Development of a Sham Protocol to Investigate Transcutaneous Tibial Nerve Stimulation in Randomised, Sham-Controlled, Double-Blind Clinical Trials

Transcutaneous tibial nerve stimulation (TTNS) is a promising treatment for neurogenic lower urinary tract symptoms. However, the evidence is limited due to a general lack of randomised controlled trials (RCTs) and, also, inconsistency in the sham and blinding conditions. In the context of much-needed RCTs, we aimed to develop a suitable sham-control protocol for a clinical setting to maintain blinding but avoid meaningful stimulation of the tibial nerve. Three potential electrode positions (lateral malleolus/5th metatarsal/plantar calcaneus) and two electrode sizes (diameter: 2.5 cm/3.2 cm) were tested to determine which combination provided the optimal sham configuration for a TTNS approach, based on a visible motor response. Sixteen healthy volunteers underwent sensory and motor assessments for each sham configuration. Eight out of them came back for an extra TTNS visit. Sensory thresholds were present for all sham configurations, with linear regression models revealing a significant effect regarding electrode position (highest at plantar calcaneus) but not size. In addition, motor thresholds varied with the position-lowest for the 5th metatarsal. Only using this position and 3.2 cm electrodes attained a 100% response rate. Compared to TTNS, sensory and motor thresholds were generally higher for the sham configurations; meanwhile, perceived pain was only higher at the lateral malleolus. In conclusion, using the 5th metatarsal position and 3.2 cm electrodes proved to be the most suitable sham configuration. Implemented as a four-electrode setup with standardized procedures, this appears to be a suitable RCT protocol for maintaining blinding and controlling for nonspecific TTNS effects in a clinical setting

Temporal development of unfavourable urodynamic parameters during the first year after spinal cord injury

Objectives: To describe the temporal development of and risk factors for the occurrence of unfavourable urodynamic parameters during the first year after spinal cord injury (SCI). Patients and methods: This population-based longitudinal study used data from 97 adult patients with a single-event traumatic or ischaemic SCI who underwent video-urodynamic investigation (UDI) at a university SCI centre. The first occurrences of unfavourable urodynamic parameters (detrusor overactivity combined with detrusor sphincter dyssynergia [DO-DSD], maximum storage detrusor pressure ≥40 cmH2 O, bladder compliance <20 mL/cmH2 O, vesico-ureteric reflux [VUR] and any unfavourable parameter [composite outcome]) were evaluated using time-to-event analysis. Results: The majority of the population (87/97 [90%]) had at least one unfavourable urodynamic parameter. Most unfavourable urodynamic parameters were initially identified during the 1- or 3-month UDI, including 92% of the DO-DSD (78/85), 82% of the maximum storage pressure ≥40 cmH2 O (31/38), and 100% of the VUR (seven of seven) observations. No low bladder compliance was observed. The risk of DO-DSD was elevated in patients with thoracic SCI compared to those with lumbar SCI (adjusted hazard ratio [aHR] 2.38, 95% confidence interval [CI] 1.16-4.89). Risk of maximum storage detrusor pressure ≥40 cmH2 O was higher in males than females (aHR 8.33, 95% CI 2.51-27.66), in patients with a cervical SCI compared to those with lumbar SCI (aHR 14.89, 95% CI 3.28-67.55), and in patients with AIS Grade B or C compared to AIS Grade D SCI (aHR 6.17, 95% CI 1.78-21.39). No risk factors were identified for the composite outcome of any unfavourable urodynamic parameter. Conclusions: The first UDI should take place within 3 months after SCI as to facilitate early diagnosis of unfavourable urodynamic parameters and timely treatment. Neuro-urological guidelines and individualised management strategies for patients with SCI may be strengthened by considering sex and SCI characteristics in the scheduling of UDIs. Keywords: #Urology; longitudinal studies; spinal cord injuries; survival analysis; urinary bladder, neurogenic; urinary bladder, overactive; urodynamic

Urodynamics Are Essential to Predict the Risk for Upper Urinary Tract Damage after Acute Spinal Cord Injury

We used clinical parameters to develop a prediction model for the occurrence of urodynamic risk factors for upper urinary tract (UUT) damage during the first year after acute spinal cord injury (SCI). A total of 97 patients underwent urodynamic investigation at 1, 3, 6, and 12 months after acute SCI, within the framework of a population-based longitudinal study at a single university SCI center. Candidate predictors included demographic characteristics and neurological and functional statuses 1 month after SCI. Outcomes included urodynamic risk factors for UUT damage: detrusor overactivity combined with detrusor sphincter dyssynergia, maximum storage detrusor pressure (pDetmax) ≥ 40 cmH$_{2}$O, bladder compliance < 20 mL/cmH$_{2}$O, and vesicoureteral reflux. Multivariable logistic regression was used for the prediction model development and internal validation, using the area under the receiver operating curve (aROC) to assess model discrimination. Two models showed fair discrimination for pDetmax ≥ 40 cmH$_{2}$O: (i) upper extremity motor score and sex, aROC 0.79 (95% CI: 0.69-0.89), C-statistic 0.78 (95% CI: 0.69-0.87), and (ii) neurological level, American Spinal Injury Association Impairment Scale grade, and sex, aROC 0.78 (95% CI: 0.68-0.89), C-statistic 0.76 (95% CI: 0.68-0.85). We identified two models that provided fair predictive values for urodynamic risk factors of UUT damage during the first year after SCI. Pending external validation, these models may be useful for clinical trial planning, although less so for individual-level patient management. Therefore, urodynamics remains essential for reliably identifying patients at risk of UUT damage

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

Urethral pressure profile assessment after artificial urinary sphincter implantation (FlowSecure and AMS-800): A case series

The AMS-800 ™ artificial urinary sphincter has become the ‘gold standard’ in the treatment of male stress urinary incontinence. In 2006, the novel artificial urinary sphincter FlowSecure ™ containing a stress relief balloon providing low cuff pressures at rest with conditional pressure elevation during periods of stress has been launched. We assessed the intraurethral pressure in the cuff area of the AMS-800 and the FlowSecure by urethral pressure profile in four patients each. Urethral pressure profile was performed at rest and during coughing. In addition, continence situation and patient satisfaction after artificial urinary sphincter implantation was assessed. At rest, median pressure in the cuff region was 74 (38–117, FlowSecure) cm H 2 O and 102 (95–110, AMS-800) cm H 2 O. During coughing, pressure peaks rose to 135 (54–162, FlowSecure) cm H 2 O and 202 (128–216, AMS-800) cm H 2 O. Median pad usage before artificial urinary sphincter implantation in the FlowSecure and the AMS-800 group was 4 (3–4) and 4.5 (2–6) pads/24 h, respectively. At the time of urodynamic investigation, median pad usage declined to 1.5 (0–4) pads/24 h in the FlowSecure and to 1 (1–2) pads/24 h in the AMS-800 group. Seven of eight patients reported on a satisfactory quality of life, and one patient remained unhappy after FlowSecure implantation. It remains unclear if the trade-off in favour of lower cuff pressures, and consecutively lower intraurethral pressures, holds truly long-term benefits regarding device revision, explantation and patient satisfaction

Detrusor acontractility after acute spinal cord injury: Myth or reality?

PURPOSE We assessed urodynamic parameters within the first 40 days after spinal cord injury (SCI) investigating whether the detrusor is acontractile during the acute phase of SCI. PATIENTS AND METHODS We performed a prospective cohort study including 54 patients with neurogenic lower urinary tract dysfunction (NLUTD) due to acute SCI undergoing urodynamic investigation (UDI) within the first 40 days after injury at a single university SCI center. RESULTS and Limitations: Of the 54 patients, UDI revealed an acontractile detrusor in only 20 (37%) but unfavorable urodynamic parameters in a total of 34 (63%) patients. Detrusor overactivity was found in 32 patients, detrusor sphincter dyssynergia in 25, maximum storage detrusor pressure >40cmH2O in 17, vesico-uretero-renal reflux in 3 and low bladder compliance (<20mL/cmH2O) in 1 patient (more than one unfavorable urodynamic parameter possible). CONCLUSIONS In contrast to the common notion of an acontractile detrusor during acute SCI, almost two-thirds of our patients showed unfavorable urodynamic parameters within the first 40 days after SCI. Considering that early treatment of NLUTD in patients with acute SCI might improve long-term urological outcome, UDI should be performed timely to optimize patient-tailored therapy

The Challenge of Asymptomatic Bacteriuria and Symptomatic Urinary Tract Infections in Patients with Neurogenic Lower Urinary Tract Dysfunction

PURPOSE We investigated prevalence of asymptomatic bacteriuria and incidence of symptomatic urinary tract infections (UTI) in patients with neurogenic lower urinary tract dysfunction (NLUTD) undergoing urodynamics and assessed predictors for symptomatic UTI. PATIENTS AND METHODS A prospective consecutive series of 317 patients (106 women, 211 men) with NLUTD was evaluated. Of them, 111 (35%) voided spontaneously, 141 (44%) relied on intermittent self-catheterization and 65 (21%) on an indwelling catheter. Before urodynamics, urine samples were collected by sterile catheterization for dipstick testing and urine culture. We assessed the association between patient characteristics and the occurrence of symptomatic UTIs following urodynamics in patients with asymptomatic bacteriuria and developed a prediction model based on the most important risk factors. RESULTS Urine cultures before urodynamics were negative in 123 (39%) and positive in 194 (61%) patients. (32%) and e (18%) were the most frequent bacteria. Of 194 patients with positive culture, 35 (18%) had at least one symptomatic UTI. In patients with a history of previous UTIs, the overall estimated probability of a symptomatic UTI was 45%, irrespective of the underlying neurological disorder. CONCLUSIONS About one out of five patients with asymptomatic bacteriuria will develop a symptomatic UTI in the follow-up year. This rather low overall probability precludes routine antibiotic prophylaxis or treatment in patients with NLUTD having asymptomatic bacteriuria as 4 out of 5 patients would be overtreated. However, in patients with a history of previous symptomatic UTIs antibiotic prescription might be justified

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

Antibiotic prophylaxis may not be necessary in patients with asymptomatic bacteriuria undergoing intradetrusor onabotulinumtoxinA injections for neurogenic detrusor overactivity

Many of the patients undergoing intradetrusor onabotulinumtoxinA injections for refractory neurogenic detrusor overactivity (NDO) present with chronic bacteriuria. In these patients, antibiotic prophylaxis has been widely recommended since bacteriuria might impair treatment efficacy and cause urinary tract infections (UTI) but the evidence is limited. The aim of this study was to evaluate if an antibiotic prophylaxis is needed in patients with asymptomatic bacteriuria undergoing intradetrusor onabotulinumtoxinA injections. Between 06/2012 and 12/2014, a consecutive series of 154 patients undergoing a total of 273 treatment cycles were prospectively evaluated. Before treatment urine samples were collected, patients with no clinical signs for UTI underwent onabotulinumtoxinA injections, no antibiotic prophylaxis was given. Asymptomatic bacteriuria was found in 73% (200/273 treatments). Following treatment, UTI occurred in 5% (9/200) and 7% (5/73) of patients with and without bacteriuria, respectively. Intradetrusor onabotulinumtoxinA injections were clinically and urodynamically successful in 70% (192/273). There was no association between bacteriuria and treatment-related adverse events (odds ratio 0.64, 95% CI 0.23-1.81, p = 0.4) nor between bacteriuria and therapy failure (odds ratio 0.78, 95% CI 0.43-1.43, p = 0.4). Thus, we conclude that antibiotic prophylaxis needs to be critically reconsidered in patients undergoing intradetrusor onabotulinumtoxinA injections, especially taking into account the alarming antibiotic resistance worldwide

More Than 15 Years of Experience with Intradetrusor OnabotulinumtoxinA Injections for Treating Refractory Neurogenic Detrusor Overactivity: Lessons to Be Learned

BACKGROUND Intradetrusor onabotulinumtoxinA (BoNT-ONA) injections have become a well-established therapy for refractory neurogenic detrusor overactivity (NDO). However, little is known about long-term outcome and patients' adherence to this treatment. OBJECTIVE To assess long-term outcomes of intradetrusor BoNT-ONA injections and patients' adherence to treatment. DESIGN, SETTING, AND PARTICIPANTS A consecutive series of 52 patients who underwent first intradetrusor BoNT-ONA injections for refractory NDO >10 yr ago were evaluated retrospectively and prospectively at a single university spinal cord injury (SCI) centre. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary outcome was current neuro-urologic treatment. Secondary outcomes were urodynamic parameters. For data comparison, the paired/unpaired t test, chi-square test, and McNemar test were used. RESULTS AND LIMITATIONS Mean duration since first intradetrusor BoNT-ONA injections was 12±2 yr. Most patients (61% [32 of 52]) suffered from SCI, 15% (8 of 52) from spina bifida, 14% (7 of 52) from multiple sclerosis (MS), and the remaining (10% [5 of 52]) from other neurologic disorders. Almost 60% (31 of 52) of all patients are continuing with intradetrusor BoNT-ONA injections but only 14% (1 of 7) of the patients with MS. Lack of clinical and/or urodynamic response (21% [11 of 52]) and switching to another treatment (antimuscarinics and/or neuromodulation) despite appropriate BoNT-ONA efficacy (19% [10 of 52]) were the reasons for discontinuation. In patients continuing BoNT-ONA treatment, the positive effect was sustained after repeat injections (p<0.05). CONCLUSIONS Although intradetrusor BoNT-ONA injections are a highly effective therapy for refractory NDO, approximately 40% of the patients discontinue treatment over time. All prospective neurologic patients should be given this information, and it needs to be considered in the treatment decision-making process. PATIENT SUMMARY Approximately 60% of the patients treated with intradetrusor onabotulinumtoxinA injections for refractory neurogenic detrusor overactivity continue this therapy long term with good therapeutic effects. STUDY REGISTRATION NUMBER NCT01293110