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Fingolimod was the first oral disease-modifying treatment approved for relapsing-remitting multiple sclerosis (MS) that serves as a sphingosine-1-phosphate receptor (S1PR) agonist. The efficacy is primarily mediated by S1PR subtype 1 activation, leading to agonist-induced down-modulation of receptor expression and further functional antagonism, blocking the egression of auto-aggressive lymphocytes from the lymph nodes in the peripheral compartment. The role of S1P signaling in the regulation of other pathways in human organisms through different S1PR subtypes has received much attention due to its immune-modulatory function and its significance for the regeneration of the central nervous system. The more selective second-generation S1PR modulators have improved safety and tolerability profiles. This review has been carried out based on current data on S1PR modulators, emphasizing the benefits of recent advances in this emergent class of immunomodulatory treatment for MS. Ongoing clinical research suggests that S1PR modulators represent an alternative to first-line therapies in selected cases of MS. A better understanding of the relevance of selective S1PR pathways and the ambition to optimize selective modulation has improved the safety and tolerability of S1PR modulators in MS therapy and opened new perspectives for the treatment of other diseases.

Performance impairment as an effect of prolonged engagement in a specific task is commonly observed. Although this is a well-known effect in everyday life, little is known about how this affects central cognitive functions such as working memory (WM) processes. In the current study, we ask how time-on-task affects WM gating processes and thus processes regulating WM maintenance and updating. To this end, we combined electroencephalography methods and recordings of the pupil diameter as an indirect of the norepinephrine (NE) system activity. Our results showed that only WM gate opening but not closing processes showed time-on-task effects. On the neurophysiological level, this was associated with modulation of dorsolateral prefrontal theta band synchronization processes, which vanished with time-on-task during WM gate opening. Interestingly, also the modulatory pattern of the NE system, as inferred using pupil diameter data, changed. At the beginning, a strong correlation of pupil diameter data and theta band synchronization processes during WM gate opening is observed. This modulatory effect vanished at the end of the experiment. The results show that time-on-task has very specific effects on WM gate opening and closing processes and suggests an important role of NE system in the time-on-task effect on WM gate opening process.

Real-world evidence in multiple sclerosis (MS) is limited by the availability of data elements in individual real-world datasets. We introduce a novel, growing database which links administrative claims and medical records from an MS patient management system, allowing for the complete capture of patient profiles. Using the AOK PLUS sickness fund and the Multiple Sclerosis Documentation System MSDS3D from the Center of Clinical Neuroscience (ZKN) in Germany, a linked MS-specific database was developed (MSDS-AOK PLUS). Patients treated at ZKN and insured by AOK PLUS were recruited and asked for informed consent. For linkage, insurance IDs were mapped to registry IDs. After the deletion of insurance IDs, an anonymized dataset was provided to a university-affiliate, IPAM e.V., for further research applications. The dataset combines a complete record of patient diagnoses, treatment, healthcare resource use, and costs (AOK PLUS), with detailed clinical parameters including functional performance and patient-reported outcomes (MSDS3D). The dataset currently captures 500 patients; however, is actively expanding. To demonstrate its potential, we present a use case describing characteristics, treatment, resource use, and costs of a patient subsample. By linking administrative claims to clinical information in medical charts, the novel MSDS-AOK PLUS database can increase the quality and scope of real-world studies in MS.

Background Alemtuzumab is an effective therapy for relapsing multiple sclerosis. Autoimmune thyroid events are a common adverse event. Objective Describe endocrine and multiple sclerosis outcomes over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients in the phase 3 CARE-MS I, II, and extension studies who experienced adverse thyroid events. Methods Endocrine and multiple sclerosis outcomes were evaluated over 6 years. Thyroid event cases, excluding those pre-existing or occurring after Year 6, were adjudicated retrospectively by expert endocrinologists independently of the sponsor and investigators. Results Thyroid events were reported for 378/811 (46.6%) alemtuzumab-treated patients. Following adjudication, endocrinologists reached consensus on 286 cases (75.7%). Of these, 39.5% were adjudicated to Graves’ disease, 2.5% Hashimoto's disease switching to hyperthyroidism, 15.4% Hashimoto's disease, 4.9% Graves’ disease switching to hypothyroidism, 10.1% transient thyroiditis, and 27.6% with uncertain diagnosis; inclusion of anti-thyroid antibody status reduced the number of uncertain diagnoses. Multiple sclerosis outcomes of those with and without thyroid events were similar. Conclusion Adjudicated thyroid events occurring over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients were primarily autoimmune. Thyroid events were considered manageable and did not affect disease course. Thyroid autoimmunity is a common but manageable adverse event in alemtuzumab-treated relapsing multiple sclerosis patients. ClinicalTrials.gov Registration Numbers: CARE-MS I (NCT00530348); CARE-MS II (NCT00548405); CARE-MS Extension (NCT00930553)

In multiple sclerosis (MS), confirmed disability progression (CDP) can be either the result of progression independent of relapse activity (PIRA) or relapse-associated worsening (RAW). However, the economic effect of PIRA and RAW on societal economic costs in patients with MS is not well understood. To determine societal economic costs of patients achieving disease activity free status (DAF) and compare them with those having PIRA and RAW events. We used a roving EDSS score analysis to detect PIRA and RAW events with confirmation after at least 6 months. We estimated the age-, gender-, EDSS-adjusted effects of PIRA and RAW on total, direct medical, direct non-medical and indirect societal economic costs. Patients achieving DAF were assigned to as reference. Overall, 1959 patients were analyzed. Total mean quarterly societal economic costs including disease-modifying therapies (DMTs) were 6929€ (SD: 2886€) per patient averaged over a period of 2 years. Excluding DMTs, patients achieving DAF had total mean quarterly costs of 1703€ (SD: 2489€). PIRA caused 29% (IRR: 1.29; CI 1.06–1.50, p

Absolute (molar) quantification of clinically relevant proteins determines their reference values in liquid and solid biopsies. FastCAT (for Fast-track QconCAT) method employs multiple short (

SummaryCladribine (CLAD) is a purine nucleoside analog approved in tablet form to treat highly active multiple sclerosis (MS). CLAD tablets are the first oral therapy with an infrequent dosing schedule, administered in two annual treatment courses, each divided into two treatment cycles comprising 4–5 days of treatment. The efficacy and safety of CLAD tablets have been verified in randomized controlled clinical trials. Clinical observational studies are performed in more representative populations and over more extended periods, and thus provide valuable complementary insights. Here, we summarize the available evidence for CLAD tablets from post-marketing trials, including two observational, four long-term extensions, and two comparative studies. The patients in the post-marketing setting differed from the cohort recruited in the pivotal phase III trials regarding demographics and MS-related disability. The limited number of studies with small cohorts corroborate the disease-modifying capacity of oral CLAD and report on a durable benefit after active treatment periods. Skin-related adverse events were common in the studies focusing on safety aspects. In addition, single cases of CLAD-associated autoimmune events have been reported. Lastly, CLAD tablets appear safe regarding COVID-19 concerns, and patients mount a robust humoral immune response to SARS-CoV‑2 vaccination. We conclude that the current real-world evidence for CLAD tablets as immune reconstitution therapy for treatment of MS is based on a small number of studies and a population distinct from the cohorts randomized in the pivotal phase III trials. Further research should advance the understanding of long-term disease control after active treatment periods and the mitigation of adverse events.

Multiple sclerosis (MS) patients receiving natalizumab and who are at risk of developing progressive multifocal leukoencephalopathy (PML) often switch to other high-efficacy disease-modifying therapies including fingolimod as a risk mitigation strategy, which could impact treatment safety and effectiveness. The TRANSITION study aimed to evaluate the safety of fingolimod over two years in patients with MS after switching from natalizumab in a real-world setting. The safety and effectiveness were assessed by monitoring serious and other adverse events (SAEs, AEs). We assessed effectiveness by recording relapses, Expanded Disability Status Scale (EDSS) scores, and MRI activity. Of 637 patients enrolled, 505 completed the study (mean age, 42 years). Overall, 72.8% and 12.7% experienced AEs and SAEs respectively. The most common AEs were fatigue, headache, and urinary tract infection; no cases of PML were observed. Fingolimod treatment resulted in low disease activity. Patients with ≤8 weeks washout period had a markedly lower risk of relapses (4.5%) than those with >8 weeks (51.4%). In patients switching from natalizumab to fingolimod, no new safety signals with overall low relapse activity were observed in patients with washout latencies of ≤8 weeks before fingolimod initiation. Fingolimod was found to be safe and effective in patients transitioning from natalizumab.

Consistent treatment adherence is an important determinant of durable response in multiple sclerosis (MS). Published data indicate that adherence to 80% of prescribed doses may be considered optimal. Feedback of electronic application monitoring data to patients has been considered a promising means to support high adherence.The 2-year prospective non-interventional study REBIFLECT conducted at outpatient neurological centers (731 patients at 134 study sites in Germany) investigated whether treatment adherence to subcutaneous (sc) interferon beta-1 injection during a 1-year period is enhanced by regular physician-patient talks reflecting dosing data recorded by the application device in the context of clinical data or disease parameters. Qualitative adherence was defined as number of weeks with properly distributed injections per total number of weeks with prescribed injections. Quantitative adherence was defined as number of administered injections per prescribed injections.Overall median qualitative adherence was 90.5%. Approximately 70% of patients with adherence data available in the respective periods had a qualitative treatment adherence of 80-100%. With a mean of 97.9% quantitative adherence was very high and remained stable in the 2-year observation period. The stability of this effect is demonstrated by the subgroup with just one reflection talk (≥ 100%) and only a slight decrease in the subgroup with more than five reflection talks (97.9%).Treatment adherence with the Rebismart

One of the core problems for people with multiple sclerosis (pwMS) is the impairment of their ability to walk, which can be severely restrictive in everyday life. Therefore, monitoring of ambulatory function is of great importance to be able to effectively counteract disease progression. An extensive gait analysis, such as the Dresden protocol for multidimensional walking assessment, covers several facets of walking impairment including a 2-min walk test, in which the distance taken by the patient in two minutes is measured by an odometer. Using this approach, it is questionable how precise the measuring methods are at recording the distance traveled. In this project, we investigate whether the current measurement can be replaced by a digital measurement method based on accelerometers (six Opal sensors from the Mobility Lab system) that are attached to the patient’s body. We developed two algorithms using these data and compared the validity of these approaches using the results from 2-min walk tests from 562 pwMS that were collected with a gold-standard odometer. In 48.4% of pwMS, we detected an average relative measurement error of less than 5%, while results from 25.8% of the pwMS showed a relative measurement error of up to 10%. The algorithm had difficulties correctly calculating the walking distances in another 25.8% of pwMS; these results showed a measurement error of more than 20%. A main reason for this moderate performance was the variety of pathologically altered gait patterns in pwMS that may complicate the step detection. Overall, both algorithms achieved favorable levels of agreement (r = 0.884 and r = 0.980) with the odometer. Finally, we present suggestions for improvement of the measurement system to be implemented in the future.

For incurable diseases, such as multiple sclerosis (MS), the prevention of progression and the preservation of quality of life play a crucial role over the entire therapy period. In MS, patients tend to become ill at a younger age and are so variable in terms of their disease course that there is no standard therapy. Therefore, it is necessary to enable a therapy that is as personalized as possible and to respond promptly to any changes, whether with noticeable symptoms or symptomless. Here, measurable parameters of biological processes can be used, which provide good information with regard to prognostic and diagnostic aspects, disease activity and response to therapy, so-called biomarkers Increasing digitalization and the availability of easy-to-use devices and technology also enable healthcare professionals to use a new class of digital biomarkers—digital health technologies—to explain, influence and/or predict health-related outcomes. The technology and devices from which these digital biomarkers stem are quite broad, and range from wearables that collect patients’ activity during digitalized functional tests (e.g., the Multiple Sclerosis Performance Test, dual-tasking performance and speech) to digitalized diagnostic procedures (e.g., optical coherence tomography) and software-supported magnetic resonance imaging evaluation. These technologies offer a timesaving way to collect valuable data on a regular basis over a long period of time, not only once or twice a year during patients’ routine visit at the clinic. Therefore, they lead to real-life data acquisition, closer patient monitoring and thus a patient dataset useful for precision medicine. Despite the great benefit of such increasing digitalization, for now, the path to implementing digital biomarkers is widely unknown or inconsistent. Challenges around validation, infrastructure, evidence generation, consistent data collection and analysis still persist. In this narrative review, we explore existing and future opportunities to capture clinical digital biomarkers in the care of people with MS, which may lead to a digital twin of the patient. To do this, we searched published papers for existing opportunities to capture clinical digital biomarkers for different functional systems in the context of MS, and also gathered perspectives on digital biomarkers under development or already existing as a research approach.

MOBILE and ENHANCE were similarly designed randomized trials of walking-impaired adults with relapsing-remitting or progressive multiple sclerosis (MS) who received placebo or 10 mg prolonged-release (PR)-fampridine twice daily for 24 weeks. Both studies showed sustained and clinically meaningful improvement in broad measures of walking and balance over 24 weeks of PR-fampridine treatment.To evaluate the functional benefits and safety of PR-fampridineData from the intention-to-treat (ITT) populations of MOBILE and ENHANCE studies were pooled in aIn the ITT population (The pooled analysis of MOBILE and ENHANCE confirms previous evidence that treatment with PR-fampridine results in clinically meaningful improvements in walking, mobility and balance, self-reported physical impact of MS, and quality of life and is effective across a broad range of PwMS.

Inhibitory control has multiple facets, and one possible distinction can be made between 'inhibition of interferences' and the 'inhibition of actions'. Both facets of inhibitory control show an interdependency. Even though some neurophysiological processes underlying this interdependency have been examined, the role of neuro-modulatory processes in their interplay are not understood. In the current study, we examine the role of the norepinephrine (NE) system in these processes. We did so by combining a Go/Nogo and Simon task. We recorded the EEG and pupil diameter data as an indirect index of NE system activity during the task. EEG theta band activity data and pupil diameter data were then integrated after conducting a temporal signal decomposition of the EEG data. We show that particularly theta band activity coding stimulus-response translation processes associated with middle frontal cortices, but not stimulus-driven processes are modulated by the interplay between the 'inhibition of interferences' and the 'inhibition of actions'. Modulations in stimulus-response translation processes were systematically correlated with pupil-diameter responses. The pattern of correlations suggests that phasic NE system activity particularly modulates stimulus-response mapping processes during conflict monitoring in incongruent Nogo trials, which may explain behavioral performance effects. Phasic NE system activity reflects essential modulators of the interplay between the 'inhibition of interferences' and the 'inhibition of actions'.

Background Evidence suggests that early highly efficacious therapy in relapsing multiple sclerosis is superior to escalation strategies. Objective A cost-consequence analysis simulated different treatment scenarios with ofatumumab (OMB), dimethyl fumarate (DMF) and glatiramer acetate (GA): immediate OMB initiation as first treatment, early switch to OMB after 1 year on DMF/GA, late switch after 5 years or no switch. Methods An EDSS-based Markov model with a 10-year time horizon was applied. Cycle transitions included EDSS progression, improvement or stabilization, treatment discontinuation, relapse or death. Input data were extracted from OMB trials, a network meta-analysis, published literature, and publicly available sources. Results The late switch compared to the immediate OMB scenario resulted in a lower proportion of patients with EDSS 0–3 (Δ − 7.5% DMF; Δ − 10.3% GA), more relapses (Δ + 0.72 DMF; Δ + 1.23 GA) and lower employment rates (Δ − 4.0% DMF; Δ − 5.6% GA). The same applies to late versus early switches. No switch scenarios resulted in worse outcomes. Higher drug acquisition costs in the immediate OMB and early switch scenarios were almost compensated by lower costs for patient care and productivity loss. Conclusion Immediate OMB treatment and an early switch improves clinical and productivity outcomes while remaining almost cost neutral compared to late or no switches.

The new study program "Multiple Sclerosis Management" is aimed at physicians, therapists, nurses, scientists, pharmacists, psychologists and biologists who want to specialize in the field of multiple sclerosis (MS). After successful accreditation in 2019, the first students have been in the master's program offered by Dresden International University (DIU) since 2020. Over a period of four semesters, it can be completed part-time and largely digitally. The master's program is divided into six modules focusing on basics, clinical and diagnostic aspects, MS studies and statistics, disease-modifying and symptomatic therapy, disease monitoring and documentation. The teaching includes theoretical parts and numerous practical units. A further goal is to derive therapeutic intervention plans and problem-solving strategies from scientific publications and clinical studies, to develop them further and to apply them in patient care. The lecturers come from Germany, Austria and Switzerland and are predominantly professors. The German Multiple Sclerosis Society is the patron of the course. This article presents the study program in detail.Der neue Studiengang „Multiple Sklerose Management“ richtet sich an Ärzt*innen, Therapeut*innen, Pflegepersonal, Wissenschaftler*innen, Apotheker*innen, Psycholog*innen und Biolog*innen, die sich im Bereich der Multiplen Sklerose (MS) spezialisieren wollen. Nach erfolgreicher Akkreditierung im Jahr 2019 befindet sich die erste Matrikel seit 2020 in dem von der Dresden International University (DIU) angebotenen Masterstudiengang. Über eine Dauer von 4 Semestern kann er berufsbegleitend und größtenteils digital absolviert werden. Der Masterstudiengang gliedert sich in 6 Module mit den Schwerpunkten Grundlagen, Klinik und Diagnostik, MS-Studien und Statistik, krankheitsmodifizierende und symptomatische Therapie, Krankheitsmonitoring und Dokumentation. Der Unterricht beinhaltet theoretische Anteile und zahlreiche Praxiseinheiten. Ein weiteres Ziel ist es, aus wissenschaftlichen Publikationen und klinischen Studien therapeutische Interventionspläne und Problemlösungsstrategien abzuleiten, sie weiterzuentwickeln und in der Patientenversorgung anzuwenden. Die Dozent*innen stammen aus Deutschland, Österreich und der Schweiz und sind überwiegend Professor*innen. Die Schirmherrschaft für den Studiengang übernimmt die Deutsche Multiple Sklerose Gesellschaft. Dieser Beitrag stellt den Studiengang im Detail vor.

In light of the increasing number of economic burden studies and heterogeneity in methodology and reporting standards, there is a need for robust evidence synthesis on an umbrella review level.We performed the first review of reviews of cost-of-illness studies in multiple sclerosis. Focusing on disaggregated costs by disease characteristics (disability level, relapse, disease course), we also characterized the underlying methodological evidence base of individual (primary) studies.We identified 17 reviews encompassing 111 unique primary studies, and a high degree of overlap across reviews. Costs were substantial, rising with disability level, relapse episodes, and disease progression. Disability was the key cost driver. Compared to mild disability, total costs for moderate disability were 1.4-2.3-fold higher and 1.8-2.9-fold higher for severe disability. With escalating disability, the share of costs outside the health system (indirect costs, informal care) increasingly outweighed the share of direct medical costs. Of all 111 primary studies, 72% gathered resource use/loss data by patient self-report. Associated costs were mostly reported by disability level (75%), followed by relapse (48%) and disease course (21%). In conclusion, although heterogeneity can make in-depth comparisons of costs across studies impossible, important patterns are broadly apparent.

Many challenges exist in the precise diagnosis and clinical management of secondary progressive multiple sclerosis (SPMS) because of the lack of definitive clinical, imaging, immunologic, or pathologic criteria that demarcate the transition from relapsing-remitting MS to SPMS. This review provides an overview of the diagnostic criteria/definition and the heterogeneity associated with different SPMS patient populations; it also emphasizes the importance of available prospective/retrospective tools to identify patients with SPMS earlier in the disease course so that approved disease-modifying therapies and nonpharmacological strategies will translate into better outcomes. Delivery of such interventions necessitates an evolving patient-clinician dialog within the context of a multidisciplinary team.

B cell-depleting therapies such as ocrelizumab (OCR) are highly effective in people with multiple sclerosis (MS). Especially at treatment start and initial infusion, infusion-related reactions (IRR) are a common adverse event. The relevance of acute changes of cell-depleting therapies on peripheral immune compartments and routine lab testing is important for clinical practice. We systematically analyzed routine blood parameters, detailed blood immunophenotyping and serum cytokine profiles in 45 MS patients starting on OCR. Blood samples were collected before and after corticosteroid premedication and directly after each OCR infusion of the first three ocrelizumab infusions. Blood B cells were rapidly depleted and accompanied only by a mild cytokine release at the first OCR infusion. Cytokine release was not significantly detectable from a third application in line with decreasing IRRs. B cell depletion was accompanied by short-lived changes in other immune cell populations in number, activation and cytokine secretion after each OCR infusion. Standard lab parameters did not show any clinically relevant changes. Our data demonstrate only mild changes during the first OCR infusion, which are not present any more during long-term treatment.

International audience; Background: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.Methods: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.Results: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P

(1) Background: Persons with multiple sclerosis (pwMS) are often characterized as ideal adopters of new digital healthcare trends, but it is worth thinking about whether and which pwMS will be targeted and served by a particular eHealth service like a patient portal. With our study, we wanted to explore needs and barriers for subgroups of pwMS and their caregivers when interacting with eHealth services in care and daily living. (2) Methods: This study comprises results from two surveys: one collecting data from pwMS and their relatives (as informal caregivers) and another one providing information on the opinions and attitudes of healthcare professionals (HCPs). Data were analyzed descriptively and via generalized linear models. (3) Results: 185 pwMS, 25 informal caregivers, and 24 HCPs in the field of MS participated. Nine out of ten pwMS used information technology on a daily base. Individual impairments like in vision and cognition resulted in individual needs like the desire to actively monitor their disease course or communicate with their physician in person. HCPs reported that a complete medication overview, additional medication information, overview of future visits and a reminder of medication intake would be very helpful eHealth features for pwMS, while they themselves preferred features organizing and enriching future visits. (4) Conclusions: A closer look at the various profiles of eHealth adoption in pwMS and their caregivers indicated that there is a broad and robust enthusiasm across several subgroups that does not exclude anyone in general, but constitutes specific areas of interest. For pwMS, the focus was on eHealth services that connect previously collected information and make them easily accessible and understandable.

To evaluate the 5-year real-world benefit-risk profile of fingolimod in patients with relapsing-remitting MS (RRMS) in Germany.Post-Authorization Non-interventional German sAfety study of GilEnyA (PANGAEA) is a non-interventional real-world study to prospectively assess the effectiveness and safety of fingolimod in routine clinical practice in Germany. The follow-up period comprised 5 years. Patients were included if they had been diagnosed with RRMS and had been prescribed fingolimod as part of clinical routine. There were no exclusion criteria except the contraindications for fingolimod as defined in the European label. The effectiveness and safety analysis set comprised 4032 and 4067 RRMS patients, respectively.At the time of the 5-year follow-up of PANGAEA, 66.57% of patients still continued fingolimod therapy. Annualized relapse rates decreased from baseline 1.5 ± 1.15 to 0.42 ± 0.734 at year 1 and 0.21 ± 0.483 at year 5, and the disability status remained stable, as demonstrated by the Expanded Disability Status Scale mean change from baseline (0.1 ± 2.51), the decrease of the Multiple Sclerosis Severity Score from 5.1 ± 2.59 at baseline to 3.9 ± 2.31 at the 60-months follow-up, and the percentage of patients with 'no change' in the Clinical Global Impression scale at the 60-months follow-up (78.11%). Adverse events (AE) occurring in 75.04% of patients were in line with the known safety profile of fingolimod and were mostly non-serious AE (33.62%) and non-serious adverse drug reactions (50.59%; serious AE 4.98%; serious ADR 10.82%).PANGAEA demonstrated the sustained beneficial effectiveness and safety of fingolimod in the long-term real-world treatment of patients with RRMS.

Background: Interventions targeting the adaptive immune response are needed in multiple sclerosis (MS). Objective: Evaluate laquinimod’s efficacy, safety, and tolerability in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: CONCERTO was a randomized, double-blind, placebo-controlled, phase-3 study. RRMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 or 1.2 mg or placebo for ⩽24 months ( n = 727, n = 732, and n = 740, respectively). Primary endpoint was time to 3-month confirmed disability progression (CDP). The laquinimod 1.2-mg dose arm was discontinued (1 January 2016) due to cardiovascular events at high doses. Safety was monitored throughout the study. Results: CONCERTO did not meet the primary endpoint of significant effect with laquinimod 0.6-mg versus placebo on 3-month CDP (hazard ratio: 0.94; 95% confidence interval: 0.67–1.31; p = 0.706). Secondary endpoint p values were nominal and non-inferential. Laquinimod 0.6 mg demonstrated 40% reduction in percent brain volume change from baseline to Month 15 versus placebo ( p Conclusion: Laquinimod 0.6 mg demonstrated only nominally significant effects on clinical relapses and magnetic resonance imaging (MRI) outcomes and was generally well tolerated. Clinical trial registration number: ClinicalTrials.gov (NCT01707992).

The non-interventional long-Term study foR obsErvAtion of Treatment with alemtuzumab in active relapsing–remitting MS (TREAT-MS) study collects the so far largest real-life cohort regarding utilization, long-term effectiveness, and safety of alemtuzumab, a humanized monoclonal antibody directed against the cell surface glycoprotein CD52, in adult patients with active relapsing–remitting multiple sclerosis (RRMS). An interim analysis of baseline parameters at inclusion of a non-interventional real-world study about alemtuzumab in Germany including previous multiple sclerosis (MS) medication utilization, MS activity, severity, and duration, as well as comorbidities was performed. Of the 883 patients, 71.6% were women. Mean age was 35.7 ± 9.2 years, time since first MS symptoms (=disease duration) is 8.0 ± 6.8 years, and Expanded Disability Status Scale (EDSS) is 2.7 ± 1.8 points (range, 0.0–7.5 points). The number of relapses in the 12 and 24 months prior to inclusion were 1.6 ± 1.2 and 2.2 ± 1.8, respectively. Of the patients, 14.4% were treatment naive, while for the majority, a wide spectrum of MS disease-modifying treatments (DMTs) and treatment sequences were documented. Overall, interferon beta (IFN-beta) was reported most frequently (52.4%), followed by fingolimod (35.2%), natalizumab (34.9%), and glatiramer acetate (28.9%). Patients with longer disease duration and higher EDSS had a higher number of previous DMTs. Compared to the pivotal phase 2/3 studies, RRMS patients starting alemtuzumab treatment had a longer disease duration in real-world conditions. There was variety of different treatment sequences before the final switch to alemtuzumab. In the future, linking these treatment sequences or other baseline characteristics with effectiveness and safety outcomes might be useful to support treatment decisions. Registered at Paul-Ehrlich-Institut under NIS 281.

Since 2020, the master’s program “Multiple Sclerosis Management” has been running at Dresden International University, offering structured training to become a multiple sclerosis specialist. Due to the COVID-19 pandemic, many planned teaching formats had to be changed to online teaching. The subject of this paper was the investigation of a cloud-based digital hub and student evaluation of the program. Authors analyzed use cases of computer-supported collaborative learning and student evaluation of courses and modules using the Gioia method and descriptive statistics. The use of a cloud-based digital hub as a central data platform proved to be highly successful for learning and teaching, as well as for close interaction between lecturers and students. Students rated the courses very positively in terms of content, knowledge transfer and interaction. The implementation of the master’s program was successful despite the challenges of the COVID-19 pandemic. The resulting extensive use of digital tools demonstrates the “new normal” of future learning, with even more emphasis on successful online formats that also increase interaction between lecturers and students in particular. At the same time, there will continue to be tailored face-to-face events to specifically increase learning success.

In multiple sclerosis (MS), gait impairment is one of the most prominent symptoms. For a sensitive assessment of pathological gait patterns, a comprehensive analysis and processing of several gait analysis systems is necessary. The objective of this work was to determine the best diagnostic gait system (DIERS pedogait, GAITRite system, and Mobility Lab) using six machine learning algorithms for the differentiation between people with multiple sclerosis (pwMS) and healthy controls, between pwMS with and without fatigue and between pwMS with mild and moderate impairment. The data of the three gait systems were assessed on 54 pwMS and 38 healthy controls. Gaussian Naive Bayes, Decision Tree, k-Nearest Neighbor, and Support Vector Machines (SVM) with linear, radial basis function (rbf) and polynomial kernel were applied for the detection of subtle walking changes. The best performance for a healthy-sick classification was achieved on the DIERS data with a SVM rbf kernel (κ = 0.49 ± 0.11). For differentiating between pwMS with mild and moderate disability, the GAITRite data with the SVM linear kernel (κ = 0.61 ± 0.06) showed the best performance. This study demonstrates that machine learning methods are suitable for identifying pathologic gait patterns in early MS.

Background: Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing–remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF’s distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile. Objective: To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study. Methods: EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory. Results: As of March 2018, 696 patients were enrolled; median exposure was 59.9 (range: 0.1–98.9) weeks. Adverse events (AEs) occurred in 84.6% (589/696) of patients; the majority were mild (31.2%; 217/696) or moderate (46.8%; 326/696) in severity. Overall treatment discontinuation was 14.9%; 6.3% due to AEs and Conclusion: Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS.

Background:Alemtuzumab is administered as two annual courses for relapsing-remitting multiple sclerosis (MS). Patients may relapse before completing the two-course regimen. Objective: The objective was to evaluate 6-year outcomes in patients who relapsed between alemtuzumab Courses 1 and 2 (early relapsers). Methods:Post hoc analysis of patients from the Comparison of Alemtuzumab and Rebif (R) Efficacy in Multiple Sclerosis (CARE-MS) studies who enrolled in the extension. Results:Early relapsers (CARE-MS I: 15%; CARE-MS II: 24%) had more relapses in 1-2 years pre-alemtuzumab and higher mean baseline Expanded Disability Status Scale score than patients without relapse. Their annualized relapse rate declined from Year 1 (CARE-MS I: 1.3; CARE-MS II: 1.2) to Year 2 following Course 2 (0.3; 0.5) and remained low thereafter. Over 6 years, 60% remained free of 6-month confirmed disability worsening; 24% (CARE-MS I) and 34% (CARE-MS II) achieved 6-month confirmed disability improvement. During Year 6, 69% (CARE-MS I) and 68% (CARE-MS II) were free of magnetic resonance imaging (MRI) disease activity. Median percent yearly brain volume loss (Year 1: -0.67% (CARE-MS I); -0.47% (CARE-MS II)) declined after Course 2 (Year 6: -0.24%; -0.13%). Conclusion: Early relapsers' outcomes improved after completing the second alemtuzumab course. These findings support administering the approved two-course regimen to maximize clinical benefit. ClinicalTrials.gov registration numbers:CARE-MS I, II, extension: NCT00530348, NCT00548405, NCT00930553. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The CARE-MS I, CARE-MS II, and CAMMS03409 studies were funded by Sanofi and Bayer HealthCare Pharmaceuticals. Only Sanofi contributed to the conduct of the studies; collection, management, analysis, and interpretation of the data; review of the manuscript. Apart from the Sanofi employees listed as authors, the funders had no role in preparation, approval, and decision to submit the manuscript for publication. Van Wijmeersch, B (reprint author), Hasselt Univ, Fac Med & Life Sci, Campus Hasselt,Martelarenlaan 42, B-3500 Hasselt, Belgium. bart.vanwijmeersch@uhasselt.be

Personalisiertes Management der Multiplen Sklerose erfordert die Beurteilung moglichst quantifizierbarer Krankheitmerkmale. Die Ansatze reichen von „patient-reported outcomes“ uber bildgebende und elektrophysiologische Verfahren bis zu molekularen und digitalen Biomarkern.

Patient-reported outcomes (PROs) are increasingly used in multiple sclerosis (MS) research and clinical practice for understanding the effects that the disease and its treatments have on patients' lives. PROs are captured directly from patients and include symptoms, function, health status, and health-related quality of life. No universal guidance on appropriateness of each applied tool exists. However, collecting clear and comprehensive outcome measures represents the first step of patient centered therapeutic management. The importance of PRO assessment is expected to continue to grow in the future. But in current MS reality, PROs are selected and used without a clear justification, and only few PROs are of adequate psychometric quality. There is a clear need for the development of high-quality; MS-specific PROs that assess the true concerns of patients and that evaluate the impact of both clinical and non-clinical interventions on a variety of outcomes. In this perspective review, we describe the importance of and methods for using PRO in MS by defining and identifying the used PROs in MS. Moreover, we will outline the challenges and key unanswered questions for routine use of PROs in MS discussing potential interventions to accelerate the integration of PROs in the clinical management of MS.

Based on a small number of cases, interferon beta (IFN-β) has been added to the list of drugs that might induce pulmonary arterial hypertension (PAH) in the current European guidelines for the diagnosis and treatment of pulmonary hypertension. Here, we propose that multiple sclerosis patients who are genetically predisposed to PAH may be at higher risk to develop disease when treated with IFN-β. We included two patients with multiple sclerosis who developed a manifest PAH after five amd eight years on IFN-β 1a therapy, respectively (without confirmed right heart catheterization). In both patients, PAH markedly improved after discontinuation of IFN-β 1a and initiation of targeted PAH therapy. For genetic analysis, we used a PAH-gene panel based on next-generation sequencing of 16 PAH and 38 candidate genes. In one of the two patients, we could identify a nonsense variant in the PAH gene ATP13A3 . The second patient showed a missense variant of the CYP1B1 gene, which might be linked to PAH predisposition. The results of this study support the hypothesis that multiple sclerosis patients who receive IFN-β 1a therapy might be at higher risk for the development of manifest PAH, if they carry a pathogenic variant or sequence variant genetically predisposing to the disease. However, further studies are necessary to systematically investigate the presence of predisposing PAH gene variants in these patients.

Fingolimod (FTY) is known to have multiple effects on the immune system and the central nervous system (CNS) in patients with multiple sclerosis (MS). In this study, we evaluated the immunological and neurobiological effects of FTY in MS. Blood and cerebrospinal fluid (CSF) samples were collected from 15 MS patients before first FTY administration and after 4 months of FTY therapy. Immunophenotyping and evaluation of sphingosine-1-phosphate (S1P), neurofilament light chain (NFL), S-100 and neuron-specific enolase (NSE) levels were conducted. After 4 months of FTY therapy, absolute cell count in CSF was decreased from 6.33 to 2.43 MPt/l, accompanied by decreases of CD3+ (2.22 to 0.65 MPt/l) and of CD4+ counts (1.60 to 0.39 MPt/l). In blood, CD3+ (1.05 to 0.09 GPt/l), CD4+ (0.80 to 0.02 GPt/l), CD8+ (0.23 to 0.04 GPt/l) and CD19+ (0.21 to 0.01GPt/l) cell counts were as well reduced. CD14+ cell count remained stable over the same period (0.24 to 0.26GPt/l). NFL and S1P levels in CSF and blood were reduced over time (NFL: CSF 1759 to 1359 pg/l, blood 8.42 to 7.36 pg/l; S1P: CSF 2.12 to 0.71 nmol/l, blood 392.1 to 312.9 nmol/l). Strong correlations between CSF and blood NFL levels were observed. Neuronal damage markers such as S-100 (1.86 to 1.69 μg/l) and NSE (9.53 to 8.67 μg/l) were reduced to a lesser degree than other markers. FTY exerted significant effects on immunological and neurobiological markers in the central and peripheral compartment. Decreases in levels of neuroinflammatory and neurodegenerative markers were already evident after 4 months of treatment. Four-month serum NFL level appears to be a useful marker for FTY efficacy that correlates well with changes in the CNS compartment. KEY MESSAGES: FTY has important immunological effects in both central and peripheral compartments. Cellular effects of FTY effects are more pronounced in the blood than in the CSF. FTY reduces S1P and NFL levels in CSF and serum. Serum NFL appears to be a useful marker for FTY therapy.

Several lines of evidence suggest that there is a close interrelation between the degree of noise in neural circuits and the activity of the norepinephrine (NE) system, yet the precise nexus between these aspects is far from being understood during human information processing and cognitive control in particular. We examine this nexus during response inhibition in n = 47 healthy participants. Using high-density EEG recordings, we estimate neural noise by calculating “1/ f noise” of those data and integrate these EEG parameters with pupil diameter data as an established indirect index of NE system activity. We show that neural noise is reduced when cognitive control processes to inhibit a prepotent/automated response are exerted. These neural noise variations were confined to the theta frequency band, which has also been shown to play a central role during response inhibition and cognitive control. There were strong positive correlations between the 1 /f neural noise parameter and the pupil diameter data within the first 250 ms after the Nogo stimulus presentation at centro-parietal electrode sites. No such correlations were evident during automated responding on Go trials. Source localization analyses using standardized low-resolution brain electromagnetic tomography show that inferior parietal areas are activated in this time period in Nogo trials. The data suggest an interrelation of NE system activity and neural noise within early stages of information processing associated with inferior parietal areas when cognitive control processes are required. The data provide the first direct evidence for the nexus between NE system activity and the modulation of neural noise during inhibitory control in humans. NEW & NOTEWORTHY This is the first study showing that there is a nexus between norepinephrine system activity and the modulation of neural noise or scale-free neural activity during inhibitory control in humans. It does so by integrating pupil diameter data with analysis of EEG neural noise.

Background: Alemtuzumab is a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS), and immune thrombocytopenia (ITP) has been identified as a risk. Objective: To examine ITP incidence, treatment, and outcomes during the clinical development of alemtuzumab for RRMS and discuss postmarketing experience outside clinical trials. Methods: CAMMS223 and Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) I and II investigated two annual courses of alemtuzumab 12 mg (or 24 mg in CAMMS223/CARE-MS II) versus subcutaneous interferon beta-1a three times per week. Patients completing core studies could enroll in an extension. Monthly monitoring for ITP continued until 48 months after the last alemtuzumab infusion. Results: Of 1485 alemtuzumab-treated MS patients in the clinical development program, 33 (2.2%) developed ITP (alemtuzumab 12 mg, 24 [2.0%]; alemtuzumab 24 mg, 9 [3.3%]) over median 6.1 years of follow-up after the first infusion; most had a sustained response to first-line ITP therapy with corticosteroids, platelets, and/or intravenous immunoglobulin. All cases occurred within 48 months of the last alemtuzumab infusion. Postmarketing surveillance data suggest that the ITP incidence is not higher in clinical practice than in clinical trials. Conclusion: Alemtuzumab-associated ITP occurs in approximately 2% of patients and is responsive to therapy. Careful monitoring is key for detection and favorable outcomes.

Background Previously, consensus MS care standards were defined by MS specialist neurologists from 19 countries. We developed, piloted and refined an Excel-based quality improvement tool to enable MS services to benchmark against these standards. Here, we examine the refined tool. Objective To determine the applicability of the quality improvement tool in different healthcare settings. Methods MS centres across the globe were invited to pilot the quality improvement tool by coding the medical records of 36 adults with MS. We invited feedback on user friendliness, quality improvement tool usefulness and relevance of data collected. Results Seventeen centres from 14 countries participated; 14 completed the post-service evaluation survey. Over 50% of responders rated the tool ‘very easy’ or ‘easy’ to use and ‘very relevant’ to their service. Almost 85% of responders (11/13) planned to introduce changes to their service, including improvements in documentation, communication, interactions with colleagues and referrals; 85% would use a future shorter version of the tool. Conclusions The quality improvement tool can enable MS centres globally to benchmark their services. Widespread uptake of a shorter tool may help MS centres to work towards achieving consensus standards for brain health-focused care. Incorporation into routine clinical practice would drive adoption.

Background Walking impairment is a hallmark of multiple sclerosis (MS). It affects > 90% of individuals over time, reducing independence and negatively impacting health-related quality of life, productivity, and daily activities. Walking impairment is consistently reported as one of the most distressing impairments by individuals with MS. Prolonged-release (PR)-fampridine previously has been shown to improve objectively measured walking speed in walking-impaired adults with MS. The impact of PR-fampridine from the perspective of the individual with MS warrants full and detailed examination. Objective The objective of this study was to evaluate whether PR-fampridine has a clinically meaningful effect on self-reported walking ability in walking-impaired participants with MS. Methods ENHANCE was a phase III, randomized, double-blind, placebo-controlled study of PR-fampridine 10 mg twice daily in walking-impaired individuals age 18–70 years with either relapsing or progressive forms of MS and an Expanded Disability Status Scale (EDSS) score of 4.0–7.0 at screening. Participants were stratified by EDSS score (≤ 6.0 or 6.5–7.0) at randomization to ensure a balanced level of disability in the treatment groups. The primary endpoint was the proportion of participants with a mean improvement in the 12-item Multiple Sclerosis Walking Scale (MSWS-12) score exceeding the predefined threshold for clinically meaningful improvement (≥ 8 points) over 24 weeks. Secondary endpoints included the proportion with ≥ 15% improvement in Timed Up and Go (TUG) speed, and mean changes in Multiple Sclerosis Impact Scale physical impact subscale (MSIS-29 PHYS), Berg Balance Scale (BBS), and ABILHAND scores over 24 weeks. Results In total, 636 participants with MS were randomized (PR-fampridine, n = 317; placebo, n = 319; modified intention-to-treat sample: PR-fampridine, n = 315; placebo, n = 318). At baseline in the PR-fampridine and placebo groups, 46% and 51% had a progressive form of MS, median [range] EDSS scores were 6.0 [4.0–7.0] and 5.5 [4.0–7.0], mean [range] MSWS-12 scores were 63.6 [0–100] and 65.4 [0–100], and mean [range] TUG speed was 0.38 [0.0–1.0] and 0.38 [0.0–1.2] feet/s, respectively. A significantly higher percentage of PR-fampridine-treated participants (136/315 [43.2%]) had clinically meaningful improvement in MSWS-12 score over 24 weeks versus placebo (107/318 [33.6%]; odds ratio 1.61 [95% confidence interval 1.15–2.26]; p = 0.006). For PR-fampridine versus placebo, significantly more participants had a ≥ 15% improvement in TUG speed, and there was significantly greater mean improvement in MSIS-29 PHYS score (p

Natalizumab, a recombinant humanized monoclonal antibody directed against the α4 subunit of the integrins α4ß1 and α4ß7, has been approved for the treatment of active relapsing‐remitting MS. Although natalizumab is a highly beneficial drug that effectively reduces the risk of sustained disability progression and the rate of clinical relapses, some patients do not respond to it, and some are at higher risk of developing progressive multifocal leukoencephalopathy (PML). The histopathological effects after natalizumab therapy are still unknown. We, therefore, performed a detailed histological characterization of the CNS inflammatory cell infiltrate of 24 brain specimens from natalizumab treated patients, consisting of 20 biopsies and 4 autopsies and 21 MS controls. To complement the analysis, immune cells in blood and cerebrospinal fluid (CSF) of 30 natalizumab‐treated patients and 42 MS controls were quantified by flow cytometry. Inflammatory infiltrates within lesions were mainly composed of T cells and macrophages, some B cells, plasma cells, and dendritic cells. There was no significant difference in the numbers of T cells or macrophages and microglial cells in lesions of natalizumab‐treated patients as compared to controls. A shift towards cytotoxic T cells of a memory phenotype was observed in the CSF. Plasma cells were significantly increased in active demyelinating lesions of natalizumab‐treated patients, but no correlation to clinical disability was observed. Dendritic cells within lesions were found to be reduced with longer ongoing therapy duration. Our findings suggest that natalizumab does not completely prevent immune cells from entering the CNS and is associated with an accumulation of plasma cells, the pathogenic and clinical significance of which is not known. As B cells are considered to serve as a reservoir of the JC virus, the observed plasma cell accumulation and reduction in dendritic cells in the CNS of natalizumab‐treated patients may potentially play a role in PML development., Häusler et al. characterized the CNS inflammation after natalizumab treatment. They found that despite the treatment, immune cells may enter the CNS and even an accumulation of plasma cells occurs, the pathogenic and clinical significance of which is unknown. The accumulation of plasma cells and an additionally observed reduction in dendritic cells, which are important for viral defense, may play a role in PML development.

(1) Background: Fingolimod (Gilenya®) was the first oral treatment for patients with relapsing-remitting multiple sclerosis (RRMS). Since its approval, the treatment landscape has changed enormously. (2) Methods: Data of PANGAEA and PANGAEA 2.0, two German real-world studies, were descriptively analysed for possible evolution of patient profiles and treatment behavior. Both are prospective, multi-center, non-interventional, long-term studies on fingolimod use in RRMS in real life. Data of 4229 PANGAEA patients (recruited 2011–2013) and 2441 PANGAEA 2.0 patients (recruited 2015–2018) were available. Baseline data included demographics, RRMS characteristics and disease severity. (3) Results: The mean age of PANGAEA and PANGAEA 2.0 patients was similar (38.8 vs. 39.2 years). Patients in PANGAEA 2.0 had shorter disease duration (7.1 vs. 8.2 years) and fewer relapses in the year before baseline (1.2 vs. 1.6). Disease severity at baseline estimated by EDSS and SDMT was lower in PANGAEA 2.0 patients compared to PANGAEA (EDSS difference 1.0 points, SDMT difference 3.3 points). (4) Conclusions: The results hint at an influence of changes in the treatment guidelines and the label on fingolimod patients profiles over time. Patients tended to have lower disease activity at fingolimod initiation, suggesting an earlier intervention. This indicates increased experience in using fingolimod for sub-optimally treated RRMS patients and a change in mindset towards an early treatment optimization.

BACKGROUND A digital tool, Multiple Sclerosis Progression Discussion Tool (MSProDiscuss), was developed to facilitate discussions between health care professionals (HCPs) and patients in evaluating early, subtle signs of multiple sclerosis (MS) disease progression. OBJECTIVE The aim of this study is to report the findings on the usability and usefulness of MSProDiscuss in a real-world clinical setting. METHODS In this cross-sectional, web-based survey, HCPs across 34 countries completed an initial individual questionnaire (comprising 7 questions on comprehensibility, usability, and usefulness after using MSProDiscuss during each patient consultation) and a final questionnaire (comprising 13 questions on comprehensibility, usability, usefulness, and integration and adoption into clinical practice to capture the HCPs’ overall experience of using the tool). The responses were provided on a 5-point Likert scale. All analyses were descriptive, and no statistical comparisons were made. RESULTS In total, 301 HCPs tested the tool in 6974 people with MS, of whom 77% (5370/6974) had relapsing-remitting MS, including those suspected to be transitioning to secondary progressive MS. The time taken to complete MSProDiscuss was reported to be in the range of 1 to 4 minutes in 97.3% (6786/6974; initial) to 98.2% (269/274; final) of the cases. In 93.54% (6524/6974; initial) to 97.1% (266/274; final) of the cases, the HCPs agreed (4 or 5 on the Likert scale) that patients were able to comprehend the questions in the tool. The HCPs were willing to use the tool again in the same patient, 90.47% (6310/6974; initial) of the cases. The HCPs reported MSProDiscuss to be useful in discussing MS symptoms and their impact on daily activities (6121/6974, 87.76% initial and 252/274, 92% final) and cognitive function (5482/6974, 78.61% initial and 271/274, 79.2% final), as well as in discussing progression in general (6102/6974, 87.49% initial and 246/274, 89.8% final). While completing the final questionnaire, 94.9% (260/274) of the HCPs agreed that the questions were similar to those asked in regular consultation, and the tool helped to better understand the impact of MS symptoms on daily activities (249/274, 90.9%) and cognitive function (220/274, 80.3%). Overall, 92% (252/274) of the HCPs reported that they would recommend MSProDiscuss to a colleague, and 85.8% (235/274) were willing to integrate it into their clinical practice. CONCLUSIONS MSProDiscuss is a usable and useful tool to facilitate a physician-patient discussion on MS disease progression in daily clinical practice. Most of the HCPs agreed that the tool is easy to use and were willing to integrate MSProDiscuss into their daily clinical practice.

Introduction: Our goal was to investigate whether biomarkers of cerebral damage are found in autoimmune-mediated epilepsy (AIE) and whether these can differentiate AIE from other seizure disorders.Methods: We retrospectively searched our cerebrospinal fluid (CSF) database for patients with definite AIE, hippocampal sclerosis due to other causes (HS), genetic generalized epilepsy (GGE), and psychogenic, non-epileptic seizures (PNES). We measured serum and CSF tau, neurofilament 1 (NFL), glial fibrillary acid protein (GFAP), and ubiquitin-carboxy-terminal hydrolase L1 with a single-molecule array.Results: We identified suitable samples from patients with AIE (n = 13) with different antibodies and compared them to HS (n = 13), GGE (n = 7), and PNES (n = 8). The NFL levels were significantly elevated in the serum (p = 0.0009) and CSF (p < 0.0019) of AIE patients. The AIE group was significantly older, while the disease duration was significantly shorter than in the control groups. NFL correlated significantly with age in all groups, and the NFL levels of AIE patients were hardly higher than those of healthy elderly people published elsewhere.Conclusions: Our data indicate that the elevated NFL levels in AIE patients are most likely due to the higher age in this group and not due to the underlying inflammation. Unless larger prospective studies with intra-individual, longitudinal analyses and treatment responses would contradict our findings, NFL in serum might yet become a biomarker for disease activity and differential diagnosis.

During the course of Multiple Sclerosis (MS), most patients with relapsing remitting MS (RRMS) convert to secondary progressive MS (SPMS), an MS-phenotype associated with a steady deterioration of functional ability independent from relapses and worsened prognosis. Due to the heterogeneity of this conversion, SPMS-diagnosis is often challenging and made retrospectively with a delay of several years. In this review, we first discuss advantages and limitations of screening tools for early SPMS-detection such as the SPMS nomogram, the MS prediction score, and the best SPMS definition approach. These screening tools might help to shorten the phase of diagnostic uncertainty. We then focus on the development of MSProDiscuss, a novel web-based tool that helps the treating neurologist to systematically assesses parameters highly relevant for SPMS-conversion during routine anamnesis. These parameters involve disease activity, symptoms, and impacts of the patient's overall symptoms. In a recent validation study, MSProDiscuss demonstrated high sensitivity, specificity, and interrater reliability. MSProDiscuss does not impose an additional time burden on the treating neurologist and its results are easy to interpret by a simple traffic light system. In first usability tests, it was therefore assessed as a helpful tool for the clinical routine. The early detection of clinically significant progression by diagnostic tools such as MSProDiscuss could open a time-window for therapeutic interventions.Die Mehrheit der Patienten mit schubförmiger remittierender Multipler Sklerose (RRMS) konvertiert im langfristigen Verlauf ihrer Erkrankung zu einer sekundär-progredienten Verlaufsform (SPMS), die durch eine schubunabhängige Behinderungszunahme charakterisiert und mit einer deutlich schlechteren Prognose assoziiert ist. Aufgrund der Heterogenität der SPMS-Transition ist dieser Übergang nur schwer feststellbar, daher wird in der Regel eine SPMS-Diagnose nur retrospektiv und oft mit mehrjähriger Verzögerung gestellt. In dieser Übersichtsarbeit stellen wir Ansätze für eine frühere SPMS-Diagnose wie das SPMS-Nomogramm, den MS Prediction Score oder den Best Definition Ansatz vor, die beitragen könnten, die Phase der diagnostischen Unsicherheit zu verkürzen. Im Fokus dieser Übersichtsarbeit steht die Entwicklung von MSProDiscuss, einem neuen webbasierten Tool, durch das der Arzt systematisch und während der Routineanamnese alle progressionsrelevanten Parameter der Krankheitsaktivität, Symptomatik und täglichen Beeinträchtigungen aus Patientenperspektive erheben kann. In einer aktuellen Validierungsstudie zeigte MSProDiscuss eine hohe Sensitivität, Spezifität und Interrater-Reliabilität bei der Identifizierung von SPMS-Patienten und Patienten im SPMS-Übergang. Da MSProDiscuss aufgrund des geringen Zeitbedarfs zu keiner Mehrbelastung des behandelnden Neurologen führt und sein Ergebnis mittels eines einfachen Ampelsystems leicht interpretiert werden kann, wurde es in ersten Usability-Tests als äußerst hilfreiches diagnostisches Werkzeug für die neurologische Praxis bewertet. Die frühzeitige Identifizierung von signifikanter klinischer Progression durch diagnostische Tools wie MSProDiscuss könnte beitragen, ein Zeitfenster für mögliche therapeutische Interventionen zu öffnen.

BackgroundChorea-acanthocytosis (ChAc) is a neurodegenerative disease caused by mutations in the VPS13A gene. It is characterized by several neurological symptoms and the appearance of acanthocytes. Elevated tyrosine kinase Lyn activity has been recently identified as one of the key pathophysiological mechanisms and therefore represents a promising drug target.MethodsWe evaluated an individual off-label treatment with the FDA-approved tyrosine kinase inhibitor dasatinib (100 mg/d, 25.8-50.4 weeks) of three ChAc patients. Alongside with a thorough safety monitoring, we assessed motor and non-motor scales (e.g. MDS-UPDRS, UHDRS, quality of life) as well as routine and experimental laboratory parameters (e.g. serum neurofilament, Lyn kinase activity, actin cytoskeleton in red blood cells).ResultsDasatinib appeared to be reasonably safe. The clinical parameters remained stable without significant improvement or deterioration. Regain of deep tendon reflexes was observed in one patient. Creatine kinase, serum neurofilament levels and acanthocyte count did not reveal consistent effects. However, reduction of initially elevated Lyn kinase activity and accumulated autophagy markers as well as partial restoration of actin cytoskeleton was found in red blood cells.DiscussionWe report on the first treatment approach with disease-modifying intention in ChAc. The experimental parameters indicate target engagement in red blood cells, while clinical effects on the central nervous system could not be proven within a rather short treatment time. Limited knowledge on the natural history of ChAc and the lack of appropriate biomarkers remain major barriers for “clinical trial readiness”. Here, we suggest a panel of outcome parameters for future clinical trials in ChAc.

Background: Fingolimod (Gilenya®) is approved for adult and pediatric patients with highly active relapsing–remitting multiple sclerosis (RRMS).Objectives: The objective was to describe the effectiveness of fingolimod in young adults compared to older patients in clinical practice.Methods: PANGAEA is the largest prospective, multi-center, non-interventional, long-term study evaluating fingolimod in RRMS. We descriptively analyzed demographics, MS characteristics, and severity in two subgroups of young adults (≤20 and >20 to ≤30 years) and older patients (>30 years).Results: Young adults had lower Expanded Disability Status Scale (EDSS) scores compared to older patients (1.8 and 2.3 vs. 3.2) at baseline. The mean EDSS scores remained stable over 5 years in all subgroups. Young adults had higher annual relapse rates (2.0 and 1.7 vs. 1.4) at study entry, which were reduced by approximately 80% in all subgroups over 5 years. The proportion of patients with no clinical disease activity in year 4 was 52.6 and 73.4 vs. 66.9% in patients ≤20, >20 to ≤30 years and >30 years, respectively. The symbol digit modalities test score increased by 15.25 ± 8.3 and 8.3 ± 11.3 (mean ± SD) from baseline in patients >20 to ≤30 and >30 years.Conclusions: Real-world evidence suggests a long-term treatment benefit of fingolimod in young RRMS patients.

ObjectiveWe investigated the predictive value of the enzyme-linked immunospot technique (ELISPOT) in identifying patients with relapsing-remitting multiple sclerosis (RRMS) who will respond to treatment with glatiramer acetate (GA) or interferon-β (IFN-β), based on the brain-reactive B-cell activity of peripheral blood cells.MethodsIn this retrospective, cross-sectional, real-world multicenter study, we identified patients with RRMS in the NeuroTransData MS registry and stratified them based on their documented treatment response (relapse-free in the first 12 months of treatment) to GA or IFN-β. The GA group comprised 73 patients who responded to GA and 35 nonresponders. The IFN-β group comprised 62 responders to IFN-β and 37 nonresponders. Patients with previous or current therapy affecting B-cell activity were excluded. We polyclonally stimulated mononuclear cells from peripheral blood samples (collected after participant selection) and investigated brain-reactive B-cell activity after incubation on brain tissue lysate-coated ELISPOT plates. Validity metrics of the ELISPOT testing results were calculated (Python 3.6.8) in relation to the clinical responsiveness in the 2 treatment groups.ResultsThe ELISPOT B-cell activity assay showed a sensitivity of 0.74, a specificity of 0.76, a positive predictive value of 0.78, a negative predictive value of 0.28, and a diagnostic OR of 8.99 in predicting clinical response to GA vs IFN-β therapy in patients with RRMS.ConclusionMeasurement of brain-reactive B-cell activity by ELISPOT provides clinically meaningful predictive probabilities of individual patients' treatment response to GA or IFN-β. The assay has the potential to improve the selection of optimal first-line treatment for individual patients with RRMS.Classification of EvidenceThis study provides Class II evidence that in patients with RRMS, the brain reactivity of their peripheral-blood B cells predicts clinical response to GA and IFN-β.

Supplemental material, sj-pdf-1-tan-10.1177_1756286421993999 for Improved gastrointestinal profile with diroximel fumarate is associated with a positive impact on quality of life compared with dimethyl fumarate: results from the randomized, double-blind, phase III EVOLVE-MS-2 study by Annette Wundes, Sibyl Wray, Ralf Gold, Barry A. Singer, Elzbieta Jasinska, Tjalf Ziemssen, Jerome de Seze, Pavle Repovic, Hailu Chen, Jerome Hanna, Jordan Messer, Catherine Miller and Robert T. Naismith in Therapeutic Advances in Neurological Disorders