Michele Spinelli

New Percutaneous Technique of Sacral Nerve Stimulation Has High Initial Success Rate: Preliminary Results

OBJECTIVE We report on the new technique of sacral nerve stimulation in the treatment of voiding dysfunction. This new technique is characterized by percutaneous approach to the sacral nerves resulting in minimally invasiveness of the procedure and the ability to have patient awake during the electrode placement. METHODS Since December 1999, we prospectively evaluated patients who underwent this novel percutaneous technique approach. Thirty-two patients (10 male, 22 female, mean age 43 years) were included and no complications were reported. Average follow-up time was 11 months (range 2-25 months). Main elements of the new technique are also described. The needle is inserted into the sacral foramen to a desired location (usually S3) and metal stylet is then inserted through the needle. With metal stylet only in the foramen, two dilators are successively inserted and the chronic lead is placed through the plastic dilator. Only a very small skin incision is necessary to allow the anchor fixation. RESULTS Out of the 32 patients who underwent the percutaneous lead placement, 22 received the neurostimulator (IPG). Out of the remaining 10 patients, 4 are still in screening and 6 had unsuccessful results (<50% improvement) and therefore did not undergo the second stage (neurostimulator placement). From the 22 implanted patients, 20 reported 90% improvement in their primary voiding symptoms, 1 had an improvement between 50 and 70% and 1 patient was explanted due to IPG damage following magnetic resonance imaging. There were total of four lead displacements, two occurred where the silicone anchoring was used and the other two occurred when no anchoring was done. CONCLUSION Success rate of this technique in selecting patients for the permanent implant is significantly higher than currently reported in the literature. Very beneficial clinical outcome of the implanted patients confirms better patient selection with no complications. Our experience with this technique shows the feasibility of percutaneous lead placement with major advantages such as: (1) use of local anesthesia and possibility to test sensitive responses during implant, (2) the possibility for more accurate patient selection by using the definitive lead for a longer test period before proceeding with the neurostimulator (IPG) implant. The presented percutaneous technique requiring fascial lead fixation represents a safe and effective method of Sacral Neuromodulation Therapy.

INTRAVESICAL RESINIFERATOXIN FOR THE TREATMENT OF HYPERSENSITIVE DISORDER: A RANDOMIZED PLACEBO CONTROLLED STUDY

PURPOSE Present therapeutic approaches to control hypersensitive disorder of the lower urinary tract and bladder pain are clinically and scientifically unsatisfactory. We performed a randomized placebo controlled study with followup after 1 and 3 months using intravesical resiniferatoxin to treat hypersensitive disorder and bladder pain. MATERIALS AND METHODS We prospectively randomized 18 patients into 2 groups to receive a single dose of 10 nM. resiniferatoxin intravesically (group 1) or a placebo saline solution only (group 2). All patients had at least a 6-month history of frequency, nocturia, urgency and symptoms of pelvic pain as well as no urinary tract infection within the last 3 months, functional disorders of the lower urinary tract, or other vesical or urethral pathology. Pretreatment voiding pattern and pain score were recorded. Patients were evaluated after 30 days (primary end point) and 3 months (secondary end point). RESULTS The 2 groups were adequately homogeneous in regard to patient age, sex ratio, disease duration, voiding pattern and pain score. At the primary end point mean frequency plus or minus standard error of mean was decreased from 12. 444 +/- 0.70 voids to 7.111 +/- 0.67 and nocturia from 3.777 +/- 0. 27 to 1.666 +/- 0.16 (p <0.01). We observed a lesser significant improvement in mean frequency in group 1 at the secondary end point to 10.444 +/- 0.94 voids (p <0.05). No significant modification was noted in patients assigned to placebo. Mean pain score significantly decreased in group 1 at the primary end point from 5.555 +/- 0.29 to 2.666 +/- 0.23 (p <0.01) but not at the secondary end point (4.777 +/- 0.66, p >0.05). No statistically significant improvement in mean pain score was observed in placebo group 2. During resiniferatoxin infusion 4 group 1 patients noticed a light warm or burning sensation at the suprapubic and/or urethral level. CONCLUSIONS Intravesical resiniferatoxin may significantly improve the voiding pattern and pain score in patients with hypersensitive disorder and bladder pain. Because resiniferatoxin did not cause a significant warm or burning sensation at the suprapubic and/or urethral level, it may be considered a new strategy for treating hypersensitive disorder and bladder pain. However, further studies are necessary to confirm our results and define the resiniferatoxin mechanism of action, dose and necessary treatment schedule.

Neuromodulation for fecal incontinence: Outcome in 16 patients with definitive implant

PURPOSE: Sacral nerve modulation appears to offer a valid treatment option for some patients with fecal incontinence and functional defects of the internal anal sphincter or of the striated muscle. METHODS: Sixteen patients with fecal incontinence (4 males; mean age, 51.4 (range, 27–79) years) with intact or surgically repaired (n=1) anal sphincter underwent permanent sacral nerve stimulation implant. Cause was traumatic in two patients, and associated disorders included scleroderma (2 patients) and spastic paraparesis (1 patient); eight (50 percent) of the patients also had urinary incontinence, and two (12.5 percent) had nonobstructive urinary retention. All patients were selected on the basis of positive findings from at least one peripheral nerve evaluation. The stimulating electrode was positioned in the S2 (1 patient), S3 (14 patients), or S4 (1 patient) sacral foramen. RESULTS: Mean follow-up was 15.5 (range, 3–45) months. Mean preimplant Williams score decreased from 4.1±0.9 (range, 2–5) to 1.25±0.5 (range, 1–2) (P=0.01, Wilcoxon test), and the number of incontinence accidents for liquid or solid stool in 14 days decreased from 11.5±4.8 (range, 2–20) before implant to 0.6±0.9 (range, 0–2) at the last follow-up. Important manometric data were an increase in mean maximal pressure at rest of 37.7±14.9 mmHg (implantable pulse generator 49.1±18.7,P=0.04) and in mean maximal pressure during squeeze (prestimulation 67.3±21.1 mmHg, implantable pulse generator 82.6±21.0,P=0.09). CONCLUSIONS: Neuromodulation can be considered an option for fecal incontinence. However, an accurate clinical and instrumental evaluation and careful patient selection are required to optimize outcome.

CHRONIC SACRAL NEUROMODULATION IN PATIENTS WITH LOWER URINARY TRACT SYMPTOMS: RESULTS FROM A NATIONAL REGISTER

PURPOSE The Italian Register was created in February 1997 to collect the national results of sacral neuromodulation. All Italian centers at which sacral neuromodulation is performed were invited to participate in our study. We present the results from retrospective and prospective registers. MATERIALS AND METHODS A total of 196 patients underwent permanent implantation of sacral neuromodulation and were enrolled in the Italian register. There were 18 males and 75 females in the retrospective, and 28 males and 75 females in the prospective studies. Students t test was used to compare paired values, and the Wilcoxon rank sum and nonparametric tests were used when necessary. RESULTS Mean incontinent episodes daily plus or minus standard deviation for patients with detrusor instability went from 5.4 +/- 3.9 to 1.1 +/- 1.6 (median 5 and 0, respectively) at 12-month followup (p <0.001). For idiopathic retention average residual volume decreased from 277 to 108 cc (median 287 and 80, respectively), and 50% of patients stopped catheterization and another 13% catheterized once daily at 1-year after implantation. With neurogenic voiding disturbances, the results fluctuated with time from a minimum of 33% to a maximum 66% of patients who did not catheterize at 6-month followup and 12 months after implantation, respectively. At 12-month followup, 50% of patients with hyperreflexia had less than 1 incontinent episode daily. The problem was completely solved in 66% of patients in the retention group. Of patients in the urge incontinent population 39% were completely dry and 23% had less than 1 incontinent episode daily. CONCLUSIONS Sacral neuromodulation is effective therapy for treating lower urinary tract symptoms resistant to less invasive therapy.

Intravesical Resiniferatoxin for the Treatment of Detrusor Hyperreflexia Refractory to Capsaicin in Patients with Chronic Spinal Cord Diseases

OBJECTIVE Resiniferatoxin (RTX), a substance isolated from some species of Euphorbia, a cactus-like plant, shows pharmacological effects similar to those of capsaicin. We have studied the possibility of treating detrusor hyperreflexia refractory to intravesical capsaicin in patients with chronic spinal cord injuries, thereby providing insight into the mechanism of action of RTX on sensory neurons and its possible future pharmacological and clinical use. MATERIALS AND METHODS RTX saline solution (30 ml at a concentration of 10(-5) M) was instilled into the bladder of 7 patients with detrusor hyperreflexia, refractory to intravesical capsaicin therapy, and left in place for 30 min. Effects on bladder function were monitored during the treatment and at follow-up (15 days and 4 weeks later). RESULTS Fifteen days after RTX, the mean cystomanometric capacity increased significantly from 190 ml +/- 20 ml to 407.14 ml +/- 121.06 (p < 0.01), and it remained high four weeks later (421.66 +/- 74.40 p < 0.01). After 15 days, four patients had a pharmacologically induced detrusor areflexia. They emptied their bladders by clean intermittent catheterization. After four weeks, only two patients still had a pharmacologically induced detrusor areflexia. Clinically, three patients remained dry, and the other three reported a significant improvement in their incontinence and symptoms (frequency, urgency and nocturia). CONCLUSIONS By interfering with sensory unmyelinated fibers, intravesical RTX seems to be a promising treatment option for selected cases of detrusor hyperreflexia. The ideal dosage and treatment interval have not yet been established, and further studies are necessary to confirm our preliminary results.

Intravesical Infusion of Resiniferatoxin by a Temporary In Situ Drug Delivery System to Treat Interstitial Cystitis: A Pilot Study

PURPOSE Interstitial cystitis (IC), a syndrome characterized by motor and sensory dysfunction of the lower urinary tract, represents a diagnostic and therapeutic challenge even to highly skilled physicians. We investigated the technical feasibility and the clinical efficacy of a prolonged intravesical instillation of RTX by in situ drug delivery system in patients with IC. MATERIAL AND METHODS 5 female patients (mean age 48.7 years) received a prolonged infusion of a saline solution containing 10nM of resiniferatoxin at the flow rate 25microl/h by the MiniMed 407C Infusion Pump (MiniMed Sylmar, CA, USA), connected to sovrapubic 5Fr mono Pigtail catheter, for 10 days. All patients reported frequency, nocturia and urgency, and symptoms of pelvic pain for at least six months. They showed the absence of urinary tract infection within the last three months, the absence of functional disorders of lower urinary tract and no other vesical or urethral pathology. The pre-treatment (PT) frequency/volume (FV) chart and a pain score (VAS score) were recorded. Patients were evaluated after 30 days from the end of infusion (primary end point, PEP) and after three months (secondary end point, SEP). RESULTS At PEP frequency reduced from 11.3+/-1.39 to 7.4+/-1.51 (p<0.01) and nocturia from 3.6+/-0.54 to 1.2+/-0.44 (p<0.01). A highly significant reduction of pain score was observed at PEP: it decreased to 2.4+/-0.54 from 6.7+/-0.83 (p<0.01). The pain score remained significantly lower at SEP (3.2+/-0.44 p<0.05). Nocturia was also statistically reduced at SEP (1.9+/-0.74) as well as frequency (8.7+/-1.76). No side effects were reported during the infusion as well as after the removal of the catheter. CONCLUSION The present study demonstrates that the prolonged intravesical instillation of a drug by in situ drug delivery system is a feasible procedure and seems to support the efficacy of RTX in the treatment of IC patients. However further studies are necessary and mandatory to confirm our results and to define the exact action mechanism of prolonged infusion of RTX, the dosage and the treatment schedule.

QUALITY OF LIFE ASSESSMENT IN PATIENTS WHO UNDERGO SACRAL NEUROMODULATION IMPLANTATION FOR URGE INCONTINENCE: AN ADDITIONAL TOOL FOR EVALUATING OUTCOME

PURPOSE We investigated the impact of sacral neuromodulation on quality of life and assessed the importance of quality of life for determining the success of sacral neuromodulation in patients with detrusor hyperactivity, including instability and hyperreflexia. We also compared it with parameters documented in a voiding diary. MATERIALS AND METHODS From May 1998 to December 2000, 82 female and 31 male patients 17 to 79 years old (mean age 51.1) with urge incontinence (63), urgency/frequency (5), voiding disturbance (41) and pelvic pain (4) resistant to conservative treatment were enrolled in a national prospective registry after showing a positive response to percutaneous nerve evaluation testing. Of the patients 47 who were 32 to 79 years old (mean age 59.2) with urge incontinence due to detrusor instability and 16 who were 27 to 51 years old (mean age 51.5) with hyperreflexia were asked to complete a validated self-reporting incontinence domain specific quality of life questionnaire before, and 3, 6, 9, 12, 18, 24 and 36 months after implantation. RESULTS Compared with baseline the quality of life index significantly improved at each followup, which strongly correlated with the decrease in the number of incontinence episodes. CONCLUSIONS Evaluating quality of life may be an additional useful tool for assessing the results of sacral neuromodulation for urge incontinence. Our study confirms that sacral neuromodulation is effective therapy for urge incontinence that can have a positive effect on patient quality of life.

Urodynamic effects of intravesical nociceptin/orphanin FQ in neurogenic detrusor overactivity: a randomized, placebo-controlled, double-blind study

OBJECTIVES To evaluate the acute urodynamic effects of the neuropeptide nociceptin/orphanin FQ (N/OFQ) in a selected group of patients with neurogenic detrusor overactivity incontinence in a randomized, placebo-controlled, double-blind study. METHODS The study involved 14 patients who presented with neurogenic detrusor overactivity due to spinal cord injury. They were randomized to receive intravesical infusion of 1 microM N/OFQ or the same dose of [desPhe(1)]N/OFQ (the placebo). The urodynamic parameters were the bladder capacity, volume threshold for the appearance of detrusor overactivity, and the maximal bladder pressure. The study was performed on a double-blind basis: neither the patients nor the doctors who performed the instillation could distinguish the solution containing N/OFQ from that containing [desPhe(1)]N/OFQ. Data are expressed as the mean +/- SD of seven determinations. Data were statistically analyzed using the Student t test for paired or unpaired data and P <0.05 was set as the criterion for a statistically significant difference. RESULTS The two groups were well balanced with respect to mean age, male/female ratio, etiology of spinal cord disease, and years from the lesion. Also, the baseline mean values of bladder capacity, volume threshold for the appearance of detrusor overactivity, and maximal bladder pressure were similar. The intravesical infusion of the solution containing 1 microM N/OFQ produced the following changes: bladder capacity and volume threshold for the appearance of detrusor overactivity significantly increased from 139 +/- 48 mL to 240 +/- 61 mL, and from 84 +/- 32 mL to 201 +/- 68 mL, respectively. Maximal bladder pressure decreased from 81 +/- 25 cm H(2)O to 66 +/- 12 cm H(2)O; however, this difference was not statistically significant. The intravesical infusion of the solution containing 1 microM [desPhe(1)]N/OFQ did not produce any statistically significant modification of the urodynamic parameters. CONCLUSIONS The results of this study confirm and extend previous results showing that N/OFQ, but not the placebo, elicits a robust acute inhibitory effect on the micturition reflex in patients with a neurogenic bladder. These findings apply nociceptin orphan peptide receptor agonists as potential novel drugs for the treatment of neurogenic urinary incontinence.

URODYNAMIC AND CLINICAL EVIDENCE OF ACUTE INHIBITORY EFFECTS OF INTRAVESICAL NOCICEPTIN/ORPHANIN FQ ON DETRUSOR OVERACTIVITY IN HUMANS: A PILOT STUDY

PURPOSE Management of neurogenic incontinence is complex and available treatments are not satisfactory. Nociceptin/orphanin FQ, a recently discovered neuropeptide, has been reported to inhibit the voiding reflex in the rat. These experimental results prompted us to investigate the urodynamic and clinical effects of intravesical instillation of nociceptin/orphanin FQ in humans. MATERIAL AND METHODS Our study involved 5 normal subjects (group 1) with a mean age of 40.4 years (range 21 to 54) and 9 patients (group 2) 40.4 years (24 to 54). All patients in group 2 presented with detrusor hyperreflexia refractory to standard therapy. They were invited to undergo a filling cystometrogram with saline solution and after 30 minutes, a new one with a solution containing 1 microM. nociceptin/orphanin FQ. The urodynamic parameters that were recorded included bladder capacity, volume threshold for the appearance of detrusor hyperreflexia and maximum bladder pressure. Clinical and urodynamic followup was performed after 15 days. The data were statistically analyzed with 1-way analysis of variance followed by the Dunnett test for multiple comparison considered statistically significant with p <0.05. RESULTS Intravesical instillation of 1 microM. nociceptin/orphanin FQ in group 1 did not produce significant functional changes. This infusion in group 2 produced a statistically significant increase in mean bladder capacity and volume threshold for the appearance of detrusor hyperreflexia from 164 plus or minus standard deviation (SD) 84 to 301 +/- 118 and 93 plus or minus SD 41 to 231 +/- 104 ml. (p <0.05, respectively). Mean maximum bladder pressure decreased from 79 plus or minus SD 25 to 54 +/- 44 cm. water but was not statistically significant (p = 0.19). After 15 days an absence of clinical improvement was noticed in group 2, and the urodynamic control did not show any significant changes compared to the values before nociceptin/orphanin FQ treatment. No severe symptomatic reactions were observed during infusion of 1 microM. nociceptin/orphanin FQ. CONCLUSIONS Our results demonstrate that nociceptin/orphanin FQ is able to elicit a robust inhibitory effect on voiding reflex in group 2 but not 1. The ideal dosage, route of administration of nociceptin/orphanin FQ and treatment interval are not yet established.

Intravesical vanilloids and neurogenic incontinence: ten years experience.

Introduction: In this study we critically review our ‘10-year’ experience with intravesical vanilloids (capsaicin and resiniferatoxin) in the treatment of neurogenic incontinence, addressing the issue of their introduction into daily clinical practice. Materials and Methods: From July 1992 to June 2001, 54 patients suffering from detrusor hyperreflexia, due to spinal cord injuries, received intravesical instillation of capsaicin, and from January 1995 to June 2001, 47 patients received intravesical instillation of resiniferatoxin (RTX) in order to treat bladder dysfunction and symptoms. All patients presented detrusor hyperreflexia refractory to oral and/or intravesical oxibutynin and they displayed high-voiding pressure associated with frequent urine leakage. Capsaicin was used at a concentration of 10 mM; RTX was tested in two different concentrations: 10 nM and 10 µM. The outcome was considered according to simple parameters: (i) the number of patients who reported an improvement in clinical status (patient dry between clean intermittent catheterization) and urodynamic status (a bladder capacity 50% higher than pretreatment capacity, lasting more than 3 months after the instillation); (ii) the number of patients who continued intravesical therapy; (iii) the number of instillations they received; (iv) the length of the interval between 2 consecutive instillations, and (v) alternative therapies when vanilloids failed. Results: The topical intravesical instillation of capsaicin produced an improvement in symptoms and urodynamic parameters, in 29 patients (53.7%) after 3 months. In these 29 patients only 7 (24.13%) continued to received capsaicin in June 2001. The mean follow-up was 32.28 ± 14.20 (range 8–52) months, the mean number of instillations was 6.14 ± 2.54 (range 2–10) and the mean interval between the 2 consecutive instillations was 7.14 ± 2.60 (range 4–12) months. The topical intravesical instillation of RTX produced an improvement in symptoms and urodynamic parameters in 73.33% of patients (a total of 45 patients) who received 10 µM. 18 of them (54.54%) continued to received RTX in June 2001. The mean follow-up was 27.88 ± 10.95 (range 11–49) months, the mean number of instillations was 4.33 ± 1.60 (range 2–8). The mean interval between 2 consecutive instillations was 9.61 ± 2.99 (ranged 4–16) months. Conclusion: The results obtained using RTX seem to be very promising with regard to efficacy and tolerance, particularly in comparison with capsaicin. Even if the number of patients who received capsaicin and RTX remains small, the intravesical vanilloid receptor agonist RTX could offer an attractive alternative to oral medications in the treatment of neurogenic incontinence.