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Abstract The use of extracorporeal membrane oxygenation (ECMO) has grown rapidly, driven by the COVID-19 pandemic. Despite its widespread adoption, neurological complications pose a significant risk, impacting both mortality and survivors’ quality of life. Detecting these complications is challenging due to sedation and the heterogeneous nature of ECMO-associated neurological injury. Still, consensus of neurologic monitoring during ECMO is lacking since utilization and effectiveness of current neuromonitoring methods are limited. Especially in view of the heterogeneous nature of neurological injury during ECMO support an easily acquirable biomarker tracing neuronal damage independently from the underlying pathomechanism would be favorable. In a single-center prospective study on 34 severe acute respiratory distress syndrome (ARDS) patients undergoing ECMO, we explored the potential of serum neurofilament light chain levels (NfL) as a biomarker for neurological complications and its predictive power towards the overall outcome of ECMO patients. Individuals experiencing neurological complications (41%) demonstrated a notable rise in NfL levels (Tbaseline median 92.95 pg/ml; T24h median 132 pg/ml (IQR 88.6–924 pg/ml), p = 0.008; T7d median 248 pg/ml (IQR 157–1090 pg/ml), p = 0.001). Moreover, under ECMO therapy, these patients exhibited markedly elevated concentrations compared to those without neurological complications (T24h median 70.75 pg/ml (IQR 22.2–290 pg/ml), p = 0.023; T7d median 128 pg/ml (IQR 51.8–244 pg/ml), p = 0.002). There was no significant difference in the NfL dynamics between surviving patients and those who died during or shortly after ECMO therapy. While NfL indicates neuro-axonal damage during intensive care with ECMO therapy, we could not identify any correlation between survival outcome and the levels of NfL, indicating that NfL may not serve as a prognostic marker for survival. Nevertheless, additional studies involving a larger patient cohort are required.

Abstract Introduction In EVOLVE-MS-1 (NCT02634307), mean absolute lymphocyte count (ALC) on diroximel fumarate (DRF) declined from baseline by approximately 28% in year 1, then stabilized, similar to ALC decline observed with dimethyl fumarate (DMF). Prior studies reported that clinical efficacy of DMF was not substantially different in patients with and without lymphopenia. Methods EVOLVE-MS-1—an open-label, 96-week, phase 3 study—assessed DRF safety and exploratory efficacy in patients with relapsing–remitting multiple sclerosis. This study analyzes efficacy-related outcomes comparing (1) patients with lymphopenia (≥ 1 ALC below lower limit of normal [LLN]) and without (all ALCs ≥ LLN); (2) across quartiles stratified by week 96 ALC decline from baseline: Q1 (≥ 47% decline); Q2 (30% to

Background Best supportive care (BSC) measures are an essential component for the management of primary progressive multiple sclerosis (PPMS). Objectives RETRO PPMS (ML39631) is the first study to systematically analyze the therapeutic journey and standard of BSC of patients with PPMS in Germany. Design This multicenter, non-interventional study retrospectively analyzed patient charts. Methods: Data were recorded up until the first infusion of ocrelizumab (July 2018 to October 2021). Medical history, disease status, disease activity and treatments were assessed from 12 months before PPMS diagnosis until study start. Acute interventions, BSC parameters and rehabilitation measures from the past 27 months were assessed. Results The core analysis population (N = 462) had a mean age (range) of 57.4 (27–85) years and mean disease duration of 13.7 (0.3–55.2) years. The most frequently reported symptoms were muscle spasticity, bladder disorder, ataxia, gait disturbance and fatigue. The most commonly used treatment was physical/occupational therapy (66.5% of patients); 47.2% received off-label treatment with corticosteroids/disease-modifying therapies. BSC measures for many symptoms were strikingly rare – especially for fatigue and cognitive impairment. Conclusion This analysis uncovers severe BSC deficits for many debilitating PPMS symptoms. There is still a large unmet need for innovative multidisciplinary care concepts and improvements in neurological primary and secondary care.

BackgroundSiponimod, a second-generation, selective sphingosine 1-phosphate receptor (S1PR) 1 and 5 modulator, represents an important therapeutic choice for active secondary progressive multiple sclerosis (SPMS). Besides the beneficial immunomodulatory effects, siponimod impacts cardiovascular function through S1PR1 modulation. Short-term vagomimetic effects on cardiac activity have proved to be mitigated by dose titration. However, long-term consequences are less known.ObjectivesThis study aimed to investigate the long-term impact of siponimod on cardiac autonomic modulation in people with SPMS (pwSPMS).MethodsHeart rate variability (HRV) and vascular hemodynamic parameters were evaluated using Multiple Trigonometric Regressive Spectral analysis in 47 pwSPMS before siponimod therapy and after one, three, six and 12 months of treatment. Autonomic activation tests (tilt test for the sympathetic and deep breathing test for the parasympathetic cardiac modulation) were performed at each examination.ResultspwSPMS preserved regular cardiovascular modulation responses during the autonomic tests reflected in the variation of several HRV parameters, such as RMSSD, pNN50, total power of HRV, high-frequency and low-frequency bands of the spectral domain or hemodynamic vascular parameters (Cwk, Zao, TPR, MAP) and baroreflex sensitivity (BRS). In the long-term follow-up, RMSSD, pNN50, total power, BRS and CwK presented a significant decrease, underlining a reduction of the parasympathetic and a shift towards sympathetic predominance in cardiac autonomic modulation that tends to stabilise after 1 year of treatment.ConclusionDue to dose titration, the short-term effects of siponimod on cardiac autonomic modulation are mitigated. The long-term impact on cardiac autonomic modulation is similar to fingolimod. The autonomic activation tests showed normal cardiovascular responses during 1-year follow-up in pwSPMS, confirming the safety profile of siponimod. Further research on autonomic function could reveal whether the observed sympathetic activation is a compensatory response to S1P signaling intervention or a feature of the disease, while also shedding light on the role of S1PR modulation in MS.

Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by central nervous system demyelination and axonal degeneration. Fatigue affects a major portion of MS patients, significantly impairing their daily activities and quality of life. Despite its prevalence, the mechanisms underlying fatigue in MS are poorly understood, and measuring fatigue remains a challenging task. This study evaluates the efficacy of automated speech analysis in detecting fatigue in MS patients. MS patients underwent a detailed clinical assessment and performed a comprehensive speech protocol. Using features from three different free speech tasks and a proprietary cognition score, our support vector machine model achieved an AUC on the ROC of 0.74 in detecting fatigue. Using only free speech features evoked from a picture description task we obtained an AUC of 0.68. This indicates that specific free speech patterns can be useful in detecting fatigue. Moreover, cognitive fatigue was significantly associated with lower speech ratio in free speech (ρ = −0.283, p = 0.001), suggesting that it may represent a specific marker of fatigue in MS patients. Together, our results show that automated speech analysis, of a single narrative free speech task, offers an objective, ecologically valid and low-burden method for fatigue assessment. Speech analysis tools offer promising potential applications in clinical practice for improving disease monitoring and management.

ABSTRACTBooster vaccinations against SARS-CoV-2 are recommended 6–12 months after the last dose or infection in elderly and high-risk groups. The present analysis aims to evaluate whether an interval shorter than 12 months is required in multiple sclerosis patients receiving ofatumumab. Neutralizing antibody status over 1 year in patients receiving booster vaccination in the non-interventional, multicenter KYRIOS study under continued ofatumumab treatment was analyzed. Fifteen patients were included. At the time of the first booster vaccination, ten patients were seropositive for neutralizing antibodies, four patients were seronegative, and for one patient, no baseline levels were available. All patients who were seropositive at baseline showed >2-fold increase in neutralizing antibody titers after the first booster and two patients (20%) showed a >10-fold increase. Among seronegative patients, three (75%) had a >10-fold increase in neutralizing antibody titers. Seropositivity was maintained in almost all patients until month 12. One initially seronegative patient had less than 2-fold increase in neutralizing antibody titers after the booster vaccination and can be considered a non-responder. Most patients with continued ofatumumab treatment are able to maintain permanent seropositivity and therefore presumably constant protection against severe courses of COVID-19 if repeated booster vaccinations are applied.

Multiple sclerosis (MS) is a devastating immune-mediated disorder of the central nervous system resulting in progressive disability accumulation. As there is no cure available yet for MS, the primary therapeutic objective is to reduce relapses and to slow down disability progression as early as possible during the disease to maintain and/or improve health-related quality of life. However, optimizing treatment for people with MS (pwMS) is complex and challenging due to the many factors involved and in particular, the high degree of clinical and sub-clinical heterogeneity in disease progression among pwMS. In this paper, we discuss these many different challenges complicating treatment optimization for pwMS as well as how a shift towards a more pro-active, data-driven and personalized medicine approach could potentially improve patient outcomes for pwMS. We describe how the ‘Clinical Impact through AI-assisted MS Care’ (CLAIMS) project serves as a recent example of how to realize such a shift towards personalized treatment optimization for pwMS through the development of a platform that offers a holistic view of all relevant patient data and biomarkers, and then using this data to enable AI-supported prognostic modelling.

BackgroundThe primary treatment for acute relapses in multiple sclerosis (MS) is the intravenous administration of high-dose methylprednisolone (IVMP). However, the mechanisms through which corticosteroid treatment impacts acute neuroinflammation in people with MS (pwMS) remain not fully understood. In particular, the changes induced by glucocorticoids (GCs) on cells of the innate immune system and the differences between patients with distinct immunotherapies have received little attention to date.MethodsWe conducted immunophenotyping using flow cytometry on peripheral blood mononuclear cells of pwMS who received IVMP treatment during a relapse. We compared the impact of an IVMP treatment on a broad variety of immune cell subsets within three groups: twelve patients who were treatment-naïve to disease modifying therapies (wDMT) to ten patients on platform therapies (PT) and eighteen patients on fingolimod therapy (FTY).ResultsWe observed pronounced interindividual short- and intermediate-term effects of IVMP on distinct immune cells subsets. In addition to the well-documented decrease in T-helper cells (Th cells), we detected significant alterations after the first IVMP infusion within the innate immune response among neutrophil, eosinophil and basophil granulocytes, monocytes and plasmacytoid dendritic cells (pDCs). When comparing patients wDMT to the PT and FTY cohorts, we found that IVMP had a similar impact on innate immune cells across all treatment groups. However, we did not observe a significant further decline in T lymphocyte counts during IVMP in patients with pre-existing lymphopenia under FTY treatment. Although T cell apoptosis is considered the main mechanism of action of GCs, patients with FTY still reported symptom improvement following IVMP treatment.ConclusionIn addition to T cell suppression, our data suggests that further immunoregulatory mechanisms of GC, particularly on cells of the innate immune response, are of greater significance than previously understood. Due to the regulation of the adaptive immune cells by DMTs, the impact of GC on these cells varies depending on the underlying DMT. Additional studies involving larger cohorts and cerebrospinal fluid samples are necessary to gain a deeper understanding of the immune response to GC in pwMS with different DMTs during relapse to define and explain differences in clinical response profiles.

Abstract Introduction Multiple sclerosis (MS) is a disabling disease with unpredictable clinical manifestations. As clinical assessments may not fully capture the impact of MS on quality of life, they can be complemented by patient-reported outcome (PRO) measures to provide a more comprehensive picture of MS disease state and impact. The objectives of this study were to explore the experiences of people with relapsing–remitting MS, including symptoms and impacts on daily life, and to provide a conceptual model of MS outcomes. Methods A literature review of studies that evaluated the experiences of people with MS was completed and combined with semi-structured concept elicitation interviews conducted with 14 people with relapsing–remitting MS in the USA. Results The average age of the 14 participants was 43.9 (range 25–64) years, most were White (78.6%) and female (78.6%), and the mean duration since diagnosis was 6.6 (2–10) years. The most bothersome symptoms identified included fatigue (n = 9), cognitive dysfunction (n = 5), mobility/difficulty with walking (n = 3), and vision problems (n = 3). The most commonly reported impacts on daily life were balance problems/instability (n = 13), work life/productivity (n = 12), difficulty walking (n = 11), daily activities/household chores (n = 11), and leisure activities (n = 10). Conclusion There was a high frequency of concepts associated with physical function, fatigue, and sensory-motor actions. A conceptual model was developed that captures the disease symptoms, impairments, and impacts identified in the interviews as well as known processes and symptoms identified in the literature search. This model underpins the appropriateness of PRO instruments, such as the PROMIS Fatigue (MS) 8a and PROMIS Physical Function (MS) 15a, which evaluate symptoms and impacts that matter most to people with MS.

Abstract Medical digital twins are computational models of human biology relevant to a given medical condition, which are tailored to an individual patient, thereby predicting the course of disease and individualized treatments, an important goal of personalized medicine. The immune system, which has a central role in many diseases, is highly heterogeneous between individuals, and thus poses a major challenge for this technology. In February 2023, an international group of experts convened for two days to discuss these challenges related to immune digital twins. The group consisted of clinicians, immunologists, biologists, and mathematical modelers, representative of the interdisciplinary nature of medical digital twin development. A video recording of the entire event is available. This paper presents a synopsis of the discussions, brief descriptions of ongoing digital twin projects at different stages of progress. It also proposes a 5-year action plan for further developing this technology. The main recommendations are to identify and pursue a small number of promising use cases, to develop stimulation-specific assays of immune function in a clinical setting, and to develop a database of existing computational immune models, as well as advanced modeling technology and infrastructure.

Abstract Objective Repeated intravenous administration of anti‐CD20 depleting monoclonal antibodies 6 months apart is among the highly effective treatment options in multiple sclerosis (MS). Here, we aimed to investigate peripheral immune cell subset depletion kinetics following either rituximab (RTX) or ocrelizumab (OCR) infusions in people with MS (pwMS). Methods We studied pwMS treated de‐novo with either RTX (n = 7) or OCR (n = 8). The examinations were scheduled before the initiation of anti‐CD20 therapy and every 12 weeks for up to 15 months. Immunophenotyping of immune cell subsets in peripheral blood was performed by multiparametric fluorescence cytometry. Results A significant, persistent decrease of CD19+ B cells was observed already with the first anti‐CD20 infusion (p

Abstract Different stages of Parkinson’s disease (PD) are defined by clinical criteria, while late-stage PD is marked by the onset of morbidity milestones and rapid clinical deterioration. Based on neuropathological evidence, degeneration in the dopaminergic system occurs primarily in the early stage of PD, raising the question of what drives disease progression in late-stage PD. This study aimed to investigate whether late-stage PD is associated with increased neurodegeneration dynamics rather than functional decompensation using the blood-based biomarker serum neurofilament light chain (sNfL) as a proxy for the rate of neurodegeneration. The study included 118 patients with PD in the transition and late-stage (minimum disease duration 5 years, mean (SD) disease duration 15 (±7) years). The presence of clinical milestones (hallucinations, dementia, recurrent falls, and admission to a nursing home) and mortality were determined based on chart review. We found that sNfL was higher in patients who presented with at least one clinical milestone and increased with a higher number of milestones (Spearman’s ρ = 0.66, p

In recent years, Raman spectroscopy has garnered growing interest in the field of biomedical research. It offers a non-invasive and label-free approach to defining the molecular fingerprint of immune cells. We utilized Raman spectroscopy on optically trapped immune cells to investigate their molecular compositions. While numerous immune cell types have been studied in the past, the characterization of living human CD3/CD28-stimulated T cell subsets remains incomplete. In this study, we demonstrate the capability of Raman spectroscopy to readily distinguish between naïve and stimulated CD4 and CD8 cells. Additionally, we compared these cells with monocytes and discovered remarkable similarities between stimulated T cells and monocytes. This paper contributes to expanding our knowledge of Raman spectroscopy of immune cells and serves as a launching point for future clinical applications.

Abstract Background In patients with relapsing remitting multiple sclerosis (RRMS) on low‐efficacy disease modifying therapies (DMT), the optimal strategy on how to escalate treatment once needed, remains unknown. Methods: We studied RRMS patients on low‐efficacy DMTs listed in the Swiss National Treatment Registry, who underwent escalation to either medium‐ or high‐efficacy DMTs. Propensity score‐based matching was applied using 12 clinically relevant variables. Both groups were also separately matched with control subjects who did not escalate therapy. Time to relapse and to disability worsening were evaluated using Cox proportional hazard models. Results: Of 1037 eligible patients, we 1:1 matched 450 MS patients who switched from low‐efficacy to medium‐efficacy (n = 225; 76.0% females, aged 42.4 ± 9.9 years [mean ± SD], median EDSS 3.0 [IQR 2–4]) or high‐efficacy DMTs (n = 225; 72.4% females, aged 42.2 ± 10.6 years, median EDSS 3.0 [IQR 2–4]). Escalation to high‐efficacy DMTs was associated with lower hazards of relapses than medium‐efficacy DMTs (HR = 0.67, 95% CI 0.47–0.95, p = .027) or control subjects (HR = 0.61, 95% CI 0.44–0.84, p = .003). By contrast, escalation from low to medium‐efficacy DMTs did not alter the hazard for relapses when compared to controls (i.e. patients on low‐efficacy DMT who did not escalate DMT during follow‐up) Conclusion: Our nationwide registry analysis suggests that, once escalation from a low‐efficacy DMT is indicated, switching directly to a high‐efficacy treatment is superior to a stepwise escalation starting with a moderate‐efficacy treatment.

Summary: Multiple sclerosis (MS) as a chronic, degenerative autoimmune disease of the central nervous system has a longitudinal and heterogeneous course with increasing treatment options and risk profiles requiring constant monitoring of a growing number of parameters. Despite treatment guidelines, there is a lack of strategic and individualised monitoring pathways, including respective quality indicators (QIs). To address this, we systematically developed transparent, traceable, and measurable QIs for MS monitoring. Through literature review, expert discussions, and consensus-building, existing QIs were identified and refined. In a two-stage online Delphi process involving MS specialists (on average 53 years old and with 25 years of professional experience), the QIs were evaluated for content, clarity, and intelligibility, resulting in a set of 24 QIs and checklists to assess the quality of care. The final QIs provide a structured approach to document, monitor, and enhance the quality of care for people with MS across their treatment journey.

Background: While evidence highlights the effectiveness of initiating disease-modifying therapy with a high-efficacy medication for multiple sclerosis (MS) patients with poor prognostic factors, it remains unclear whether this approach has been adopted by a broad range of MS providers in Germany yet. Objective: To assess the adoption of the early highly effective treatment (EHT) compared to the treat-to-target treatment approach with the option of escalating treatment efficacy over time in Germany based on real-world evidence data. Design: Patient-level pharmacy dispensing data from the Permea platform were analysed from 2020 to 2022. Methods: In total, 29,529 therapy beginners (>18 years) were included to analyse shifts in treatment approaches over time and switching behaviour. Medication classification adhered to the German Society of Neurology guidelines and designated fumarates, glatiramer acetate, teriflunomide and interferons as low-efficacy category 1 medications; cladribine and S1P-modulators as medium-efficacy category 2 medications; and alemtuzumab, natalizumab, ocrelizumab, ofatumumab and rituximab (off-label) as high-efficacy category 3 medications. Results: Our results show that 70.0% of patients redeemed their first prescription for category 1 medication, 16.3% for category 2 and 13.7% for category 3 medications. The proportion of prescriptions filled shifted from 2020 to 2022 with a decrease of 14.7% for category 1 drugs and an increase of 12.5% for category 3 drugs. 93.2% of patients stayed on their initially prescribed medication category. 3.2% of category 1 and 3.7% of category 2 therapy beginners escalated to category 3 medication. 3.4% of category 3 medication users de-escalated their treatment to category 1 or category 2. Conclusion: While most individuals started their treatment according to the treat-to-target approach and remained on their initially prescribed medication category, there has been a steadily increasing shift towards the EHT approach since 2020. These insights demonstrate that, while not officially recommended by German guidelines, MS providers increasingly adopt the EHT approach.

A fundamental challenge for personalized medicine is to capture enough of the complexity of an individual patient to determine an optimal way to keep them healthy or restore their health. This will require personalized computational models of sufficient resolution and with enough mechanistic information to provide actionable information to the clinician. Such personalized models are increasingly referred to as medical digital twins. Digital twin technology for health applications is still in its infancy, and extensive research and development is required. This article focuses on several projects in different stages of development that can lead to specific—and practical–medical digital twins or digital twin modeling platforms. It emerged from a two-day forum on problems related to medical digital twins, particularly those involving an immune system component. Open access video recordings of the forum discussions are available.

The authors would like to make the following corrections to this published paper [...]

Machine learning (ML) has emerged as a powerful tool in multiple sclerosis (MS) research, enabling more accurate diagnosis, prognosis prediction, and treatment optimization. However, the complexity of developing and deploying ML models poses challenges for domain experts without extensive programming knowledge. We propose a novel domain-specific language (DSL) that simplifies the process of selecting features, choosing appropriate ML models, and defining training rules for MS research. The DSL offers three approaches: AutoML for automated model and feature selection, manual selection for expert-guided customization, and a customizable mode allowing for fine-grained control. The DSL was implemented and evaluated using real-world MS data. By establishing task-specific DSLs, we have successfully identified workflows that enhance the filtering of ML models and features. This method is crucial in determining the T2-related MRI features that accurately predict both process speed time and walk speed. We assess the effectiveness of using our DSL to enhance ML models and identify feature importance within our private data, aiming to reveal the relationships between features. The proposed DSL empowers domain experts to leverage ML in MS research without extensive programming knowledge. By integrating MLOps practices, it streamlines the ML lifecycle, promoting trustworthy AI through explainability, interpretability, and collaboration. This work demonstrates the potential of DSLs in democratizing ML in MS and paves the way for future research in adaptive and evolving DSL architectures.

Disease-modifying therapies (DMTs) impact the cellular immune response to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccines in patients with multiple sclerosis (pwMS). In this study, we aim to elucidate the characteristics of the involved antigen-specific T cells via the measurement of broad cytokine profiles in pwMS on various DMTs. We examined SARS-CoV-2-specific T cell responses in whole blood cultures characterized by the release of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-13, IL-17A, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α), as well as antibodies (AB) targeting the SARS-CoV-2 spike protein in pwMS following either two or three doses of mRNA or viral vector vaccines (VVV). For mRNA vaccination non-responders, the NVX-CoV2373 protein-based vaccine was administered, and immune responses were evaluated. Our findings indicate that immune responses to SARS-CoV-2 vaccines in pwMS are skewed towards a Th1 phenotype, characterized by IL-2 and IFN-γ. Additionally, a Th2 response characterized by IL-5, and to a lesser extent IL-4, IL-10, and IL-13, is observed. Therefore, the measurement of IL-2 and IL-5 levels could complement traditional IFN-γ assays to more comprehensively characterize the cellular responses to SARS-CoV-2 vaccines. Our results provide a comprehensive cytokine profile for pwMS receiving different DMTs and offer valuable insights for designing vaccination strategies in this patient population.

Recent advances in the field of artificial intelligence (AI) could yield new insights into the potential causes of multiple sclerosis (MS) and factors influencing its course as the use of AI opens new possibilities regarding the interpretation and use of big data from not only a cross-sectional, but also a longitudinal perspective. For each patient with MS, there is a vast amount of multimodal data being accumulated over time. But for the application of AI and related technologies, these data need to be available in a machine-readable format and need to be collected in a standardized and structured manner. Through the use of mobile electronic devices and the internet it has also become possible to provide healthcare services from remote and collect information on a patient’s state of health outside of regular check-ups on site. Against this background, we argue that the concept of pathways in healthcare now could be applied to structure the collection of information across multiple devices and stakeholders in the virtual sphere, enabling us to exploit the full potential of AI technology by e.g., building digital twins. By going digital and using pathways, we can virtually link patients and their caregivers. Stakeholders then could rely on digital pathways for evidence-based guidance in the sequence of procedures and selection of therapy options based on advanced analytics supported by AI as well as for communication and education purposes. As far as we aware of, however, pathway modelling with respect to MS management and treatment has not been thoroughly investigated yet and still needs to be discussed. In this paper, we thus present our ideas for a modular-integrative framework for the development of digital patient pathways for MS treatment.

BackgroundThe aim of this study was to examine the societal costs of polypharmacy in patients with multiple sclerosis (MS). We therefore focused on the association between the number of medications on the level of care (LOC), the German classification of the need for care, and the number of therapy sessions (TTU).MethodsIn addition to demographic information and medication, 101 MS patients performed the Multiple Sclerosis Health Resource Utilization Survey (MS-HRS). Medications were subdivided into a total number of medications (TD), MS-related medication [MSD, i.e., disease-modifying drugs (DMDs) and symptomatic treatment (SD)], and medication for comorbidities (CDs). Multivariate linear regression models were performed to estimate if the amount of each medication type affects LOC or TTU.ResultsPolypharmacy appeared in 54 patients at the time of the survey. The relative risk (RR) of LOC 1 increased significantly by 2.46 (p = 0.001) per TD and by 2.55 (p = 0.004) per MSD, but not per CD (RR 1.44; p = 0.092). The effect of RR on MSD was driven by SD (RR 2.2; p = 0.013) but not DMD (RR 2.6; p = 0.4). RR of MSD remained significant for LOC 2 (1.77; p = 0.009) and LOC 3/4 (1.91; p = 0.015), with a strong trend in RR of SD, but not DMD. TTU increased significantly per MSD (p = 0.012), but not per TD (p = 0.081) and CD (p = 0.724).ConclusionThe number of MSDs is related to the likelihood of a higher level of care and the number of therapy sessions and is therefore a good indication of the extent of the societal costs.

BackgroundThe Expanded Disability Status Scale (EDSS) quantifies disability and measures disease progression in multiple sclerosis (MS), however is not available in administrative claims databases.ObjectivesTo develop a claims-based algorithm for deriving EDSS and validate it against a clinical dataset capturing true EDSS values from medical records.MethodsWe built a unique linked dataset combining claims data from the German AOK PLUS sickness fund and medical records from the Multiple Sclerosis Management System 3D (MSDS3D). Data were deterministically linked based on insurance numbers. We used 69 MS-related diagnostic indicators recorded with ICD-10-GM codes within 3 months before and after recorded true EDSS measures to estimate a claims-based EDSS proxy (pEDSS). Predictive performance of the pEDSS was assessed as an eight-fold (EDSS 1.0–7.0, ≥8.0), three-fold (EDSS 1.0–3.0, 4.0–5.0, ≥6.0), and binary classifier (EDSS

(1) Background: The countermovement jump (CMJ) on a force plate could be a sensitive assessment for detecting early lower-limb muscle mechanical deficits in the early stages of multiple sclerosis (MS). CMJ performance is known to be influenced by various anthropometric, physiological, and biomechanical factors, mostly investigated in children and adult athletes. Our aim was to investigate the association of age, sex, and BMI with muscle mechanical function using CMJ to provide a comprehensive overview of lower-limb motor function in people with multiple sclerosis (pwMS). (2) Methods: A cross-sectional study was conducted with pwMS (N = 164) and healthy controls (N = 98). All participants performed three maximal CMJs on a force plate. Age, sex, and BMI were collected from all participants. (3) Results: Significant age, sex, and BMI effects were found for all performance parameters, flight time, and negative and positive power for pwMS and HC, but no significant interaction effects with the group (pwMS, HC) were detected. The highest significant effects were found for sex on flight time (η2 = 0.23), jump height (η2 = 0.23), and positive power (η2 = 0.13). PwMS showed significantly lower CMJ performance compared to HC in middle-aged (31–49 years), with normal weight to overweight and in both women and men. (4) Conclusions: This study showed that age, sex, and BMI are associated with muscle mechanical function in pwMS and HC. These results may be useful in developing reference values for CMJ. This is a crucial step in integrating CMJ into the diagnostic assessment of people with early MS and developing individualized and effective neurorehabilitative therapy.

The SARS-CoV-2 pandemic profoundly impacted people with multiple sclerosis (pwMS). Disease-related aspects and demographic factors may influence vaccination rates, infection susceptibility, and severity. Despite prior research, comprehensive real-world data obtained throughout the pandemic remain limited. We investigated SARS-CoV-2 vaccination and infection patterns in a large monocentric real-world cohort. We collected prospective data from medical visits at the MS Center Dresden, Germany, from the pandemic’s beginning until 31 May 2022. Logistic regression and rank correlation analyses were used to explore associations between SARS-CoV-2 outcomes and patient characteristics. Of 2115 pwMS assessed (mean age 46.5, SD ± 12.9; median expanded disability status scale 2.5), 77.9% were under disease-modifying treatment (DMT), primarily B-cell depletion (25.4%). A total of 35.5% reported SARS-CoV-2 infections, and 77.4% were fully vaccinated. PwMS with increased disability, older age, and comorbidities were associated with higher vaccination rates, possibly due to the awareness of these populations regarding complications of SARS-CoV-2 infections. Infections were more common in younger females, people with a lower degree of disability, those with relapsing MS, and those who were not vaccinated. PwMS on B-cell depletion reported more infections than untreated pwMS and those receiving other types of disease-modifying therapy, despite higher vaccination rates. Most infections were mild, with no severity differences according to demographic or disease-related factors, except for gender. Notably, all fatal cases occurred in unvaccinated pwMS. Our studies suggest that demographic and disease-related factors, especially age and the use of B-cell depletion, significantly influenced SARS-CoV-2 vaccination and infection rates in our cohort. These factors may be considered in future preventive campaigns in further pandemics.

Fatigue is one of the most disabling symptoms of Multiple Sclerosis (MS), affecting more than 80% of patients over the disease course. Nevertheless, it has a multi-faceted and complex nature, making its diagnosis, evaluation, and treatment extremely challenging in clinical practice. In the last years, digital supporting tools have emerged to support the care of people with MS. These include not only smartphone or table-based apps, but also wearable devices or novel techniques such as virtual reality. Furthermore, an additional effective and cost-efficient tool for the therapeutic management of people with fatigue is becoming increasingly available. Virtual reality and e-Health are viable and modern tools to both assess and treat fatigue, with a variety of applications and adaptability to patient needs and disability levels. Most importantly, they can be employed in the patient's home setting and can not only bridge clinic visits but also be complementary to the monitoring and treatment means for those MS patients who live far away from healthcare structures. In this narrative review, we discuss the current knowledge and future perspectives in the digital management of fatigue in MS. These may also serve as sources for research of novel digital biomarkers in the identification of disease activity and progression.

Background: While substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS), a high percentage of treated patients still show progression and persistent inflammatory activity. Autologous haematopoietic stem cell transplantation (AHSCT) aims at eliminating a pathogenic immune repertoire through intense short-term immunosuppression that enables subsequent regeneration of a new and healthy immune system to re-establish immune tolerance for a long period of time. A number of mostly open-label, uncontrolled studies conducted over the past 20 years collected about 4000 cases. They uniformly reported high efficacy of AHSCT in controlling MS inflammatory disease activity, more markedly beneficial in relapsing-remitting MS. Immunological studies provided evidence for qualitative immune resetting following AHSCT. These data and improved safety profiles of transplantation procedures spurred interest in using AHSCT as a treatment option for MS. Objective: To develop expert consensus recommendations on AHSCT in Germany and outline a registry study project. Methods: An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of virtual meetings. Results: We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS based on the Swiss criteria. Current data indicate that patients who are most likely to benefit from AHSCT have relapsing-remitting MS and are young, ambulatory and have high disease activity. Treatment data with AHSCT will be collected within the German REgistry Cohort of autologous haematopoietic stem CeLl trAnsplantation In MS (RECLAIM). Conclusion: Further clinical trials, including registry-based analyses, are urgently needed to better define the patient characteristics, efficacy and safety profile of AHSCT compared with other high-efficacy therapies and to optimally position it as a treatment option in different MS disease stages.

Background and objectives: Alemtuzumab demonstrated superior efficacy versus subcutaneous interferon (IFN) beta-1a in participants with relapsing-remitting multiple sclerosis in the 2-year CARE-MS I and II trials. Efficacy was maintained in the 4-year CARE-MS extension, during which alemtuzumab-treated participants (‘alemtuzumab-only’) could receive additional courses upon disease activity, and IFN-treated participants switched to alemtuzumab (‘IFN-alemtuzumab’). Participants who completed the CARE-MS extension could enroll in the open-label TOPAZ study which assessed safety and efficacy for 5–7 years (11–13 years after alemtuzumab/IFN initiation). Methods: Participants received additional alemtuzumab courses as needed. Assessments included adverse events (AEs; primary outcome), annualized relapse rate (ARR), 6-month confirmed disability worsening [CDW; ⩾1.0-point Expanded Disability Status Scale (EDSS) score increase or ⩾1.5 if baseline EDSS = 0], and 6-month confirmed disease improvement [CDI; >1.0-point EDSS decrease (baseline score ⩾2.0)]. Results: 43.5% of alemtuzumab-only participants from CARE-MS II and 54.2% from CARE-MS I received no additional alemtuzumab courses; 30.0% and 20.9%, respectively, received one additional course (the median). Incidences of AEs, including thyroid AEs and infections, declined over time. The safety profile of alemtuzumab was similar for participants who received zero, one, or two additional courses. For CARE-MS II participants, who had inadequate response to previous treatment, ARR remained low during Years 3–13 for the alemtuzumab-only [0.17; 95% confidence interval (CI) 0.15–0.20] and IFN-alemtuzumab (0.14; 0.11–0.17) groups. At Year 11, the proportions of participants who were either free from CDW or who had CDI were higher in the alemtuzumab-only group (58% and 49%, respectively) than in the IFN-alemtuzumab group (51% and 37%). For CARE-MS I participants, who were previously treatment-naïve, clinical outcomes remained improved, and no between-group differences were apparent. Conclusion: Safety risks associated with alemtuzumab treatment declined over time. Clinical benefits were maintained up to 11–13 years, and most participants did not require more than one additional course. Clinicaltrials.gov identifiers: NCT00530348; NCT00548405; NCT00930553; NCT02255656

Abstract Objective Evaluation of serum neurofilament light chain (sNfL), measured using high‐throughput assays on widely accessible platforms in large, real‐world MS populations, is a critical step for sNfL to be utilized in clinical practice. Methods Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is a network of healthcare institutions in the United States and Europe collecting standardized clinical/imaging data and biospecimens during routine clinic visits. sNfL was measured in 6974 MS and 201 healthy control (HC) participants, using a high‐throughput, scalable immunoassay. Results Elevated sNfL levels for age (sNfL‐E) were found in 1238 MS participants (17.8%). Factors associated with sNfL‐E included male sex, younger age, progressive disease subtype, diabetes mellitus, impaired renal function, and active smoking. Higher body mass index (BMI) was associated with lower odds of elevated sNfL. Active treatment with disease‐modifying therapy was associated with lower odds of sNfL‐E. MS participants with sNfL‐E exhibited worse neurological function (patient‐reported disability, walking speed, manual dexterity, and cognitive processing speed), lower brain parenchymal fraction, and higher T2 lesion volume. Longitudinal analyses revealed accelerated short‐term rates of whole brain atrophy in sNfL‐E participants and higher odds of new T2 lesion development, although both MS participants with or without sNfL‐E exhibited faster rates of whole brain atrophy compared to HC. Findings were consistent in analyses examining age‐normative sNfL Z‐scores as a continuous variable. Interpretation Elevated sNfL is associated with clinical disability, inflammatory disease activity, and whole brain atrophy in MS, but interpretation needs to account for comorbidities including impaired renal function, diabetes, and smoking.

Abstract Background Therapeutic options targeting inflammation in multiple sclerosis (MS) have evolved rapidly for relapsing–remitting MS, whereas few therapies are available for progressive forms of MS, in particular secondary progressive MS (SPMS). The approval of siponimod for SPMS has allowed for optimism in the otherwise discouraging therapeutic landscape. Methods We conducted a retrospective, multicenter, non-interventional study analyzing the efficacy and safety of siponimod under real-world conditions in 227 SPMS patients. According to the retrospective study framework, data was acquired at prespecified time points. Clinical readouts were assessed every three months. Disease progression was determined as increase in expanded disability status scale (EDSS), radiological progression, or the occurrence of new relapses under treatment. For safety analyses, adverse events (AE) and reasons for discontinuation were documented. The collected data points were analyzed at baseline and after 6, 12 and 18 months. However, data were predominately collected at the 6- and 12-month time points as many patients were lost to follow-up. In a group consisting of 41 patients, a more detailed investigation regarding disease progression was conducted, including data from measurement of cognitive and motoric functions. Results Under siponimod therapy, 64.8% of patients experienced sustained clinical disease stability at 12 months. Out of the stable patients 21.4% of patients improved. Of the remaining patients, 31.5% experienced EDSS progression, 3.7% worsened without meeting the threshold for progression. Relapses occurred in 7.4%. Radiological disease activity was detected in 24.1% of patients after six months of treatment and in 29.6% of patients at 12 months follow-up. The in-depth cohort consisting of 41 patients demonstrated no substantial changes in cognitive abilities measured by Paced Auditory Serial Addition Test and Symbol Digit Modalities Test or motoric functions measured with Timed 25-Foot Walk, 100-m timed test, and 9-Hole Peg Test throughout the 12-month study period. Radiological assessment showed a stable volume of white and grey matter, as well as a stable lesion count at 12 months follow-up. AE were observed in nearly half of the included patients, with lymphopenia being the most common. Due to disease progression or AE, 31.2% of patients discontinued therapy. Conclusion Treatment with siponimod had an overall stabilizing effect regarding clinical and radiological outcome measures. However, there is a need for more intensive treatment management and monitoring to identify disease progression and AE.

Objective: This pilot study explores the influence of acute alcohol exposure on cell mechanical properties of steady-state and activated leukocytes conducted with real-time deformability cytometry.Methods: Nineteen healthy male volunteers were enrolled to investigate the effect of binge drinking on biophysical properties and cell counts of peripheral blood leukocytes. Each participant consumed an individualized amount of alcohol to achieve a blood alcohol concentration of 1.2 ‰ as a mean peak. In addition, we also incubated whole blood samples from healthy donors with various ethanol concentrations and performed stimulation experiments using lipopolysaccharide and CytoStim™ in the presence of ethanol.Results: Our findings indicate that the biophysical properties of steady-state leukocytes are not significantly affected by a single episode of binge drinking within the first two hours. However, we observed significant alterations in relative cell counts and a shift toward a memory T cell phenotype. Moreover, exposure to ethanol during stimulation appears to inhibit the cytoskeleton reorganization of monocytes, as evidenced by a hindered increase in cell deformability.Conclusion: Our observations indicate the promising potential of cell mechanical analysis in understanding the influence of ethanol on immune cell functions. Nevertheless, additional investigations in this field are warranted to validate biophysical properties as biomarkers or prognostic indicators for alcohol-related changes in the immune system.

IntroductionGiven its wide availability and cost-effectiveness, multidimensional flow cytometry (mFC) became a core method in the field of immunology allowing for the analysis of a broad range of individual cells providing insights into cell subset composition, cellular behavior, and cell-to-cell interactions. Formerly, the analysis of mFC data solely relied on manual gating strategies. With the advent of novel computational approaches, (semi-)automated gating strategies and analysis tools complemented manual approaches.MethodsUsing Bayesian network analysis, we developed a mathematical model for the dependencies of different obtained mFC markers. The algorithm creates a Bayesian network that is a HC tree when including raw, ungated mFC data of a randomly selected healthy control cohort (HC). The HC tree is used to classify whether the observed marker distribution (either patients with amyotrophic lateral sclerosis (ALS) or HC) is predicted. The relative number of cells where the probability q is equal to zero is calculated reflecting the similarity in the marker distribution between a randomly chosen mFC file (ALS or HC) and the HC tree.ResultsIncluding peripheral blood mFC data from 68 ALS and 35 HC, the algorithm could correctly identify 64/68 ALS cases. Tuning of parameters revealed that the combination of 7 markers, 200 bins, and 20 patients achieved the highest AUC on a significance level of p < 0.0001. The markers CD4 and CD38 showed the highest zero probability. We successfully validated our approach by including a second, independent ALS and HC cohort (55 ALS and 30 HC). In this case, all ALS were correctly identified and side scatter and CD20 yielded the highest zero probability. Finally, both datasets were analyzed by the commercially available algorithm ‘Citrus’, which indicated superior ability of Bayesian network analysis when including raw, ungated mFC data.DiscussionBayesian network analysis might present a novel approach for classifying mFC data, which does not rely on reduction techniques, thus, allowing to retain information on the entire dataset. Future studies will have to assess the performance when discriminating clinically relevant differential diagnoses to evaluate the complementary diagnostic benefit of Bayesian network analysis to the clinical routine workup.

ImportanceImmunological response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is important, especially in people with multiple sclerosis (pwMS) on immunosuppressive therapies.ObjectiveThis study aims to determine whether adjuvanted protein-based vaccine NVX-CoV2373 is able to induce an immune response to SARS-CoV-2 in pwMS with inadequate responses to prior triple mRNA/viral vector vaccination.Design, setting, and participantsWe conducted a single-center, prospective longitudinal cohort study at the MS Center in Dresden, Germany. In total, 65 participants were included in the study in accordance with the following eligibility criteria: age > 18 years, immunomodulatory treatment, and insufficient T-cellular and humoral response to prior vaccination with at least two doses of SARS-CoV-2 mRNA (BNT162b2, mRNA-1273) or viral vector vaccines (AZD1222, Ad26.COV2.S).InterventionsIntramuscular vaccination with two doses of NVX-CoV2373 at baseline and 3 weeks of follow-up.Main outcomes and measuresThe development of SARS-CoV-2-specific antibodies and T-cell responses was evaluated.ResultsFor the final analysis, data from 47 patients on stable treatment with sphingosine-1-phosphate receptor (S1PR) modulators and 17 on ocrelizumab were available. The tolerability of the NVX-CoV2373 vaccination was overall good and comparable to the one reported for the general population. After the second NVX-CoV2373 vaccination, 59% of S1PR-modulated patients developed antispike IgG antibodies above the predefined cutoff of 200 binding antibody units (BAU)/ml (mean, 1,204.37 [95% CI, 693.15, 2,092.65] BAU/ml), whereas no clinically significant T-cell response was found. In the subgroup of the patients on ocrelizumab treatment, 23.5% developed antispike IgG > 200 BAU/ml (mean, 116.3 [95% CI, 47.04, 287.51] BAU/ml) and 53% showed positive spike-specific T-cellular responses (IFN-gamma release to antigen 1: mean, 0.2 [95% CI, 0.11, 0.31] IU/ml; antigen 2: mean, 0.24 [95% CI, 0.14, 0.37]) after the second vaccination.ConclusionsVaccination with two doses of NVX-CoV2373 was able to elicit a SARS-CoV-2-specific immune response in pwMS lacking adequate immune responses to previous mRNA/viral vector vaccination. For patients receiving S1PR modulators, an increase in anti-SARS-CoV-2 IgG antibodies was detected after NVX-CoV2373 vaccination, whereas in ocrelizumab-treated patients, the increase of antiviral T-cell responses was more pronounced. Our data may impact clinical decision-making by influencing the preference for NVX-CoV2373 vaccination in pwMS receiving treatment with S1PR modulation or anti-CD20 treatment.

ObjectiveThe study aimed to investigate the effect of exercise on immune cell count and cell mechanical properties in people with multiple sclerosis (pwMS) on different disease-modifying treatments (DMT) vs. healthy controls (HCs).MethodsA cohort of 16 HCs and 45 pwMS, including patients with lymphopenia (alemtuzumab and fingolimod) as well as increased lymphocyte counts (natalizumab), was evaluated for exercise-mediated effects on immune cell counts and lymphocyte deformability. As exercise paradigms, climbing stairs at normal speed or as fast as possible and cycling were used, while blood samples were collected before, immediately, and 20 as well as 60 min post-exercise. Immune cell subtypes and lymphocyte deformability were analyzed using multicolor flow cytometry and real-time deformability cytometry.ResultsAn increase in lymphocytes and selected subsets was observed following exercise in HCs and all pwMS on different DMTs. Patients with lymphopenia exhibited an increase in absolute lymphocyte counts and immune cell subsets till just below or into the reference range. An increase above the upper limit of the reference range was detected in patients on natalizumab. Exercise-induced alterations were observable even in low and more pronounced in high-intensity physical activities. Lymphocyte deformability was found to be only mildly affected by the investigated exercise regimes.ConclusionPeople with multiple sclerosis (PwMS) treated with alemtuzumab, fingolimod, and natalizumab respond to acute exercise with a comparable temporal pattern characterized by the increase of immune cell subsets as HCs. The magnitude of response is influenced by exercise intensity. Exercise-mediated effects should be considered when interpreting laboratory values in patients on immunomodulatory therapy. The impact of exercise on biophysical properties should be further elucidated.

Background Multiple Sclerosis (MS) is a chronic and progressive neurological autoimmune disease currently affecting 250,000 individuals in Germany. Patients suffering from the disease can be severely impaired in their day-to-day activities. BRISA is a digital app specifically designed to help MS patients monitor their disease by regularly tracking symptoms. Lengthy and time-consuming questionnaires for patient-reported outcomes (PRO) are the standard method to assess the patients’ current condition. Here, we examine whether simplified versions of these questionnaires can provide comparable information regarding individual symptom presentations in BRISA users. Methods 828 users were included in the analysis. Patients who provided onboarding information and answered at least one questionnaire and the corresponding simplified smiley symptoms assessment were included. Correlation of questionnaire and symptom scores was calculated using Pearson's correlation. Results Our analysis cohort predominantly consisted of female, 26–55-year-olds. Relapsing-remitting MS (RRMS) was the most common MS type recorded. Most patients were diagnosed 2–5 years ago. Questionnaires regarding fatigue and vision impairment were among the most answered, those regarding bowel movement and sexual satisfaction received fewest responses. Overall, the scores from questionnaires and symptoms correlated positively. Scoring correlation could also be shown across the subgroups divided by gender, age groups, type of MS, and time since diagnosis of the disease. Conclusion Scores recorded from traditional PRO questionnaires can be reflected more easily as a trend in a simplified scale using smileys. Nevertheless, traditional questionnaires are needed to also maintain a more objective assessment. In conclusion, the patient will benefit most from an adaptive combination of regular traditional PRO questionnaire assessments and simplified symptom recording.

Objectives We describe the development of Your Multiple Sclerosis Questionnaire and present the real-world usability testing results of Your Multiple Sclerosis Questionnaire. Methods The Your Multiple Sclerosis Questionnaire tool was developed in four stages to collect feedback from people living with MS (plwMS), patient organizations, and clinicians on content, format, and applicability. To assess its usability, 13 clinicians across 7 countries completed an online survey after using the tool with plwMS in a total of 261 consultations from September, 2020 to July, 2021. Results The initial Your Multiple Sclerosis Questionnaire version was based on findings from previous research developing MSProDiscuss™, a clinician-completed tool. Subsequently, insights from plwMS obtained during cognitive debriefing, patient councils and advisory boards led to changes including the addition of mood and sexual problems and the definition of relapse. All 13 clinicians completed the individual survey, whereas 10 clinicians completed the final survey. Clinicians “strongly agreed” or “agreed” that Your Multiple Sclerosis Questionnaire was easy to use and understand (98.5%; 257/261 patient consultations). The clinicians were willing to use the tool again with the same patient (98.1%; 256/261 patient consultations). All clinicians who completed the final survey (100%; 10/10) reported the tool to have a positive influence on their clinical practice, helped patients engage with their MS, facilitated discussion with patients, and complemented neurological assessment. Conclusion Your Multiple Sclerosis Questionnaire benefits both plwMS and clinicians by facilitating a structured discussion and engaging the plwMS to self-monitor and self-manage. Your Multiple Sclerosis Questionnaire is compatible with telemedicine practice and integration of the tool into electronic health records would enable tracking of the disease evolution and individual monitoring of MS symptoms over time.

Our objective was to analyze longitudinal cellular and humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in people with multiple sclerosis (pwMS) on B-cell depleting treatment (BCDT) compared to pwMS without immunotherapy. We further evaluated the impact of COVID-19 infection and vaccination timing. PwMS (n = 439) on BCDT (ocrelizumab, rituximab, ofatumumab) or without immunotherapy were recruited for this prospective cohort study between June 2021 and June 2022. SARS-CoV-2 spike-specific antibodies and interferon-γ release of CD4 and CD8 T-cells upon stimulation with spike protein peptide pools were analyzed at different timepoints (after primary vaccination, 3 and 6 months after primary vaccination, after booster vaccination, 3 months after booster). Humoral response to SARS-CoV-2 was consistently lower whereas T-cell response was higher in patients with BCDT compared to controls. Cellular and humoral responses decreased over time after primary vaccination and increased again upon booster vaccination, with significantly higher antibody titers after booster than after primary vaccination in both untreated and B-cell-depleted pwMS. COVID-19 infection further led to a significant increase in SARS-CoV-2-specific responses. Despite attenuated B-cell responses, a third vaccination for patients with BCDT seems recommendable, since at least partial protection can be expected from the strong T-cell response. Moreover, our data show that an assessment of T-cell responses may be helpful in B-cell-depleted patients to evaluate the efficacy of SARS-CoV-2 vaccination.

Abstract Deep brain stimulation (DBS) is a potent symptomatic therapy for Parkinson’s disease, but it is debated whether it causes or prevents neurodegeneration. We used serum neurofilament light chain (NFL) as a reporter for neuronal damage and found no difference between 92 patients with chronic STN-DBS and 57 patients on best medical treatment. Serum NFL transiently increased after DBS surgery whereas the initiation of STN stimulation did not affect NFL levels, suggesting that DBS surgery can be associated with neuronal damage whereas stimulation itself is not.

Background: Real-word evidence from diverse data sources is increasingly important in terms of generating rapid insights to effectively manage patient populations, especially during major public health disruptions such as the ongoing COVID-19 pandemic. Patients with chronic and inflammatory diseases - such as multiple sclerosis (MS) - were reported to experience potentially negative effects due to the use of immunosuppressive drugs in combination with a COVID-19 infection. In this research, we explored the impact of the COVID-19 pandemic on medication use in patients with MS in Germany. Methods: Patient-level pharmacy dispensing data from the Permea platform - covering approximately 44% of all community pharmacy dispensing in Germany - were analysed from 2019 − 2021. Longitudinal use patterns of MS medication and antidepressants and patient demographics were assessed. Daily variation in MS medication use was specifically studied around the dates of the first and second lockdowns in Germany. Results: We included data from 539,400 prescriptions which included at least 1 MS drug. The medication data showed a stable level of monthly prescriptions for MS medication at 2.02 ± 0.03 prescriptions per pharmacy during the study period. Although there was a sharp increase in daily prescriptions before the first lockdown (from an average 660.08 ± 137.59 daily prescriptions in the observed period to a maximum dispensing number of 998 daily prescriptions), the overall number of prescriptions remained at pre-pandemic levels (603 ± 90.31 daily prescriptions in 2019). Similar trends were observed for monthly co-prescribed antidepressant use per pharmacy (0.10 ± 0.01 in 2019–0.11 ± 0.02 in 2020). Conclusion: Throughout the COVID-19 pandemic, the use of MS medications and co-prescribed antidepressants was stable. These insights from real-world data demonstrate the value of evidence-based insights for managing patient care.

The brain is the key organ that orchestrates the stress response which translates to the retina. The retina is an extension of the brain and retinal symptoms in subjects with neurodegenerative diseases substantiated the eye as a window to the brain. The retina is used in this study to determine whether chronic stress reflects neurodegenerative signs indicative of neurodegenerative conditions. A three-year prospective cohort (n = 333; aged 46 ± 9 years) was stratified into stress-phenotype cases (n = 212) and controls (n = 121) by applying the Malan stress-phenotype index. Neurodegenerative risk markers included ischemia (astrocytic S100 calcium-binding protein B/S100B); 24-h blood pressure, proteomics; inflammation (tumor-necrosis-factor-α/TNF-α); neuronal damage (neuron-specific-enolase); anti-apoptosis of retinal-ganglion-cells (beta-nerve-growth-factor), astrocytic activity (glial-fibrillary-acidic-protein); hematocrit (viscosity) and retinal follow-up data [vessels; stress-optic-neuropathy]. Stress-optic-neuropathy risk was calculated from two indices: a newly derived diastolic-ocular-perfusion-pressure cut-point ≥68 mmHg relating to the stress-phenotype; combined with an established cup-to-disk ratio cut-point ≥0.3. Higher stress-optic-neuropathy (39% vs. 17%) and hypertension (73% vs. 16%) prevalence was observed in the stress-phenotype cases vs. controls. Elevated diastolic-ocular-perfusion-pressure, indicating hypoperfusion, was related to arterial narrowing and trend for ischemia increases in the stress-phenotype. Ischemia in the stress-phenotype at baseline, follow-up and three-year changes was related to consistent inflammation (TNF-α and cytokine-interleukin-17-receptor-A), neuron-specific-enolase increases, consistent apoptosis (chitinase-3-like protein 1, low beta-nerve-growth-factor), glial-fibrillary-acidic-protein decreases, elevated viscosity, vein widening as risk marker of endothelial dysfunction in the blood-retinal barrier, lower vein count, and elevated stress-optic-neuropathy. The stress-phenotype and related neurodegenerative signs of ongoing brain ischemia, apoptosis and endothelial dysfunction compromised blood–retinal barrier permeability and optic nerve integrity. In fact, the stress-phenotype could identify persons at high risk of neurodegeneration to indicate a neurodegenerative condition.

Objective Due to the growing complexity in monitoring and treatment of many disorders, disease-specific care and research networks offer patients certified healthcare. However, the networks’ ability to provide health services close to patients’ homes usually remains vague. Digital Health Technologies (DHTs) help to provide better care, especially if implemented in a targeted manner in regions undersupplied by specialised networks. Therefore, we used a car travel time-based isochrone approach to identify care gaps using the example of the neuroinflammation-focused German healthcare and research networks for multiple sclerosis (MS), myasthenia gravis (MG), myositis and immune-mediated neuropathy. Methods Excellence centres were mapped, and isochrones for 30, 60, 90 and 120 minutes were calculated. The resulting geometric figures were aggregated and used to mask the global human settlement population grid 2019 to estimate German inhabitants that can reach centres within the given periods. Results While 96.48% of Germans can drive to an MS-focused centre within one hour, coverage is lower for the rare disease networks for MG (48.3%), myositis (43.1%) and immune-mediated neuropathy (56.7%). Within 120 minutes, more than 80% of Germans can reach a centre of any network. Besides the generally worse covered rural regions such as North-Eastern Germany, the rare disease networks also show network-specific regional underrepresentation. Conclusion An isochrone-based approach helps identify regions where specialised care is hard to reach, which might be especially troublesome in the case of an often disabled patient collective. Patient care could be improved by focusing deployments of disease-specific DHTs on these areas.

Background: Natalizumab is a highly effective monoclonal antibody for the treatment of multiple sclerosis (MS), which can diffuse in different anatomical compartments, including cerebrospinal fluid (CSF) and milk. Objectives: Starting from incidental detection of natalizumab in the CSF of MS patients, the objective of this study was to develope a flow-cytometry-based assay and apply it to quantify natalizumab in body fluids, including milk collected from nursing patients over 180 days and in patients with neutralizing antibodies against natalizumab. Methods: CSF, milk and sera samples from patients with multiple sclerosis were tested by flow-cytometry for binding to a VLA-4 expressing cell line or to a control cell line. A standard curve was prepared by incubating the same cells with natalizumab at 50 μg/ml and serially diluted to 0.005 ng/ml. Binding specificity was confirmed using an anti-natalizumab neutralizing antibody. Results: Our assay was sensitive enough to detect natalizumab in CSF, with a lower detection limit of 1.5 ng/ml. Neutralizing antibodies against natalizumab inhibited binding to the cell line. In breastmilk, the peak concentration was observed during the first 2 weeks after infusion and the average concentration over the observation time was 173.3 ng/ml, with a trend toward increased average milk concentration over subsequent administrations. Conclusion: Routine use of such an assay would enable a better understanding of the safety of therapeutic antibody administration during pregnancy and lactation.

Abstract Objective The aim of this study was to evaluate neurofilament light chain as blood biomarker for disease activity in children and adolescents with different types of spinal muscular atrophy (SMA) and establish pediatric reference values. Methods We measured neurofilament light chain levels in serum (sNfL) and cerebral spinal fluid (cNfL) of 18 children with SMA and varying numbers of SMN2 copies receiving nusinersen by single‐molecule array (SiMoA) assay and analyzed correlations with baseline characteristics and motor development. Additionally, we examined sNfL in 97 neurologically healthy children. Results Median sNfL levels in treatment‐naïve SMA patients with 2 SMN2 copies are higher than in those with >2 SMN2 copies (P 2 SMN2 copies (r = –0.1, P = 0.744). Interpretation Reference sNfL values of our large pediatric control cohort may be applied for future studies. Strong correlations between sNfL and cNfL together with motor function suggest that sNfL may be a suitable biomarker for disease activity in children with 2 SMN2 copies and those with >2 SMN2 copies within their initial stages during early childhood.

Background: Systematic data are lacking on the immune response toward SARS-CoV-2 mRNA vaccination in SPMS patients on disease-modifying therapies (DMTs). Objective: The AMA-VACC clinical trial was designed to characterize immune responses to SARS-CoV-2 mRNA vaccines in siponimod-treated SPMS patients. Design: AMA-VACC is an ongoing three-cohort, multicenter, open-label, prospective clinical study. Methods: The study included patients at risk for SPMS or patients with SPMS diagnosis. Patients received SARS-CoV-2 mRNA vaccine as part of their clinical routine during ongoing siponimod treatment (cohort 1), during siponimod treatment interruption (cohort 2), or while on dimethyl fumarate, glatiramer acetate, beta-interferons, teriflunomide, or no current therapy (cohort 3). SARS-CoV-2-specific neutralizing antibodies and T-cell responses were measured 1 week and 1 month after the second dose of vaccination. Results: In total, 17 patients, 4 patients, and 20 patients were recruited into cohorts 1, 2, and 3, respectively. The primary endpoint of seroconversion for SARS-CoV-2-neutralizing antibodies at week 1 was reached by 52.9%, 75.0%, and 90.0% of patients in cohorts 1, 2, and 3, respectively. For 64.7% of patients in cohort 1, all patients in cohort 2, and 95% of patients in cohort 3, seroconversion was observed at either week 1 or month 1 or both time points. After 1 week, 71.4% of cohort 1, 75.0% of cohort 2, and 85.0% of cohort 3 were positive for either SARS-CoV-2-neutralizing antibodies or SARS-CoV-2-specific T-cells or both. After 1 month, the rates were 56.3%, 100.0%, and 95.0%, respectively. Conclusion: The study shows that the majority of siponimod patients mount humoral and cellular immune response under continuous siponimod treatment. The data do not sufficiently support interruption of treatment for the purpose of vaccination. Registration: EU Clinical Trials Register: EudraCT 2020-005752-38 ( www.clinicaltrialsregister.eu ); ClinicalTrials.gov: NCT04792567 ( https://clinicaltrials.gov ).

Sphingosine 1-phosphate (S1P) receptor (S1PR) modulators have a complex mechanism of action, which are among the most efficient therapeutic options in multiple sclerosis (MS) and represent a promising approach for other immune-mediated diseases. The S1P signaling pathway involves the activation of five extracellular S1PR subtypes (S1PR1–S1PR5) that are ubiquitous and have a wide range of effects. Besides the immunomodulatory beneficial outcome in MS, S1P signaling regulates the cardiovascular function via S1PR1–S1PR3 subtypes, which reside on cardiac myocytes, endothelial, and vascular smooth muscle cells. In our review, we describe the mechanisms and clinical effects of S1PR modulators on the cardiovascular system. In the past, mostly short-term effects of S1PR modulators on the cardiovascular system have been studied, while data on long-term effects still need to be investigated. Immediate effects detected after treatment initiation are due to parasympathetic overactivation. In contrast, long-term effects may arise from a shift of the autonomic regulation toward sympathetic predominance along with S1PR1 downregulation. A mild increase in blood pressure has been reported in long-term studies, as well as decreased baroreflex sensitivity. In most studies, sustained hypertension was found to represent a significant adverse event related to treatment. The shift in the autonomic control and blood pressure values could not be just a consequence of disease progression but also related to S1PR modulation. Reduced cardiac autonomic activation and decreased heart rate variability during the long-term treatment with S1PR modulators may increase the risk for subsequent cardiac events. For second-generation S1PR modulators, this observation has to be confirmed in further studies with longer follow-ups. The periodic surveillance of cardiovascular function and detection of any cardiac autonomic dysfunction can help predict cardiac outcomes not only after the first dose but also throughout treatment. Plain Language Summary What is the cardiovascular effect of S1P receptor modulator therapy in multiple sclerosis? Sphingosine 1-phosphate (S1P) receptor (S1PR) modulators are among the most efficient therapies for multiple sclerosis. As small molecules, they are not only acting on the immune but on cardiovascular and nervous systems as well. Short-term effects of S1PR modulators on the cardiovascular system have already been extensively described, while long-term effects are less known. Our review describes the mechanisms of action and the short- and long-term effects of these therapeutic agents on the cardiovascular system in different clinical trials. We systematically reviewed the literature that had been published by January 2022. One hundred seven articles were initially identified by title and abstract using targeted keywords, and thirty-nine articles with relevance to cardiovascular effects of S1PR therapy in multiple sclerosis patients were thereafter considered, including their references for further accurate clarification. Studies on fingolimod, the first S1PR modulator approved for treating multiple sclerosis, primarily support the safety profile of this therapeutic class. The second-generation therapeutic agents along with a different treatment initiation approach helped mitigate several of the cardiovascular adverse effects that had previously been observed at the start of treatment. The heart rate may decrease when initiating S1PR modulators and, less commonly, the atrioventricular conduction may be prolonged, requiring cardiac monitoring for the first 6 h of medication. Continuous therapy with S1PR modulators can increase blood pressure values; therefore, the presence of arterial hypertension should be checked during long-term treatment. Periodic surveillance of the cardiovascular and autonomic functions can help predict cardiac outcomes and prevent possible adverse events in S1PR modulators treatment. Further studies with longer follow-ups are needed, especially for the second-generation of S1PR modulators, to confirm the safety profile of this therapeutic class.