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Background and purpose: To investigate the relation of age at disease onset and clinical outcomes across the lifespan from adolescence in patients with multiple sclerosis (MS) on disease‐modifying therapy (DMT). Methods: We analysed data from the Swiss Association for Joint Tasks of Health Insurers database containing data from 14 718 patients with MS. Patients were included in this analysis when they were on DMT for at least 1 year. The influence of age at disease onset on future relapses and disability worsening was explored using multivariable Cox proportional hazard regression models. Results: Data from 9705 patients with MS were analysed. Pediatric‐onset MS patients (n = 236) had higher relapse rates and marginally slower disability worsening rates compared with adult‐onset MS (n = 9469). The risk of relapses was highest in childhood and decreased continuously to about 35 years of age. It remained stable for about a decade and then again continuously decreased. In contrast, disability worsening hazards remained stable from childhood to about 32 years of age and then increased sharply around the age of 45 years. Conclusions: Age is an important factor independently affecting clinical outcomes in MS. This should be considered when designing clinical trials or choosing DMT. [ABSTRACT FROM AUTHOR]

Objectives: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). Methods: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. Results: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R2: 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited (R2: 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability. Conclusions: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed. [ABSTRACT FROM AUTHOR]

The article provides an overview of research concerning multiple sclerosis presented at a talk. They include "Quality of Life Measures in Multiple Sclerosis," by B. G. Vickrey, "Use of Quality of Life in MS Trials," by T. Riise and M. W. Nortvedt, "Measuring Outcomes in Clinical Services," by C. A. Young and "Brain Rehabilitation and Brain Plasticity," by I. H. Robertson.

Discusses the use of composite scores in the quantification of deterioration in multiple sclerosis. Description of important dimensions of disease to be reflected in a clinical assessment tool; Details of the three statistical approaches used in clinical trials; Conclusion.

Thiolactones (TL) can be readily incorporated into polymeric materials and have been extensively used as a ligation strategy despite their limited reactivity toward amine-containing substrates. Comparatively, iminiumthiolactones (ITL) are much more reactive, yet to this day, only the nonsubstituted ITL known as Traut's reagent is commercially available and used. In this work, we advance current TL/ITL chemistry by introducing reactive side groups to the ITL heterocycle in the γ-position, which can be orthogonally modified without affecting the ITL heterocycle itself. To study the reactivity of γ-functional ITLs, we subject one of our derivatives (γ-allyl-functional ITL 3b ) to model reactions with several peptides and a chosen protein (lysozyme C). Using mild reaction conditions, we successfully demonstrate that the γ-functional ITL exhibits orthogonal and enhanced reactivity in a single or double modification while introducing a new functional handle to the biological substrate. We believe that γ-functional ITLs will advance the original Traut chemistry and open promising opportunities for the bioconjugation of biological building blocks to existing functional molecules, polymers, and materials.

Background: Disability progression independent of relapses (PIRA) has been described as a frequent phenomenon in relapsing-remitting multiple sclerosis (RRMS)., Objective: To compare the occurrence of disability progression in relapse-free RRMS patients on interferon-beta/glatiramer acetate (IFN/GA) versus fingolimod., Methods: This study is based on data from the Swiss association for joint tasks of health insurers. Time to relapse and 12-month confirmed disability progression were compared between treatment groups using multivariable Cox regression analysis with confounder adjustment. Inverse-probability weighting was applied to correct for the bias that patients on fingolimod have a higher chance to remain relapse-free than patients on IFN/GA., Results: We included 1640 patients (64% IFN/GA, 36% fingolimod, median total follow-up time = 4-5 years). Disease-modifying treatment (DMT) groups were well balanced with regard to potential confounders. Disability progression was observed in 155 patients (8.8%) on IFN/GA and 51 (7.6%) on fingolimod, of which 44 and 23 were relapse-free during the initial DMT, respectively. Adjusted standard regression analysis on all patients indicated that those on fingolimod experience less frequently disability progression compared with IFN/GA (hazard ratio = 0.53 (95% confidence interval = 0.37-0.76)). After bias correction, this was also true for patients without relapses (hazard ratio=0.56 (95% confidence interval = 0.32-0.98)., Conclusion: Our analysis indicates that fingolimod is superior to IFN/GA in preventing disability progression in both relapsing and relapse-free , young, newly diagnosed RRMS patients.

Background: Dimethyl fumarate and fingolimod are oral disease modifying treatments (DMTs) that reduce relapse activity and slow disability worsening in relapsing-remitting multiple sclerosis (RRMS)., Objective: To compare the effectiveness of dimethyl fumarate and fingolimod in a real-world setting, where both agents are licensed as a first-line DMT for the treatment of RRMS., Methods: We identified patients with RRMS commencing dimethyl fumarate or fingolimod in the Swiss Federation for Common Tasks of Health Insurances (SVK) Registry between August 2014 and July 2019. Propensity score-matching was applied to select subpopulations with comparable baseline characteristics. Relapses and disability outcomes were compared in paired, pairwise-censored analyses., Results: Of the 2113 included patients, 1922 were matched (dimethyl fumarate, n = 961; fingolimod, n = 961). Relapse rates did not differ between the groups (incident rate ratio 1.0, 95%CI 0.8-1.2, p = 0.86). Moreover, no difference in the hazard of 1-year confirmed disability worsening (hazard ratio [HR] 0.9; 95%CI 0.6-1.6; p = 0.80) or disability improvement (HR 0.9; 95%CI 0.6-1.2; p = 0.40) was detected. These findings were consistent both for treatment-naïve patients and patients switching from another DMT., Conclusion: Dimethyl fumarate and fingolimod have comparable effectiveness regarding reduction of relapses and disability worsening in RRMS.

Background and Purpose: To investigate the relation of age at disease onset and clinical outcomes across the lifespan from adolescence in patients with multiple sclerosis (MS) on disease-modifying therapy (DMT)., Methods: We analysed data from the Swiss Association for Joint Tasks of Health Insurers database containing data from 14 718 patients with MS. Patients were included in this analysis when they were on DMT for at least 1 year. The influence of age at disease onset on future relapses and disability worsening was explored using multivariable Cox proportional hazard regression models., Results: Data from 9705 patients with MS were analysed. Pediatric-onset MS patients (n = 236) had higher relapse rates and marginally slower disability worsening rates compared with adult-onset MS (n = 9469). The risk of relapses was highest in childhood and decreased continuously to about 35 years of age. It remained stable for about a decade and then again continuously decreased. In contrast, disability worsening hazards remained stable from childhood to about 32 years of age and then increased sharply around the age of 45 years., Conclusions: Age is an important factor independently affecting clinical outcomes in MS. This should be considered when designing clinical trials or choosing DMT., (© 2020 European Academy of Neurology.)

Reichardt's empirical ET(30) polarity parameter has been established as appropriate polarity scale for ionic liquids. In this study, the relationships of ET(30) of ionic liquids with the empirical Kamlet-Taft polarity parameters α (hydrogen bond donating ability), β (hydrogen bond accepting ability) and π* (dipolarity/polarizability) as well as Catalán's parameter set SA (solvent acidity), SB (solvent basicity), SP (solvent polarizability) and SdP (solvent dipolarity) are examined by means of multiple square correlation analyses. Several subtasks were carried out to address this main concern. First, the influence of anion structure on ET(30) polarity parameters for various ionic liquids are investigated by use of nine differently substituted pyridinio phenolate betaine dyes of the Reichardt type. It is assumed that halide anions can have an effect on the ET(30) parameter. In the second part, the Kamlet-Taft π* parameters have been independently determined for several protic ionic liquids using 4-tert-butyl-2-(dicyanomethylene)-5-[4-(diethylamino)-benzylidene]-Δ3-thiazoline (Th) and N,N-diethyl-4-nitroaniline (DENA) to show the impact of the hydrogen bond donating ability of the IL on the actual π* values as function of probe. α and SA values have been measured using the dicyano-bis(1,10-phenanthroline) iron(ii) complex (Fe) as HBD probe. Finally, the newly determined Reichardt ET(30), Kamlet-Taft and Catalán parameters of ionic liquids were used in addition to literature data to prove correlations of ET(30) with α and π* as well as of ET(30) with SA and SdP. Linear correlations of SdP with the molar concentration of the ionic liquid are highlighted.

Introduction:  Meningococcal septicemia is not merely an acute disease with a high lethality, but patients surviving the fulminant phase can suffer from serious long-term sequelae., Materials and Methods:  The records of 165 patients admitted to the hospital from 1968 to 2008 with the diagnosis of meningococcal septicemia were retrospectively reviewed for early signs at presentation, intensive care management, acute symptoms, the necessity of plastic and orthopaedic surgical management, and long-term orthopaedic sequelae. Possible predictors of these conditions were determined., Results:  Overall lethality was 17.5%, and mean time of hospitalization time was 28 days. Integument involvement occurred in 45%, often resulting in the necessity of plastic surgical procedures. Young age is a significant indicator or skin involvement. Amputations were necessary in 9% of all cases, affecting the lower extremities more often than the upper extremities. Six percent of all children suffered from long-term orthopaedic sequelae, such as growth retardation and angular deformities, appearing up to 11 years (mean 4.9 years) after onset of the acute disease. The incidence of amputations and long-term orthopaedic sequelae correlated significantly with severity of the disease., Conclusion:  Meningococcal septicemia can entail devastating long-term consequences in children surviving the acute phase of the disease. Sequelae may become apparent only years later and cause further damage. To prevent this, a systematic follow-up till adulthood is necessary., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: No randomized controlled trials have compared the efficacy of fingolimod or natalizumab as second-line treatment in patients with relapsing-remitting multiple sclerosis (RRMS)., Objective: To compare clinical outcomes after escalation to fingolimod versus natalizumab in patients with clinically active RRMS., Methods: Using the registry of the Swiss Federation for Common Tasks of Health Insurances, we identified patients with RRMS and ≥1 relapse in the year before switching from interferon beta or glatiramer acetate to fingolimod or natalizumab. Propensity score matching was used to select patients with comparable baseline characteristics. Relapse and Expanded Disability Status Scale (EDSS) outcomes were compared in paired, pairwise-censored analyses., Results: Of the 547 included patients, 358 were matched (fingolimod, n = 179; natalizumab, n = 179). Median follow-up time was 1.8 years (interquartile range 0.9-2.9). Patients switching to natalizumab had a lower risk of relapses (incidence rate ratio 0.5, 95% confidence interval (CI) 0.3-0.8, p = 0.001) and were more likely to experience EDSS improvement (hazard ratio (HR) 1.8, 95% CI 1.1-2.7, p = 0.01) compared to fingolimod. We found no differences in the proportion of patients free from EDSS progression (HR 0.9, 95% CI 0.5-1.5, p = 0.62)., Conclusion: Natalizumab seems to be more effective in reducing relapse rate and improving disability compared with fingolimod.

Objectives: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b)., Methods: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied., Results: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R(2): 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited (R(2): 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability., Conclusions: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed., (© The Author(s), 2015.)

Background: In Switzerland, the first course of intravenous steroids for treatment of episodes of demyelinating CNS disease is usually administered in an inpatient setting. We prospectively evaluated short term tolerance of treatment with special emphasis on sleep quality., Methods: Patients with a first event of presumed demyelinating disease (CIS), multiple sclerosis relapses (MS) or sub-acute disease progression were treated with a 5-day regimen of intravenous methylprednisolone (IVMP) in our inpatient clinic. Patients' experience was documented by self-report questionnaires including a standardised depression scale (ADSL). Laboratory tests were performed on a routine basis. Fasting glucose, blood pressure and pulse were measured before every infusion. Activity and sleep patterns were analysed by wrist actigraphs during the 5 day infusion period and at follow-up after 1-2 months., Results: A total of 66 patients participated in the study. Of these, 55 were steroid treatment naïve, and 11 patients, who had received intravenous steroid relapse treatment before, were admitted because of disabling symptoms. Mood disturbances were reported before steroid treatment, however significantly less often at the end of the steroid pulse and during follow-up. Sleep efficiency as measured by wrist actimetry was high before, during and after steroid treatment., Conclusion: Therapy was well tolerated without severe side effects in CIS and MS patients. Sleep efficiency was not disturbed. In conclusion there are no obstacles to change from an inpatient to an outpatient setting for the steroid treatment of relapses in MS and CIS, but rare psychotic reactions to steroid treatment are not predictable.

Multiple sclerosis (MS) causes a broad range of neurological symptoms. Most common is poor balance control. However, knowledge of deficient balance control in mildly affected MS patients who are complaining of balance impairment but have normal clinical balance tests (CBT) is limited. This knowledge might provide insights into the normal and pathophysiological mechanisms underlying stance and gait. We analysed differences in trunk sway between mildly disabled MS patients with and without subjective balance impairment (SBI), all with normal CBT. The sway was measured for a battery of stance and gait balance tests (static and dynamic posturography) and compared to that of age- and sex-matched healthy subjects. Eight of 21 patients (38%) with an Expanded Disability Status Scale of 1.0-3.0 complained of SBI during daily activities. For standing on both legs with eyes closed on a normal and on a foam surface, patients in the no SBI group showed significant differences in the range of trunk roll (lateral) sway angle and velocity, compared to normal persons. Patients in the SBI group had significantly greater lateral sway than the no SBI group, and sway was also greater than normal in the pitch (anterior-posterior) direction. Sway for one-legged stance on foam was also greater in the SBI group compared to the no SBI and normal groups. We found a specific laterally directed impairment of balance in all patients, consistent with a deficit in proprioceptive processing, which was greater in the SBI group than in the no SBI group. This finding most likely explains the subjective symptoms of imbalance in patients with MS with normal CBT.

To study whether onset of infantile spasms manifests seasonal variation, as previously reported, and whether any such seasonality is associated with treatment response and long-term outcome, data for 57 patients were retrospectively reviewed. The data were collected from hospital files and through a mail survey of children with infantile spasms born from 1980 to 2002 and monitored at the University Children's Hospital of Berne, Switzerland. The mean age at time of onset of infantile spasms was 7 months (range, 0.75-40), at diagnosis 8 months (range, 1-42) and at follow-up 11.3 years (range, 1-23 years). In 77% of participants, the etiology of infantile spasms was known (symptomatic); in the remaining 23% it was not known (nonsymptomatic). In contrast to previous findings, onset of infantile spasms was not associated with calendar month, photoperiod, or global solar radiation. Long-term prognosis was poor: 4 of the 57 (7%) children died; 49 (86%) had cognitive impairment and 40 (70%) had physical impairment; 31 (54%) had cerebral palsy, 37 had (65%) persistent seizures, and 9 (16%) had Lennox-Gastaut syndrome. Symptomatic infantile spasms were associated with worse cognitive outcome (P < 0.001), but treatment modality and overall duration of infantile spasms were not. There was no association of calendar month or photoperiod at onset with cognitive outcome or treatment response., (Copyright 2010 Elsevier Inc. All rights reserved.)

Respiratory disorders with stridor are a frequent cause of admission for children in an emergency department. Laryngospasm, as an isolated symptom of epilepsy, is a rare phenomenon [1, 3, 5]. Other respiratory symptoms of epilepsy, rarely seen in childhood, might be apnoeic spells [2, 4]. We report on a child with laryngospasm due to focal epileptic seizures.

In order to evaluate whether plasma levels of the potent vasoconstrictor endothelin-1 (ET-1) are increased in patients with multiple sclerosis (MS) and whether these patients exhibit an ET-1-mediated vascular dysregulation, ET-1 plasma levels were measured in 30 patients with MS. Blood flow velocities in the ophthalmic artery, central retinal artery, central retinal vein, short lateral posterior ciliary artery, and short medial posterior ciliary artery were assessed in parallel. ET-1 plasma levels were significantly increased in MS patients when compared to sex- and age-matched healthy controls (2.0 +/- 0.4 pg/ml, range 1.1-2.8 vs. 1.5 +/- 0.2 pg/ml, range 0.9-2.0; p < 0.001). Moreover, the patients exhibited significant alterations of extraocular blood flow. The role of ET-1 in the inflammatory process remains to be clarified., (Copyright 2003 S. Karger AG, Basel)

Matrix metalloproteinases (MMPs) are a family of endopeptidases capable of enzymatic digestion of subendothelial basement membrane and other components of the extracellular matrix. Expression of MMP-2, -3, -7 and -9 is increased around multiple sclerosis plaques and in brain tissue in experimental allergic encephalomyelitis. To measure quantitatively the expression of these MMPs and their endogenous inhibitors (TIMP-1 and -2), we analysed samples from 52 patients with relapsing-remitting and primary progressive multiple sclerosis by ELISA (enzyme-linked immunosorbent assay) and substrate-gel electrophoresis (zymography). MMP-9 was increased over controls in 100% of relapsing-remitting multiple sclerosis cases, with similar levels detected in relapses and clinically stable phases of disease. In primary progressive multiple sclerosis, MMP-9 was increased in 57% of CSF samples, but concentrations were below those encountered in the relapsing-remitting form. The selective upregulation of MMP-9 suggests that T-cells and macrophages invading the brain parenchyma and the CSF space are the predominant source of MMP-9 in multiple sclerosis. TIMPs and other MMPs (MMP-2 and -3) were not upregulated or not detectable (MMP-7) in CSF of patients with relapsing-remitting and primary progressive multiple sclerosis. The sustained increase of MMP-9 in clinically stable multiple sclerosis supports the concept that multiple sclerosis is associated with ongoing proteolysis that may result in progressive tissue damage. The selective inhibition of MMP-9 could be a useful approach for the prevention of disease progression in multiple sclerosis.