Clinical Predictors of Neurogenic Lower Urinary Tract Dysfunction in Persons with Multiple Sclerosis.

BACKGROUND: Multiple sclerosis patients often develop neurogenic lower urinary tract dysfunction with a potential risk of upper urinary tract damage. Diagnostic tools are urodynamics, bladder diary, uroflowmetry, and post-void residual, but recommendations for their use are controversial. OBJECTIVE: We aimed to identify clinical parameters indicative of neurogenic lower urinary tract dysfunction in multiple sclerosis patients. METHODS: 207 patients were prospectively assessed independent of the presence of lower urinary tract symptoms. We analyzed Expanded Disability Status Scale scores, uroflowmetry, post-void residual, rate of urinary tract infections, standardized voiding frequency, and voided volume in correlation with urodynamic findings. RESULTS: We found a significant correlation between post-void residual (odds ratio (OR) 4.17, confidence interval (CI) 1.20-22.46), urinary tract infection rate (OR 3.91, CI 1.13-21.0), voided volume (OR 4.53, CI 1.85-11.99), increased standardized voiding frequency (OR 7.40, CI 2.15-39.66), and urodynamic findings indicative of neurogenic lower urinary tract dysfunction. Expanded Disability Status Scale shows no correlation. Those parameters (except post-void residual) are also associated with reduced bladder compliance, as potential risk for kidney damage. CONCLUSION: Therefore, bladder diary and urinary tract infection rate should be routinely assessed to identify patients who require urodynamics.

[Current aspects of neurogenic dysfunctions of the lower urinary tract in multiple sclerosis]. / Aktuelles zu neurogenen Dysfunktionen des unteren Harntraktes bei Multipler Sklerose.

BACKGROUND: In the clinical management of patients with multiple sclerosis (MS), the challenge is to make an early diagnosis and initiate adequate treatment of neurogenic disorders of the lower urinary tract (NLUTD). Various national guidelines provide practical recommendations which are sometimes discordant. OBJECTIVE: To develop a simple evidence-based algorithm for detecting NLUTD in patients with MS that could be taken as a principle for deriving therapeutic consequences. MATERIAL AND METHODS: A prospective multicenter study was initiated as a direct result of two multidisciplinary conferences. The aim was to identify statistically and clinically relevant parameters for the routine diagnosis of NLUTD in patients with MS. Urodynamic abnormalities served as the gold standard. At three subsequent consensus conferences, the results of the study were discussed, a diagnostic algorithm was developed and consensus was reached on a first-line treatment. RESULTS AND DISCUSSION: The proposed algorithm enables the detection of NLUTD in patients with MS with the help of four statistically significant predictors: 1) the residual urine volume, 2) the number of urinary tract infections (UTI) within the last 6 months, 3) the standardized micturition frequency and 4) the presence/absence of urinary incontinence. The newly developed algorithm has proved to be efficient with the following results: approximately 75% of the patients do not need a urodynamic examination for a first-line treatment decision. In 25% of cases, urodynamic examinations are essential for an adequate treatment decision. Routine assessments include the patient medical history, residual urine volume measurement, a micturition diary and a uroflowmetry (optional).

Real-World Goal Setting and Use of Outcome Measures According to the International Classification of Functioning, Disability and Health: A European Survey of Physical Therapy Practice in Multiple Sclerosis.

Goal setting is a core component of physical therapy in multiple sclerosis (MS). It is unknown whether and to what extent goals are set at different levels of the International Classification of Functioning, Disability and Health (ICF), and whether, and to which, standardized outcome measures are used in real life for evaluation at the different ICF levels. Our aim was to describe the real-world use of goal setting and outcome measures in Europe. An online cross-sectional survey, completed by 212 physical therapists (PTs) specialized in MS from 26 European countries, was conducted. Differences between European regions and relationships between goals and assessments were analyzed. PTs regularly set goals, but did not always apply the Specific, Measurable, Achievable, Realistic, Timed (SMART) criteria. Regions did not differ in the range of activities assessed, but in goals set (e.g., Western and Northern regions set significantly more goals regarding leisure and work) and outcome measures used (e.g., the Berg Balance Scale was more frequently used in Northern regions). Quality of life was not routinely assessed, despite being viewed as an important therapy goal. Discrepancies existed both in goal setting and assessment across European regions. ICF assists in understanding these discrepancies and in guiding improved health-care for the future.

Neurourological assessment in people with multiple sclerosis (MS): a new evaluated algorithm.

BACKGROUND: Neurogenic lower urinary tract dysfunction (NULTD) is common in patients with multiple sclerosis (MS); nevertheless, it is often underestimated, underdiagnosed, and undertreated due to patients' sense of shame, variability of symptoms, as well as lack of communication between neurologists and urologists, despite the availability of several guidelines based on scientific evidence and expert opinion. OBJECTIVE: This study was conducted to develop an easy-to-perform algorithm for diagnosing neurogenic lower urinary tract disease in patients with MS for daily neurological and urological routine, including the identification of red flags. METHODS: In consensus group meetings, interprofessional experts (neurologists, urologists, neurourologists, nurses, nurse practitioners, occupational therapists, physical therapists as well as representatives of national MS centers, self-care groups, social care, residential care, and health-aid-providers) developed a diagnostic algorithm to detect NULTD in patients with MS. Subsequently, the group evaluated the algorithm in 121 patients with MS using micturition diary, post-void residual volume, uroflowmetry, and urodynamic studies. Statistical analysis was conducted on the basis of logistic regression models to compare patients with normal and abnormal urodynamic examinations. Differentiation was performed using selected diagnostic parameters as well as standard performance measures for binary classifiers to assess prognostic quality. RESULTS: The following four parameters allowed to diagnose NLUTD in patients with MS: post-void residual urine volume, rate of urinary tract infections during the past 6 months, micturition frequency, and incontinence. According to statistical analysis, the following thresholds could be defined: post-void residual volume (PVR) ≥70 mL (Odds Ratio (OR) = 1.24; 95% CI:[1.07,1.62]), urinary tract infection (UTI) rate - none in 6 months (OR = 2.03; 95% CI:[1.04,6.68]), and micturition frequency >13/day, standardized on 2000 mL urine excretion (OR = 1.24; 95% CI:[1.07,1.49]). Uroflowmetry served as a further predictor of urodynamically measurable urinary bladder dysfunction (OR = 4.80; 95% CI: [1.41, 19.21]). Interestingly, patients without any complaints of NLUTD had an abnormal urodynamic examination in >50% of the cases. The entire algorithm has a sensitivity of 95%. CONCLUSIONS: All patients with MS should undergo a basic examination to detect NLUTDs. Within the algorithm developed in this study, four easy-to-collect parameters may reveal NLUTD in patients with MS.

Tetrahydrocannabinol and cannabidiol oromucosal spray in resistant multiple sclerosis spasticity: consistency of response across subgroups from the SAVANT randomized clinical trial.

Objective: To determine whether differences in disability status, spasticity severity, and spasticity duration at treatment start in patients with resistant multiple sclerosis (MS) spasticity might influence response to add-on tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray (nabiximols) versus further re-adjustment of optimized first-line antispasticity medication.Methods: Using the database from the Sativex® as Add-on therapy Vs. further optimized first-line ANTispastics (SAVANT) study, this post hoc analysis evaluated spasticity severity (0-10 numerical rating scale [NRS] scores) and pain severity (0-10 NRS scores) evolution from randomization (baseline) to week 12 (end of double-blind treatment) in defined subgroups: Expanded disability status scale [EDSS] score subgroups (<6 and ≥6); spasticity severity 0-10 NRS score subgroups (4 to ≤6 and >6), and spasticity duration subgroups (<5 and ≥5 years).Results: THC:CBD oromucosal spray (nabiximols) halved mean severity scores for spasticity and pain in all subgroups. Active treatment significantly improved mean spasticity severity scores versus placebo from week 4 onwards in both EDSS subgroups, in the severe spasticity subgroup, and in both spasticity duration subgroups. Active treatment significantly improved mean pain severity scores versus placebo in the ≥6 EDSS subgroup, in the severe spasticity subgroup and in both spasticity duration subgroups.Conclusion: Add-on THC:CBD oromucosal spray (nabiximols) consistently relieves resistant spasticity across subgroups defined by baseline EDSS score, spasticity severity NRS score and spasticity duration. Patients with moderate resistant MS spasticity benefit numerically from treatment; patients with severe resistant spasticity achieve significant therapeutic gains. Spasticity-associated pain often improves similarly in the same subgroups.

Content and Delivery of Physical Therapy in Multiple Sclerosis across Europe: A Survey.

Background: Guidelines and general recommendations are available for multiple sclerosis rehabilitation, but no specific guidance exists for physical therapists. Describing aspects of physical therapy content and delivery in multiple sclerosis and its determinants and analysing whether general recommendations connected with physical therapy are implemented in practice is important for interpreting clinical and research evidence. Methods: An online cross-sectional survey of physical therapists specialized in multiple sclerosis (212 specialists from 26 European countries) was used. Results: There was distinct diversity in service delivery and content across Europe. Perceived accessibility of physical therapy varied from most accessible in the Western region, and least in the Southern region. Sixty-four physical therapists adjusted their approach according to different disability levels, less so in the Eastern region. Duration, frequency and dose of sessions differed between regions, being highest in Southern and Western regions. "Hands on treatment" was the most commonly used therapeutic approach in all apart from the Northern regions, where "word instruction" (providing advice and information) prevailed. Conclusions: The content and delivery of physical therapy differs across Europe. Recommendations concerning access to treatment and adjustment according to disability do not appear to be widely implemented in clinical practice.

Physiotherapeutic interventions in multiple sclerosis across Europe: Regions and other factors that matter.

BACKGROUND: A wide variety of interventions exists in physical therapy (PT), but knowledge about their use across different geographical regions is limited. This study investigated the use of PT interventions in people with multiple sclerosis (MS) across Europe. It aimed to determine whether regions differ in applying interventions, and explore whether factors other than regions play a role in their use. METHODS: In an online cross-sectional survey, 212 respondents from 115 European workplaces providing PT services to people with MS representing 26 countries (four European regions) participated. Cluster analysis, Pearson Chi-squared test and a Poisson regression model were used to analyze the data. RESULTS: Thirteen of 45 listed PT interventions were used by more than 75% of centers, while nine interventions were used by less than 25%. For 12 interventions, regions differed markedly in their use. Cluster analysis of centers identified four clusters similar in their intervention use. Cluster assignment did not fully align with regions. While center region was important, center size, number and gender of physical therapists working in the center, and time since qualification also played a role. Cluster analysis exploring the use of the interventions provided the basis for a categorization of PT interventions in line with their primary focus: 1. Physical activity (fitness/endurance/resistance) training; 2. Neuroproprioceptive "facilitation/inhibition"; 3. Motor/skill acquisition (individualized therapy led); 4. Technology based interventions. CONCLUSIONS: To our knowledge this is the first study that has explored this topic in MS. The results broaden our understanding of the different PT interventions used in MS, as well as the context of their use.

Cannabinoids therapeutic use: what is our current understanding following the introduction of THC, THC:CBD oromucosal spray and others?

INTRODUCTION: The complexity of the endocannabinoid (eCB) system is becoming better understood and new drivers of eCB signaling are emerging. Modulation of the activities of the eCB system can be therapeutic in a number of diseases. Research into the eCB system has been paralleled by the development of agents that interact with cannabinoid receptors. In this regard it should be remembered that herbal cannabis contains a myriad of active ingredients, and the individual cannabinoids have quite distinct biological activities requiring independent studies. Areas covered: This article reviews the most important current data involving the eCB system in relation to human diseases, to reflect the present (based mainly on the most used prescription cannabinoid medicine, THC/CBD oromucosal spray) and potential future uses of cannabinoid-based therapy. Expert commentary: From the different therapeutic possibilities, THC/CBD oromucosal spray has been in clinical use for approximately five years in numerous countries world-wide for the management of multiple sclerosis (MS)-related moderate to severe resistant spasticity. Clinical trials have confirmed its efficacy and tolerability. Other diseases in which different cannabinoids are currently being investigated include various pain states, Alzheimer's disease, Parkinson's disease, Huntington's disease and epilepsy. The continued characterization of individual cannabinoids in different diseases remains important.

The organisation of physiotherapy for people with multiple sclerosis across Europe: a multicentre questionnaire survey.

BACKGROUND: Understanding the organisational set-up of physiotherapy services across different countries is increasingly important as clinicians around the world use evidence to improve their practice. This also has to be taken into consideration when multi-centre international clinical trials are conducted. This survey aimed to systematically describe organisational aspects of physiotherapy services for people with multiple sclerosis (MS) across Europe. METHODS: Representatives from 72 rehabilitation facilities within 23 European countries completed an online web-based questionnaire survey between 2013 and 2014. Countries were categorised according to four European regions (defined by United Nations Statistics). Similarities and differences between regions were examined. RESULTS: Most participating centres specialized in rehabilitation (82 %) and neurology (60 %), with only 38 % specialising in MS. Of these, the Western based Specialist MS centres were predominately based on outpatient services (median MS inpatient ratio 0.14), whilst the Eastern based European services were mostly inpatient in nature (median MS inpatient ratio 0.5). In almost all participating countries, medical doctors - specialists in neurology (60 %) and in rehabilitation (64 %) - were responsible for referral to/prescription of physiotherapy. The most frequent reason for referral to/prescription of physiotherapy was the worsening of symptoms (78 % of centres). Physiotherapists were the most common members of the rehabilitation team; comprising 49 % of the team in Eastern countries compared to approximately 30 % in the rest of Europe. Teamwork was commonly adopted; 86 % of centres based in Western countries utilised the interdisciplinary model, whilst the multidisciplinary model was utilised in Eastern based countries (p = 0.046). CONCLUSION: This survey is the first to provide data about organisational aspects of physiotherapy for people with MS across Europe. Overall, care in key organisational aspects of service provision is broadly similar across regions, although some variations, for example the models of teamwork utilised, are apparent. Organisational framework specifics should be considered anytime a multi-centre study is conducted and results from such studies are applied.

Direct observation of prefreezing at the interface melt-solid in polymer crystallization.

Crystallization is almost always initiated at an interface to a solid. This observation is classically explained by the assumption of a reduced barrier for crystal nucleation at the interface. However, an interface can also induce crystallization by prefreezing (i.e., the formation of a crystalline layer that is already stable above the bulk melting temperature). We present an atomic force microscopy (AFM)-based in situ observation of a prefreezing process at the interface of a polymeric model system and a crystalline solid. Explicitly, we show an interfacial ordered layer that forms well above the bulk melting temperature with thickness that increases on approaching melt-solid coexistence. Below the melting temperature, the ordered layer initiates crystal growth into the bulk, leading to an oriented, homogeneous semicrystalline structure.

Linguistic and psychometric validation of the MSSS-88 questionnaire for patients with multiple sclerosis and spasticity in Germany.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory disease where many of the patients suffer from spasticity impacting their quality-of-life. The purpose of this paper was to linguistically validate and psychometrically test the Multiple Sclerosis Spasticity Scale (MSSS-88) in German speaking MS patients. METHODS: The study had two stages: 1) forward/backward translations of the original MSSS-88 scale into German, discussions with MS-experts and cognitive debriefings with MS patients; 2) psychometric evaluation of the German version. Data collection took part in an observational multi-centre study in Germany (MOVE2). RESULTS: The German translation of the MSSS-88 scale was discussed with three MS-experts; followed by two cognitive debriefing sessions with 12 MS patients. For psychometric evaluation the MSSS-88 was filled in by 87 MS patients with a mean age of 50.2 ± 10.4 years; 26.4% of them had severe spasticity. Data quality was acceptable. Missing data for items of the MSSS-88 were low (range 0-5.75%). Psychometric testing of the MSSS-88 revealed excellent values for reliability and validity. Significant differences between groups regarding severity, grading, type and self-ratings of MS-spasticity and sleep disturbances were found. Sensitivity to change could be demonstrated for the MSSS-88 in the group of MS patients treated with cannabinoid oromucosal spray vs. non-treated patients. In the treated group significant changes with a moderate effect size were found for 'muscle spasms', 'emotional health' and 'pain/discomfort'. No significant changes could be detected in the non-treated group. CONCLUSION: Preliminary evidence from this small study supports reliability, validity, and responsiveness of the German version of the MSSS-88 for measuring the impact of spasticity in MS.

Long-term effectiveness and safety of nabiximols (tetrahydrocannabinol/cannabidiol oromucosal spray) in clinical practice.

BACKGROUND: Nabiximols (Sativex®), in a cannabinoid-based oromucosal spray, is an add-on therapy option for patients with moderate to severe multiple sclerosis spasticity (MSS) resistant to other medications. The study objective was to provide long-term data on clinical outcomes, tolerability, quality of life and treatment satisfaction for MSS patients receiving nabiximols in routine care. METHODS: This was the 12-month prolongation of the MOVE 2 study, an observational, prospective, multi-centre 3-month non-interventional study conducted in a routine care setting across Germany. Structured documentation forms, questionnaires and validated instruments were used for data collection. RESULTS: In total, 52 patients were included in the effectiveness analysis after 12 months. The mean spasticity numerical rating scale (NRS, 0-10) score decreased significantly from 6.0 ± 1.8 points at MOVE 2 baseline to 4.8 ± 1.9 points after 1 month and remained on this level after 12 months (4.5 ± 2.0 points); in patients classified as 'initial responders' (≥20% NRS improvement after 1 month) similar results were found (baseline: 6.3 ± 1.4 points; after 1 month: 4.0 ± 1.0 points; after 12 months: 4.3 ± 1.9 points). The majority of patients (84%) did not report adverse events. CONCLUSION: Real-life data confirm the long-term effectiveness and tolerability of nabiximols for the treatment of resistant MSS in everyday clinical practice.

Nabiximols (THC/CBD oromucosal spray, Sativex®) in clinical practice--results of a multicenter, non-interventional study (MOVE 2) in patients with multiple sclerosis spasticity.

BACKGROUND: Nabiximols (Sativex®), a cannabinoid-based oromucosal spray, is an add-on therapy for patients with moderate to severe multiple sclerosis spasticity (MSS) resistant to other medications. The primary objective was to provide real-life observational data of clinical experience of nabiximols in contrast to formal clinical trials of effectiveness. METHODS: This was an observational, prospective, multicenter, non-interventional study with a follow-up period of 3-4 months, conducted in routine care setting in Germany. Patients with moderate to severe MSS were included at nabiximols' initiation. Structured documentation forms, questionnaires and validated instruments were used for data collection at inclusion, 1 and 3 months after inclusion. RESULTS: Overall, 335 patients were assessed of whom 276 fitted the criteria and were included in the effectiveness analysis. After 1 month, nabiximols provided relief of resistant MSS in 74.6% of patients according to specialist assessment; mean spasticity 0-10 numerical rating scale (NRS) score decreased from 6.1 ± 1.8 to 5.2 ± 2.0 points; in patients with NRS improvement ≥20% mean NRS score decreased by 40%. After 3 months, 55.3% of patients had continued to use nabiximols and the mean NRS score had decreased by 25% from baseline. 17% of patients reported adverse events. CONCLUSION: Real-life data confirm nabiximols as an effective and well-tolerated treatment option for resistant MSS in clinical practice.

Burden of disease in multiple sclerosis patients with spasticity in Germany: mobility improvement study (Move I).

OBJECTIVES: To describe the current management patterns of multiple sclerosis (MS) patients with spasticity in Germany and the impact of MS spasticity on quality of life (QoL) and associated costs. METHODS: Non-interventional, multicentre, cross-sectional and retrospective burden-of-disease study including 414 MS patients with spasticity (age from 25 to 80 years) from 42 clinical practices across Germany. All patients were diagnosed with MS-related spasticity based on neurological examination at least 12 months before inclusion in the study. Three different forms were completed on different aspects of the disease: the patient questionnaire, the chart documentation form and the physician questionnaire. RESULTS: Mild, moderate and severe spasticity were found in 27.3, 44.0 and 28.7 % of patients, respectively. Associated symptoms and QoL scores were worse in patients with higher degrees of spasticity. In particular, higher mean scores for sleep impairment (mild vs. severe, 2.1 vs. 4.3), mean spasm count (3/day vs. 10.1/day), mean WEIMuS fatigue score (15.8 vs. 19.8), increased walking time (9.6 vs. 20.2 s) and lower mean QoL scores (MSQoL-54 physical subscale, 54.9 vs. 39.5; EQ-5D, 0.60 vs. 0.30) were reported in patients with severe spasticity in comparison to patients with mild spasticity. Patient management mainly comprised physiotherapy (mild vs. severe, 65.5 vs. 85.7 %) and medication (84.2 vs. 64.8 %) with baclofen. The average cost for patients with mild spasticity was €2,268/year, increasing to €8,688/patient/year for patients with severe spasticity. The health insurance costs showed the same trend. CONCLUSIONS: MS patients with spasticity suffer a significant burden because of resulting disabilities and reduced QoL, especially in cases of severe spasticity. Moreover, spasticity causes high costs that increase with increasing severity.

Investigation of the different stable states of the cantilever oscillation in an atomic force microscope.

We present an algorithm which allows us to identify all possible stable states of the cantilever oscillation of an AFM operated in the intermittent contact mode within the harmonic approximation. The oscillatory states are qualified as quasi-free, net-attractive and net-repulsive solutions. Using a generic model for the tip-sample interaction the influence of a number of important experimental parameters on the state of oscillation is systematically studied. The analysis gives conditions under which an AFM can be operated in a chosen state. As an exemplary experimental application we compare selected measurements on a semicrystalline polymer acquired in the net-repulsive and the net-attractive mode with simulations based on the approach introduced here. The experiments indicate that a small indentation below one nanometer in the net-attractive mode is enough to produce phase contrast.

Emerging evidence-based physical rehabilitation for multiple sclerosis - towards an inventory of current content across Europe.

In Europe, theoretical approaches to physical therapy and rehabilitation in multiple sclerosis often appear significantly different. While there is general agreement that rehabilitation plays an important role in maintaining and improving function in persons with multiple sclerosis, no consensus exists on what may be the most effective approach to achieve the best possible functionality within an individual's limitations.The objective of this paper is to initiate an analysis of currently applied physical interventions for people with multiple sclerosis throughout Europe during inpatient or outpatient rehabilitation programs. A study of the content of rehabilitation may show presently performed treatment methods revealing the basic considerations that nowadays guide clinicians implicitly or explicitly in the treatment of persons with multiple sclerosis. Following this first step, comparative studies can be set up.

Hierarchical organization of poly(ethylene oxide)-block-poly(isobutylene) and hydrophobically modified Fe(2)O(3) nanoparticles at the air/water interface and on solid supports.

Langmuir monolayers and Langmuir-Blodgett (LB) film morphologies of block copolymers and hydrophobically modified iron oxide nanoparticles were studied by surface pressure-mean molecular area (pi-mmA) measurements and by tapping mode atomic force microscopy (AFM). The amphiphilic diblock copolymers consisted of a hydrophilic poly(ethylene oxide) (PEO) block and a hydrophobic poly(isobutylene) (PIB) block. The pi-mmA isotherm of PEO(97)-b-PIB(37) (the subscripts refer to the respective degrees of polymerization) at the air/water interface had an extended plateau reflecting the extension of PEO chains into the water subphase at a surface pressure of 10 mN.m(-1), which is absent for the more hydrophobic PEO(19)-b-PIB(130). Iron oxide (Fe(2)O(3)) nanoparticles capped with oleic acid ligands as the shell were dispersed in the amphiphilic block copolymers at the air/water interface to prevent macroscopic aggregation of the particles. When the nanoparticles were mixed with PEO(97)-b-PIB(37), using a particle to polymer chain ratio of 1:100, macroscopic aggregation of the nanoparticles was not observed, and the pi-mmA isotherm was dominated by PEO(97)-b-PIB(37). Monolayers of block copolymers were transferred at different surface pressures from the air/water interface to hydrophilic silicon substrates using the Langmuir-Blodgett technique. The AFM images of PEO(97)-b-PIB(37) LB films depicted not only the typical finger-like morphology of the crystallized PEO blocks but also PIB blocks arranged in vertical columns growing perpendicular to the substrate surface. The columns are characteristic for PEO(19)-b-PIB(130) LB films after transfer at high surface pressures and can be assigned to a mesomorphic PIB phase with ordered chains. Finally, it was observed that small clusters of a few Fe(2)O(3) nanoparticles occupy the top of PIB phases after compression and transfer of the block copolymer nanoparticle mixtures to solid supports.