Search

Background: Reporting of sex-specific analyses in multiple sclerosis (MS) is sparse. Disability accrual results from relapses (relapse-associated worsening) and independent thereof (progression independent of relapses)., Objectives: A population of MS patients during relapse treated per standard of care was analyzed for sex differences and short-term relapse outcome (3-6 months) as measured by Expanded Disability Status Scale (EDSS) change., Design: Single-center retrospective study., Methods: We analyzed 134 MS relapses between March 2016 and August 2020. All events required relapse treatment (steroids and/or plasma exchange). Demographic, disease, and paraclinical characteristics [cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI)] were displayed separated by sex. Multivariable linear regression was run to identify factors associated with short-term EDSS change., Results: Mean age at relapse was 38.4 years (95% confidence interval: 36.3-40.4) with a proportion of 71.6% women in our cohort. Smoking was more than twice as prevalent in men (65.8%) than women (32.3%). In- and after-relapse EDSSs were higher in men [men: 3.3 (2.8-3.9), women: 2.7 (2.4-3.0); men: 3.0 (1.3-3.6); women: 1.8 (1.5-2.1)] despite similar relapse intervention. Paraclinical parameters revealed no sex differences. Our primary model identified female sex, younger age, and higher EDSS at relapse to be associated with EDSS improvement. A higher immunoglobulin G (IgG) quotient (CSF/serum) was associated with poorer short-term outcome [mean days between first relapse treatment and last EDSS assessment 130.2 (79.3-181.0)]., Conclusion: Sex and gender differences are important in outcome analyses of MS relapses. Effective treatment regimens need to respect putative markers for a worse outcome to modify long-term prognosis such as clinical and demographic variables, complemented by intrathecal IgG synthesis. Prospective trials should be designed to address these differences and confirm our results., Competing Interests: PT, AV, FW, SM, and PR declare no disclosures relevant to the manuscript. CF received speaker honoraria and/or travel compensation for activities with Biogen, Sanofi Genzyme, Novartis, and Merck and research support from Chiesi, not related to this work. LD received travel grants from Merck, Biogen, Roche, and Bayer Schweiz. She also received speaker’s/advisor honoraria from Biogen, Novartis, Roche, Merck, Lundbeck, Swiss MS Society, and National Swiss Ice Hockey League. She is a member of the Advisory Board of the Swiss MS Society. She also serves as Guest-Co Editor for Brain Sciences (2022/2023) and as Guest-Editor for Journal of Central Nervous System Disease (2022/2023). HH speaker/advisor honorary from Merck, Biogen, Janssen, Teva/Mepha. She received research support within the last 5 years from Biogen. She received travel grants from Biogen, Roche, Janssen, and Merck. RW received speaker/advisor honoraria from Bayer Healthcare, Biogen, Siemens Healthineers. He received research support from Biogen, the Swiss Innovation Agency, the U.S. National Institute of Health, and the Swiss National Foundation. AC received speakers’/board honoraria from Actelion (Janssen/J&J), Almirall, Bayer, Biogen, Celgene (BMS), Genzyme, Merck KGaA (Darmstadt, Germany), Novartis, Roche, and Teva, all for hospital research funds. He received research support from Biogen, Genzyme, and UCB, the European Union, and the Swiss National Foundation. He serves as an associate editor of the European Journal of Neurology, on the editorial board for Clinical and Translational Neuroscience, and as a topic editor for the Journal of International Medical Research. RH received speaker/advisor honorary from Merck, Novartis, Roche, Biogen, Alexion, Sanofi, Janssen, Bristol-Myers Squibb, Teva/Mepha, and Almirall. He received research support within the last 5 years from Roche, Merck, Sanofi, Biogen, Chiesi, and Bristol-Myers Squibb. He also received research grants from the Swiss MS Society and is a member of the Advisory Board of the Swiss MS Society. He also serves as an associated editor for Journal of Central Nervous System disease. AS received speaker honoraria and/or travel compensation for activities with Bristol Myers Squibb, CSL Behring, Novartis, and Roche, and research support by the Baasch Medicus Foundation, the Medical Faculty of the University of Bern, and the Swiss MS Society., (© The Author(s), 2024.)

Background: Depression has a major impact on the disease burden of multiple sclerosis (MS). Analyses of overlapping MS and depression risk factors [smoking, vitamin D (25-OH-VD) and Epstein-Barr virus (EBV) infection] and sex, age, disease characteristics and neuroimaging features associated with depressive symptoms in early MS are scarce., Objectives: To assess an association of MS risk factors with depressive symptoms within the German NationMS cohort., Design: Cross-sectional analysis within a multicenter observational study., Methods: Baseline data of n  = 781 adults with newly diagnosed clinically isolated syndrome or relapsing-remitting MS qualified for analysis. Global and region-specific magnetic resonance imaging (MRI)-volumetry parameters were available for n  = 327 patients. Association of demographic factors, MS characteristics and risk factors [sex, age, smoking, disease course, presence of current relapse, expanded disability status scale (EDSS) score, fatigue (fatigue scale motor cognition), 25-OH-VD serum concentration, EBV nuclear antigen-1 IgG (EBNA1-IgG) serum levels] and depressive symptoms (Beck Depression Inventory-II, BDI-II) was tested as a primary outcome by multivariable linear regression. Non-parametric correlation and group comparison were performed for associations of MRI parameters and depressive symptoms., Results: Mean age was 34.3 years (95% confidence interval: 33.6-35.0). The female-to-male ratio was 2.3:1. At least minimal depressive symptoms (BDI-II > 8) were present in n  = 256 (32.8%), 25-OH-VD deficiency (<20 ng/ml) in n  = 398 (51.0%), n  = 246 (31.5%) participants were smokers. Presence of current relapse [coefficient ( c ) = 1.48, p  = 0.016], more severe fatigue ( c  = 0.26, p  < 0.0001), lower 25-OH-VD ( c  = -0.03, p  = 0.034) and smoking ( c  = 0.35, p  = 0.008) were associated with higher BDI-II scores. Sex, age, disease course, EDSS, month of visit, EBNA1-IgG levels and brain volumes at baseline were not., Conclusion: Depressive symptoms need to be assessed in early MS. Patients during relapse seem especially vulnerable to depressive symptoms. Contributing factors such as fatigue, vitamin D deficiency and smoking, could specifically be targeted in future interventions and should be investigated in prospective studies., (© The Author(s), 2023.)

Background: Evidence on mortality risks associated with MS-immunotherapies during the SARS-CoV2 pandemic derived thus far mainly from single country experiences., Objective: In this analysis, we aim to determine the frequency of COVID-19 associated fatality reports of patients receiving an MS-immunotherapy as reported to the international Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from February 2020 to March 2021., Methods: In all, 1071 cases for this cross-sectional analysis were retrieved from FAERS and a multivariable logistic regression was performed. We adjusted for sex, age, region, month of report to FDA, immunotherapy-class and additionally for healthcare-system and pandemic-related metrics., Result: Anti-CD20 therapies (60%) followed by sphingosine-1 phosphate modulators (12%) and dimethylfumarat (10%) were reported most frequently. In 50% of the cases, MS-phenotype is not reported, relapsing MS in 35% and progressive MS in 15%. Besides older age (odds ratio [OR]: 1.1; 95% confidence interval [CI]: 1.07-1.13; p  < 0.01), anti-CD20 therapies were significantly associated with a higher risk of death (OR: 4.1; 95% CI: 1.17-14.46; p  = 0.03), whereas female sex was associated with a reduced mortality risk (OR: 0.4, 95% CI: 0.22-0.72; p  < 0.01)., Conclusion: Using international open access data and a multidisciplinary approach for risk prediction, we identified an increased mortality risk associated with anti-CD20 therapies, which is in line with national and multi-national cohort studies., Competing Interests: Pistor M declares that he has no competing interests in relation to this study. Pistor M was funded by a translational research grant by the Department of Neurology, University Hospital Bern and received a research grant from the Swiss MS Society. Hoepner R received speaker/advisor honorary from Merck, Novartis, Roche, Biogen, Alexion, Sanofi, Bristol-Myers Squibb, and Almirall. He received research support within the last 5 years from Roche, Merck, Sanofi, Biogen, and Bristol-Myers Squibb. He also received research grants from the Swiss MS Society. Hoepner AGF and Lin Y declare that they have no conflict of interest. They have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. Hoepner AGF and Lin Y acknowledge funding from the European Union’s Horizon 2020 research and innovation program for research on Fintech (Grant No. H2020-ICT-825215), and Science Foundation Ireland (Award 19/FIP/AI/7539). The views expressed in this paper are not necessarily shared by other members of the Platform for Sustainable Finance or DG FISMA. Jung S declares that he has no competing interests in relation to this study. Bassetti CL declares that he has no competing interests in relation to this study. Chan A has served on advisory boards for, and received funding for travel or speaker honoraria from, Actelion-Janssen, Almirall, Bayer, Biogen, Celgene, Sanofi-Genzyme, Merck, Novartis, Roche, and Teva, all for hospital research funds; and research support from Biogen, Genzyme and UCB. Chan A is associate editor of the European Journal of Neurology and serves on the editorial board for Clinical and Translational Neuroscience and as topic editor for the Journal of International Medical Research. Salmen A received speaker honoraria and/or travel compensation for activities with Almirall Hermal GmbH, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme and research support by the Swiss MS Society., (© The Author(s), 2022.)

Aims: To retrospectively analyse the Bernese radiologically isolated syndrome (RIS) cohort with the goal of developing a prediction score for conversion to multiple sclerosis (MS)., Methods: A total of 31 patients with RIS were identified by screening medical records of neurological patients seen at the University Hospital of Bern between 2004 and 2017 for the diagnoses 'radiologically isolated syndrome' and 'RIS' adhering to 2009 Okuda recommendations. We analysed clinical, paraclinical and magnetic resonance imaging data during a maximum follow-up period of 3 years and identified significant predictors of conversion to MS., Results: Data were available for 31 patients meeting 2009 Okuda RIS criteria. During the 3 years of follow up, 5/31 RIS patients converted to relapsing-remitting (RR) MS. In our univariate analysis, gadolinium (Gd) enhancement, brainstem and cerebellar hemisphere lesions, immune cell count and albumin concentration in cerebrospinal fluid (CSF), and anti-nuclear antibody (ANA) positivity in serum were identified as significant predictors of conversion to MS. Integrating these factors into our 'RIS-MS prediction score' enabled us to calculate a cut-off for prediction of conversion to MS within 3 years with high specificity [1.0, 95% confidence interval (CI) 0.84-1.00) and acceptable sensitivity (0.6, 95% CI 0.17-0.93)]., Conclusion: Our RIS-MS prediction score, if validated in an independent cohort, integrating radiological (Gd enhancement, brainstem and cerebellar hemisphere lesions) and paraclinical factors (ANA in serum, cell count and albumin in CSF) could be a useful prognostic tool for early recognition of RIS patients with a high risk of clinical progression to MS., Competing Interests: Conflict of interest statement: PC-I, FW and LW report no disclosures or conflicts of interest in relation to this manuscript. LD has received travel grants from Bayer, Biogen, Roche and Merck, as well as speaker honoraria from Merck and Biogen, not related to this work. She reports no conflicts of interest related to this manuscript. AC has served on advisory boards for, and received funding for travel or speaker honoraria from, Actelion-Janssen, Almirall, Bayer, Biogen, Celgene, Sanofi-Genzyme, Merck, Novartis, Roche and Teva, all for hospital research funds; and research support from Biogen, Genzyme and UCB. AC is associate editor of the European Journal of Neurology and serves on the editorial board for Clinical and Translational Neuroscience and as topic editor for the Journal of International Medical Research. He reports no conflicts of interest related to this manuscript. AS has received speaker honoraria and/or travel compensation for activities with Almirall Hermal GmbH, Biogen, Merck, Novartis, Roche and Sanofi Genzyme, and research support of the Swiss MS society not related to this work. She reports no conflicts of interest related to this manuscript. RH has received research and travel grants from Roche, Novartis and Biogen Idec and speaker honoraria from Biogen, Novartis, Merck, Celgene and Almirall, not related to this work. He reports no conflicts of interest related to this manuscript. CF has received travel grants from Biogen and Sanofi Genzyme, as well as speaker honoraria from Biogen and Merck, not related to this work. He reports no conflicts of interest related to this manuscript., (© The Author(s), 2021.)

Background: Glucocorticoid (GC) pulse therapy is used for multiple sclerosis (MS) relapse treatment; however, GC resistance is a common problem. Considering that GC dosing is individual with several response-influencing factors, establishing a predictive model, which supports clinicians to estimate the maximum GC dose above which no additional therapeutic value can be expected presents a huge clinical need., Method: We established two, independent retrospective cohorts of MS patients. The first was an explorative cohort for model generation, while the second was established for its validation. Using the explorative cohort, a multivariate regression analysis with the GC dose used as the dependent variable and serum vitamin D (25D) concentration, sex, age, EDSS, contrast enhancement on cranial magnetic resonance imaging (MRI), immune therapy, and the involvement of the optic nerve as independent variables was established., Results: In the explorative cohort, 113 MS patients were included. 25-hydroxyvitamin D (25D) serum concentration and the presence of optic neuritis were independent predictors of the GC dose needed to treat MS relapses [(25D): -25.95 (95% confidence interval (CI)): -47.40 to -4.49; p  = 0.018; optic neuritis: 2040.51 (95% CI: 584.64-3496.36), p  = 0.006]. Validation of the multivariate linear regression model was performed within a second cohort. Here, the predicted GC dose did not differ significantly from the dose administered in clinical routine (mean difference: -843.54; 95% CI: -2078.08-391.00; n  = 30, p  = 0.173)., Conclusion: Our model could predict the GC dose given in clinical, routine MS relapse care, above which clinicians estimate no further benefit. Further studies should validate and improve our algorithm to help the implementation of predictive models in GC dosing., Competing Interests: Conflict of interest statement: J Gili-Kovács reports no disclosures. R Hoepner has received research and travel grants from Roche, Novartis, and Biogen Idec and speaker honoraria from Biogen, Novartis, Merck, Celgene, and Almirall, not related to this work. He reports no conflicts of interest related to this manuscript. A Salmen received speaker honoraria and/or travel compensation for activities with Almirall Hermal GmbH, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme, and research support by the Swiss MS Society, not related to this work. M Bagnoud reports no disclosures. R Gold received research support, and speaker’s honoraria from Bayer Schering, Biogen, Celgene, Chugai, Eisai, Janssen Pharmaceuticals, Merck Serono, Nikkiso Pharma, Novartis, Roche, Sandoz, Sanofi-Genzyme, and TEVA. They received consulting honoraria from ZLB Behring, Baxter, Novartis, and Talecris. They have personal stock options in Bayer, Merck, and Roche. A Chan has served on advisory boards for, and received funding for travel or speaker honoraria from, Actelion-Janssen, Almirall, Bayer, Biogen, Celgene, Sanofi-Genzyme, Merck, Novartis, Roche, and Teva, all for hospital research funds; and research support from Biogen, Genzyme, and UCB. A. Chan is associate editor of the European Journal of Neurology and serves on the editorial board for Clinical and Translational Neuroscience and as topic editor for the Journal of International Medical Research. M Briner received travel grants from Merck, Biogen, and Genzyme., (© The Author(s), 2021.)

Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Background: Blood-brain barrier dysfunction in active multiple sclerosis (MS) lesions leads to pathological changes of cerebrospinal fluid (CSF). Theoretically, CSF analyses could help to predict relapse recovery and the course of disability. In this monocentric study, we investigated the impact of CSF findings assessed during the first relapse of MS on the short-term course of disability., Methods: We performed a retrospective observational study including MS patients with available CSF data after onset of first MS relapse. Clinical symptoms had to be accompanied by gadolinium-enhanced lesion on magnetic resonance imaging. Expanded Disability Status Scale (EDSS) assessments at timepoint of relapse and after relapse recovery were studied to analyze disability. A two-step multivariate linear regression analysis adjusted for EDSS at spinal tab, duration of symptoms, sex, time until post relapse EDSS assessment, immunotherapy post relapse, and relapse treatment with glucocorticoids/plasma exchange to predict relapse associated disability was run., Results: In the first step of the regression model, pathological albumin quotient (QAlb) [regression coefficient 0.50, 95% confidence interval (CI) (0.07-0.92), p  = 0.02, n  = 99] and CSF protein concentration [regression coefficient 0.84, 95% CI (0.33-1.35), p  = 0.001, n  = 99] predicted EDSS after relapse recovery. In the second step, the sum score of both predictors [range 0-2; n per value: 0 ( n  = 73), 1 ( n  = 10), 2 ( n  = 15)] confirmed the negative impact on course of disability after relapse [regression coefficient 0.38, 95% CI (0.13-0.62), p  = 0.003, n  = 98]. In this final multivariate linear regression model ( p  < 0.001; R 2 0.34), also EDSS at lumbar puncture [regression coefficient 0.58, 95% CI (0.35-0.81), p  < 0.001, n  = 98] and time between symptom onset and CSF evaluation [regression coefficient 0.03, 95% CI (0.006-0.048), p  = 0.01, n  = 98] forecast subsequent disability., Discussion: Our study conducted in MS patients during first relapse confirmed that both increased CSF protein concentration and pathological QAlb have a negative impact on EDSS after relapse. As secondary finding, we identified time from symptom onset to lumbar puncture as predictor of disability recovery after relapse., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Competing Interests: Conflict of Interest Statement: The authors declare no conflict of interest in preparing this article.

Background: Fingolimod (FTY) is the first oral medication approved for multiple sclerosis therapy. Until now, little has been known about the effects of FTY withdrawal regarding disease activity and development of tumefactive demyelinating lesions (TDLs), as already described in patients who discontinue natalizumab., Methods: In this study we present the clinical and radiological findings of two patients who had a severe rebound after FTY withdrawal and compare these with patients identified by a PubMed data bank analysis using the search term 'fingolimod rebound'. In total, 10 patients, of whom three developed TDLs, are presented., Results: Patients suffering from TDLs were free of clinical and radiological signs of disease activity under FTY therapy (100% versus 57%, compared with patients without TDLs) and had rebounds after a mean of 14.6 weeks (standard deviation 11.5) [patients without TDLs 11.7 (standard deviation 3.4)]., Conclusion: We propose that a good therapeutic response to FTY might be predisposing for a severe rebound after withdrawal. Consequently, therapy switches should be planned carefully with a short therapy free interval.

Objective: Little is known about seizures in natalizumab-associated progressive multifocal leukoencephalopathy (NAT-PML)., Methods: A review of clinical records of 15 NAT-PML patients with multiple sclerosis (MS) treated at a German university hospital., Results: Some 53% (8/15) of our patients developed seizures with often multiple semiologies (seven grand mal, three simple partial motor and two psychomotor seizures). Series of seizures or status epilepticus occurred in seven of these eight. Seizure onset was on average 61 days after onset of NAT-PML and was associated with immune reconstitution inflammatory syndrome (IRIS) in five of eight patients. After having observed severe seizures during NAT-PML in seven of our first nine patients, we started preventive antiepileptic treatment (PAT) with levetiracetam (1000-1750 mg/day). Patient subgroups analyzed for seizures and PAT did not differ in baseline characteristics. Only one of six patients, who received PAT, had a seizure compared with seven of nine patients without PAT (2-tailed Fisher's exact test, p = 0.04)., Conclusions: Although the small sample size and retrospective nature of the study are limitations, we propose to treat NAT-PML patients with PAT early after diagnosis, as seizures seem to be common and severe in NAT-PML.