Stimulation of the cuneiform nucleus enables training and boosts recovery after spinal cord injury.

Severe spinal cord injuries result in permanent paraparesis in spite of the frequent sparing of small portions of white matter. Spared fibre tracts are often incapable of maintaining and modulating the activity of lower spinal motor centres. Effects of rehabilitative training thus remain limited. Here, we activated spared descending brainstem fibres by electrical deep brain stimulation of the cuneiform nucleus of the mesencephalic locomotor region, the main control centre for locomotion in the brainstem, in adult female Lewis rats. We show that deep brain stimulation of the cuneiform nucleus enhances the weak remaining motor drive in highly paraparetic rats with severe, incomplete spinal cord injuries and enables high-intensity locomotor training. Stimulation of the cuneiform nucleus during rehabilitative aquatraining after subchronic (n = 8 stimulated versus n = 7 unstimulated versus n = 7 untrained rats) and chronic (n = 14 stimulated versus n = 9 unstimulated versus n = 9 untrained rats) spinal cord injury re-established substantial locomotion and improved long-term recovery of motor function. We additionally identified a safety window of stimulation parameters ensuring context-specific locomotor control in intact rats (n = 18) and illustrate the importance of timing of treatment initiation after spinal cord injury (n = 14). This study highlights stimulation of the cuneiform nucleus as a highly promising therapeutic strategy to enhance motor recovery after subchronic and chronic incomplete spinal cord injury with direct clinical applicability.

Molecular Characterization of Non-Neurogenic and Neurogenic Lower Urinary Tract Dysfunction (LUTD) in SCI-Induced and Partial Bladder Outlet Obstruction Mouse Models.

We examined bladder function following spinal cord injury (SCI) by repeated urodynamic investigation (UDI), including external urethral sphincter (EUS) electromyography (EMG) in awake restrained mice and correlated micturition parameters to gene expression and morphological changes in the bladder. A partial bladder outlet obstruction (pBOO) model was used for comparison to elucidate both the common and specific features of obstructive and neurogenic lower urinary tract dysfunction (LUTD). Thirty female C57Bl/6J mice in each group received an implanted bladder catheter with additional electrodes placed next to the EUS in the SCI group. UDI assessments were performed weekly for 7 weeks (pBOO group) or 8 weeks (SCI group), after which bladders were harvested for histological and transcriptome analysis. SCI mice developed detrusor sphincter dyssynergia (DSD) one week after injury with high-pressure oscillations and a significantly increased maximal bladder pressure Pmax and were unable to void spontaneously during the whole observation period. They showed an increased bladder-to-bodyweight ratio, bladder fibrosis, and transcriptome changes indicative of extracellular matrix remodeling and alterations of neuronal signaling and muscle contraction. In contrast, pBOO led to a significantly increased Pmax after one week, which normalized at later time points. Increased bladder-to-bodyweight ratio and pronounced gene expression changes involving immune and inflammatory pathways were observed 7 weeks after pBOO. Comparative transcriptome analysis of SCI and pBOO bladders revealed the activation of Wnt and TGF-beta signaling in both the neurogenic and obstructive LUTD and highlighted FGF2 as a major upregulated transcription factor during organ remodeling. We conclude that SCI-induced DSD in mice leads to profound changes in neuronal signaling and muscle contractility, leading to bladder fibrosis. In a similar time frame, significant bladder remodeling following pBOO allowed for functional compensation, preserving normal micturition parameters.

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.

The Gigantocellular Reticular Nucleus Plays a Significant Role in Locomotor Recovery after Incomplete Spinal Cord Injury.

Traditionally, the brainstem has been seen as hardwired and poorly capable of plastic adaptations following spinal cord injury (SCI). Data acquired over the past decades, however, suggest differently: following SCI in various animal models (lamprey, chick, rodents, nonhuman primates), different forms of spontaneous anatomic plasticity of reticulospinal projections, many of them originating from the gigantocellular reticular nucleus (NRG), have been observed. In line with these anatomic observations, animals and humans with incomplete SCI often show various degrees of spontaneous motor recovery of hindlimb/leg function. Here, we investigated the functional relevance of two different modes of reticulospinal fiber growth after cervical hemisection, local rewiring of axotomized projections at the lesion site versus compensatory outgrowth of spared axons, using projection-specific, adeno-associated virus-mediated chemogenetic neuronal silencing. Detailed assessment of joint movements and limb kinetics during overground locomotion in female adult rats showed that locally rewired as well as compensatory NRG fibers were responsible for different aspects of recovered forelimb and hindlimb functions (i.e., stability, strength, coordination, speed, or timing). During walking and swimming, both locally rewired as well as compensatory NRG plasticity were crucial for recovered function, while the contribution of locally rewired NRG plasticity to wading performance was limited. Our data demonstrate comprehensively that locally rewired as well as compensatory plasticity of reticulospinal axons functionally contribute to the observed spontaneous improvement of stepping performance after incomplete SCI and are at least partially causative to the observed recovery of function, which can also be observed in human patients with spinal hemisection lesions.SIGNIFICANCE STATEMENT Following unilateral hemisection of the spinal cord, reticulospinal projections are destroyed on the injured side, resulting in impaired locomotion. Over time, a high degree of recovery can be observed in lesioned animals, like in human hemicord patients. In the rat, recovery is accompanied by pronounced spontaneous plasticity of axotomized and spared reticulospinal axons. We demonstrate the causative relevance of locally rewired as well as compensatory reticulospinal plasticity for the recovery of locomotor functions following spinal hemisection, using chemogenetic tools to selectively silence newly formed connections in behaviorally recovered animals. Moving from a correlative to a causative understanding of the role of neuroanatomical plasticity for functional recovery is fundamental for successful translation of treatment approaches from experimental studies to the clinics.

Anti-Nogo-A Antibodies As a Potential Causal Therapy for Lower Urinary Tract Dysfunction after Spinal Cord Injury.

Loss of bladder control is common after spinal cord injury (SCI) and no causal therapies are available. Here we investigated whether function-blocking antibodies against the nerve-fiber growth inhibitory protein Nogo-A applied to rats with severe SCI could prevent development of neurogenic lower urinary tract dysfunction. Bladder function of rats with SCI was repeatedly assessed by urodynamic examination in fully awake animals. Four weeks after SCI, detrusor sphincter dyssynergia had developed in all untreated or control antibody-infused animals. In contrast, 2 weeks of intrathecal anti-Nogo-A antibody treatment led to significantly reduced aberrant maximum detrusor pressure during voiding and a reduction of the abnormal EMG high-frequency activity in the external urethral sphincter. Anatomically, we found higher densities of fibers originating from the pontine micturition center in the lumbosacral gray matter in the anti-Nogo-A antibody-treated animals, as well as a reduced number of inhibitory interneurons in lamina X. These results suggest that anti-Nogo-A therapy could also have positive effects on bladder function clinically.SIGNIFICANCE STATEMENT After spinal cord injury, loss of bladder control is common. Detrusor sphincter dyssynergia is a potentially life-threatening consequence. Currently, only symptomatic treatment options are available. First causal treatment options are urgently needed in humans. In this work, we show that function-blocking antibodies against the nerve-fiber growth inhibitory protein Nogo-A applied to rats with severe spinal cord injury could prevent development of neurogenic lower urinary tract dysfunction, in particular detrusor sphincter dyssynergia. Anti-Nogo-A therapy has entered phase II clinical trial in humans and might therefore soon be the first causal treatment option for neurogenic lower urinary tract dysfunction.

Cardiac electrophysiology catheters for electrophysiological assessments of the lower urinary tract-A proof of concept ex vivo study in viable ureters.

AIMS: To explore the feasibility of minimally invasive catheter-based electrophysiology studies in the urinary tract. This is a well-known method used in cardiology to investigate and treat arrhythmias. METHODS: We developed an experimental platform which allows electrophysiological recordings with cardiac catheters and conventional needle electrodes in ex vivo pig ureters. The action potential was triggered by a stimulating electrode. We considered 13 porcine ureters (freshly collected and harvested in organ bath), 7 of which were used to optimize the setup and define the stimulation parameters; we performed the recordings in the remaining six ureters. The electrical propagation of the generated action potential was tracked with multiple sensing electrodes, from which propagation directions, velocities, refractory periods, and pacing thresholds were extracted. RESULTS: We recorded propagating electrical activity in four ureters using needle electrodes and in two ureters using cardiac catheters. Propagation velocities for forward direction (from kidney to bladder) derived by the two methods were similar (15.1 ± 2.6 mm/s for cardiac catheters, 15.6 ± 2.3 mm/s for needle recordings). Pacing thresholds, activation patters, and refractory times were provided for the ureteric smooth muscle. Retrograde propagations and corresponding velocities were also observed and measured. CONCLUSIONS: This study is a proof-of-concept showing that electrical activity can be measured "from the inside" of urinary cavities using catheters and that obtained results are comparable with the more invasive needle recordings. Catheter-based electrophysiology may allow, in the clinical setting, for: i) a more differentiated understanding of urological disorders such as overactive bladder and ii) new therapeutic approaches (e.g., targeted tissue ablation).

Desmopressin for treating nocturia in patients with multiple sclerosis: A systematic review: A report from the Neuro-Urology Promotion Committee of the International Continence Society (ICS).

AIMS: To systematically assess all available evidence on efficacy and safety of desmopressin for treating nocturia in patients with multiple sclerosis (MS). METHODS: This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies were identified by electronic search of Cochrane register, Embase, Medline, Scopus (last search March 3, 2018) and by screening of reference lists and reviews. RESULTS: After screening of 7015 abstracts, 8 prospective, and 1 retrospective studies were included enrolling a total of 178 patients. The mean patient age ranged between 43 and 51 years. A significant decrease in the number of micturitions per night was reported in 5 studies. An increase in the maximum hours of uninterrupted sleep was only found in two studies. A significant reduction of the volume of nocturnal incontinence was described in one study. The patient satisfaction rates ranged from 56% to 82%. The rate of adverse events was between 0% and 57.9%. The rate of hyponatremia ranged from 0% to 23.5% and other commonly reported adverse events were headache, nausea, fluid retention, rhinitis/epistaxis, malaise, and swollen ankles. Risk of bias and confounding was relevant in all studies. CONCLUSIONS: Preliminary data suggest that desmopressin might be effective for treating nocturia in patients with MS. However, adverse events are relatively common, the overall quality of evidence is low and the number of studied patients is very limited. Further studies with newer formulations of desmopressin are highly warranted.

Alpha-blockers for treating neurogenic lower urinary tract dysfunction in patients with multiple sclerosis: A systematic review and meta-analysis. A report from the Neuro-Urology Promotion Committee of the International Continence Society (ICS).

AIM: We aimed to systematically assess the evidence on the efficacy and safety of alpha-blockers in patients with multiple sclerosis (MS) suffering from neurogenic lower urinary tract dysfunction (NLUTD). METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used to perform this systematic review. An electronic search of Cochrane register, Embase, Medline, Scopus (last search 3 March 2018) and screening of reference lists as well as reviews were used to identify the studies. Articles were included if they reported on efficacy/safety of alpha-blockers for the treatment of NLUTD in patients with MS. RESULTS: After screening of 7'015 abstracts, three studies enrolling a total of 50 patients were included: one randomized, placebo-controlled, single-blind trial and two prospective cohort studies. Alpha-blocker treatment was successful in 50% to 96% of the patients. Pooling data from the three included studies, the relative risk for successful alpha-blocker treatment was 3.89 (95% confidence interval 2.7-7.0). The general safety profile of alpha-blockers was favorable with 8% of the patients reporting adverse events. CONCLUSIONS: Alpha-blockers may be effective and safe for treating NLUTD in female and male patients with MS but the studies were small and the overall quality of evidence was low. To make definitive conclusions, well designed randomized controlled trials are highly warranted.

Axotomized Corticospinal Neurons Increase Supra-Lesional Innervation and Remain Crucial for Skilled Reaching after Bilateral Pyramidotomy.

Skilled upper limb function heavily depends on the corticospinal tract. After bilateral lesions to this tract, motor control is disrupted but can be partially substituted by other motor systems to allow functional recovery. However, the remaining roles of motor cortex and especially of axotomized corticospinal neurons (CSNs) are not well understood. Using the single pellet retrieval task in adult rats, we induced significant recovery of skilled reaching after bilateral pyramidotomy by rehabilitative reaching training, and show that reach-related motor cortex activity, recorded in layer V, topographically reappeared shortly after axotomy. Using a chemogenetic neuronal silencing technique, we found that axotomized CSNs retained a crucial role for the recovered pellet retrieval success. The axotomized CSNs sprouted extensively in the red nucleus supplying new innervation to its magnocellular and parvocellular parts. Specific silencing of the rubrospinal tract (RST) also strongly abolished the recovered pellet retrieval success, suggesting a role of this cervically projecting nucleus in relaying cortical motor control. In summary, our results show that after bilateral corticospinal axotomy, motor cortex still actively engages in forelimb motor control and axotomized CSNs are crucially involved in the recovered reaching movement, potentially by relaying motor control via the RST.

Prediction of autonomic dysreflexia during urodynamics: a prospective cohort study.

BACKGROUND: Autonomic dysreflexia is a severe and potentially life-threatening condition in patients with spinal cord injury, as it can lead to myocardial ischemia, brain hemorrhage, or even death. Urodynamic investigation is the gold standard to assess neurogenic lower urinary tract dysfunction due to spinal cord injury and reveal crucial pathological findings, such as neurogenic detrusor overactivity. However, neurogenic detrusor overactivity and urodynamic investigation are known to be leading triggers of autonomic dysreflexia. Therefore, we aimed to determine predictors of autonomic dysreflexia in individuals with spinal cord injury during urodynamic investigation. METHODS: This prospective cohort study included 300 patients with spinal cord injuries and complete datasets of continuous non-invasive cardiovascular monitoring, recorded during same session repeat urodynamic investigation. We used logistic regression to reveal predictors of autonomic dysreflexia during urodynamic investigation. RESULTS: We found that level of injury and presence of neurogenic detrusor overactivity were the only two independent significant predictors for autonomic dysreflexia during urodynamic investigation. A lesion at spinal segment T6 or above (odds ratio (OR) 5.5, 95% CI 3.2-9.4) compared to one at T7 or below, and presence of neurogenic detrusor overactivity (OR 2.7, 95% confidence interval (CI) 1.4-4.9) were associated with a significant increased odds of autonomic dysreflexia during urodynamic investigation. Both odds persisted after adjustment for age, sex, and completeness and stage of injury (adjusted OR (AOR) 6.6, 95% CI 3.8-11.7, and AOR 2.2, 95% CI 1.1-4.5, respectively). Further stratification by lesion level showed level-dependent significantly increased adjusted odds of autonomic dysreflexia, i.e., from C1-C4 (AOR 16.2, 95% CI 5.9-57.9) to T4-T6 (AOR 2.6, 95% CI 1.3-5.2), compared to lesions at T7 or below. CONCLUSIONS: In patients with neurogenic lower urinary tract dysfunction due to spinal cord injury, autonomic dysreflexia is independently predicted by lesion level and presence of neurogenic detrusor overactivity. Considering the health risks associated with autonomic dysreflexia, such as seizures, stroke, retinal bleeding, or even death, we recommend both continuous cardiovascular monitoring during urodynamic investigation in all spinal cord-injured patients with emphasis on those with cervical lesions, and appropriate neurogenic detrusor overactivity treatment to reduce the probability of potentially life-threatening complications. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01293110 .

High EDSS can predict risk for upper urinary tract damage in patients with multiple sclerosis.

BACKGROUND: Neurogenic lower urinary tract dysfunction (NLUTD) is very common in patients with multiple sclerosis (MS), and it might jeopardize renal function and thereby increase mortality. Although there are well-known urodynamic risk factors for upper urinary tract damage, no clinical prediction parameters are available. OBJECTIVE: We aimed to assess clinical parameters potentially predicting urodynamic risk factors for upper urinary tract damage. METHODS: A consecutive series of 141 patients with MS referred from neurologists for primary neuro-urological work-up including urodynamics were prospectively evaluated. Clinical parameters taken into account were age, sex, duration, and clinical course of MS and Expanded Disability Status Scale (EDSS). RESULTS: Multivariate modeling revealed EDSS as a clinical parameter significantly associated with urodynamic risk factors for upper urinary tract damage (odds ratio = 1.34, 95% confidence interval (CI) = 1.06-1.71, p = 0.02). Using receiver operator characteristic (ROC) curves, an EDSS of 5.0 as cutoff showed a sensitivity of 86%-87% and a specificity of 52% for at least one urodynamic risk factor for upper urinary tract damage. CONCLUSION: High EDSS is significantly associated with urodynamic risk factors for upper urinary tract damage and allows a risk-dependent stratification in daily neurological clinical practice to identify MS patients requiring further neuro-urological assessment and treatment.

Effect of Thoracic Epidural Ropivacaine versus Bupivacaine on Lower Urinary Tract Function: A Randomized Clinical Trial.

BACKGROUND: Thoracic epidural analgesia with bupivacaine resulted in clinically relevant postvoid residuals due to detrusor underactivity. This study aimed to compare the risk of bladder dysfunction with ropivacaine versus bupivacaine using postvoid residuals and maximum flow rates. Our hypothesis was that ropivacaine would result in lower postvoid residuals, because ropivacaine has been shown to have less effect on motor blockade. METHODS: In this single-center, parallel-group, randomized, double-blind superiority trial, 42 patients undergoing open renal surgery were equally allocated to receive epidural bupivacaine 0.125% or ropivacaine 0.2%, and 36 were finally included. Inclusion criterion was normal bladder function. Patients underwent urodynamic investigations preoperatively and during thoracic epidural analgesia. Primary outcome was the difference in postvoid residual preoperatively and during thoracic epidural analgesia postoperatively. Secondary outcomes were changes in maximum flow rate between and within the groups. RESULTS: Median difference in postvoid residual (ml) from baseline to postoperatively was 300 (range, 30 to 510; P < 0.001) for bupivacaine and 125 (range, -30 to 350; P = 0.011) for ropivacaine, with a significant mean difference between groups (-175; 95% CI, -295 to -40; P = 0.012). Median difference in maximum flow rate (ml/s) was more pronounced with bupivacaine (-12; range, -28 to 3; P < 0.001) than with ropivacaine (-4; range, -16 to 7; P = 0.025) with a significant mean difference between groups (7; 95% CI, 0 to 12; P = 0.028). Pain scores were similar. No adverse events occurred. CONCLUSIONS: Postvoid residuals were significantly lower using ropivacaine compared to bupivacaine for thoracic epidural analgesia reflecting less impairment of detrusor function with ropivacaine.

Reproductive organ-sparing cystectomy significantly improves continence in women after orthotopic bladder substitution without affecting oncological outcome.

OBJECTIVES: To compare functional and oncological outcomes of reproductive organ-sparing cystectomy (ROSC) compared with standard cystectomy (SC) in women undergoing orthotopic bladder substitution (OBS). PATIENTS AND METHODS: Between 1995 and 2016, 121 consecutive women undergoing OBS were prospectively included in this single-centre non-randomized clinical follow-up study comprising an ROSC and an SC group. Urinary continence, the need for intermittent self-catheterization (ISC), lateral standing micturition cystourethrogram (MCUG), urethral pressure profile findings, if available, and oncological outcomes were assessed and compared between ROSC and SC. RESULTS: After 12 months, patients who had undergone ROSC with OBS had significantly higher daytime and nighttime continence rates than patients who had undergone SC with OBS (87.5% vs 63.5%; P = 0.027 and 87.5% vs 57.7%; P = 0.008), whereas no significant differences were found between groups in ISC rates (12.5% vs 12.94%; P > 0.99). The degree of attempted nerve-sparing (none, unilateral, bilateral) positively affected continence rates in both groups. No significant differences were found in local recurrence rates (0% vs 9.4%; P = 0.126), 5- and 10-year overall survival rates (80.9% and 80.9% vs 64.9% and 55.7%; P = 0.443) or 5- and 10-year cancer-specific survival rates (84.3% and 84.3% vs 73% and 66.2%; P = 0.431). CONCLUSION: Superior continence rates were found for ROSC with an OBS compared with SC, without a negative impact on oncological outcome. ROSC should, therefore, be offered to women receiving an OBS whenever justifiable.

Early neurological care of patients with spinal cord injury.

PURPOSE: Considering the major clinical challenges of managing patients with spinal cord injury (SCI), we summarized the relevant aspects of the early (within 1 year after SCI) neurological care emphasizing common standards. METHODS: This review was performed according to the methodology recommended by the Joint SIU-ICUD International Consultation. Embase and Medline databases were used to identify literature relevant to the early neurological care of SCI patients. Recommendations were developed by consensus and graded using a modified Oxford system which identifies level of evidence (LOE) and grade of recommendation (GOR). RESULTS: Emergency health care providers must address altered mental status, evidence of intoxication, suspected extremity fracture/distracting injury, focal neurological deficit and spinal pain/tenderness to determine the risk of SCI in a trauma patient [LOE 1, GOR A]. Neurogenic shock must be recognized and treated [LOE 3, GOR A]. Spine surgeons should consider early decompression and spine fixation/stabilization, where indicated, and should promote early active rehabilitation to improve functional recovery [LOE 2, GOR B]. Clinicians should refer SCI patients to specialized SCI rehabilitation centers [LOE 4, GOR B], must apply interventions to prevent venous thromboembolism (i.e., compression devices and low-molecular weight heparin/unfractionated heparin) after acute SCI respecting contraindications [LOE 1, GOR A]. Contemporary guidelines to manage pain must be employed [LOE 1, GOR A] and methods to reduce the risk of pressure ulcers should be used [LOE 3, GOR B]. CONCLUSIONS: Early treatment, prevention of associated complications and individualized patient-targeted rehabilitation programs provided by a specialized interdisciplinary team are crucial to optimize the outcome after SCI.

Early urological care of patients with spinal cord injury.

PURPOSE: After spinal cord injury (SCI), the initial goals of urological management include maintaining safe storage of urine with efficient bladder emptying, maximising urinary continence, and minimising the risk of urological complications. METHODS: This review was performed according to the methodology recommended by the Joint SIU-ICUD International Consultation. Embase and Medline databases were used to identify literature relevant to the early urological care of SCI patients. Recommendations were developed by consensus and graded using a modified Oxford system which identifies level of evidence (LOE) and grade of recommendation (GOR). RESULTS: Clinicians must ensure appropriate bladder emptying immediately after SCI (LOE 3, GOR A) and perform the initial neuro-urological assessment within 3 months after injury (LOE 3, GOR A), including history, validated questionnaires, bladder diary, physical examination, measurement of renal function, and urinary tract imaging (LOE 4, GOR B). Urodynamics, if available video-urodynamics, must be performed to detect and specify lower urinary tract dysfunction (LOE 1, GOR A). Spontaneous voiding and/or intermittent catheterization must be considered in appropriate patients once they are medically stable (LOE 3, GOR A). Antimuscarinics are the first-line and intradetrusor botulinum toxin A injections are the second-line treatment for neurogenic detrusor overactivity (LOE 1, GOR A). Irreversible surgical interventions should be delayed until the second year after injury due to the potential for neurological recovery (LOE 4, GOR B). CONCLUSIONS: Careful clinical assessment and pertinent urological testing including urodynamic investigation are necessary for appropriate counselling and treatment of new SCI patients.

Intravesical vanilloids for treating neurogenic lower urinary tract dysfunction in patients with multiple sclerosis: A systematic review and meta-analysis. A report from the Neuro-Urology Promotion Committee of the International Continence Society (ICS).

AIMS: To systematically assess all available evidence on efficacy and safety of vanilloids for treating neurogenic lower urinary tract dysfunction (NLUTD) in patients with multiple sclerosis (MS). METHODS: This systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies were identified by electronic search of Cochrane register, Embase, Medline, Scopus, (last search January 8, 2016). RESULTS: After screening of 7848 abstracts, 4 randomized controlled trials (RCTs) and 3 prospective cohort studies were included. Pooled data from three RCTs evaluating intravesical capsaicin showed the standardized mean difference to be -2.16 (95% confidence interval [CI] -2.87 to -1.45) in incontinence episodes per 24 h and -0.54 (95%CI -1.03 to -0.05) in voids per 24 h. There was no statistically significant effect on maximum cystometric capacity and maximum storage detrusor pressure. Overall, adverse events were reported by >50% of the patients, most commonly were pelvic pain, facial flush, worsening of incontinence, autonomic dysreflexia, urinary tract infection and haematuria. Risk of bias and confounding was relevant in both RCTs and non-RCTs. CONCLUSIONS: Preliminary data suggest that intravesical vanilloids might be effective for treating NLUTD in patients with MS. However, the safety profile seems unfavorable, the overall quality of evidence is low and no licensed substance is currently available warranting well-designed, adequately sampled and properly powered RCTs.

Urodynamic measurements reflect physiological bladder function in rats.

AIMS: Our objective was to investigate and compare bladder function in rats assessed by metabolic cage and by urodynamic measurements in fully awake animals. METHODS: Bladder function of female Lewis rats was investigated in naïve animals by metabolic cage at baseline, 14-16 days after bladder catheter and external urethral sphincter electromyography electrode implantation in fully awake animals by urodynamics, and again by metabolic cage. RESULTS: Investigating the same animals (n = 8), voided volume, average flow, and duration of voiding were similar (P > 0.05) in naïve animals measured by metabolic cage and after catheter implantation by urodynamic measurements and by metabolic cage. In naïve animals measured by metabolic cage, voided volumes were significantly different in the light (resting phase) versus the dark (active phase) part of the 24 h cycle (mean difference 0.14 mL, 21%, P = 0.004, n = 27). CONCLUSIONS: Lower urinary tract function assessed by metabolic cage or by urodynamic meaurements in fully awake rats was indistinguishable. Thus, catheter implantation did not significantly change physiological bladder function. This shows that urodynamic measurements in awake animals are an appropriate approach to study lower urinary tract function in health and disease in animal models, directly paralleling the human diagnostic procedures.

Catheterization for treating neurogenic lower urinary tract dysfunction in patients with multiple sclerosis: A systematic review. A report from the Neuro-Urology Promotion Committee of the International Continence Society (ICS).

AIM: To systematically assess all available evidence on efficacy and safety of catheterization for treating neurogenic lower urinary tract dysfunction (NLUTD) in patients with multiple sclerosis (MS). METHODS: This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies were identified by electronic search of Embase, Medline, Scopus, Cochrane register (last search March 3, 2018) and by screening of reference lists and reviews. RESULTS: After screening 7'015 articles, we included four studies (one prospective and two retrospective cohort studies, one retrospective cross-sectional study), in which a total of 445 patients were enrolled. No randomized controlled trial was available. Catheterization substantially increased quality of life, post void residual, and incontinence episodes in all included studies. Pooling of data for meta-analysis was not possible due to the heterogeneity of reported outcomes. Adverse events were reported in two studies only. Risk of bias and confounding was intermediate. CONCLUSIONS: Preliminary data suggests beneficial effects of catheterization on the urological outcome in patients with MS. However, although intermittent and indwelling catheterization is used frequently in daily clinical practice in the MS population, the evidence base is very limited and well-designed, properly sampled, and powered studies are urgently needed.

Heterogeneity in reporting on urinary outcome and cure after surgical interventions for stress urinary incontinence in adult neuro-urological patients: A systematic review.

AIMS: To describe all outcome parameters and definitions of cure used to report on outcome of surgical interventions for stress urinary incontinence (SUI) in neuro-urological (NU) patients. METHODS: This systematic review was performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The study protocol was registered and published (CRD42016033303; http://www.crd.york.ac.uk/PROSPERO). Medline, Embase, Cochrane controlled trials databases, and clinicaltrial.gov were systematically searched for relevant publications until February 2017. RESULTS: A total of 3168 abstracts were screened. Seventeen studies reporting on SUI surgeries in NU patients were included. Sixteen different outcome parameters and nine definitions of cure were used. Six studies reported on objective outcome parameters mainly derived from urodynamic investigations. All studies reported on one or more subjective outcome parameters. Patient-reported pad use (reported during interview) was the most commonly used outcome parameter. Only three of 17 studies used standardized questionnaires (two on impact of incontinence and one on quality of life). Overall, a high risk of bias was found. CONCLUSIONS: We found a considerable heterogeneity in outcome parameters and definitions of cure used to report on outcome of surgical interventions for SUI in NU patients. The results of this systematic review may begin the dialogue to a future consensus on this topic. Standardization of outcome parameters and definitions of cure would enable researchers and clinicians to consistently compare outcomes of different studies and therapies.

Value of urodynamic findings in predicting upper urinary tract damage in neuro-urological patients: A systematic review.

AIM: The main goals of neurogenic lower urinary tract dysfunction (NLUTD) management are preventing upper urinary tract damage (UUTD), improving continence, and quality of life. Here, we aimed to systematically assess all available evidence on urodynamics predicting UUTD in patients with NLUTD. METHODS: A systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement was performed in March 2017. Only neuro-urological patients assessed by urodynamics were included. Any outcome of upper urinary tract function were evaluated. RESULTS: Forty-nine studies (1 randomized controlled trial, 9 prospective, and 39 retrospective case series) reported urodynamic data on 4930 neuro-urological patients. Of those, 2828 (98%) were spina bifida (SB) children. The total number of adults was 2044, mainly having spinal cord injury (SCI) (60%). A low bladder compliance was found in 568 (46.3%) and 341 (29.3%) of the paediatric and adult population, respectively. Hydronephrosis (HDN) was detected in 557 children (27.8%) in 19/28 studies and 178 adults (14.6%), mainly SCI, in 14/21 studies. Nine out of 30 multiple sclerosis (MS) patients affected by HDN (16.8%) showed low compliance in 4/14 studies. CONCLUSIONS: Patients with SB and SCI have a higher risk of developing UUTD (mainly reported as HDN) compared to those with MS. Reduced compliance and high DLPP were major risk factors for UUTD. Although our findings clarify the mandatory role of urodynamics in the management of NLUTD, standardization and better implementation of assessments in daily practice may further improve outcomes of neuro-urological patients based on objective measurements, that is, urodynamics.