Multiple sclerosis (MS) is the most common autoimmune inflammatory disease of the central nervous system in Europe, often causing severe physical, cognitive and emotional impairments. Currently, it ...is unclear whether the healthcare provisions of people with MS (PwMS) are in line with the recommendations for treatment based on guidelines or patients' needs. The main objectives of the study are as follows: (a) to investigate how well PwMS are treated; and (b) to develop a needs-oriented, patient-centred care model.
This mixed-methods study focuses on adult PwMS living in Lower Saxony, a federal state in Germany. The qualitative study comprises focus groups with PwMS, physicians and people involved in the healthcare process as well as a future workshop. The quantitative study comprises a cross-sectional online survey and addresses the patient-relevant outcomes and needs, as previously determined by literature searches and focus groups. It will be administered to all PwMS who are insured by the statutory health insurance company involved in the project (n~7,000). The survey data will be linked to the longitudinal secondary data from the statutory health insurance company and data from the German MS registry where available. The linked and single data sources will be statistically analysed.
By comprehensively comparing the current healthcare provisions with the needs and requirements of PwMS, the strengths and weaknesses of the overall healthcare process and provision of assistive devices can be identified. The barriers and facilitators of the health service providers and their impact on daily life will be explored (qualitative analyses). Reliable recommendations for improvements will be given based on a study population drawn from the largest statutory health insurance company in Lower Saxony (quantitative analyses). However, the inherent advantages and limitations of the qualitative and quantitative research approaches need to be considered.
The study is registered at German Clinical Trials Register DRKS00021741.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Metastatic spinal cord compression often requires urgent treatment selection, which could be facilitated by strong prognostic factors. Because only the type of primary tumor and pretreatment ...ambulatory status are known as prognostic factors for functional outcome, we investigated the prognostic value of the time of motor deficit development before radiotherapy (RT).
Ninety-eight patients were included between November 1998 and April 2000. Three subgroups were formed, according to time of motor deficit development before RT: 1-7 days (n = 31), 8-14 days (n = 31), and >14 days (n = 36). Ambulatory rates and motor function were evaluated for < or =24 weeks after RT. In a multivariate analysis, all three prognostic factors and radiation parameters were included.
In the >14-day subgroup, improvement occurred significantly (p < 0.001) more often than in the other subgroups (86% vs. 29% and 10%) and the posttreatment ambulatory rate was significantly higher (86% vs. 55% and 35%, p = 0.026). Multivariate analysis revealed the time of development of motor deficits before RT to be the strongest prognostic factor.
Functional outcome is significantly better with slower development of motor deficits before RT. This new, independent, prognostic factor must be considered in future trials aiming to define an optimal RT schedule.
Background
Public stroke awareness and knowledge may be supportive for stroke prevention and emergency care-seeking behavior after the acute event, which is highly important for early treatment ...onset.
Aims
In an urban population in Northern Germany (Hannover), a six-month stroke educational campaign was conducted. We expected an increase in stroke knowledge and awareness thereafter.
Methods
Computer-assisted telephone interviews were randomly conducted among 1004 representative participants before and 1010 immediately after the educational multimedia campaign. The computer-assisted telephone interviews focused on questions about stroke knowledge and interventions remembered.
Results
Knowledge of stroke risk factors increased during the campaign for overweight, physical inactivity, old age, and stroke in family (P < 0·05). The knowledge of stroke warning signs was low, although it significantly increased during the campaign (P < 0·001) as paresis/weakness (46%) and speech problems (31%) were most frequently named. The majority of respondents indicated that the first action after suffering from stroke should be calling emergency care (74% before vs. 84% after campaign, P < 0·001).
Conclusions
Our data indicate that stroke knowledge and awareness, which could provide earlier presentation to the emergency unit for timely treatment onset, are still low in urban Northern Germany but may decisively be increased by educational campaigns.
No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective ...sphingosine 1-phosphate (S1P) receptor1,5 modulator, on disability progression in patients with SPMS.
This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144.
1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups.
Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS.
Novartis Pharma AG.
Introduction
There is a great need for fully automated plasma assays that can measure amyloid beta (Aβ) pathology and predict future Alzheimer's disease (AD) dementia.
Methods
Two cohorts (n = 920) ...were examined: Panel A+ (n = 32 cognitively unimpaired CU, n = 106 mild cognitive impairment MCI, and n = 89 AD) and BioFINDER‐1 (n = 461 CU, n = 232 MCI). Plasma Aβ42/Aβ40, phosphorylated tau (p‐tau)181, two p‐tau217 variants, ApoE4 protein, neurofilament light, and GFAP were measured using Elecsys prototype immunoassays.
Results
The best biomarker for discriminating Aβ‐positive versus Aβ‐negative participants was Aβ42/Aβ40 (are under the curve AUC 0.83–0.87). Combining Aβ42/Aβ40, p‐tau181, and ApoE4 improved the AUCs significantly (0.90 to 0.93; P< 0.01). Adding additional biomarkers had marginal effects (ΔAUC ≤0.01). In BioFINDER, p‐tau181, p‐tau217, and ApoE4 predicted AD dementia within 6 years in CU (AUC 0.88) and p‐tau181, p‐tau217, and Aβ42/Aβ40 in MCI (AUC 0.87).
Discussion
The high accuracies for Aβ pathology and future AD dementia using fully automated instruments are promising for implementing plasma biomarkers in clinical trials and clinical routine.
The end‐plate species of acetylcholinesterase (AChE) is an asymmetric enzyme consisting of a collagenic tail subunit composed of three collagenic strands (ColQ), each attached to a tetramer of the T ...isoform of the catalytic subunit (AChET) via a proline‐rich attachment domain. The principal function of the tail subunit is to anchor asymmetric AChE in the synaptic basal lamina. Human end‐plate AChE deficiency was recently shown to be caused by mutations in COLQ. We here report nine novel COLQ mutations in 7 patients with end‐plate AChE deficiency. We examine the effects of the mutations on the assembly of asymmetric AChE by coexpressing each genetically engineered COLQ mutant with ACHET in COS cells. We classify the newly recognized and previously reported COLQ mutations into four classes according to their position in ColQ and their effect on AChE expression. We find that missense mutations in the proline‐rich attachment domain abrogate attachment of catalytic subunits, that truncation mutations in the ColQ collagen domain prevent the assembly of asymmetric AChE, that hydrophobic missense residues in the C‐terminal domain prevent triple helical assembly of the ColQ collagen domain, and that other mutations in the C‐terminal region produce asymmetric species of AChE that are likely insertion incompetent. Ann Neurol 2000;47:162–170.
Objective: The objective of this study was to assess the effect of treatment with interferon (IFN) β-1a, 44 µg subcutaneously (sc) three times weekly (tiw), on clinical and magnetic resonance imaging ...(MRI) outcomes in patients with relapsing multiple sclerosis (MS) following mitoxantrone therapy.
Methods: This was an open-label, randomized, multicentre, rater-blinded, 96-week observational study conducted in Germany. Clinically stable patients with relapsing forms of MS, who had discontinued mitoxantrone treatment 1–6 months before study entry, were randomized to IFN β-1a sc 44 µg tiw, or no treatment. The primary endpoint was time to first relapse. Secondary endpoints included the number of relapse-free patients, disease activity assessed by MRI and time to 3-month confirmed Expanded Disability Status Scale (EDSS) progression, all at week 96.
Results: A total of 30 patients were randomized (intent-to-treat population: 14 IFN β-1a, 15 untreated; one patient from the safety population discontinued the study after 25 days owing to an adverse event and without providing any postbaseline efficacy data, and was thus excluded from the intent-to-treat population). Overall, 71.4% (10/14) of patients in the IFN β-1a group remained relapse free over 96 weeks, versus 46.7% (7/15) in the untreated group (p = 0.26). IFN β-1a delayed the time to first relapse versus no treatment (p = 0.14); time to first relapse (25th percentile) was 95.4 (IFN β-1a) versus 46.0 weeks (no treatment). Confirmed EDSS progression was observed in five patients in each treatment group. Mean change in EDSS score was 0.3 in both groups (p = 0.79). Changes in the number or volume of T1 and T2 lesions at week 96 were not significantly different between treatment groups (p > 0.05). There were no new or unexpected adverse events related to IFN β-1a treatment.
Conclusions: Several endpoints appeared to show a benefit of IFN β-1a treatment, but no significant differences could be detected owing to the small sample. Therefore, these data only permit, at best, tentative conclusions about the disease course in patients with MS after de-escalation from mitoxantrone and continuation with or without IFN β-1a. Larger confirmatory studies are required.
Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features ...characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited, and its efficacy remains controversial. In this study, we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological and genetic predictors of the immunotherapy response and long-term outcome. Patients were recruited from the GENERATE (German Network for Research on Autoimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined. We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder at least one symptom present in 38% (20/53). At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless, 21% (11/53) still had an isolated brainstem syndrome and/or a characteristic sleep disorder only. About one third of patients 28% (15/53) reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titre increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 55% (24/44) was associated with higher serum anti-IgLON5 IgG titres. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first 6 weeks was a predictor for therapy response. Sixty-eight per cent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome. In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response.
Systematic electrocardiogram (ECG) monitoring improves detection of covert atrial fibrillation in stroke survivors but the effect on secondary prevention is unknown. We aimed to assess the effect of ...systematic ECG monitoring of patients in hospital on the rate of oral anticoagulant use after 12 months.
In this investigator-initiated, randomised, open-label, parallel-group multicentre study with masked endpoint adjudication, we recruited patients aged at least 18 years with acute ischaemic stroke or transient ischaemic attack without known atrial fibrillation in 38 certified stroke units in Germany. Patients were randomly assigned (1:1) to usual diagnostic procedures for atrial fibrillation detection (control group) or additional Holter-ECG recording for up to 7 days in hospital (intervention group). Patients were stratified by centre using a random permuted block design. The primary outcome was the proportion of patients on oral anticoagulants at 12 months after the index event in the intention-to-treat population. Secondary outcomes included the number of patients with newly diagnosed atrial fibrillation in hospital and the composite of recurrent stroke, major bleeding, myocardial infarction, or death after 6 months, 12 months, and 24 months. This trial was registered with ClinicalTrials.gov, NCT02204267, and is completed and closed for participants.
Between Dec 9, 2014, and Sept 11, 2017, 3465 patients were randomly assigned, 1735 (50·1%) to the intervention group and 1730 (49·9%) to the control group. Oral anticoagulation status was available in 2920 (84·3%) patients at 12 months (1484 50·8% in the intervention group and 1436 49·2% in the control group). For the primary outcome, at 12 months, 203 (13·7%) of 1484 patients in the intervention group versus 169 (11·8%) of 1436 in the control group were on oral anticoagulants (odds ratio OR 1·2 95% CI 0·9–1·5; p=0·13). Atrial fibrillation was newly detected in patients in hospital in 97 (5·8%) of 1714 in the intervention group versus 68 (4·0%) of 1717 in the control group (hazard ratio HR 1·4 95% CI 1·0–2·0; p=0·024). The composite of cardiovascular outcomes and death did not differ between patients randomly assigned to the intervention group versus the control group at 24 months (232 13·5% of 1714 vs 249 14·5% of 1717; HR 0·9 0·8–1·1; p=0·43). Skin reactions due to study ECG electrodes were reported in 56 (3·3%) patients in the intervention group. All-cause death occured in 73 (4·3%) patients in the intervention group and in 103 (6·0%) patients in the control group (OR 0·7 0·5–0·9).
Systematic core centrally reviewed ECG monitoring is feasible and increases the detection rate of atrial fibrillation in unselected patients hospitalised with acute ischaemic stroke or transient ischaemic attack, if added to usual diagnostic care in certified German stroke units. However, we found no effect of systematic ECG monitoring on the rate of oral anticoagulant use after 12 months and further efforts are needed to improve secondary stroke prevention.
Bayer Vital.
For the German translation of the abstract see Supplementary Materials section.
Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various ...disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, and Switzerland).
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