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).

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.

Multidisciplinary management of multiple sclerosis symptoms.

BACKGROUND: Effective management of multisymptomatic chronic diseases such as multiple sclerosis (MS) requires a multimodal, interdisciplinary approach. At MS clinics, numerous healthcare specialties are coordinated to provide patients with quality clinical care for all aspects of their disease. Settings and resource availability may vary between countries. Four specific specialty services from different EU countries are examined in more detail. SUMMARY: The multidisciplinary neurorehabilitation team in Rennes, France, provides specialized consultations (e.g. spasticity, urodynamic unit, devices), inpatient and outpatient intensive rehabilitation programs and therapeutic education. Management approaches are based on a patient's level of impairment as assessed by the Expanded Disability Status Scale. In Girona, Spain, neuropsychologists perform assessments as part of the neurological protocol for all patients with MS. Depending on the level of impairment and patients' characteristics (e.g. working or not working), cognitive deficits may be treated at home or at a neurorehabilitation center. In Barcelona, Spain, neuro-ophthalmologists are involved in the differential diagnosis and follow-up care of MS patients with visual disturbances; particular attention is given to patients' vision-related quality of life. Pain specialists at the Marianne Strauß Klinik in Berg, Germany, have developed a system for classifying MS pain syndromes and differentiating MS-related pain from non MS-related pain. Chronic pain management involves numerous disciplines and requires active engagement by patients in developing treatment plans. Key Messages: MS affects several body systems and patients invariably require specialized interdisciplinary support. Insight into services provided by various specialties and their fit within multidisciplinary care models at MS centers may facilitate the design or refinement of care models in other locations.

Clinical experience with THC:CBD oromucosal spray in patients with multiple sclerosis-related spasticity.

This detailed medical charts' data collection study conducted at a multiple sclerosis (MS) clinic in Germany evaluated the effectiveness of tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray in patients with resistant MS spasticity. Over a 15-month timeframe, THC:CBD spray was initiated in 166 patients. Mean follow-up was 9 months. In all, 120 patients remained on treatment for a response rate of 72%. THC:CBD spray was used as add-on therapy in 95 patients and as monotherapy in 25 patients to achieve best-possible therapeutic results. Among responders, the mean spasticity 0-10 numerical rating scale (NRS) score decreased by 57%, from 7.0 before treatment to 3.0 within 10 days of starting THC:CBD spray. The mean dosage was 4 sprays/day. Most patients who withdrew from treatment (40/46) had been receiving THC:CBD spray for less than 60 days. Main reasons for treatment discontinuation were: adverse drug reactions, mainly dizziness, fatigue and oral discomfort (23 patients; 13.9%); lack of efficacy (14 patients; 8.4%); or need for a baclofen pump (9 patients; 5.4%). No new safety signals were noted with THC:CBD spray during the evaluation period. In this routine clinical practice setting at an MS clinic in Germany, THC:CBD spray was effective and well tolerated as add-on therapy or as monotherapy in a relevant proportion of patients with resistant MS spasticity.

Current management of pain associated with multiple sclerosis.

While pain is a common problem in patients with multiple sclerosis (MS), it is not frequently mentioned by patients and a more direct approach is required in order to obtain information about pain from patients. Many patients with MS experience more than one pain syndrome; combinations of dysaesthesia, headaches and/or back or muscle and joint pain are frequent. For each pain syndrome a clear diagnosis and therapeutic concept needs to be established. Pain in MS can be classified into four diagnostically and therapeutically relevant categories: (i) neuropathic pain due to MS (pain directly related to MS); (ii) pain indirectly related to MS; (iii) MS treatment-related pain; and (iv) pain unrelated to MS. Painful paroxysmal symptoms such as trigeminal neuralgia (TN), or painful tonic spasms are treated with antiepileptics as first choice, e.g. carbamazepine, oxcarbazepine, lamotrigine, gabapentin, pregabalin, etc. Painful 'burning' dysaesthesias, the most frequent chronic pain syndrome, are treated with TCAs such as amitriptyline, or antiepileptics such as gabapentin, pregabalin, lamotrigine, etc. Combinations of drugs with different modes of action can be particularly useful for reducing adverse effects. While escalation therapy may require opioids, there are encouraging results from studies regarding cannabinoids, but their future role in the treatment of MS-related pain has still to be determined. Pain related to spasticity often improves with adequate physiotherapy. Drug treatment includes antispastic agents such as baclofen or tizanidine and in patients with phasic spasticity, gabapentin or levetiracetam are administered. In patients with severe spasticity, botulinum toxin injections or intrathecal baclofen merit consideration. While physiotherapy may ameliorate malposition-induced joint and muscle pain, additional drug treatment with paracetamol (acetaminophen) or NSAIDs may be useful. Moreover, painful pressure lesions should be avoided by using optimally adjusted aids. Treatment-related pain associated with MS can occur with subcutaneous injections of interferon-beta or glatiramer acetate, and may be reduced by optimizing the injection technique and by local cooling. Systemic (particularly 'flu-like') adverse effects of interferons, e.g. myalgias, can be reduced by administering paracetamol, ibuprofen or naproxen. A potential increase in the frequency of pre-existing headaches after starting treatment with interferons may require optimization of headache attack therapy or even prophylactic treatment. Pain unrelated to MS, such as back pain or headache, is common in patients with MS and may deteriorate as a result of the disease. In summary, a careful analysis of each pain syndrome will allow the design of the appropriate treatment plan using various medical and nonmedical options (multimodal therapy), and will thus help to improve the quality of life (QOL) of the patients.

Late-onset tumor necrosis factor receptor-associated periodic syndrome in multiple sclerosis patients carrying the TNFRSF1A R92Q mutation.

OBJECTIVE: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal-dominantly inherited autoinflammatory disorder caused by mutations in the TNFRSF1A gene. It is characterized by episodes of autoinflammation usually associated with fever, abdominal pain, myalgia, exanthema, arthralgia/arthritis, and ocular involvement. We undertook this study to investigate the prevalence of TRAPS in patients with multiple sclerosis (MS) who reported, in addition to their neurologic symptoms, at least 2 other symptoms compatible with TRAPS. METHODS: Twenty-five unrelated MS patients were prospectively screened for TNFRSF1A mutations. In addition, blood samples from 365 unrelated MS patients and 407 unrelated Caucasian controls were analyzed to determine the R92Q carrier frequency. RESULTS: Six of 25 adult MS patients (24%) with symptoms suggestive of TRAPS were found to carry the identical arginine-to-glutamine substitution at amino acid position 92 (R92Q or p.Arg121Gln) encoded by exon 4 of the TNFRSF1A gene. All R92Q heterozygotes had similar symptoms, including arthralgias/arthritis, myalgias, urticarial rash, and severe fatigue, which began before the onset of MS. In 5 of the 6 patients, we could identify family members who had TRAPS symptoms and had inherited the identical mutation. The R92Q exchange was also detected in 17 of 365 unselected MS patients (4.66%) and in 12 of 407 controls (2.95%) (P = 0.112). Three patients were heterozygous carriers of MEFV variants, in 1 patient in combination with the R92Q mutation. CONCLUSION: Autoinflammatory syndromes and especially late-onset TRAPS should be considered in MS patients who report symptoms such as arthralgias/arthritis, myalgias, urticarial rash, and severe fatigue.

Steps towards a miniaturized, robust and autonomous measurement device for the long-term monitoring of patient activity: ActiBelt.

We describe the first steps in the development of a wearable measurement device for measuring a subject's three-dimensional acceleration. The ultimate aim is a standard measurement instrument integrated in a belt buckle that allows objective evaluation of treatment and rehabilitation measures in patients, in particular for disabling chronic diseases such as multiple sclerosis. In a first step we combined standard hardware elements to record test data from healthy volunteers. We then developed algorithms to automatically distinguish between different stages of activity, such as jogging, walking, lying, standing and sitting, and to detect and count steps. Distinction between standing and sitting is the most difficult to accomplish. As a first validation, we calculated the distance traveled from data of 17 experiments and a total of 4.5 h, for which one proband was walking and running for a known distance, and compared the results with two commercially available pedometers. We could show that the relative error for the ActiBelt is only half of that for the two pedometers. Apart from developing much smaller, robust and integrated hardware, we describe ideas on how to develop algorithms that allow extraction of a "baseline step pattern" in analogy to baseline ECG to define and detect clinically relevant deviations.

The effect of glatiramer acetate treatment on pre-existing headaches in patients with MS.

During the first 6 months of glatiramer acetate therapy in 82 consecutive patients with multiple sclerosis, in only 6% frequency of pre-existing headaches increased by more than 50%. This is less than the headache aggravation reported in an earlier study in up to 35% of patients during the first 6 months on interferon beta.

Osmotic force-controlled microrheometry of entangled actin networks.

In studying a magnetic bead's creep response to force pulses in an entangled actin network we have found a novel regime where the bead motion obeys a power law x(t) approximately t(1/2) over two decades in time. It is flanked by a short-time regime with x(t) approximately t(3/4) and a viscous with x(t)approximately t. In the intermediate regime the creep compliance depends on the actin concentration c as c(-beta) with beta approximately 1.1 +/- 0.3. We explain this behavior in terms of osmotic restoring force generated by the piling up of filaments in front of the moving bead. A model based on this concept predicts intermediate x(t) approximately t(1/2) and long-time regimes x(t) approximately t in which the compliance varies as c(-4/3), in agreement with experiment.

Microviscoelasticity of the apical cell surface of human umbilical vein endothelial cells (HUVEC) within confluent monolayers.

We studied the local viscoelasticity of the apical membrane of human umbilical vein endothelial cells within confluent layers by magnetic tweezers microrheometry. Magnetic beads are coupled to various integrins by coating with fibronectin or invasin. By analyzing the deflection of beads evoked by various force scenarios we demonstrate that the cell envelope behaves as a linear viscoelastic body if forces up to 2 nN are applied for short times (<20 s) but can respond in an adaptive way if stress pulses are applied longer (>30 s). The time-dependent shear relaxation modulus G(t) exhibits three time regimes: a fast response (t < 0.05 s) where the relaxation modulus G(t) obeys a power law G(t) approximately t(-0.82+/-0.02); a plateau-like behavior (at 0.05 s < t < 0.15 s); and a slow flow-like response which is, however, partially reversible. Strain field mapping experiments with colloidal probes show that local forces induce a strain field exhibiting a range of zeta = 10 +/- 1 microm, but which could only be observed if nonmagnetic beads were coupled to the cell surface by invasin. By application of the theory of elasticity of planar bodies we estimated a surface shear modulus of 2.5 x10(-4) N/m. By assuming a thickness of the actin cortex of approximately 0.5 microm we estimate a Young modulus micro approximately 400 Pa for the apical membrane. The value agrees with a plateau modulus of an entangled or weakly cross-linked actin network of an actin concentration of 100 microM (mesh size 0.2 microm). This result together with our observation of a strong reduction of the shear modulus by the actin destabilizing agent latrunculin A suggests that the shear modulus measured by our technique is determined by the actin cortex. The effect of two ligands inducing actin stress fiber formation and centripetal contraction of cells (associated with the formation of gaps in the confluent cell monolayer) on the viscoelastic responses were studied: histamine and lysophosphatidic acid (LPA). Histamine evoked a dramatic increase of the cell stiffness by >1 order of magnitude within <30 s, which is attributed to a transient rise of the intracellular Ca(2+) level, since DMSO exerted a similar effect. The stiffening is accompanied by a concomitant rounding of the cells as observed by microinterferometry and relaxes partially in the timescale of 5 min, whereas gaps between cells close after approximately 30 min. LPA did not exert a remarkable and reproducible effect other than an occasional very weak transient increase of the shear stiffness, which shows that the gap formation activated by LPA is mediated by a different mechanism than that induced by histamine.