Neurogenic Lower Urinary Tract Dysfunction in the First Year After Spinal Cord Injury: A Descriptive Study of Urodynamic Findings.

PURPOSE: We aimed to provide a real-world description of neurogenic lower urinary tract dysfunction within the first year after spinal cord injury with a focus on unfavorable urodynamic parameters that are associated with urological morbidity. MATERIALS AND METHODS: Urodynamic investigations from 97 patients with traumatic or ischemic acute spinal cord injury and managed according to the European Association of Urology Guidelines on Neuro-Urology were analyzed at a single university spinal cord injury center at 1 month, 3 months, 6 months, and 12 months after injury. Unfavorable urodynamic parameters were defined as detrusor overactivity in combination with detrusor sphincter dyssynergia, maximum storage detrusor pressure of 40 cm H2O or higher, bladder compliance less than 20 mL/cm H2O, and vesicoureteral reflux of any grade. RESULTS: One or more unfavorable urodynamic parameter was observed in 87 out of 97 patients (90%) within the first year after spinal cord injury. Eighty-eight percent of the patients showed detrusor overactivity with detrusor sphincter dyssynergia, 39% a maximum storage detrusor pressure of 40 cm H2O or higher, and 7% vesicoureteral reflux. No patient developed a low-compliance bladder. CONCLUSIONS: Using a standardized urodynamic follow-up schedule, we found unfavorable urodynamic parameters in a majority of the population within the first year after spinal cord injury. As early treatment based on urodynamic findings might reduce the risk of deterioration of upper and lower urinary tract function, thereby improving long-term outcomes, there is need for further research regarding recommendations for a urodynamic follow-up schedule during the first year after spinal cord injury.

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.

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.

Sex differences in urological management during spinal cord injury rehabilitation: results from a prospective multicenter longitudinal cohort study.

STUDY DESIGN: Prospective, multicenter, longitudinal cohort study. OBJECTIVES: To describe female-male differences in first-line urological management during spinal cord injury (SCI) rehabilitation. SETTING: Inpatient specialized post-acute SCI rehabilitation in Switzerland. METHODS: Data on bladder storage medication (antimuscarinic and beta-3 agonist) use, suprapubic catheter placement, demographic and SCI characteristics was collected within 40 days of SCI and at rehabilitation discharge from May 2013-September 2021. Prevalence and indicators of bladder storage medication and suprapubic catheter use at discharge were investigated with sex-stratified descriptive and logistic regression analyses. RESULTS: In 748 patients (219 females, 29%), bladder storage medication use at discharge had a prevalence of 24% (95% CI: 18-29%) for females and 30% (95% CI: 26-34%) for males and was indicated by cervical AIS grade A, B, C and traumatic SCI in both sexes. Thoracic AIS grade A, B, C SCI (males), and lumbar/sacral AIS grade A, B, C SCI (females) predicted higher odds of bladder storage medication use (SCI characteristic*sex interaction, p < 0.01). Prevalence of suprapubic catheter use at discharge was 22% (95% CI: 17-28%) for females and 17% (95% CI: 14-20%) for males. Suprapubic catheter use was indicated by cervical AIS grade A, B, C SCI, and age >60 in both sexes. Females with thoracic grade A, B, C SCI tended to have higher odds of suprapubic catheter use (SCI characteristic*sex interaction, p = 0.013). CONCLUSIONS: We identified sex differences in urological management especially in persons with AIS grade C or higher sub-cervical SCI. There is scope for well-powered, female-specific research in SCI in order to understand the underlying mechanisms and support patient-tailored management.

Lower urinary tract electrical sensory assessment: a systematic review and meta-analysis.

OBJECTIVES: To summarize the current literature on lower urinary tract electrical sensory assessment (LUTESA), with regard to current perception thresholds (CPTs) and sensory evoked potentials (SEPs), and to discuss the applied methods in terms of technical aspects, confounding factors, and potential for lower urinary tract (LUT) diagnostics. METHODS: The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Medline (PubMed), Embase and Scopus were searched on 13 October 2020. Meta-analyses were performed and methodological qualities of the included studies were defined by assessing risk of bias (RoB) as well as confounding. RESULTS: After screening 9925 articles, 80 studies (five randomized controlled trials [RCTs] and 75 non-RCTs) were included, comprising a total of 3732 patients and 692 healthy subjects (HS). Of these studies, 61 investigated CPTs exclusively and 19 reported on SEPs, with or without corresponding CPTs. The recording of LUTCPTs and SEPs was shown to represent a safe and reliable assessment of LUT afferent nerve function in HS and patients. LUTESA demonstrated significant differences in LUT sensitivity between HS and neurological patients, as well as after interventions such as pelvic surgery or drug treatments. Pooled analyses showed that several stimulation variables (e.g. stimulation frequency, location) as well as patient characteristics might affect the main outcome measures of LUTESA (CPTs, SEP latencies, peak-to-peak amplitudes, responder rate). RoB and confounding was high in most studies. CONCLUSIONS: Preliminary data show that CPT and SEP recordings are valuable tools to more objectively assess LUT afferent nerve function. LUTESA complements already established diagnostics such as urodynamics, allowing a more comprehensive patient evaluation. The high RoB and confounding rate was related to inconsistency and inaccuracy in reporting rather than the technique itself. LUTESA standardization and well-designed RCTs are crucial to implement LUTESA as a clinical assessment tool.

Considering non-bladder aetiologies of overactive bladder: a functional neuroimaging study.

OBJECTIVES: To better understand the neuropathophysiology of overactive bladder (OAB) in women by characterising supraspinal activity in response to bladder distention and cold stimulation. SUBJECTS/PATIENTS AND METHODS: We recruited 24 female participants, 12 with OAB (median [interquartile range, IQR] age 40 [32-42] years) and 12 healthy controls (HCs) without lower urinary tract (LUT) symptoms (median [IQR] age 34 [28-44] years), and assessed LUT and cognitive function through neuro-urological examination, 3-day bladder diary, urodynamic investigation, and questionnaires. Functional magnetic resonance (MR) imaging using a 3-T scanner was performed in all participants during automated, repetitive bladder filling and draining (block design) with 100 mL body temperature (37 °C) saline using a MR-compatible and MR-synchronised infusion-drainage device until strong desire to void (HIGH-FILLING/DRAINING) and bladder filling with cold saline (4 °C, i.e. COLD). Whole-brain and region-of-interest analyses were conducted using Statistical Parametric Mapping, version 12. RESULTS: Significant between-group differences were found for 3-day bladder diary variables (i.e. voiding frequency/24 h, P < 0.001; voided volume/void, P = 0.04; and urinary incontinence [UI] episodes/24 h, P = 0.007), questionnaire scores (International Consultation on Incontinence Questionnaire-Female LUT symptoms [overall, filling, and UI scores, all P < 0.001]; the Overactive Bladder Questionnaire short form [symptoms and quality-of-life scores, both P < 0.001]; the Hospital Anxiety and Depression Scale [anxiety P = 0.004 and depression P = 0.003 scores]), as well as urodynamic variables (strong desire to void, P = 0.02; maximum cystometric capacity, P = 0.007; and presence of detrusor overactivity, P = 0.002). Age, weight and cognitive function (i.e. Mini-Mental State Examination, P = 1.0) were similar between groups (P > 0.05). In patients with OAB, the HIGH task elicited activity in the superior temporal gyrus, ventrolateral prefrontal cortex (VLPFC), and mid-cingulate cortex; and the COLD task elicited activity in the VLPFC, cerebellum, and basal ganglia. Compared to HCs, patients with OAB showed significantly stronger cerebellar activity during HIGH-FILLING and significantly less activity in the insula and VLPFC during HIGH-DRAINING. CONCLUSIONS: The present findings suggest a sensory processing and modulation deficiency in our OAB group, probably as part of their underlying pathophysiology, as they lacked activity in essential sensory processing areas, such as the insula. Instead, accessory areas, such as the cerebellum, showed significantly stronger activation compared to HCs, presumably supporting pelvic-floor motor activity to prevent UI. The novel findings of the present study provide physiological evidence of the necessity to consider non-bladder aetiologies of bladder symptoms.

Optimizing clinical trial design using prospective cohort study data: a case study in neuro-urology.

STUDY DESIGN: Simulations using data from a prospective cohort study. OBJECTIVES: To illustrate how prospective cohort data can be employed in randomized controlled trial (RCT) planning to assess feasibility and operational challenges, using TASCI (Transcutaneous tibial nerve stimulation in patients with Acute Spinal Cord Injury to prevent neurogenic detrusor overactivity: a nationwide randomized, sham-controlled, double-blind clinical trial) as a case study. SETTING: Spinal cord injury (SCI) rehabilitation centers in Switzerland. METHODS: TASCI is nested in the multicenter Swiss Spinal Cord Injury Cohort Study (SwiSCI), which prospectively includes patients with acute SCI. In simulations, data from 640 patients, collected by SwiSCI, were used to investigate different scenarios of patient eligibility and study consent, as well as the performance of the randomization list. Descriptive analysis was used to describe the population of interest and the simulation results; multivariable logistic regression analysis was performed to identify predictors of discharge within the TASCI intervention time period. RESULTS: The recruitment target of 114 patients is obtainable within the originally envisioned 3-year time period under the most favorable recruitment scenario examined. The distribution of the primary prognostic factor produced imbalance in the randomization lists and informed further discussion of the cut-off values used in stratification. Influxes of patients resulted in overlapping intervention periods for multiple participants, which guided resource allocation. Early discharge was related to the primary prognostic factor and study center, but is only anticipated in about 8% of participants. CONCLUSIONS: Prospective cohort data are a very valuable resource for planning RCTs.

Quantitative electrical pain threshold assessment in the lower urinary tract.

AIMS: Assessing the reliability of electrical pain threshold (PT) and evaluating the impact of stimulation frequency at different locations in the healthy lower urinary tract (LUT). METHODS: Ninety subjects (age: 18.3-35.8 years, 40 females, 50 males) were randomly allocated to one stimulation site (bladder dome [BD], trigone, proximal, membranous (only males), or distal urethra). Using 0.5 Hz/1.1 Hz/1.6 Hz electrical stimulation (square wave, pulse width:1 ms), current perception thresholds (CPTs), PTs and tolerance thresholds were assessed at two visits. Analyses were performed using linear mixed models, intraclass correlation coefficients (ICC) and Bland-Altman method. RESULTS: PTs vary in relation to stimulation frequency, location and between genders. PT decreased with higher stimulation frequency. The highest PTs were measured at the BD and membranous urethra with males reporting higher PTs than females. Reliability of PT assessments according to ICC was good to excellent across all frequencies, locations, and genders (ICC = 0.61-0.97), except for BD and distal urethra in females showing poor to fair reliability (BD: all frequencies, distal urethra: 0.5 Hz). CONCLUSIONS: PTs can be safely and reliably assessed from bladder and urethral locations. Semi-objective PT assessment may provide additional information on functionality and sensitivity of the LUT slow fiber afferents and complement findings from urodynamic investigations and CPT assessments. In conclusion, the developed methodology may open new opportunities for using electrical stimulation paradigms for LUT PT assessments and diagnostics. All this allows a more precise, location-specific characterization of pain origin and pain reaction towards therapy.

Scalp Topography of Lower Urinary Tract Sensory Evoked Potentials.

Impaired lower urinary tract (LUT) afferents often cause LUT symptoms. Assessment of LUT afferent pathways is possible using bipolar cortical sensory evoked potential (SEP) recordings with the active electrode at the vertex during electrical stimulation in the LUT. This study aimed to investigate the topographical distribution and microstates of lower urinary tract sensory evoked potentials (LUTSEPs) using different stimulation frequencies. Ninety healthy subjects (18-36 years old, 40 women) were randomly assigned to one of five stimulation locations [bladder dome; trigone; proximal, membranous (men only) or distal urethra]. Cycles of 0.5 Hz/1.1 Hz/1.6 Hz electrical stimulation were applied using a custom-made catheter. Cortical activity was recorded from 64 surface electrodes. Marker setting was performed manually on an individual subject-level for the P1, N1, and P2 components of vertex recordings. N1 and P2 topographies presented with central negativities and positivities around the vertex. Regarding topographical distribution, Randomization Graphical User interface (RAGU) analyses revealed consistent frequency effects and microstates for N1/P2. Higher stimulation frequencies resulted in decreasing map strength for P1, N1, and P2. LUTSEP topographies suggest central generators in the somatosensory cortex, which are not detectable in a bipolar set-up. The observed frequency effect indicates fiber refractoriness at higher frequencies. The multichannel approach allows more comprehensive assessment of LUTSEPs and might therefore be sensitive to pathological changes. Examinations in patients with LUT symptoms are needed to further investigate this biomarker.

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.

Reliability of supraspinal correlates to lower urinary tract stimulation in healthy participants - A fMRI study.

Previous functional neuroimaging studies provided evidence for a specific supraspinal network involved in lower urinary tract (LUT) control. However, data on the reliability of blood oxygenation level-dependent (BOLD) signal changes during LUT task-related functional magnetic resonance imaging (fMRI) across separate measurements are lacking. Proof of the latter is crucial to evaluate whether fMRI can be used to assess supraspinal responses to LUT treatments. Therefore, we prospectively assessed task-specific supraspinal responses from 20 healthy participants undergoing two fMRI measurements (test-retest) within 5-8 weeks. The fMRI measurements, conducted in a 3T magnetic resonance (MR) scanner, comprised a block design of repetitive bladder filling and drainage using an automated MR-compatible and MR-synchronized infusion-drainage device. Following transurethral catheterization and bladder pre-filling with body warm saline until participants perceived a persistent desire to void (START condition), fMRI was recorded during repetitive blocks (each 15 s) of INFUSION and WITHDRAWAL of 100 mL body warm saline into respectively from the bladder. BOLD signal changes were calculated for INFUSION minus START. In addition to whole brain analysis, we assessed BOLD signal changes within multiple 'a priori' region of interest (ROI), i.e. brain areas known to be involved in the LUT control from previous literature. To evaluate reliability of the fMRI results between visits, we applied different types of analyses: coefficient of variation (CV), intraclass correlation coefficient (ICC), Sørensen-Dice index, Bland-Altman method, and block-wise BOLD signal comparison. All participants completed the study without adverse events. The desire to void was rated significantly higher for INFUSION compared to START or WITHDRAWAL at both measurements without any effect of visit. At whole brain level, significant (p < 0.05, cluster corrected, k ≥ 41 voxels) BOLD signal changes were found for the contrast INFUSION compared to START in several brain areas. Overlap of activation maps from both measurements were observed in the orbitofrontal cortex, insula, ventrolateral prefrontal cortex (VLPFC), and inferior parietal lobe. The two highest ICCs, based on a ROI's mean beta weight, were 0.55 (right insular cortex) and 0.47 (VLPFC). Spatial congruency (Sørensen-Dice index) of all voxels within each ROI between measurements was highest in the insular cortex (left 0.55, right 0.44). In addition, the mean beta weight of the right insula and right VLPFC demonstrated the lowest CV and narrowest Bland and Altman 95% limits of agreement. In conclusion, the right insula and right VLPFC were revealed as the two most reliable task-specific ROIs using our automated, MR-synchronized protocol. Achieving high reliability using a viscero-sensory/interoceptive task such as repetitive bladder filling remains challenging and further endeavour is highly warranted to better understand which factors influence fMRI outcomes and finally to assess LUT treatment effects on the supraspinal level.

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.

Sensory evoked cortical potentials of the lower urinary tract in healthy men.

AIMS: To assess the afferent innervation of various locations in the male lower urinary tract (LUT) using sensory evoked cortical potentials (SEPs). METHODS: Twelve healthy men (mean age: 29.6 ± 7.2 years, mean height: 1.8 ± 0.1 m) underwent repetitive slow (0.5 Hz/1 ms) and fast (3 Hz/0.2 ms) electrical stimulations of bladder (dome/trigone) and urethral (proximal/membranous/distal) locations with simultaneous cortical SEP recording (Cz-Fz). Latencies (ms) and peak-to-peak amplitudes (µV) for SEP components P1, N1, and P2 were analyzed. Tibial SEPs were assessed as methodological control. The reproducibility was investigated from between visits and inter-rater assessments using Bland-Altman plots. Statistical tests comprised analysis of variance (ANOVA), linear regressions, and paired t-tests. Values are given as mean ± standard deviation. RESULTS: Typical LUTSEPs with P1, N1, and P2 components were successfully detected (100% responder rate) for slow but less successfully for fast stimulation. The slow stimulation provided reproducible LUTSEPs with position specific N1 latencies: dome 125.6 ± 21.3 ms, trigone 122.9 ± 20.5 ms, proximal- 116.1 ± 21.4 ms, membraneous- 118.8 ± 29.3 ms, and distal urethra 108.8 ± 17.8 ms. Despite good inter-rater agreement, latency variability between and within subjects was higher for LUTSEPs than for tibial SEPs. N1 latencies became shorter (P < 0.01) with increasing subject age for bladder dome and distal urethra stimulation. CONCLUSIONS: LUTSEPs can be successfully obtained for different LUT locations in men using slow electrical stimulation. Location specific differences in N1 latencies may indicate different local afferent innervation. Larger variability of LUTSEPs versus tibial SEPs may be related to the more challenging approach and afferent fibre access within the LUT. Further studies optimizing measurement and analysis approach are required.

A novel infusion-drainage device to assess lower urinary tract function in neuro-imaging.

OBJECTIVE: To evaluate the applicability and precision of a novel infusion-drainage device (IDD) for standardized filling paradigms in neuro-urology and functional magnetic resonance imaging (fMRI) studies of lower urinary tract (LUT) function/dysfunction. SUBJECTS/PATIENTS AND METHODS: The IDD is based on electrohydrostatic actuation which was previously proven feasible in a prototype setup. The current design includes hydraulic cylinders and a motorized slider to provide force and motion. Methodological aspects have been assessed in a technical application laboratory as well as in healthy subjects (n=33) and patients with LUT dysfunction (n=3) undergoing fMRI during bladder stimulation. After catheterization, the bladder was pre-filled until a persistent desire to void was reported by each subject. The scan paradigm comprised automated, repetitive bladder filling and withdrawal of 100 mL body warm (37 °C) saline, interleaved with rest and sensation rating. Neuroimaging data were analysed using Statistical Parametric Mapping version 12 (SMP12). RESULTS: Volume delivery accuracy was between 99.1±1.2% and 99.9±0.2%, for different flow rates and volumes. Magnetic resonance (MR) compatibility was demonstrated by a small decrease in signal-to-noise ratio (SNR), i.e. 1.13% for anatomical and 0.54% for functional scans, and a decrease of 1.76% for time-variant SNR. Automated, repetitive bladder-filling elicited robust (P = 0.05, family-wise error corrected) brain activity in areas previously reported to be involved in supraspinal LUT control. There was a high synchronism between the LUT stimulation and the blood oxygenation level-dependent (BOLD) signal changes in such areas. CONCLUSION: We were able to develop an MR-compatible and MR-synchronized IDD to routinely stimulate the LUT during fMRI in a standardized manner. The device provides LUT stimulation at high system accuracy resulting in significant supraspinal BOLD signal changes in interoceptive and LUT control areas in synchronicity to the applied stimuli. The IDD is commercially available, portable and multi-configurable. Such a device may help to improve precision and standardization of LUT tasks in neuro-imaging studies on supraspinal LUT control, and may therefore facilitate multi-site studies and comparability between different LUT investigations in the future.

Sensory function assessment of the human male lower urinary tract using current perception thresholds.

AIMS: To evaluate the feasibility and reliability of current perception threshold (CPT) measurement for sensory assessment of distinct locations in the male lower urinary tract (LUT). METHODS: Twelve male subjects (>18 years) without LUT symptoms or medical comorbidities were eligible. CPTs were determined twice (interval: 7-20 days) at the bladder dome, trigone and the proximal, membranous, and distal urethra. Square wave electrical stimulation of 3 Hz/0.2 ms and 0.5 Hz/1 ms was applied using a transurethral 8F catheter placed under fluoroscopic control. Bladder volume was kept constant (60 mL) using a second 10F catheter. Repetitive measurements and reliability were assessed by analysis of variance (ANOVA) and intraclass correlation coefficient (ICC). RESULTS: The ANOVA revealed significant main effects for stimulation site (P = 0.008) and type of stimulation (P < 0.001) with lower CPTs for 0.5 Hz/1 ms compared to 3 Hz/0.2 ms. There was no significant effect for visit number (P = 0.061). CPTs were higher for bladder dome than for proximal (0.5 Hz/1 ms: P = 0.022; 3 Hz/0.2 ms: P = 0.022) and distal urethra (0.5 Hz/1 ms: P = 0.026; 3 Hz/0.2 ms: P = 0.030). Reliability of CPT measurements was excellent to good (ICC = 0.67-0.96) except for the bladder dome (5 Hz/1 ms: ICC = 0.45; 3 Hz/0.2 ms: ICC = 0.20) and distal urethra (3 Hz/0.2 ms: ICC = 0.57). CONCLUSIONS: CPTs can be reliably detected at different LUT locations. However, alert and compliant subjects are essential. CPTs of LUT may become a complementary assessment method providing information on responsiveness and sensitivity of afferent LUT nerves. This is especially relevant for urethral afferents, which are not covered by standard urodynamic investigations. Neurourol. Urodynam. 36:469-473, 2017. © 2016 Wiley Periodicals, Inc.

Protocol for a prospective, randomized study on neurophysiological assessment of lower urinary tract function in a healthy cohort.

BACKGROUND: Lower urinary tract symptoms are highly prevalent and a large proportion of these symptoms are known to be associated with a dysfunction of the afferent pathways. Diagnostic tools for an objective and reproducible assessment of afferent nerve function of the lower urinary tract are missing. Previous studies showed first feasibility results of sensory evoked potential recordings following electrical stimulation of the lower urinary tract in healthy subjects and patients. Nevertheless, a refinement of the methodology is necessary. METHODS: This study is a prospective, randomized trial conducted at Balgrist University Hospital, Zürich, Switzerland. Ninety healthy subjects (forty females and fifty males) without lower urinary tract symptoms are planned to be included in the study. All subjects will undergo a screening visit (including standardized questionnaires, 3-day bladder diary, urinalysis, medical history taking, vital signs, physical examination, neuro-urological examination) followed by two measurement visits separated by an interval of 3 to 4 weeks. Electrical stimulations (0.5Hz-5Hz, bipolar, square wave, pulse width 1 ms) will be applied using a custom-made transurethral catheter at different locations of the lower urinary tract including bladder dome, trigone, proximal urethra, membranous urethra and distal urethra. Every subject will be randomly stimulated at one specific site of the lower urinary tract. Sensory evoked potentials (SEP) will be recorded using a 64-channel EEG cap. For an SEP segmental work-up we will place additional electrodes on the scalp (Cpz) and above the spine (C2 and L1). Visit two and three will be conducted identically for reliability assessment. DISCUSSION: The measurement of lower urinary tract SEPs elicited by electrical stimulation at different locations of the lower urinary tract has the potential to serve as a neurophysiological biomarker for lower urinary tract afferent nerve function in patients with lower urinary tract symptoms or disorders. For implementation of such a diagnostic tool into clinical practice, an optimized setup with efficient and reliable measurements and data acquisition is crucial. In addition, normative data from a larger cohort of healthy subjects would provide information on variability, potential confounding factors and cut-off values for investigations in patients with lower urinary tract dysfunction/symptoms. TRIAL REGISTRATION: Clinicaltrials.gov; Identifier: NCT02272309 .

Sensory evoked potentials of the bladder and urethra in middle-aged women: the effect of age.

OBJECTIVES: To investigate feasibility, reproducibility and age dependency of sensory evoked cortical potentials (SEPs) after electrical stimulation of different locations in the lower urinary tract (LUT) in a cohort of middle-aged healthy women. SUBJECTS AND METHODS: In a group of 10 healthy middle-aged women [mean (sd) height 165 (5) cm and age 43 (6) years), electrical stimulation (0.5 and 3 Hz) was applied to the bladder dome, trigone, and proximal and distal urethra. SEPs were recorded at the Cz electrode with reference to Fz. All measurements were repeated three times with an interval of 3-5 weeks. Current perception thresholds (CPT), SEP latencies and amplitudes were analysed. Results were compared with a group of younger women published previously. RESULTS: LUT SEPs demonstrated two positive (P1, P2) and one negative peak (N1). The mean (sd) N1 latency was 108.9 (7.8), 116.2 (10.7), 113.2 (13.4) and 131.3 (35.6) ms for the bladder dome, trigone, proximal and distal urethra, respectively. N1 latencies, except for the distal urethra, were significantly shorter than those in younger women. Taking all data, i.e. young and middle-aged women, into account, there was a significant negative correlation between the variable age and CPT/dome (r = -0.462, P = 0.04) and N1 latency/dome (r = -0.605, P = 0.005) and a significant positive correlation between the variable age and N1P2 amplitude/dome (r = 0.542, P = 0.014). CONCLUSION: LUT SEPs can be induced in middle-aged women with reliable N1 responses. Unexpectedly, N1 responses reveal a shortening with increasing age particularly when compared with younger women. Changes in sensory afferents may be explained by age-related qualitative reorganisations within the urothelium and suburothelium potentially altering afferent nerve excitability, which may have an impact on the development of non-neurological LUT symptoms (LUTS, e.g. overactive bladder) in women.

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.

Improved inter-subject alignment of the lumbosacral cord for group-level in vivo gray and white matter assessments: A scan-rescan MRI study at 3T.

INTRODUCTION: Magnetic resonance imaging (MRI) enables the investigation of pathological changes in gray and white matter at the lumbosacral enlargement (LSE) and conus medullaris (CM). However, conducting group-level analyses of MRI metrics in the lumbosacral spinal cord is challenging due to variability in CM length, lack of established image-based landmarks, and unknown scan-rescan reliability. This study aimed to improve inter-subject alignment of the lumbosacral cord to facilitate group-level analyses of MRI metrics. Additionally, we evaluated the scan-rescan reliability of MRI-based cross-sectional area (CSA) measurements and diffusion tensor imaging (DTI) metrics. METHODS: Fifteen participants (10 healthy volunteers and 5 patients with spinal cord injury) underwent axial T2*-weighted and diffusion MRI at 3T. We assessed the reliability of spinal cord and gray matter-based landmarks for inter-subject alignment of the lumbosacral cord, the inter-subject variability of MRI metrics before and after adjusting for the CM length, the intra- and inter-rater reliability of CSA measurements, and the scan-rescan reliability of CSA measurements and DTI metrics. RESULTS: The slice with the largest gray matter CSA as an LSE landmark exhibited the highest reliability, both within and across raters. Adjusting for the CM length greatly reduced the inter-subject variability of MRI metrics. The intra-rater, inter-rater, and scan-rescan reliability of MRI metrics were the highest at and around the LSE (scan-rescan coefficient of variation <3% for CSA measurements and <7% for DTI metrics within the white matter) and decreased considerably caudal to it. CONCLUSIONS: To facilitate group-level analyses, we recommend using the slice with the largest gray matter CSA as a reliable LSE landmark, along with an adjustment for the CM length. We also stress the significance of the anatomical location within the lumbosacral cord in relation to the reliability of MRI metrics. The scan-rescan reliability values serve as valuable guides for power and sample size calculations in future longitudinal studies.

White Matter Magnetic Resonance Diffusion Measures in Multiple Sclerosis with Overactive Bladder.

BACKGROUND: Lower urinary tract (LUT) symptoms are reported in more than 80% of patients with multiple sclerosis (MS), most commonly an overactive bladder (OAB). The relationship between brain white matter (WM) changes in MS and OAB symptoms is poorly understood. OBJECTIVES: We aim to evaluate (i) microstructural WM differences across MS patients (pwMS) with OAB symptoms, patients without LUT symptoms, and healthy subjects using diffusion tensor imaging (DTI), and (ii) associations between clinical OAB symptom scores and DTI indices. METHODS: Twenty-nine female pwMS [mean age (SD) 43.3 years (9.4)], including seventeen with OAB [mean age (SD) 46.1 years (8.6)] and nine without LUT symptoms [mean age (SD) 37.5 years (8.9)], and fourteen healthy controls (HCs) [mean age (SD) 48.5 years (20)] were scanned in a 3T MRI with a DTI protocol. Additionally, clinical scans were performed for WM lesion segmentation. Group differences in fractional anisotropy (FA) were evaluated using tract-based spatial statistics. The Urinary Symptom Profile questionnaire assessed OAB severity. RESULTS: A statistically significant reduction in FA (p = 0.004) was identified in microstructural WM in pwMS, compared with HCs. An inverse correlation was found between FA in frontal and parietal WM lobes and OAB scores (p = 0.021) in pwMS. Areas of lower FA, although this did not reach statistical significance, were found in both frontal lobes and the rest of the non-dominant hemisphere in pwMS with OAB compared with pwMS without LUT symptoms (p = 0.072). CONCLUSIONS: This study identified that lesions affecting different WM tracts in MS can result in OAB symptoms and demonstrated the role of the WM in the neural control of LUT functions. By using DTI, the association between OAB symptom severity and WM changes were identified, adding knowledge to the current LUT working model. As MS is predominantly a WM disease, these findings suggest that regional WM involvement, including of the anterior corona radiata, anterior thalamic radiation, superior longitudinal fasciculus, and superior frontal-occipital fasciculus and a non-dominant prevalence in WM, can result in OAB symptoms. OAB symptoms in MS correlate with anisotropy changes in different white matter tracts as demonstrated by DTI. Structural impairment in WM tracts plays an important role in LUT symptoms in MS.