Botulinum toxin A detrusor injections reduce postsynaptic muscular M2, M3, P2X2, and P2X3 receptors in children and adolescents who have neurogenic detrusor overactivity: a single-blind study.

OBJECTIVE: To analyze the effect of OnabotulinumtoxinA detrusor injections on postsynaptic muscular receptors in children and adolescents with neurogenic detrusor overactivity. MATERIALS AND METHODS: A bladder augmentation became necessary in 10 children and adolescents (7 males, 3 females; median age, 12 years) who had neurogenic detrusor overactivity. Seven had previously received 1 to 8 (average 3.86) OnabotulinumtoxinA detrusor injections, but their detrusor pressure could not be maintained at tolerable levels because of low-compliance bladder. The last injection session had been completed an average of 3 months (range, 1.5-3.5 months) previously. Three patients had never received that therapy and were considered controls. On the bladder dome resections, a specific receptor analysis (muscarinic M2 and M3 and purinergic P2X1, P2X2, and P2X3) was performed with confocal immunofluorescence, and nerve fiber density was analyzed with light-microscopic 3,3'-diaminobenzidine-immunohistochemical staining. RESULTS: Receptor analysis showed a downregulation of all examined receptors after OnabotulinumtoxinA injections; the reductions in M2, M3, P2X2, and P2X3 receptors reached a significance level of P <.05 (Mann-Whitney test). The ratios of means (OnabotulinumtoxinA-to-control) were 0.26 for M2, 0.33 for M3, 0.35 for P2X1, 0.19 for P2X2, and 0.37 for P2X3. CONCLUSION: OnabotulinumtoxinA detrusor injections led to significant reductions in muscular M2, M3, P2X2, and P2X3 receptors. The reductions probably affect the generated force in the urinary bladder and could contribute to the clinically observed increase in residual urine.

Urodynamic effects of propiverine in children and adolescents with neurogenic bladder: results of a prospective long-term study.

OBJECTIVE: To evaluate prospectively the efficacy and tolerability of propiverine for long-term treatment of neurogenic detrusor overactivity (NDO) in children. MATERIALS AND METHODS: 17 children and adolescents with NDO (10 female, 7 male; average age at last consultation 13.0 years) were evaluated during long-term treatment with propiverine (0.8 mg/kg body weight/day). Outcome measurements included urodynamic parameters, continence, hydronephrosis and tolerability of propiverine. RESULTS: Average follow-up was 3.6 years (range 2.0-5.9). The average maximum detrusor pressure was 33.2 ± 4.8 cmH(2)O and bladder compliance was 20.0 ± 5.4 ml/cmH(2)O at the last follow-up visit. Maximum cystometric bladder capacity (MCBC) within the normal range was attained in 11 patients; it was still reduced (average of 61% of expected MCBC) in the remaining 6. Incontinence occurred on average once per day. Hydronephrosis was classified for each renal unit separately: grade 0 was measured in 26 and 22 cases, grade 1 or 2 in 6 and 8 cases, grade 3 or 4 in 2 and 4 cases pre and post treatment, respectively. In 6/17 patients adjuvant intravesical oxybutynin was applied, in 4 out of these 6 patients more invasive procedures, such as untethering, augmentation cystoplasty or botulinum toxin injections, were necessitated. Propiverine monotherapy was well tolerated in 11/17 patients. No serious adverse events were encountered during the study period. CONCLUSION: Long-term efficacy and tolerability of propiverine for NDO in children and adolescents is promising: clinically relevant improvements in key urodynamic outcomes were paralleled by improvements in incontinence score.

Single postoperative instillation of gemcitabine in patients with non-muscle-invasive transitional cell carcinoma of the bladder: a randomised, double-blind, placebo-controlled phase III multicentre study.

BACKGROUND: Recurrence prophylaxis with intravesical gemcitabine (GEM) was effective and safe in patients with non-muscle-invasive bladder cancer (NMIBC); efficacy as single-shot instillation remains to be proved. OBJECTIVE: To compare the efficacy of a single GEM instillation versus placebo (PBO) immediately after transurethral resection (TUR) of tumour in patients with histologically confirmed NMIBC (pTa/pT1,G1-3). DESIGN, SETTING, AND PARTICIPANTS: This was a double-blind, randomised, PBO-controlled study in patients with clinical evidence of primary or recurrent NMIBC (Ta/T1,G1-3). Of 355 patients randomised at 24 urologic centres, 328 underwent TUR and received instillation (92.4%; GEM/PBO: 166/162). In case of nonmalignancy, carcinoma in situ (CIS), > or = pT2 disease, or intraoperative complications, patients were discontinued. INTERVENTION: We used a single, postoperative 30-40-min instillation of GEM (2000 mg/100 ml of saline) or PBO (100 ml of saline) followed by continuous bladder irrigation for > or = 20 h. A second TUR (no instillation) and adjuvant bacillus Calmette-Guérin (BCG) instillations were allowed. MEASUREMENTS: Primary outcome was recurrence-free survival (RFS). Secondary outcomes included type of recurrence and adverse events. To detect a difference in RFS, 191 recurrences were required (80% power, log-rank-test, alpha = 0.050). RESULTS AND LIMITATIONS: Two hundred forty-eight patients (69.9%, GEM, PBO: 124, 124) had histologically confirmed pTa/pT1 G1-3 Gx tumour and were eligible for efficacy (GEM: 76.6% male; median age: 65 yr; PBO: 83.1% male; median age: 67 yr). Treatment groups were balanced (pTa: 75.0%, 71.0%; G1-G2: 85.5%, 87.9%; recurrent tumour: 24.2%, 21.0%; BCG: 10.5%, 16.9%). After a median follow-up of 24 mo, there were only 94 recurrences and 11 deaths. The study was terminated early based on predefined decision criteria. RFS was high in both groups (12-mo RFS [95% confidence interval (CI)]: GEM: 77.7% [68.8-84.3]; PBO: 75.3% [66.3-82.3]). There was no significant group difference (hazard ratio [HR]: 0.946 [0.64-1.39], log-rank test, p=0.777). CONCLUSIONS: In this study of NMIBC, the immediate single instillation of GEM 2000 mg/100 ml of saline after TUR was not superior to PBO in terms of RFS. Rigid continuous irrigation and improved TUR/cystoscopy techniques may have contributed to the high RFS in both groups.

Botulinum neurotoxin type A in urology: antibodies as a cause of therapy failure.

OBJECTIVES: Botulinum toxin type A (BoNT/A) proved very effective in therapy for hyperactive detrusor or sphincter dysfunction of neurogenic and non-neurogenic origin. However, therapy may fail. In a search for possible reasons, we investigated the presence of BoNT/A antibodies (BoNT/A-AB) in patients who were treated more than once and correlated the presence of antibodies with clinical findings. METHODS: In 25 patients (aged 11-75 years; average, 48.3 years) who had experienced at least one previous BoNT/A detrusor and/or sphincter injection, BoNT/A-AB was detected with the mouse diaphragm assay before and within 3 months after the current injection. Clinically, subjective and objective outcomes of this injection session were determined on an efficacy scale. RESULTS: In eight patients, BoNT/A-AB was detected; titers were clearly positive in four patients and were borderline in four patients. The subjective and objective outcomes indicated complete therapy failure in three of four patients who were positive for BoNT/A-AB. In two patients, BoNT/A-AB developed after just one injection session. CONCLUSIONS: Botulinum toxin type A antibodies can develop after injection of BoNT/A for urologic disorders and the antibodies can lead to therapy failure. In patients with clinically complete therapy failure in whom no obvious other causes can be determined (such as a progressive disease in a patient with multiple sclerosis), screening for BoNT/A-AB should be carried out.

Persistence of the synaptosomal-associated protein-25 cleavage product after intradetrusor botulinum toxin A injections in patients with myelomeningocele showing an inadequate response to treatment.

OBJECTIVE To monitor the presence and cleavage of synaptosomal-associated protein of 25 kDa (SNAP-25) by botulinum toxin type A (botox-A), in human detrusor muscle, as the effects of botox-A in the urinary bladder last significantly longer than when applied for disorders of striated muscles. PATIENTS AND METHODS Tissue samples were obtained from eight patients with end-stage neurogenic bladder at different times after injection with botox-A. The resected bladder domes were examined using biochemical and immunohistological techniques. RESULTS The presence of intact SNAP-25 in human bladder was detected, for the first time, in all samples by both Western blotting and immunofluorescence. By contrast, detection of a band potentially representing toxin-cleaved SNAP-25(A) required its enrichment by precipitation with a specific antibody. This putative product was present in four of six patients treated with botox-A 5 weeks to 11 months previously, but could not be detected in one patient 30 months after botox injection, and in an untreated control. Fluorescence microscopy showed no obvious effects of the toxin treatment on the presence and pattern of SNAP-25-positive neurones. CONCLUSIONS A limited amount of SNAP-25 appears to be cleaved in nerves that innervate the smooth detrusor muscle in most patients who had been injected with botox-A; its absolute identification was precluded by the sensitivity of the detection. This protein was detectable much longer after toxin treatment than published for rodent striated muscle, and thus could contribute to the clinically reported longer duration of the effectiveness of botox-A.

Antibodies against botulinum neurotoxin type A as a cause of treatment failure after the first detrusor injection.

Botulinum neurotoxins are increasingly used in treatment for hyperactive detrusor and sphincter function. Although reported results are promising, conditions in some patients are refractory. We report what we believe to be the first urologic case of therapy failure possibly induced by botulinum toxin antibodies after just one injection and discuss treatment alternatives based on experience in other fields.

Neuromodulatory therapies in female pelvic medicine and reconstructive surgery: biological agents.

In recent years, important improvements in the management of patients with neurogenic or non-neurogenic detrusor overactivity and urge incontinence have been brought about by the introduction of vanilloids and botulinum toxins in urology. In this review we introduce the new therapeutic options, provides basic information, and summarize the results experienced so far.

Urodynamic effects of propiverine hydrochloride in children with neurogenic detrusor overactivity: a prospective analysis.

OBJECTIVES: To evaluate prospectively the efficacy and tolerability of propiverine for treating neurogenic detrusor overactivity (NDO) in children. PATIENTS AND METHODS: Twenty children (mean age 8.9 years; median 5.6) with NDO due to an upper motor neurone lesion were enrolled (17 had myelomeningocele). In the urodynamic examination, reflex volume (RV), maximum detrusor pressure (MDP), maximum cystometric bladder capacity (MCBC) and bladder compliance (BC) before and after a twice-daily propiverine hydrochloride regimen were determined. The urodynamic follow-up was after 3-6 months. Incontinence was assessed by an incontinence score. RESULTS: The mean (sem) RV increased from 103.8 (21.3) to 174.5 (33.7) mL (P < 0.005), MDP decreased from 52.5 (7.9) to 40.1 (6.2) cmH(2)O (P < 0.05), MCBC increased from 166 (28.8) to 231.9 (34.8) mL (P < 0.005), and BC improved from 11.2 (2.8) to 30.6 (9.7) mL/cmH(2)O (P < 0.01), with propiverine treatment. The incontinence score (scale 0-3) improved from 2.4 (0.2) to 1.6 (0.3) (P < 0.05). Propiverine was well tolerated, although some children were given higher doses than recommended. CONCLUSIONS: Propiverine hydrochloride is effective and well tolerated in the treatment of children with NDO. Because of its dual mode of action, it is well tolerated even in children who need higher doses. Propiverine hydrochloride is a preferable alternative to oxybutynin, the anticholinergic most frequently used in children with NDO to date.

Surgery is inadvisable: massive varicocele due to portal hypertension.

The pathophysiology of idiopathic varicoceles as a dilatation of the pampiniform venous plexus has been traced to anatomical and embryological development, but is still unclear. Right or non-decompressible lesions are worrisome for retroperitoneal pathology, such as renal cell carcinoma, hydronephrosis, abdominal neoplasm or fibrosis. As a very rare finding we describe a patient who presented with an exorbitant left sided varicocele due to portal hypertension. We were well advised to avoid surgery.

Repeated botulinum-A toxin injections in treatment of children with neurogenic detrusor overactivity.

OBJECTIVES: To assess the long-term success of treatment with repeated botulinum-A toxin (BTX-A; Botox) injections into the detrusor muscle for neurogenic detrusor overactivity in children. METHODS: We reviewed the charts of 10 children (average age at first injection 11.2 years) with neurogenic detrusor overactivity who had received at least three BTX-A detrusor injections; four had received five or more injections. The total dose of BTX-A was 85 to 300 U. We measured the urodynamic outcomes 6 months after each injection and compared the results after the first injection with the results after the third and fifth injections (in the children who had five or more injections). RESULTS: The relative changes--each in comparison with the value before injection therapy--after the first versus the fifth injection were as follows: the reflex volume increased by 81% versus 88%, maximal detrusor pressure decreased by 7% versus 39%, maximal cystometric bladder capacity increased by 88% versus 72%, and bladder compliance showed no change at the 6-month follow-up visit after the first injection and an increase of 109% after the fifth injection. The results after the third injection were generally similar to those after the fifth injection. No major side effects occurred. CONCLUSIONS: Although we surveyed only a few patients, the efficacy seems clear in all the urodynamic measures after repeated BTX-A detrusor injections in children with neurogenic bladder. Also, we found no evidence of drug tolerance. Thus, BTX-A detrusor injection has gained additional importance in the treatment of these difficult-to-treat patients.

Botulinum-A toxin detrusor and sphincter injection in treatment of overactive bladder syndrome: objective outcome and patient satisfaction.

OBJECTIVE: We investigated the effect of botulinum-a toxin injections into the detrusor and external sphincter muscle in patients with overactive bladder (OAB) symptoms. METHODS: We included 44 patients - 41 women and three men with a mean age of 66.1 years - who were suffering from OAB symptoms that were refractory to anticholinergic treatment. We injected 200-300 U of BTX-A (Botox) into the detrusor muscle; 22 patients also received external sphincter injections. For outcome analysis, we used a bladder diary, a urodynamic examination, and a questionnaire that consisted of 27 validated questions. RESULTS: Changes in the bladder diary 4 weeks and 3, 6, and 9 months after BTX-A injection were as follows: Micturition frequency was reduced by 12%, 16%, 13% and 9%, respectively. Average pad use decreased from 4.2 pads per day to at most 2.4 pads per day after 6 months. Urodynamic changes were most distinct after 4 weeks: the volume when the first uninhibited detrusor contraction occurred increased from 149+/-18.2 mL to 263 +/- 24.2 mL, and maximum cystometric bladder capacity increased from 228 +/- 19.2 mL to 305 +/- 19.0 mL. Subjectively, 86% of the patients would choose this procedure for their bladder condition again. Residua 4 weeks after additional injection into the sphincter muscle were distinctly smaller than in the "only detrusor" group. CONCLUSIONS: BTX-A detrusor and sphincter injection is very effective in treating OAB symptoms. For patients who might be expected to have residual urine after injection only into the detrusor, additional injection of low doses of BTX-A into the external sphincter muscle could be one option to reduce that risk.

Botulinum-A toxin for treatment of overactive bladder without detrusor overactivity: urodynamic outcome and patient satisfaction.

OBJECTIVES: To investigate the effect of botulinum toxin type A bladder injections in the treatment of overactive bladder syndrome in the absence of detrusor overactivity. METHODS: The subjects were 7 women (average age 61.1 years, range 51 to 79) who presented with overactive bladder symptoms. Their disorder had been refractory to several classic treatment options. Urodynamic examination excluded detrusor overactivity. A total of 300 U BTX-A (Botox) was injected, of which 50 to 75 U was injected as quadrant injections into the external sphincter muscle to avoid the postoperative need for catheterization in the case of high postvoid residual urine volume. For follow-up, complete urodynamic studies were performed, and a bladder diary and validated incontinence questionnaires were given to patients at all visits at 1, 3, and 6 months. RESULTS: The bladder diaries indicated a clear reduction in daytime frequency and nocturia and a reduction in pad use. The maximal voiding volume increased significantly. The urodynamic examinations showed a significant increase in volume when the first and the strong desire to void were expressed. The maximal bladder capacity increased by 20% in 3 months. In the questionnaires, 5 of the 7 patients reported better urine control after therapy, and 6 would have chosen this therapy again for their condition. The overall satisfaction score (on a scale of 0 to 10) averaged 6.8. No side effects, such as urine retention, occurred. CONCLUSIONS: Botulinum-A toxin injection has positive effects in treating overactive bladder symptoms without detrusor overactivity. The effects were seen not only in urodynamic measures but also in patient satisfaction.

Orandi one-stage urethroplasty using the subcutaneous pedicle graft modification of Raatzsch--long-term results.

OBJECTIVE: To present long-term results obtained with the Orandi one-stage urethroplasty using a modified technique as described by Raatzsch. MATERIAL AND METHODS: Between 1980 and 1993, Raatzsch urethroplasty was used in our clinic in 202 male patients (average age 50.9 years), 53% of whom had undergone other procedures before, mainly internal urethrotomy. The mean follow-up period was 46.2 months (range 2-156 months). RESULTS: Good or improved results with no need for further surgical intervention were achieved in 128 patients (63.4%); a total of 117 procedures had to be performed in the other 74 patients in order to achieve a satisfactory outcome. The success rate was highest for penile strictures (71.8%). Complications occurred in 24.3% of cases. CONCLUSIONS: The Raatzsch modification of Orandi urethroplasty is a simple procedure that yields moderate results on long-term follow-up. Surgeons who operate regularly for urethral stricture should be aware of its long-term results, especially in the treatment of penile strictures.