bTUNED: transcutaneous tibial nerve stimulation for neurogenic lower urinary tract dysfunction.

OBJECTIVE: To present the protocol for a randomized controlled trial (RCT) evaluating the efficacy and safety of transcutaneous tibial nerve stimulation (TTNS) for refractory neurogenic lower urinary tract dysfunction (NLUTD). STUDY DESIGN AND RESULTS: bTUNED (bladder and TranscUtaneous tibial Nerve stimulation for nEurogenic lower urinary tract Dysfunction) is an international multicentre, sham-controlled, double-blind RCT investigating the efficacy and safety of TTNS. The primary outcome is success of TTNS, defined as improvements in key bladder diary variables at study end compared to baseline values. The focus of the treatment is defined by the Self-Assessment Goal Achievement (SAGA) questionnaire. Secondary outcomes are the effect of TTNS on urodynamic, neurophysiological, and bowel function outcome measures, as well as the safety of TTNS. CONCLUSIONS: A total of 240 patients with refractory NLUTD will be included and randomized 1:1 into the verum or sham TTNS group from March 2020 until August 2026. TTNS will be performed twice a week for 30 min during 6 weeks. The patients will attend baseline assessments, 12 treatment visits and follow-up assessments at the study end.

Sacral Neuromodulation for Neurogenic Lower Urinary Tract Dysfunction.

BACKGROUND: Neurogenic lower urinary tract dysfunction (NLUTD) is a highly prevalent and disabling condition; nevertheless, standard treatments often remain unsatisfactory. Sacral neuromodulation (SNM) is a well-established therapy for non-NLUTD, but there is a lack of randomized controlled trials to show benefit in patients with NLUTD. METHODS: For this sham-controlled, double-blind, multicenter trial, patients with refractory NLUTD (and intended SNM) were recruited at four Swiss SNM referral centers. After lead placement into the sacral foramina S3 (rarely, S4), all participants underwent SNM testing. If successful (≥50% improvement in key bladder diary variables), the neurostimulator was implanted for permanent stimulation. For 2 months, neuromodulation was optimized using subsensory stimulation with individually adjusted parameters. Thereafter, the neurostimulator remained on or was switched off (1:1 random allocation to group SNM ON or SNM OFF, respectively) for 2 months, followed by a neurourologic reevaluation. The primary outcome was success, as defined above, of SNM compared with baseline. RESULTS: Of 124 patients undergoing SNM testing, 65 (52%) had successfully improved lower urinary tract function. Of these, 60 patients (median age, 49.5 years; 43 women) were randomly assigned to the intervention. After 2 months of intervention, the SNM ON group demonstrated a success rate of 76%. In the SNM OFF group, 42% of patients showed sustained SNM effects despite their neurostimulator being switched off during the last 2 months (odds ratio, 4.35; 95% confidence interval, 1.43 to 13.21; P=0.009). During the entire study period, there were 11 adverse events (6 dropouts; no dropouts during the intervention phase). CONCLUSIONS: SNM effectively corrected refractory NLUTD in the short term in well-selected neurologic patients. (Funded by the Swiss National Science Foundation, Vontobel­Stiftung, Gottfried und Julia Bangerter­Rhyner Stiftung, Dr. Urs Mühlebach, and the Swiss Continence Foundation; ClinicalTrials.gov number, NCT02165774.)

Intravesical bacteriophages for treating urinary tract infections in patients undergoing transurethral resection of the prostate: a randomised, placebo-controlled, double-blind clinical trial.

BACKGROUND: Urinary tract infections (UTIs) are among the most prevalent microbial diseases and their financial burden on society is substantial. In the context of increasing antibiotic resistance, finding alternative treatments for UTIs is a top priority. We aimed to determine whether intravesical bacteriophage therapy with a commercial bacteriophage cocktail is effective in treating UTI. METHODS: We did a randomised, placebo-controlled, clinical trial, at the Alexander Tsulukidze National Centre of Urology, Tbilisi, Georgia. Men older than 18 years of age, who were scheduled for transurethral resection of the prostate (TURP), with complicated UTI or recurrent uncomplicated UTI but no signs of systemic infection, were allocated by block randomisation in a 1:1:1 ratio to receive intravesical Pyo bacteriophage (Pyophage; 20 mL) or intravesical placebo solution (20 mL) in a double-blind manner twice daily for 7 days, or systemically applied antibiotics (according to sensitivities) as an open-label standard-of-care comparator. Urine culture was taken via urinary catheter at the end of treatment (ie, day 7) or at withdrawal from the trial. The primary outcome was microbiological treatment response after 7 days of treatment, measured by urine culture; secondary outcomes included clinical and safety parameters during the treatment period. Analyses were done in a modified intention-to-treat population of patients having received at least one dose of the allocated treatment regimen. This trial is registered with ClinicalTrials.gov, NCT03140085. FINDINGS: Between June 2, 2017, and Dec 14, 2018, 474 patients were screened for eligibility and 113 (24%) patients were randomly assigned to treatment (37 to Pyophage, 38 to placebo, and 38 to antibiotic treatment). 97 patients (28 Pyophage, 32 placebo, 37 antibiotics) received at least one dose of their allocated treatment and were included in the primary analysis. Treatment success rates did not differ between groups. Normalisation of urine culture was achieved in five (18%) of 28 patients in the Pyophage group compared with nine (28%) of 32 patients in the placebo group (odds ratio [OR] 1·60 [95% CI 0·45-5·71]; p=0·47) and 13 (35%) of 37 patients in the antibiotic group (2·66 [0·79-8·82]; p=0·11). Adverse events occurred in six (21%) of 28 patients in the Pyophage group compared with 13 (41%) of 32 patients in the placebo group (OR 0·36 [95% CI 0·11-1·17]; p=0·089) and 11 (30%) of 37 patients in the antibiotic group (0·66 [0·21-2·07]; p=0·47). INTERPRETATION: Intravesical bacteriophage therapy was non-inferior to standard-of-care antibiotic treatment, but was not superior to placebo bladder irrigation, in terms of efficacy or safety in treating UTIs in patients undergoing TURP. Moreover, the bacteriophage safety profile seems to be favourable. Although bacteriophages are not yet a recognised or approved treatment option for UTIs, this trial provides new insight to optimise the design of further large-scale clinical studies to define the role of bacteriophages in UTI treatment. FUNDING: Swiss Continence Foundation, the Swiss National Science Foundation, and the Swiss Agency for Development and Cooperation. TRANSLATIONS: For the Georgian and German translations of the abstract see Supplementary Materials section.

Outcomes following percutaneous tibial nerve stimulation (PTNS) treatment for neurogenic and idiopathic overactive bladder.

PURPOSE: Percutaneous tibial nerve stimulation is a minimally invasive neuromodulation technique for treating overactive bladder symptoms. The aim of this study was to assess safety, efficacy and impact on quality of life of percutaneous tibial nerve stimulation in neurological patients reporting overactive bladder symptoms. METHODS: In this retrospective evaluation over 18 months at a tertiary healthcare centre, patients finding first-line treatments for overactive bladder ineffective or intolerable underwent a standard 12-week course of percutaneous tibial nerve stimulation (Urgent PC, Uroplasty). Symptoms were evaluated using standardised International Consultation on Incontinence Questionnaires and bladder diaries. RESULTS: Of 74 patients (52 women, 22 men, mean age 56 years), 49 (66.2%) patients had neurological disorder [19 (25.7%) multiple sclerosis and 30 (40.5%) other neurological conditions] and 25 (33.8%) idiopathic overactive bladder. Overall for the entire cohort significant improvements were recorded after 12 weeks in the following domains: 24-h frequency on bladder diary - 1.67 (- 3.0, 0.33) (p = 0.002), number of incontinent episodes on bladder diary - 0.0 (- 1, 0) (p = 0.01), incontinence severity on bladder diary 0 (- 0.33, 0) (p = 0.007), OAB symptoms - 3 (- 11.5, 5) (p = 0.01), and quality of life - 16 (- 57, 6.5) (p = 0.004). There were no significant differences in outcomes between patients with idiopathic and neurogenic overactive bladder. CONCLUSIONS: Percutaneous tibial nerve stimulation appears to be a possible promising alternative for patients with neurological disorder reporting overactive bladder symptoms who find first-line treatments either ineffective or intolerable. However, a properly designed study is required to address safety and efficacy.

Transcutaneous Tibial Nerve Stimulation for Treating Neurogenic Lower Urinary Tract Dysfunction: A Pilot Study for an International Multicenter Randomized Controlled Trial.

BACKGROUND: Tibial nerve stimulation (TNS) is an effective and safe treatment for idiopathic lower urinary tract dysfunction (LUTD), but its value in neurological patients is unclear. OBJECTIVE: To test the feasibility, acceptability, and safety of a randomized, sham-controlled, double-blind transcutaneous TNS (TTNS) setup for treating neurogenic LUTD. DESIGN, SETTING, AND PARTICIPANTS: A pilot study including nine patients with refractory neurogenic LUTD investigated prospectively at a university neuro-urology department. INTERVENTION: Randomized, sham-controlled, double-blind verum and sham TTNS was performed for 30min twice a week, for 6 wks. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes were feasibility, acceptability, and safety of the TTNS protocol. Secondarily, potential efficacy was investigated. Descriptive statistics were used. RESULTS AND LIMITATIONS: All procedures were feasible and well tolerated by all nine patients. Using verum TTNS, a motor response could be triggered in all patients and a sensory response in all but one. At the beginning and end of treatment, seven and six (78% and 67%) patients believed to receive verum TTNS, and five and six (56% and 67%) correctly guessed their group allocation, respectively. No treatment-related adverse events occurred. A comparison of baseline versus 6 wks of verum and sham TTNS led to relevant symptom and functional changes in only a limited number of piloted patients. CONCLUSIONS: Verum and sham TTNS combined with the blinding procedures proved feasible and safe. Both interventions and procedures, as well as the randomization process, were well accepted by the patients. While the subsensory threshold TTNS approach in combination with the sham condition is advantageous for patients' blinding, the clinical findings raised some doubt regarding sufficient TNS. Hence, relevant methodological adjustments concerning the adequate stimulation current and corresponding sham condition are needed before starting randomized controlled trials to clarify the value and role of TTNS in neuro-urology. PATIENT SUMMARY: Transcutaneous tibial nerve stimulation is a promising treatment option for neurogenic lower urinary tract dysfunction, but methodological adjustments in treatment application are required before further prospective studies can be initiated.

Update from TASCI, a Nationwide, Randomized, Sham-controlled, Double-blind Clinical Trial on Transcutaneous Tibial Nerve Stimulation in Patients with Acute Spinal Cord Injury to Prevent Neurogenic Detrusor Overactivity.

Transcutaneous tibial nerve stimulation has the potential to revolutionize the management of lower urinary tract dysfunction in patients with acute spinal cord injury. TASCI is a nationwide randomized, sham-controlled, double-blind clinical trial for which the preparatory phase has been successfully completed.

Factors influencing return for maintenance treatment with percutaneous tibial nerve stimulation for the management of the overactive bladder.

OBJECTIVES: To identify factors influencing return for maintenance percutaneous tibial nerve stimulation (PTNS) treatment after successful completion of a 12-week course of treatment for overactive bladder (OAB). PATIENTS AND METHODS: Patients with OAB symptoms referred for PTNS treatment underwent 12 sessions of weekly PTNS treatment and were evaluated at baseline and week 12 using the International Consultation on Incontinence Questionnaire on OAB, the International Consultation on Incontinence Questionnaire on lower urinary tract symptom-related quality of life (ICIQ-LUTSqol) and a bladder diary (BD). Responders to treatment, evaluated using two patient-reported outcome measures, were invited to return for maintenance treatment when symptoms returned. A PTNS Service Evaluation Questionnaire was used to evaluate factors influencing return for maintenance treatment. RESULTS: Seventy-three patients were evaluated (mean age 58.9 [±14.7] years, 72.6% women) and clustered into three groups: group 1 (n = 25) did not respond to 12 weekly sessions of PTNS treatment; group 2 (n = 17) responded to treatment but did not return for maintenance treatment and group 3 (n = 31) responded to treatment and returned for maintenance treatment. There were no significant differences in demographic characteristics, diagnosis, baseline symptom scores and BD variables among the three groups. Patients belonging to groups 2 and 3 experienced a significant improvement from baseline to week 12 in total OAB scores (group 2: -1.54 ± 1.85; group 3: -1.85 ± 2.28; P < 0.05); however, patients returning for maintenance treatment reported significant improvements specifically in nocturia (BD difference = -0.4 ± 0.7 [P < 0.05] and ICIQ-LUTSqol difference -0.48 ± 0.94 [P < 0.05]), and perceived benefits of the treatment with regard to their OAB symptoms compared to those not returning for maintenance treatment (difference between the two groups 25.6%; P = 0.030). Improvements in nocturia and perceived benefits predicted return for maintenance treatment based on a logistic regression analysis. Factors related to the need for repeat clinic visits, such as transportation, distance and time commitment, were not found to differ between the two groups. CONCLUSIONS: Twelve-session weekly PTNS is a safe and effective treatment for OAB. Responders to treatment returning for maintenance PTNS more often reported significant improvements in nocturia and perceived benefits over time, compared to those not returning for maintenance treatment. The BD provides a more objective assessment of treatment outcome after PTNS treatment.

Protocol for a randomized, placebo-controlled, double-blind clinical trial investigating sacral neuromodulation for neurogenic lower urinary tract dysfunction.

BACKGROUND: Sacral neuromodulation has become a well-established and widely accepted treatment for refractory non-neurogenic lower urinary tract dysfunction, but its value in patients with a neurological cause is unclear. Although there is evidence indicating that sacral neuromodulation may be effective and safe for treating neurogenic lower urinary tract dysfunction, the number of investigated patients is low and there is a lack of randomized controlled trials. METHODS AND DESIGN: This study is a prospective, randomized, placebo-controlled, double-blind multicenter trial including 4 sacral neuromodulation referral centers in Switzerland. Patients with refractory neurogenic lower urinary tract dysfunction are enrolled. After minimally invasive bilateral tined lead placement into the sacral foramina S3 and/or S4, patients undergo prolonged sacral neuromodulation testing for 3-6 weeks. In case of successful (defined as improvement of at least 50% in key bladder diary variables (i.e. number of voids and/or number of leakages, post void residual) compared to baseline values) prolonged sacral neuromodulation testing, the neuromodulator is implanted in the upper buttock. After a 2 months post-implantation phase when the neuromodulator is turned ON to optimize the effectiveness of neuromodulation using sub-sensory threshold stimulation, the patients are randomized in a 1:1 allocation in sacral neuromodulation ON or OFF. At the end of the 2 months double-blind sacral neuromodulation phase, the patients have a neuro-urological re-evaluation, unblinding takes place, and the neuromodulator is turned ON in all patients. The primary outcome measure is success of sacral neuromodulation, secondary outcome measures are adverse events, urodynamic parameters, questionnaires, and costs of sacral neuromodulation. DISCUSSION: It is of utmost importance to know whether the minimally invasive and completely reversible sacral neuromodulation would be a valuable treatment option for patients with refractory neurogenic lower urinary tract dysfunction. If this type of treatment is effective in the neurological population, it would revolutionize the management of neurogenic lower urinary tract dysfunction. TRIAL REGISTRATION NUMBER: http://www.clinicaltrials.gov; Identifier: NCT02165774.

First clinical trial of tomographic neurofeedback in attention-deficit/hyperactivity disorder: evaluation of voluntary cortical control.

OBJECTIVE: Tomographic neurofeedback (tNF) training was evaluated as a treatment for attention-deficit/hyperactivity disorder (ADHD). To investigate the specificity of the treatment, outcomes were related to learning during tNF. METHODS: Thirteen children with ADHD trained over 36 lessons to regulate their brain activity in the anterior cingulate cortex (ACC) using both theta-beta frequency and slow cortical potential (SCP) protocols. Thirty-channel electroencephalogram (EEG) was used to calculate low-resolution electromagnetic tNF and to assess the course of the training. Pre- and post-assessments included questionnaires, tests of attention, EEG recordings, and cognitive event-related potentials. RESULTS: Despite behavioural improvement and EEG artefact reduction, only partial learning was found for ACC parameters. Successful regulation was observed only for a simple feedback variant of SCP training, but with ACC-specific effects. Over training, resting EEG analysis indicated individual frequency normalisation rather than unidirectional changes across subjects. CONCLUSIONS: These results indicate that clinical improvement after ACC-tNF training can parallel artefact reduction without substantial learning of improved cortical control. However, individual normalisation of resting EEG activity and partial SCP control proved possible in this specific brain region affected in ADHD using tNF. Further studies are needed to clarify which critical aspects mediate region-specific learning in neurofeedback. SIGNIFICANCE: This study is the first to systematically investigate tNF in children suffering from a psychiatric disorder.