 Hz was significantly lower ( p < 0:01) than that in the controls (26:2 17:7), suggesting hypersensitivity (Table 2). The bladder CPT value (15:3 15:6) at 250 Hz was also significantly lower ( p < 0:01) than in the controls (50:5 28:7) (Table 2). In the neurogenic bladders determined to be underactive (n ¼ 11, including post pelvic surgery, post infra-sacral level spinal cord injury and diabetes patients), we found higher CPT values of bladder mucosal sensory functions at 5 Hz ( p < 0:05), 250 Hz ( p ¼ 0:07), and 2000 Hz ( p < 0:05) than in the control bladders, suggesting hyposensitivity (Table 2). In subpopulation of underative neurogenic bladder due to chronic diabetes, the CPT value of finger skin suggested the general peripheral neuropathy. The CPT values in the 16 patients (mean age, 63 years) (124:8 80:0, 54:9 43:5, 40:8 30:8), who complained of slight urinary disturbance with no urgency symptoms as well as showing no abnormality Table 2 Results of CPT measures Subject group n Age 5 Hz 250 Hz 2000 Hz Average bladder mucosal CPT measures (100 ¼ 1:0 ma) in three selective stimulation frequencies (Hz ¼ cycles=second) Control Supra-sacral lesion (1) Incomplete injury ** ** (2) Complete injury 3 42 not obtainable not obtainable not obtainable Slight Urinary Disturbance þ Infra-sacral Injury and DM * * DM with peripheral neuropathy * Average index finger (median nerve) CPT measures (100 ¼ 1:0 ma) Control ** DM with peripheral neuropathy * Data are shown by mean standard deviations. Statistical difference from the control values: * p < 0:05. ** p < 0:01.

4 O. Ukimura et al. / European Urology 45 (2004) Table 3 Changes of CPT values in C-fiber after infravesical resiniferatoxin (RTX) instillation therapy and changes of symptoms and urodynamic parameters in a reflex incontinence patient Clinical findings CPT (C-fiber) Before therapy Reflex incontinence (600 ml/day) 5.1 (hypersensitive) Involuntary contraction (þ) in cystometry 3rd day after RTX therapy Incontinence decreased 14 (normosensitive) 14th day after RTX therapy Almost dry by self-catheter control, 150% increase in cystometric capacity at involuntary contraction 75 (hyposensitive) in conventional urodynamic studies, were not significantly different from the values of the controls, suggesting normosensitivity (Table 2) Case report A 27 year old male, who had suffered from severe reflex incontinence because of cervical spinal cord injury caused by a traffic accident when he was 19 years old, underwent intravesical resiniferatoxin instillation therapy. Incontinence improved significantly from a total of 600 ml a day to almost dry between pre- and post-treatment using intermittent self-catheterization 5 6 times a day. Water filling cystometry demonstrated approximately 150% increase of bladder capacity at uninhibited contraction on the 3rd day after treatment. The snct 5 Hz CPT measures changed from initially 5.1 to 14 by the 3rd day after treatment, and then increased to 75 by the 21st day after treatment (Table 3). The 250 Hz and 2000 Hz CPT values showed no significant change from the treatment; the values of 250 Hz CPT (32) and 2000 Hz CPT (201) before the therapy showed no significant change at the 3rd day (30 and 235, respectively) as well as at the 21st day (51 and 184, respectively). 4. Discussion Motor urgency is the urgent desire to void synchronous with an involuntary bladder contraction; sensory urgency is the urgent desire to void in the absence of a bladder contraction [20]. The symptom of urgency could result either from motor or sensory conditions, a distinction that should be made using urodynamic studies. Conventional urodynamic evaluation of bladder sensation is recommended by assessment using filling cystometry [21]. The electrical perception threshold test for human bladder was reported in the 19th century [22].Although several possible clinical uses of the electrical perception threshold in the lower urinary tract have been reported by the pioneers of this research field [6 8,22 26],there were criticisms that electro stimulation is not a normal physiological stimulus such as bladder filling, and that absolute value of sensory threshold might vary in relation to the stimulation parameters [27,28]. The electro diagnostic sensory Nerve Conduction Threshold (snct) evaluation, which has been used since 1986 for routine clinical applications to provide objective neuroselective Current Perception Threshold (CPT) measures of cutaneous sensory nerve function, was selected for the evaluation of urinary mucosal sensory thresholds. The neuroselective blind CPT methodology combined with constant current measures facilitates its use in the assessment of bladder mucosal sensory function. The typical sensory nerve is comprised of three major subpopulations of nerve fibers with different diameter. Generally in the cutaneous sensory, the large myelinated fibers (A-beta-fiber) conduct touch and pressure sensations, the small myelinated fibers (A-delta-fiber) conduct temperature, pressure and fast pain, and the unmyelinated fibers (C-fiber) conduct temperature and slow pain conduct protective sensations that guard against serious injury. Neuro-pathological conditions can selectively impair the functioning of specific subpopulation of nerve fibers while sparing the others. In this study current perception threshold (CPT) values were successfully measured from human bladder mucosa. Although the pioneer in this research fields [6 8,23 26], previously reported the electronic mucosal threshold of urinary bladder and/or urethra sensory function they did not involve the application of a neuroselective stimulus. Afferent impulses from the urinary bladder and urethra provide a network of information promoting reflexes, which determine urinary continence and micturition. Such information has a clinical significance in urinary urgency as well as incontinence in various pathologic conditions including neurogenic bladder as well as inflammation such as interstitial cystitis. The sensory nerves of the urinary bladder and urethra have been extensively studied. The urinary bladder has both small myelinated (A-delta-fiber) and unmyelinated (C-fiber) afferents [29,30]. In animal models, electro-physiologic studies have demonstrated that the

5 74 O. Ukimura et al. / European Urology 45 (2004) normal micturition reflex is mediated by small myelinated afferents responding to bladder distention [30 32]. Our CPT measures evoked by neuroselective 250 Hz electronic transmucosal bladder stimulation, that reflects A-delta-fiber function, demonstrated a significant hyperesthesia in patients with detrusor hyperreflexia as well as hypoesthetesia in patients with underactive neurogenic bladder due to post pelvic surgery, infra-sacral lesion injury, and diabetes. These finding are parallel with the clinical findings of insensibility of distended bladder due to post pelvic surgery or infra-sacral lesion injury as well as increased bladder capacity on desire to void due to diabetic peripheral neuropathy. Possible function of A-beta-fiber in the urethra is reported to be perception of urethral flow, especially flow turbulence in dynamic phase [33]. Interestingly, in this study the 2000 Hz stimulus provided bladder mucosal CPT measures. In chronic diabetes patients with peripheral neuropathy, these 2000 Hz CPT measures from bladder mucosa as well as from the normal median nerves were significantly lower than those from the control. However, since the evidence of existence of A-beta-fiber in the bladder wall is unclear, the perception of this 2000 Hz stimuli which is understood to be selective for large myelinated fiber function remained unknown. Since the pathological bladder sensation during dynamic phases may cause serious symptoms and complications, the quantitative evaluation of sensation is clinically useful. Evaluations of possible changes in CPT values dependent on the changed rate of bladder filling as well as the urethral sensory function are necessary. On the other hand, it was reported that the unmyelinated C-fiber afferents are usually unresponsive to bladder distention and are not essential for normal micturition due to their high threshold in the physiological condition, although many of these fibers respond to chemical, noxious or cold stimuli [34,35]. Additionally, C-fiber afferents synthesize, store and release several neuropeptides including tachykinin (e.g. substance P and neurokinin A) and calcitonin gene-related peptide, and have the ability to release neuropeptides from the peripheral endings, thereby exerting an efferent function in the bladder and urethra [36]. The release of these neuropeptides in the bladder wall is known to trigger changes in smooth muscle activity and inflammatory responses including vasodilatation or vascular permeability [2]. Activation of C-fiber afferents can be blocked by administration of capsaicin, a neurotoxin. There is clear evidence that capsaicin-sensitive, C-fiber bladder afferents are involved in various pathologic conditions associated with neurogenic detrusor hyperactivity in humans. Electrical nerve stimulation is independent of receptor mediated nerve stimulation by inflammatory agents [37,38]. Spinal nerve and cord injury induces changes in 5 Hz CPT measures [9] and in the C-fiber bladder afferent pathway in parallel with the emergence of the C-fibermediated spinal micturition reflex. Our results by neuroselective electronic transmucosal bladder stimulation demonstrated a lower 5 Hz CPT indicating a hyperesthetic condition in patients with spinal cord injury. It is interesting to note that the 2000 Hz CPT measures were higher in the same patients further suggesting a neuroselective effect. The ice water test was also positive in these patients with hyperesthetic 5 Hz CPT values. Interestingly, we found that in a patient with spinal cord injury, intravesical resiniferatoxin has improved the clinical symptom of reflex incontinence in parallel with increase of bladder capacity, accompanied with a change of threshold of 5 Hz CPT measures from hyperesthesia to hypoesthetesia. The assessment of bladder sensory fuunction may contribute to appropriate selection as well as the monitoring of intravesical instillation therapy for patients with detrusor hyperreflexia. Maggi et al. [2,36] reported that the intravesical instillation of capsaicin in humans produces a warm-to-burning sensation in the suprapubic area and a concentration-dependent reduction of bladder capacity on desire to void in the cystometry study. In our study, in healthy volunteers, after multiple repeated 5 Hz stimulations, the evaluation was difficult to continue (although nothing happened just after stimulation at 250 Hz or 2000 Hz). The 5 Hz stimulation evoked the uncomfortable sensation to void, which was ascribed to be just the same as the warm-to-burning sensation in the suprapubic area. Other researchers have reported that the transcutaneous 5 Hz stimulus, but not the 2000 Hz stimulus, when administered at supra-threshold intensities evokes a heating or burning sensation as well [39]. It is interesting that Maggi reported that intravesical capsaicin is produced similar burning sensations [2,36]. This evidence suggests that the repeated neuro-selective electronic stimulation of C-fiber could induce the efferent function of C-fiber to secret kinds of neurotransmitters thus causing detrusor contraction or local inflammation responses. Neuorselective electronic stimulation could be used for a non-invasive evaluation of bladder afferent pathway. This new test could contribute to further understanding of the functions of sensory peripheral nerve fibers in the human bladder and complement current electro therapeutic approaches [24,40]. In this study, patients with incomplete spinal cord injury could have all of three perceptions, although

6 O. Ukimura et al. / European Urology 45 (2004) patients with clinically diagnosed as complete spinal cord injury had no perception. As Wyndaele reported [41], electrical stimulation could also indicate the existence of a nervous afferent pathway between the lower urinary tract and the cerebral cortex. Importantly, this test can evaluate selectively the sensory nerve condition from the periphery to the brain, and can selectively determine that a full nerve segment is operational and conducting sensory information to the brain. In addition, when we evaluate and compare the CPT values in both the skin and bladder mucosa, we neuroselectively determine severity of impairment, distinguish between general peripheral neuropathy and bladder specific sensory dysfunction. As Ro et al. reported [15], a loss of small myelinated and unmyelinated fiber function can be associated with hyeresthesia and hypoesthesia with both the 250 Hz and 5 Hz CT measures respectively. In this study, chronic hyperesthesia was observed in the patients with partial spinal cord injury. This would be consistent with the hyperreflexia. Hyperesthesia and hyerreflexia are similar in that both pathological conditions represent an increased response to a stimulus that requires an intact primary sensory and motor neuron respectively. In the patients with spinal cord injury, normal supraspinal circuit is disrupted with emergence of C-fibermediated spinal reflex in response to a reorganization of synaptic connections in the spinal cord. The emergence of a spinal reflex circuit activated by C-fiber represents a positive feedback mechanism that could be unresponsive to voluntary control by higher brain centers and be able to trigger involuntary voiding. Interestingly, Falci et al. [9] suggested a strong evidence of the existence of the extra spinal pathway of C-fiber transmission through the sympathetic nervous system in the spinal cord injury. Further study using this test may also contribute to understanding of possible mechanisms underlying plasticity in bladder reflex pathways in the patients with spinal cord injury. 5. Conclusions Quantitative neuroselective measurement of CPT values could be successfully assessed in the human bladder mucosal function. Hypersensitivity or hyposensitivity of the urinary sensory function could be determined using the CPT values in individual patients in comparison to a control. The quantitative selective estimation of the functions of three different types of sensory peripheral nerve fibers (the large myelinated fibers, the small myelinated fibers and the unmyelinated fibers) in the bladder may contribute to the appropriate selection of therapeutic strategy, such as intravesical instillation of capsaicin or resiniferatoxin, in patients with urinary sensory dysfunction. 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