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Background: Natalizumab was not shown to modify disability in progressive multiple sclerosis (MS). This matched observational study compared the effectiveness of autologous haematopoietic stem cell transplantation (AHSCT) with natalizumab in progressive MS., Methods: Patients with primary/secondary progressive MS from seven AHSCT MS centres and the MSBase registry, treated with AHSCT or natalizumab, were matched on a propensity score derived from sex, age, Expanded Disability Status Scale (EDSS), number of relapses 12/24 months before baseline, time from MS onset, the most effective prior therapy and country. The pairwise-censored groups were compared on hazards of 6-month confirmed EDSS worsening and improvement, relapses and annualised relapse rates (ARRs), using Andersen-Gill proportional hazards models and conditional negative binomial model., Results: 39 patients treated with AHSCT (37 with secondary progressive MS, mean age 37 years, EDSS 5.7, 28% with recent disability progression, ARR 0.54 during the preceding year) were matched with 65 patients treated with natalizumab. The study found no evidence for difference in hazards of confirmed EDSS worsening (HR 1.49, 95% CI 0.70 to 3.14) and improvement (HR 1.50, 95% CI 0.22 to 10.29) between AHSCT and natalizumab over up to 4 years. The relapse activity was also similar while treated with AHSCT and natalizumab (ARR: mean±SD 0.08±0.28 vs 0.08±0.25; HR 1.05, 95% CI 0.39 to 2.82). In the AHSCT group, 3 patients experienced febrile neutropenia during mobilisation, 9 patients experienced serum sickness, 6 patients required intensive care unit admission and 36 patients experienced complications after discharge. No treatment-related deaths were reported., Conclusion: This study does not support the use of AHSCT to control disability in progressive MS with advanced disability and low relapse activity., Competing Interests: Competing interests: TK served on scientific advisory boards for MS International Federation and WHO, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen; steering committee for Brain Atrophy Initiative by Sanofi Genzyme; received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi-Genzyme, Teva, BioCSL and Merck; and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. SS has nothing to disclose. IR served on scientific advisory boards/steering committees for Novartis and Merck; and received conference travel support and/or speaker honoraria from Roche, Novartis, Biogen, Teva, Sanofi-Genzyme and Merck. JM served on scientific advisory board for Roche; and received conference travel support and/or speaker honoraria from Novartis, Biogen, Roche and Merck. IS received compensation for an educational activity from Biogen. BW has nothing to disclose. MSF has nothing to disclose. HA has nothing to disclose. EKH received honoraria/research support from Biogen, Merck Serono, Novartis, Roche and Teva; and has been supported by the Czech Ministry of Education–project Cooperatio LF1, research area Neuroscience and the project National Institute for Neurological Research (Programme EXCELES, ID project no LX22NPO5107)–funded by the European Union-Next Generation EU. EK has nothing to disclose. MT received honoraria from Janssen, Gilead Sciences, Bristol-Myers Squibb, Takeda, Amgen, AbbVie, Roche, MorphoSys and Novartis; served as an advisor to Takeda, Bristol-Myers Squibb, Incyte, AbbVie, Amgen, Roche, Gilead Sciences, Janssen, MorphoSys and Novartis; and received conference travel support from Gilead Sciences, Takeda, Bristol-Myers Squibb, Roche, Janssen and AbbVie. TK has nothing to disclose. JB has nothing to disclose. RM received compensation for travelling, conference fees and consulting fees from Merck, Teva, Sanofi Genzyme, Biogen Idec, Novartis, Roche, BMS and Celgene. OT received speaker honoraria from and served on scientific advisory boards for Biogen, Sanofi-Aventis, Teva, Merck and Novartis. LB received speaker honoraria from Novartis, and consultant fees from Viatris. AKL did not declare any disclosures. BS has nothing to disclose. JS declares honoraria for educational events from Jazz, Gilead and Janssen; for advisory board membership from Medac and Vertex; and for trial IDMC membership from Kiadis Pharma., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The use of disease-modifying therapies (DMTs) in multiple sclerosis (MS) has been associated with reduced relapse rates and accumulation of disability. However, studies examining impact of DMT on risk of transition to secondary progressive MS (SPMS) leveraging population-based nationwide data are still rare. Here, we determine the population incidence of conversion to SPMS using two consecutive nation-wide cohorts, one immediately before and one after the introduction of DMT in Sweden., Methods: We included two consecutive population cohorts of relapsing-remitting MS (RRMS) from the Swedish national MS register for the periods 1975-1994 (n = 2161), before DMT availability, and 1995-2011 (n = 3510), in which DMTs, mainly first generation DMT (injectables), became available and eventually were used by 70% of patients. We explored the risk of transition to SPMS as a calendar year function encompassing the two cohorts. In addition, we determined the incidence of transition to SPMS through age strata below and above 50 years in untreated and treated patient subgroups., Results: The risk of conversion to SPMS (adjusted for current age, current time since onset, calendar year and sex) was significantly lower in the second compared with the first population cohort (hazard ratio 0.58; CI 0.48, 0.70). The risk of SPMS conversion per calendar year decreased by 2.6% annually (p < 0.001) after 1995. The risk of SPMS conversion increased with age until age 50. Thereafter, it was unchanged or decreased among those with early MS onset age (<35 years), but continued to increase with onset at higher age, with similar trends in treated and untreated subgroups., Conclusion: The incidence of SPMS conversion significantly decreased at the population level after introduction of first generation DMTs by 1995. DMT efficiency was confirmed by a downward turn of the annual trajectory of the risk of SPMS conversion after 1995. An onset age determined pattern of variable SPMS incidence in higher age appeared in both treated and untreated strata. While first generation DMT delayed conversion to SPMS, their long-term effect was only moderate., Competing Interests: Declaration of Competing Interest Helen Tedeholm received a research grant from the Swedish MS Society in 2018. Funds for research time were granted by the Western Swedish Region. Fredrik Piehl has received research grants from Genzyme, Merck KGaA, and UCB, and fees for serving as chair of DMC in clinical trials with Parexel. Jan Lycke has received travel support and/or lecture honoraria from Biogen, Novartis, Merck, Alexion, Roche, and SanofiGenzyme; has served on scientific advisory boards for Biogen, Novartis, Merck, Roche, BSM, and SanofiGenzyme; serves on the editorial board of Acta Neurologica Scandinavica; and has received unconditional research grants from Biogen and Novartis. Jenny Link has nothing to declare. Leszek Stawiarz has nothing to declare. Joachim Burman has nothing to declare. Pierre de Flon has nothing to declare. Katarina Fink has received honoraria for lectures and advisory boards from Merck, Novartis, Roche, Biogen, and Aktelion. Martin Gunnarsson has nothing to declare. Johan Mellergård has received honoraria for advisory boards from Biogen, Sanofi Genzyme and Merck and lecture honoraria from Merck. Petra Nilsson has received travel support from Bayer Schering Pharma, Merck Serono, Biogen, and Genzyme a Sanofi Company; honoraria for lectures and advisory boards from Merck Serono and Genzyme a Sanofi Company; serves on advisory boards for Novartis and Roche; lectures for Biogen; and has received unrestricted grants from Biogen. Peter Sundström has nothing to declare. Anders Svenningsson has nothing to declare. Helena Johansson has nothing to declare. Oluf Andersen serves on the editorial board of Acta Neurologica Scandinavica., (Copyright © 2022. Published by Elsevier B.V.)

Ocrelizumab and siponimod have a scientifically proven effect in progressive MS and decrease the risk of disability in the short-term. The primary endpoints in the pivotal trials of ocrelizumab and siponimod were reported as a hazard ratio of 3-month confirmed disability progression, which was reported to be 0.76-0.79. Based on this, both drugs were subsequently licensed for use in patients with progressive multiple sclerosis. Hazard ratios are not easily communicated to patients and therefore the alternative endpoint average postponement of disability was calculated with data from the pivotal trials. After two years of treatment, the average postponement of disability was 16 days per year with ocrelizumab and 19 days with siponimod. Over time, the average postponement of disability reached a plateau, when further treatment added little value. Taken together, these data suggest that these interventions have a short-lived and limited clinical effect in patients with progressive MS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is a neurodegenerative disease associated with inflammatory demyelination and astroglial activation, with neuronal and axonal damage as the leading factors of disability. We aimed to perform a meta-analysis to determine changes in CSF levels of neuronal and glial biomarkers, including neurofilament light chain (NFL), total tau (t-tau), chitinase-3-like protein 1 (CHI3L1), glial fibrillary acidic protein (GFAP), and S100B in various groups of MS (MS versus controls, clinically isolated syndrome (CIS) versus controls, CIS versus MS, relapsing-remitting MS (RRMS) versus progressive MS (PMS), and MS in relapse versus remission. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, we included 64 articles in the meta-analysis, including 4071 subjects. For investigation of sources of heterogeneity, subgroup analysis, meta-regression, and sensitivity analysis were conducted. Meta-analyses were performed for comparisons including at least three individual datasets. NFL, GFAP, t-tau, CHI3L1, and S100B were higher in MS and NFL, t-tau, and CHI3L1 were also elevated in CIS patients than controls. CHI3L1 was the only marker with higher levels in MS than CIS. GFAP levels were higher in PMS versus RRMS, and NFL, t-tau, and CHI3L1 did not differ between different subtypes. Only levels of NFL were higher in patients in relapse than remission. Meta-regression showed influence of sex and disease severity on NFL and t-tau levels, respectively and disease duration on both. Added to the role of these biomarkers in determining prognosis and treatment response, to conclude, they may serve in diagnosis of MS and distinguishing different subtypes., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: To evaluate the effect of intrathecally (IT) delivered rituximab as a therapeutic intervention for progressive multiple sclerosis (PMS) during a 3-year follow-up period., Methods: Participants of a 1-year open-label phase 1b study of IT delivered rituximab to patients with PMS were offered extended treatment with follow-up for an additional 2 years. During the extension phase, treatment with 25 mg rituximab was administered every 6 months via a subcutaneous Ommaya reservoir connected to the right frontal horn with a ventricular catheter., Results: Mild to moderate vertigo and nausea occurred in 4 out of 14 participants as temporary adverse events associated with IT rituximab infusion. During the entire 3-year period, two cases of low-virulent bacterial meningitis occurred, which were successfully treated. Walking speed deteriorated significantly during the study., Conclusions: IT administration of rituximab via a ventricular catheter was well tolerated. Considering the meningitis cases, the risk of infection was not negligible. The continued loss of walking speed indicates that IT rituximab was not able to stop disease progression., Classification of Evidence: This study provides class IV evidence that intraventricularly administered rituximab in progressive MS is associated with a risk for bacterial meningitis and does not halt disease progression., Eu Clinical Trial Register: EudraCT; 2008-002626-11 and 2012-000721-53.

Background: The relationship between proteins in different CNS extracellular compartments is unknown. In this study the levels of selected proteins in three compartments in people with progressive multiple sclerosis (PMS) were compared., Methods: During an open label, phase 1b study on intraventricular administration of rituximab for PMS, samples were collected from the interstitial space (ISS) of the brain through microdialysis. Samples were also obtained from ventricular and lumbar cerebrospinal fluid (CSF). These samples were analyzed with a multiplexed proximity extension assay, measuring the levels of 180 proteins split equally between two panels, detecting proteins associated with immunology and neurology, respectively., Results: Considerable differences in concentrations were observed between the three analyzed compartments. Compared to ventricular CSF, ISS fluid contained statistically significant higher levels of 25 proteins (84% immunology panel and 16% neurology panel). Ventricular CSF contained significantly higher levels of 54 proteins (31% immunology panel and 69% neurology panel) compared to ISS fluid, and 17 proteins (76% immunology panel and 24% neurology panel) compared to lumbar CSF. Lumbar CSF showed significantly higher levels of 115 proteins (32% immunology panel and 68% neurology panel) compared to ventricular CSF. The three compartments displayed poor correlation with a median Spearman's rho of -0.1 (IQR 0.4) between ISS and ventricular CSF and 0.3 (IQR 0.4) between ventricular and lumbar CSF., Conclusion: A substantial heterogeneity in the protein levels of samples obtained from different CNS compartments was seen. Therefore, data obtained from analysis of lumbar CSF should be interpreted with caution when making conclusions about pathophysiological processes in brain tissue.

Background: The incidence of epilepsy, a disease generally associated with increased morbidity and mortality, is increased in multiple sclerosis (MS) but its impact on MS prognosis is largely unknown., Objectives: To investigate the association between acquired epilepsy and mortality in MS and to examine the occurrence of epilepsy as a stated cause of death in MS. To examine the association between acquired epilepsy and subsequent conversion to secondary progressive MS (SPMS)., Methods: Using the Swedish MS register, we conducted a nationwide register-based cohort study including 10,383 patients with MS onset between 31/12/1991 and 31/12/2014, and with no history of epilepsy before MS onset. Data on epilepsy diagnosis and cause of death (COD) were extracted from comprehensive national registers. Cox regression was used to estimate hazard ratios (HR) of death stratified by MS course, and SPMS conversion after epilepsy diagnosis. The HRs were adjusted for age at MS onset and sex., Results: The adjusted HR of death after epilepsy diagnosis for unselected MS patients was 3.85 (95% CI: 2.53-5.85). Stratifying by disease course, the adjusted HR of death after epilepsy diagnosis in primary progressive MS was 2.28 (95% CI: 0.99-5.26) and in relapsing-onset MS (ROMS), 5.48 (95% CI: 3.33-9.04). Further subdivision of ROMS revealed the adjusted risk of death after epilepsy diagnosis in relapsing remitting MS to be 3.84 (95% CI: 1.57-9.42) and 6.66 (95% CI: 3.18-13.92) in SPMS. Epilepsy was the underlying COD in 4.55% of MS patients with epilepsy. The majority (50%) of MS patients with epilepsy had MS as their stated underlying COD. Adjusted HR of conversion to SPMS after epilepsy diagnosis was 0.83 (95% CI: 0.45-1.56)., Conclusion: Epilepsy in MS is associated with increased mortality although death from epilepsy is rare. Most MS patients with epilepsy died of MS, and epilepsy was most lethal when developed in SPMS. We thus suggest that development of epilepsy is a marker of severe MS. Despite this, we found no association between epilepsy and conversion to SPMS., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: To perform a phase 1b assessment of the safety and feasibility of intrathecally delivered rituximab as a treatment for progressive multiple sclerosis (PMS) and to evaluate the effect of treatment on disability and CSF biomarkers during a 1-year follow-up period., Methods: Three doses of rituximab (25 mg with a 1-week interval) were administered in 23 patients with PMS via a ventricular catheter inserted into the right frontal horn and connected to a subcutaneous Ommaya reservoir. Follow-ups were performed at 1, 3, 6, 9, and 12 months., Results: Mild to moderate vertigo and nausea were common but temporary adverse events associated with intrathecal rituximab infusion, which was otherwise well tolerated. The only severe adverse event was a case of low-virulent bacterial meningitis that was treated effectively. Of 7 clinical assessments, only 1 showed statistically significant improvement 1 year after treatment. No treatment effect was observed during the follow-up period among 6 CSF biomarkers., Conclusions: Intrathecal administration of rituximab was well tolerated. However, it may involve a risk for injection-related infections. The lack of a control group precludes conclusions being drawn regarding treatment efficacy., Clinicaltrialsgov Identifier: NCT01719159., Classification of Evidence: This study provides Class IV evidence that intrathecal rituximab treatment is well tolerated and feasible in PMS but involves a risk of severe infections., (© 2018 American Academy of Neurology.)

Molecular networks in neurological diseases are complex. Despite this fact, contemporary biomarkers are in most cases interpreted in isolation, leading to a significant loss of information and power. We present an analytical approach to scrutinize and combine information from biomarkers originating from multiple sources with the aim of discovering a condensed set of biomarkers that in combination could distinguish the progressive degenerative phenotype of multiple sclerosis (SPMS) from the relapsing-remitting phenotype (RRMS). Methods: Clinical and magnetic resonance imaging (MRI) data were integrated with data from protein and metabolite measurements of cerebrospinal fluid, and a method was developed to sift through all the variables to establish a small set of highly informative measurements. This prospective study included 16 SPMS patients, 30 RRMS patients and 10 controls. Protein concentrations were quantitated with multiplexed fluorescent bead-based immunoassays and ELISA. The metabolome was recorded using liquid chromatography-mass spectrometry. Clinical follow-up data of the SPMS patients were used to assess disease progression and development of disability. Results: Eleven variables were in combination able to distinguish SPMS from RRMS patients with high confidence superior to any single measurement. The identified variables consisted of three MRI variables: the size of the spinal cord and the third ventricle and the total number of T1 hypointense lesions; six proteins: galectin-9, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor alpha (TGF-α), tumor necrosis factor alpha (TNF-α), soluble CD40L (sCD40L) and platelet-derived growth factor AA (PDGF-AA); and two metabolites: 20β-dihydrocortisol (20β-DHF) and indolepyruvate. The proteins myelin basic protein (MBP) and macrophage-derived chemokine (MDC), as well as the metabolites 20β-DHF and 5,6-dihydroxyprostaglandin F1a (5,6-DH-PGF 1 ), were identified as potential biomarkers of disability progression. Conclusion: Our study demonstrates, in a limited but well-defined and data-rich cohort, the importance and value of combining multiple biomarkers to aid diagnostics and track disease progression., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Objective: To determine the cumulative incidence of epilepsy in a population-based cohort of patients with multiple sclerosis (MS) and to investigate the association between epilepsy and clinical features of MS., Methods: All available patients in the Swedish MS register (n = 14,545) and 3 age- and sex-matched controls per patient randomly selected from the population register (n = 43,635) were included. Data on clinical features of MS were retrieved from the Swedish MS register, and data on epilepsy and death were retrieved from comprehensive patient registers., Results: The cumulative incidence of epilepsy was 3.5% (95% confidence interval [CI] 3.17-3.76) in patients with MS and 1.4% (95% CI 1.30-1.52) in controls (risk ratio 2.5, 95% CI 2.19-2.76). In a Cox proportional model, MS increased the risk of epilepsy (hazard ratio 3.2, 95% CI 2.64-3.94). Patients with relapsing-remitting MS had a cumulative incidence of epilepsy of 2.2% (95% CI 1.88-2.50), whereas patients with progressive disease had a cumulative incidence of 5.5% (95% CI 4.89-6.09). The cumulative incidence rose continuously with increasing disease duration to 5.9% (95% CI 4.90-7.20) in patients with disease duration ≥34 years. Patients with an Expanded Disability Status Scale (EDSS) score ≥7 had a cumulative incidence of epilepsy of 5.3% (95% CI 3.95-7.00). Disease duration and EDSS score were associated with epilepsy after multiple logistic regression (odds ratio [OR] 1.03, 95% CI 1.01-1.04 per year, p = 0.001; and OR 1.2, 95% CI 1.09-1.26 per EDSS step, p < 0.0001)., Conclusions: Epilepsy is more common among patients with MS than in the general population, and a diagnosis of MS increases the risk of epilepsy. Our data suggest a direct link between severity of MS and epilepsy., (© 2017 American Academy of Neurology.)

YKL-40 (CHI3L1) is a glycoprotein predominantly produced by reactive astrocytes in chronic active MS lesions, which are common in secondary progressive MS. In this study, YKL-40 was investigated in different stages of MS and in relation to MRI findings. YKL-40 levels in CSF samples from two independent patient cohorts of MS patients were determined with ELISA. CSF YKL-40 was increased in patients with active relapsing-remitting MS and correlated with the number of gadolinium enhancing lesions. Patients with secondary progressive MS had similar high levels of YKL-40, whereas not active relapsing-remitting MS patients had YKL-40 levels comparable to healthy controls., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Galectin-9 is produced by activated astrocytes, induces a pro-inflammatory response in microglia and may be important to the pathogenesis of secondary progressive MS. In this study, Galectin-9 concentrations in CSF samples from healthy controls and two independent patient cohorts of MS patients were determined by ELISA. Patients from one of the cohorts underwent MRI as well. Galectin-9 concentrations in CSF were higher in SPMS patients than healthy controls and RRMS patients in both cohorts. Galectin-9 concentrations correlated with the number of lesions on T1-weighted images, but not with gadolinium enhancing lesions, IgG index or CSF cell count., (Copyright © 2016 Elsevier B.V. All rights reserved.)