Background and purpose
Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years. There is therefore a need for a reference tool compiling current data to aid ...professionals in treatment decisions. The objective was to develop an evidence‐based clinical practice guideline for the pharmacological treatment of people with MS.
Methods
This guideline has been developed using the GRADE methodology and following the updated EAN recommendations for guideline development. Clinical questions were formulated in PICO format (patient, intervention, comparator, outcome) and outcomes were prioritized according to their relevance to clinical practice. Literature searches up to December 2016 were performed and the evidence is presented narratively and, when possible, combined in a meta‐analysis. The quality of evidence was rated into four categories – very high, high, low and very low − according to the risk of bias. The recommendations with assigned strength (strong, weak) were formulated based on the quality of evidence and the risk−benefit balance. Consensus between the panelists was reached by use of the modified nominal group technique.
Results
A total of 10 questions have been agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease‐modifying drugs approved by the European Medicine Agency at the time of publication. A total of 21 recommendations were agreed by the guideline working group members after three rounds of consensus.
Conclusion
The present guideline, which includes descriptions of the evidence together with recommendations, will enable homogeneity of treatment decisions across Europe.
Accumulating evidence supports a major role of B cells in multiple sclerosis (MS) pathogenesis. How B cells are recruited to the CNS is incompletely understood. Our objective was to study B-cell ...chemokine concentrations in MS, their relationship with disease activity, and how treatment with methylprednisolone and natalizumab affected the concentration in CSF.
Using a cross-sectional design, CSF and blood samples were obtained from cohorts of patients with clinically isolated syndromes (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), or secondary progressive MS (SPMS), and noninflammatory neurologic disease control subjects. Some patients with RRMS were studied before and after treatment with methylprednisolone or natalizumab.
In CSF, concentrations of CXCL13, but not CXCL12, were higher in patients with CIS, RRMS, SPMS, and PPMS than in controls. CSF concentrations of CXCL13 correlated with the CSF B-cell count, with markers of immune activation, and with disease activity in patients with CIS and RRMS. CSF concentrations of CXCL13 decreased after treatment with high-dose methylprednisolone and natalizumab. High CSF concentrations of CXCL13 correlated with low expression of messenger RNA encoding the immunoregulatory cytokines interleukin 10 and transforming growth factor beta1, but not with the expression of T-helper type 1 (Th1) and Th17 factors.
The chemokine CXCL13 may play a major role in recruitment of B cells and T-cell subsets expressing the chemokine receptor CXCR5 to the CNS in multiple sclerosis (MS), and may be a useful biomarker for treatment effects in MS. Furthermore, CXCL13 or its receptor CXCR5 should be considered as therapeutic targets in MS.
Increasing quantities of atmospheric anthropogenic fixed nitrogen entering the open ocean could account for up to about a third of the ocean's external (nonrecycled) nitrogen supply and up to ∼30% of ...the annual new marine biological production, ∼0.3 petagram of carbon per year. This input could account for the production of up to ∼1.6 teragrams of nitrous oxide ($\text{N}_{2}\text{O}$) per year. Although ∼10% of the ocean's drawdown of atmospheric anthropogenic carbon dioxide may result from this atmospheric nitrogen fertilization, leading to a decrease in radiative forcing, up to about two-thirds of this amount may be offset by the increase in$\text{N}_{2}\text{O}$emissions. The effects of increasing atmospheric nitrogen deposition are expected to continue to grow in the future.
Tryptophan-like fluorescence (TLF) is used to indicate anthropogenic inputs of dissolved organic matter (DOM), typically from wastewater, in rivers. We hypothesised that other sources of DOM, such as ...groundwater and planktonic microbial biomass can also be important drivers of riverine TLF dynamics. We sampled 19 contrasting sites of the River Thames, UK, and its tributaries. Multivariate mixed linear models were developed for each site using 15 months of weekly water quality observations and with predictor variables selected according to the statistical significance of their linear relationship with TLF following a stepwise procedure. The variables considered for inclusion in the models were potassium (wastewater indicator), nitrate (groundwater indicator), chlorophyll-a (phytoplankton biomass), and Total bacterial Cells Counts (TCC) by flow cytometry. The wastewater indicator was included in the model of TLF at 89 % of sites. Groundwater was included in 53 % of models, particularly those with higher baseflow indices (0.50–0.86). At these sites, groundwater acted as a negative control on TLF, diluting other potential sources. Additionally, TCC was included positively in the models of six (32 %) sites. The models on the Thames itself using TCC were more rural sites with lower sewage inputs. Phytoplankton biomass (Chlorophyll-a) was only used in two (11 %) site models, despite the seasonal phytoplankton blooms. It is also notable that, the wastewater indicator did not always have the strongest evidence for inclusion in the models. For example, there was stronger evidence for the inclusion of groundwater and TCC than wastewater in 32 % and 5 % of catchments, respectively. Our study underscores the complex interplay of wastewater, groundwater, and planktonic microbes, driving riverine TLF dynamics, with their influence determined by site characteristics.
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•Wastewater omnipresent significant predictor of TLF dynamics, but importance varies•Groundwater is a dilutionary control on TLF in groundwater-dominated sub-catchments.•Microbial sources significant in 52 % of sub-catchments•Complex interplay of wastewater, baseflow and microbial sources drive TLF dynamics.•Importance of different sources depends on sub-catchment characteristics.
Large eddy simulations (LES) of wind farms have the capability to provide valuable and detailed information about the dynamics of wind turbine wakes. For this reason, their use within the wind energy ...research community is on the rise, spurring the development of new models and methods. This review surveys the most common schemes available to model the rotor, atmospheric conditions and terrain effects within current state-of-the-art LES codes, of which an overview is provided. A summary of the experimental research data available for validation of LES codes within the context of single and multiple wake situations is also supplied. Some typical results for wind turbine and wind farm flows are presented to illustrate best practices for carrying out high-fidelity LES of wind farms under various atmospheric and terrain conditions.
This article is part of the themed issue ‘Wind energy in complex terrains’.
Background and purpose: Neuromyelitis optica (NMO) or Devic′s disease is a rare inflammatory and demyelinating autoimmune disorder of the central nervous system (CNS) characterized by recurrent ...attacks of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM), which is distinct from multiple sclerosis (MS). The guidelines are designed to provide guidance for best clinical practice based on the current state of clinical and scientific knowledge.
Search strategy: Evidence for this guideline was collected by searches for original articles, case reports and meta‐analyses in the MEDLINE and Cochrane databases. In addition, clinical practice guidelines of professional neurological and rheumatological organizations were studied.
Results: Different diagnostic criteria for NMO diagnosis Wingerchuk et al. Revised NMO criteria, 2006 and Miller et al. National Multiple Sclerosis Society (NMSS) task force criteria, 2008 and features potentially indicative of NMO facilitate the diagnosis. In addition, guidance for the work‐up and diagnosis of spatially limited NMO spectrum disorders is provided by the task force. Due to lack of studies fulfilling requirement for the highest levels of evidence, the task force suggests concepts for treatment of acute exacerbations and attack prevention based on expert opinion.
Conclusions: Studies on diagnosis and management of NMO fulfilling requirements for the highest levels of evidence (class I–III rating) are limited, and diagnostic and therapeutic concepts based on expert opinion and consensus of the task force members were assembled for this guideline.
Click here for the corresponding questions to this CME article.
Data on the risk factors for venous thromboembolism among patients undergoing total hip replacement and receiving pharmacological thromboprophylaxis are limited. The purpose of this study was to ...examine potential patient-related risk factors for venous thromboembolism following total hip replacement in a nationwide follow-up study.
Using medical databases, we identified all patients who underwent primary total hip replacement and received pharmacological thromboprophylaxis in Denmark from 1995 to 2006. The outcome measure was hospitalization with venous thromboembolism within ninety days of surgery. We considered age, sex, indication for primary total hip replacement, calendar year of surgery, and comorbidity history as potential risk factors.
The overall rate of hospitalization for venous thromboembolism within ninety days following a primary total hip replacement was 1.02% (686 hospitalizations after 67,469 procedures) at a median of twenty-two days. The incidence of symptomatic deep venous thrombosis and of nonfatal pulmonary embolism was 0.7% (499 of 67,469) and 0.3% (205 of 67,469), respectively. The incidence of death due to venous thromboembolism or from all causes was 0.05% (thirty-eight patients) and 1.0% (678 patients), respectively. Patients with rheumatoid arthritis had a reduced relative risk for venous thromboembolism compared with patients with primary osteoarthritis (adjusted relative risk = 0.47; 95% confidence interval, 0.25 to 0.90). Patients with a high score on the Charlson comorbidity index had an increased relative risk for venous thromboembolism compared with patients with a low score (adjusted relative risk = 1.45; 95% confidence interval, 1.02 to 2.05). Patients with a history of cardiovascular disease (relative risk = 1.40; 95% confidence interval, 1.15 to 1.70) or prior venous thromboembolism (relative risk = 8.09; 95% confidence interval, 6.07 to 10.77) had an increased risk for venous thromboembolism compared with patients without that history.
The cumulative incidence of a venous thromboembolism within ninety days of surgery among patients with total hip replacement receiving pharmacological thromboprophylaxis was 1%. This information on the associated risk factors could be used to better anticipate the risk of venous thromboembolism for an individual patient.
Background and purpose
To assess long‐term treatment effectiveness of disease‐modifying therapy (DMT) initiated early in disease course versus later treatment start.
Methods
We included all Danish ...patients with multiple sclerosis (MS) treated with DMT through two nationwide population‐based MS registries. Patients were categorized as early treated if treatment started within 2 years after the first MS symptom (n = 2316) and later treated if treatment started between 2 and 8 years after clinical onset (n = 1479). We compared time from treatment start to progression to an Expanded Disability Status Scale (EDSS) score of 6 and mortality between cohorts as hazard ratio (HR) using a Cox proportional hazards model with adjustment for stabilized inverse probability of treatment weights. Several sensitivity analyses were conducted.
Results
The median follow‐up time of 3795 patients was 7.0 (range 0.6–19.5) years for the EDSS score of 6 outcome and 10.4 (range 1.2–20.1) years for the mortality outcome. Patients with later treatment start showed a 42% increased hazard rate of reaching an EDSS score of 6 compared with the early‐treated patients HR, 1.42; 95% confidence interval (CI), 1.18–1.70; P < 0.001. When stratified by sex, the increased hazard among later‐treated women persisted (HR, 1.53; 95% CI, 1.22–1.93; P < 0.001), whereas the HR was lower in men (1.25; 95% CI, 0.93–1.69; P = 0.15). Mortality was increased by 38% in later starters (HR, 1.38; 95% CI, 0.96–1.99; P = 0.08).
Conclusions
Patients who started treatment with DMT later reached an EDSS score of 6 more quickly compared with patients who started early and the delay showed a tendency to shorten time to death. Our results support the use of early treatment.
Observational studies have suggested that low blood pressure and blood pressure variability may partially explain adverse neurological outcome after endovascular therapy with general anaesthesia (GA) ...for acute ischaemic stroke. The aim of this study was to further examine whether blood pressure related parameters during endovascular therapy are associated with neurological outcome.
The GOLIATH trial randomised 128 patients to either GA or conscious sedation for endovascular therapy in acute ischaemic stroke. The primary outcome was 90 day modified Rankin Score. The haemodynamic protocol aimed at keeping the systolic blood pressure >140 mm Hg and mean blood pressure >70 mm Hg during the procedure. Blood pressure related parameters of interest included 20% reduction in mean blood pressure; mean blood pressure <70 mm Hg, <80 mm Hg, and <90 mm Hg, respectively; time with systolic blood pressure <140 mm Hg; procedural minimum and maximum mean and systolic blood pressure; mean blood pressure at the time of groin puncture; postreperfusion mean blood pressure; blood pressure variability; and use of vasopressors. Sensitivity analyses were performed in the subgroup of reperfused patients.
Procedural average mean and systolic blood pressures were higher in the conscious sedation group (P<0.001). The number of patients with mean blood pressure <70–90 mm Hg and systolic blood pressure <140 mm Hg, blood pressure variability, and use of vasopressors were all higher in the GA group (P<0.001). There was no statistically significant association between any of the examined blood pressure related parameters and the modified Rankin Score in the overall patient population, and in the subgroup of patients with full reperfusion.
We found no statistically significant association between blood pressure related parameters during endovascular therapy and neurological outcome.
NCT 02317237.
Abstract
Background
People with multiple sclerosis (MS) experience a wide range of unpredictable and variable symptoms. The symptomatology of MS has previously been reported in large sample registry ...studies; however, some symptoms may be underreported in registries based on clinician-reported outcomes and how the symptoms are associated with quality of life (QoL) are often not addressed.
The aim of this study was to comprehensively evaluate the frequency of selected MS related symptoms and their associations with disability and QoL in a large self-report study.
Methods
We conducted a cross-sectional questionnaire survey among all patients at the Danish Multiple Sclerosis Center, Copenhagen University Hospital, Denmark. The questionnaire included information on clinical and sociodemographic characteristics, descriptors of QoL and disability, as well as prevalence and severity of the following MS symptoms: impaired ambulation, spasticity, chronic pain, fatigue, bowel and bladder dysfunction, and sleep disturbances.
Results
Questionnaires were returned by 2244/3606 (62%). Participants without MS diagnosis or incomplete questionnaires were excluded,
n
= 235. A total of 2009 questionnaires were included for analysis (mean age 49.4 years; mean disease duration 11.7 years; and 69% were women).
The most frequently reported symptoms were bowel and bladder dysfunction (74%), fatigue (66%), sleep disturbances (59%), spasticity (51%) and impaired ambulation (38%). With exception of fatigue and sleep disturbances, all other symptoms increased in severity with higher disability level. Invisible symptoms (also referred to as hidden symptoms) such as fatigue, pain and sleep disturbances had the strongest associations with the overall QoL.
Conclusion
We found invisible symptoms highly prevalent, even at mild disability levels. Fatigue, pain and sleep disturbances had the strongest associations with the overall QoL and were more frequently reported in our study compared with previous registry-based studies. These symptoms may be underreported in registries based on clinician reported outcomes, which emphasizes the importance of including standardized patient reported outcomes in nationwide registries to better understand the impact of the symptom burden in MS.
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