Characteristics of improvements in balance control using vibro-tactile biofeedback of trunk sway for multiple sclerosis patients

Background and aims: Previously, we determined that training with vibrotactile feedback (VTfb) of trunk sway improves MS patients’ balance impairment. Here, we posed 5 questions: 1) How many weeks of VTfb training are required to obtain the best short-term carry over effect (CoE) with VTfb? 2) How long does the CoE last once VTfb training terminates? 3) Is the benefit similar for stance and gait? 4) Is position or velocity based VTfb more effective in reducing trunk sway? 5) Do patients’ subjective assessments of balance control improve? Methods: Balance control of 16 MS patients was measured with gyroscopes at the lower trunk. The gyroscopes drove directionally active VTfb in a head-band. Patients trained twice per week with VTfb for 4 weeks to determine when balance control with and without VTfb stopped improving. Thereafter, weekly assessments without VTfb over 4 weeks and at 6 months determined when CoEs ended. Results: A 20% improvement in balance to normal levels occurred with VTfb. Short term CoEs improved from 15 to 20% (p ≤0.001). Medium term (1–4 weeks) CoEs were constant at 19% (p ≤0.001). At 6 months improvement was not significant, 9%. Most improvement was for lateral sway. Equal improvement occurred when angle position or velocity drove VTfb. Subjectively, balance improvements peaked after 3 weeks of training (32%, p ≤0.05). Conclusions: 3–4 weeks VTfb training yields clinically relevant sway reductions and subjective improvements for MS patients during stance and gait. The CoEs lasted at least 1 month. Velocity-based VTfb was equally effective as position-based VTf

Characterization of social cognition impairment in multiple sclerosis

Multiple sclerosis (MS) has been associated with deficits in social cognition. However, little is known about which domains of social cognition are predominantly affected and what other factors are associated with it. The aim was (i) to characterize social cognition deficit in a group of MS outpatients and (ii) to relate impairment in social cognition to overall cognitive status, depression and fatigue.Methods: Thirty-five MS patients (mean disease duration 12.9 years, median Expanded Disability Status Scale (EDSS) 3 and 34 healthy controls (HCs) were examined using the German version of the Geneva Social Cognition Scale to measure different domains of social cognition. Standard neuropsychological testing was applied to all patients and to 20 HCs. Patient-reported outcomes included questionnaires for fatigue, depression, anxiety and executive-behavioural disturbances.Results: The mean social cognition raw score was lower in the MS patients compared to the HCs (86.5 ± 8.7 vs. 91.2 ± 5.9, P = 0.005; d = 0.6) and did not correlate with EDSS or disease duration. The difference was driven by facial affect recognition and the understanding of complex social situations (14% and 23% of patients respectively under the cut-off). The impairment in these two tasks did not correlate with general cognitive performance or depression but with fatigue.Conclusions: The impairment in our group was restricted to high order and affective social cognition tasks and independent of general cognitive performance, EDSS, disease duration and depression. Fatigue correlated with social cognition performance, which might be due to common underlying neuronal networks

Association of Spinal Cord Atrophy and Brain Paramagnetic Rim Lesions With Progression Independent of Relapse Activity in People With MS.

Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA. From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses. In total, 445 patients with MS (64.9% female; mean [SD] age at baseline 45.0 [11.4] years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; p = 0.004) and higher PRL load (incidence rate ratio [IRR] 1.93; p = 0.005). Increased spinal cord atrophy (MD-APC -1.39; p = 0.0008) and PRL burden (IRR 1.95; p = 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all p ≤ 0.002). Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS

Characterization of social cognition impairment in multiple sclerosis.

BACKGROUND AND PURPOSE Multiple sclerosis (MS) has been associated with deficits in social cognition. However, little is known about which domains of social cognition are predominantly affected and what other factors are associated with it. The aim was (i) to characterize social cognition deficit in a group of MS outpatients and (ii) to relate impairment in social cognition to overall cognitive status, depression and fatigue. METHODS Thirty-five MS patients (mean disease duration 12.9 years, median Expanded Disability Status Scale (EDSS) 3 and 34 healthy controls (HCs) were examined using the German version of the Geneva Social Cognition Scale to measure different domains of social cognition. Standard neuropsychological testing was applied to all patients and to 20 HCs. Patient-reported outcomes included questionnaires for fatigue, depression, anxiety and executive-behavioural disturbances. RESULTS The mean social cognition raw score was lower in the MS patients compared to the HCs (86.5 ± 8.7 vs. 91.2 ± 5.9, P = 0.005; d = 0.6) and did not correlate with EDSS or disease duration. The difference was driven by facial affect recognition and the understanding of complex social situations (14% and 23% of patients respectively under the cut-off). The impairment in these two tasks did not correlate with general cognitive performance or depression but with fatigue. CONCLUSIONS The impairment in our group was restricted to high order and affective social cognition tasks and independent of general cognitive performance, EDSS, disease duration and depression. Fatigue correlated with social cognition performance, which might be due to common underlying neuronal networks

T-cell response against varicella-zoster virus in fingolimod-treated MS patients

OBJECTIVE: To study the immune response against varicella-zoster virus (VZV) in patients with multiple sclerosis before and during fingolimod therapy. METHODS: The VZV-specific immune response was studied using interferon (IFN)-gamma enzyme-linked immunosorbent spot assay, proliferation assays, and upregulation of T-cell activation markers in patients before (n = 38) and after 3 months of fingolimod therapy (n = 34), in untreated (n = 33) and IFN-beta-treated (n = 25) patients with multiple sclerosis, and in healthy controls (n = 22). Viral replication was analyzed by using real-time PCR in 76 peripheral blood mononuclear cell samples and 146 saliva samples. RESULTS: Treatment with fingolimod led to a marked reduction of CD3(+) T cells with a relative decrease of naive and central memory T cells and an increase of effector memory T cells. Expression of the activation markers CD137 and CD69 upon VZV stimulation was unaltered by fingolimod. However, the absolute number of cells proliferating upon VZV stimulation was reduced in the blood of patients treated with fingolimod. Also, VZV-specific and Epstein-Barr virus (EBV)-specific IFN-gamma-producing cells were reduced after fingolimod therapy. Seven of the 35 patients treated with fingolimod showed signs of VZV or EBV reactivation in saliva compared with 3 of the 111 controls. None of the 76 tested samples showed signs of viral reactivation in the peripheral blood mononuclear cells. CONCLUSION: Patients treated with fingolimod show a slightly reduced antiviral T-cell response. This reduced response is accompanied by a subclinical reactivation of VZV or EBV in the saliva of 20% of patients treated with fingolimod

Andscapes: Concepts of nature and culture for landscape architecture in the ‘Anthropocene’

The effects of human activity have reached every square metre of the earth and beyond, such as through carbon or nitrogen emissions, which has led Nobel Laureate Paul Crutzen to propose a new geological age, the ‘Anthropocene’. In parallel to many contemporary philosophers and scientists, this notion declares that the traditional, dualistic Western understanding of nature as something independent from human influence is obsolete. The ‘Anthropocene’ needs new, unitary concepts of nature and culture. This article discusses two inspiring unitary concepts from Japan; Imanishi's seibutsu no sekei (world of living things) and Watsuji's fudo (milieu). In a reflection on two landscape architecture projects, this article comes to the conclusion that the profession is already capable of designing in a unitary mode, beyond simple dichotomies of nature and culture. This asset should be cultivated, and for this the correct usage of terms is quite important. However, this is difficult due to the fact that the traditional meaning of nature is still very influential in professional communication, and that the terms of the inspiring Japanese concepts are either too complicated or too abstract. Inspired by Kandinsky's idea of ‘and’, the unitary concept of ‘andscape’ is proposed to integrate the ideas of both Imanishi and Watsuji. By using the term ‘andscape’, a dualistic, divisive understanding of nature and culture becomes impossible—instead, the focus is on the dynamic relations between humans, animals, plants, stones, water, and all other elements in the world. This is an Author's Accepted Manuscript of an article published in Journal of landscape architecture, © Taylor & Francis, available online at: https://www.tandfonline.com/doi/full/10.1080/18626033.2014.89881

Intrathecal Immunoglobulin M Synthesis is an Independent Biomarker for Higher Disease Activity and Severity in Multiple Sclerosis.

We aimed to determine in relapsing multiple sclerosis (MS) whether intrathecal synthesis of immunoglobulin (Ig) M and IgG is associated with outcomes reflecting inflammatory activity and chronic worsening. We compared cerebrospinal fluid analysis, clinical and magnetic resonance imaging data, and serum neurofilament light chain (sNfL) levels at baseline and follow-up in 530 patients with relapsing MS. Patients were categorized by the presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (intrathecal fraction [IF]: IgG <sub>IF</sub> and IgM <sub>IF</sub> ). Relationships with the time to first relapse, sNfL concentrations, T2-weighted (T2w) lesions, MS Severity Score (MSSS), and time to initiation of high-efficacy therapy were analyzed in covariate-adjusted statistical models. By categorical analysis, in patients with IgM <sub>IF</sub> the median time to first relapse was 28 months shorter and MSSS on average higher by 1.11 steps compared with patients without intrathecal immunoglobulin synthesis. Moreover, patients with IgM <sub>IF</sub> had higher sNfL concentrations, more new/enlarging T2w lesions, and higher total T2w lesion counts (all p ≤ 0.01). These associations were absent or equally smaller in patients who were positive for only OCGB or OCGB/IgG <sub>IF</sub> . Furthermore, quantitative analyses revealed that in patients with IgM <sub>IF</sub> ≥ median, the time to first relapse and to initiation of high-efficacy therapy was shorter by 32 and by 203 months, respectively (both p < 0.01), in comparison to patients with IgM <sub>IF</sub> < median. Dose-dependent associations were also found for IgM <sub>IF</sub> but not for IgG <sub>IF</sub> with magnetic resonance imaging-defined disease activity and sNfL. This large study supports the value of intrathecal IgM synthesis as an independent biomarker of disease activity and severity in relapsing MS. ANN NEUROL 2021;90:477-489

Association of Brain Atrophy With Disease Progression Independent of Relapse Activity in Patients With Relapsing Multiple Sclerosis.

The mechanisms driving neurodegeneration and brain atrophy in relapsing multiple sclerosis (RMS) are not completely understood. To determine whether disability progression independent of relapse activity (PIRA) in patients with RMS is associated with accelerated brain tissue loss. In this observational, longitudinal cohort study with median (IQR) follow-up of 3.2 years (2.0-4.9), data were acquired from January 2012 to September 2019 in a consortium of tertiary university and nonuniversity referral hospitals. Patients were included if they had regular clinical follow-up and at least 2 brain magnetic resonance imaging (MRI) scans suitable for volumetric analysis. Data were analyzed between January 2020 and March 2021. According to the clinical evolution during the entire observation, patients were classified as those presenting (1) relapse activity only, (2) PIRA episodes only, (3) mixed activity, or (4) clinical stability. Mean difference in annual percentage change (MD-APC) in brain volume/cortical thickness between groups, calculated after propensity score matching. Brain atrophy rates, and their association with the variables of interest, were explored with linear mixed-effect models. Included were 1904 brain MRI scans from 516 patients with RMS (67.4% female; mean [SD] age, 41.4 [11.1] years; median [IQR] Expanded Disability Status Scale score, 2.0 [1.5-3.0]). Scans with insufficient quality were excluded (n = 19). Radiological inflammatory activity was associated with increased atrophy rates in several brain compartments, while an increased annualized relapse rate was linked to accelerated deep gray matter (GM) volume loss. When compared with clinically stable patients, patients with PIRA had an increased rate of brain volume loss (MD-APC, -0.36; 95% CI, -0.60 to -0.12; P = .02), mainly driven by GM loss in the cerebral cortex. Patients who were relapsing presented increased whole brain atrophy (MD-APC, -0.18; 95% CI, -0.34 to -0.02; P = .04) with respect to clinically stable patients, with accelerated GM loss in both cerebral cortex and deep GM. No differences in brain atrophy rates were measured between patients with PIRA and those presenting relapse activity. Our study shows that patients with RMS and PIRA exhibit accelerated brain atrophy, especially in the cerebral cortex. These results point to the need to recognize the insidious manifestations of PIRA in clinical practice and to further evaluate treatment strategies for patients with PIRA in clinical trials

Association of brain atrophy with disease progression independent of relapse activity in patients with relapsing multiple sclerosis

Importance: The mechanisms driving neurodegeneration and brain atrophy in relapsing multiple sclerosis (RMS) are not completely understood. Objective: To determine whether disability progression independent of relapse activity (PIRA) in patients with RMS is associated with accelerated brain tissue loss. Design, Setting, and Participants: In this observational, longitudinal cohort study with median (IQR) follow-up of 3.2 years (2.0-4.9), data were acquired from January 2012 to September 2019 in a consortium of tertiary university and nonuniversity referral hospitals. Patients were included if they had regular clinical follow-up and at least 2 brain magnetic resonance imaging (MRI) scans suitable for volumetric analysis. Data were analyzed between January 2020 and March 2021. Exposures: According to the clinical evolution during the entire observation, patients were classified as those presenting (1) relapse activity only, (2) PIRA episodes only, (3) mixed activity, or (4) clinical stability. Main Outcomes and Measures: Mean difference in annual percentage change (MD-APC) in brain volume/cortical thickness between groups, calculated after propensity score matching. Brain atrophy rates, and their association with the variables of interest, were explored with linear mixed-effect models. Results: Included were 1904 brain MRI scans from 516 patients with RMS (67.4% female; mean [SD] age, 41.4 [11.1] years; median [IQR] Expanded Disability Status Scale score, 2.0 [1.5-3.0]). Scans with insufficient quality were excluded (n = 19). Radiological inflammatory activity was associated with increased atrophy rates in several brain compartments, while an increased annualized relapse rate was linked to accelerated deep gray matter (GM) volume loss. When compared with clinically stable patients, patients with PIRA had an increased rate of brain volume loss (MD-APC, -0.36; 95% CI, -0.60 to -0.12; P =.02), mainly driven by GM loss in the cerebral cortex. Patients who were relapsing presented increased whole brain atrophy (MD-APC, -0.18; 95% CI, -0.34 to -0.02; P =.04) with respect to clinically stable patients, with accelerated GM loss in both cerebral cortex and deep GM. No differences in brain atrophy rates were measured between patients with PIRA and those presenting relapse activity. Conclusions and Relevance: Our study shows that patients with RMS and PIRA exhibit accelerated brain atrophy, especially in the cerebral cortex. These results point to the need to recognize the insidious manifestations of PIRA in clinical practice and to further evaluate treatment strategies for patients with PIRA in clinical trials.