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Introduction: Reduced quality of life (QoL) is an early feature of multiple sclerosis (MS). The effect of progression independent of relapse activity (PIRA) on QoL is poorly investigated., Objective: To assess the impact of PIRA on QoL using patient-reported outcome measures (PROMs)., Methods: In a prospective observational study, 125 newly diagnosed persons with relapsing-remitting MS (PwRRMS) were assessed over 5 years with: EuroQoL-5-Dimension-3-level (EQ-5D-3L), EQ-visual-analogous-scale (EQ-VAS) and 29-item-MS-Impact-Scale (MSIS-29). PwRRMS were dichotomized: PIRA (worsening of expanded disability status scale (EDSS), timed-25-foot-walk or 9-hole-peg-test, independent of relapses) versus non-PIRA. PwRRMS were compared at baseline, year 5 (y5) and delta values (baseline scores subtracted from y5 scores) and annually using linear-mixed-effects-models., Results: At y5, 19.2% had PIRA. PIRA versus non-PIRA PwRRMS were older ( p < 0.001). At y5 PIRA PwRRMS had lower EQ-5D-3L ( p = 0.001), higher MSIS-29-PHYS ( p < 0.001), delta values showed lower EQ-5D-3L ( p < 0.001) and EQ-VAS ( p = 0.010), higher MSIS-29-PHYS ( p = 0.004) and MSIS-29-PSYCH ( p = 0.036). Linear-mixed-effects-models showed that, compared to PIRA, non-PIRA PwRRMS had an improvement in QoL: EQ-5D-3L: β = 0.039, p < 0.001; EQ-VAS: β = 2.401, p < 0.001; MSIS-29-PHYS: β = -0.107, p < 0.001; MSIS-29-PSYCH, β = -0.115, p < 0.001, during the 5-year study period., Conclusion: Deteriorating QoL in the early course of relapsing-remitting multiple sclerosis (RRMS) is strongly associated with PIRA. Our results suggest that QoL PROMs should be monitored and recognized as an important aspect of progression., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.L. has nothing to disclose. S.S. has received compensation for lectures from Novartis and Merck and has served on scientific advisory boards for Merck. M.A. has received compensation for lectures and/or advisory boards from Biogen, Genzyme and Novartis. I.R. has received compensation for lectures from Biogen, Novartis, Merck and Sanofi and has served on advisory boards for Sanofi. J.L. has received travel support and/or lecture honoraria and has served on scientific advisory boards for Alexion, Biogen, Bristol Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche and Sanofi and has received unconditional research grants from Biogen and Novartis, and financial support from Sanofi for an investigator-initiated study. L.N. has received lecture honoraria from Biogen, Novartis, Teva, Sanofi, Merck and has served on advisory boards for Merck, Janssen and Sanofi.

Background: Serum neurofilament light (sNfL) reflects neuroaxonal damage and is now used as an outcome in treatment trials of relapsing-remitting multiple sclerosis (RRMS). However, the diagnostic properties of sNfL for monitoring disease activity in individual patients warrant further investigations., Method: Patients with suspected relapse and/or contrast-enhancing lesions (CELs) were consecutively included and performed magnetic resonance imaging (MRI) of the brain at baseline and weeks 28 and 48. Serum was obtained at baseline and 2, 4, 8, 16, 24, and 48 weeks. Neurofilament light concentration was measured using Single molecule array technology., Results: We included 44 patients, 40 with RRMS and 4 with clinically isolated syndrome. The median sNfL level peaked at 2 weeks post-baseline (14.6 ng/L, interquartile range (IQR); 9.3-31.6) and reached nadir at 48 weeks (9.1 ng/L, IQR; 5.5-15.0), equivalent to the median sNfL of controls (9.1 ng/L, IQR; 7.4-12). A baseline Z -score of more than 1.1 (area under the curve; 0.78, p < 0.0001) had a sensitivity of 81% and specificity of 70% to detect disease activity., Conclusion: One out of five patients with relapse and/or CELs did not change significantly in post-baseline sNfL levels. The utility of repeated sNfL measurements to monitor disease activity is complementary rather than a substitute for clinical and MRI measures., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CM has received compensation for lectures and serving on advisory board for Novartis, Sanofi-Aventis, Roche, and Merck. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, and Roche; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). IR has received compensation for lectures from Biogen, Novartis, and Sanofi, and has served on advisory boards for Sanofi. JL has received travel support and/or lecture honoraria and has served on scientific advisory boards for Alexion, Almirall, Biogen, Bristol Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; and has received unconditional research grants from Biogen and Novartis, and financial support from Sanofi for an investigator-initiated study. KB has served as a consultant and at advisory boards for Acumen, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai, and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. LN has received lecture honoraria from Biogen, Novartis, Teva, Sanofi, and Merck and has served on advisory boards for Merck, Janssen, and Sanofi. MA has received compensation for lectures and/or advisory boards from Biogen, Genzyme, and Novartis. SS has received compensation for lectures and/or advisory board membership from Merck. HF has nothing to declare. MJ has nothing to declare. TS has nothing to declare.

Background: Neurofilament light (NFL) has been increasingly recognized for prognostic and therapeutic decisions., Objective: To validate the utility of cerebrospinal fluid NFL (cNFL) as a biomarker in clinical practice of relapsing-remitting multiple sclerosis (RRMS)., Methods: RRMS patients ( n  = 757) who had cNFL analyzed as part of the diagnostic work-up in a single academic multiple sclerosis (MS) center, 2001-2018, were retrospectively identified. cNFL concentrations were determined with two different immunoassays and the ratio of means between them was used for normalization., Results: RRMS with relapse had 4.4 times higher median cNFL concentration (1134 [interquartile range (IQR) 499-2744] ng/L) than those without relapse (264 [125-537] ng/L, p  < 0.001) and patients with gadolinium-enhancing lesions had 3.3 times higher median NFL (1414 [606.8-3210] ng/L) than those without (426 [IQR 221-851] ng/L, p  < 0.001). The sensitivity and specificity of cNFL to detect disease activity was 75% and 98.5%, respectively. High cNFL at MS onset predicted progression to Expanded Disability Status Scale (EDSS) ⩾ 3 ( p  < 0.001, hazard ratios (HR) = 1.89, 95% CI = 1.44-2.65) and conversion to secondary progressive MS (SPMS, p  = 0.001, HR = 2.5, 95% CI = 1.4-4.2)., Conclusions: cNFL is a robust and reliable biomarker of disease activity, treatment response, and prediction of disability and conversion from RRMS to SPMS. Our data suggest that cNFL should be included in the assessment of patients at MS-onset.

Background: The disease-modifying therapies (DMTs) in relapsing-remitting multiple sclerosis (RRMS) vary in their mode of action and when therapies are changed, the consequences on inflammatory and degenerative processes are largely unknown., Objective: We investigated the effect of switching from other DMTs to fingolimod on cerebrospinal fluid (CSF) biomarkers., Methods: 43 RRMS patients were followed up after 4-12 months of fingolimod treatment. Concentrations of C-X-C motif chemokine 13 (CXCL13), chemokine (C-C motif) ligand 2 (CCL2), chitinase-3-like protein 1 (CHI3L1), glial fibrillary acidic protein (GFAP), neurofilament light protein (NFL), and neurogranin (NGRN) were analyzed by enzyme-linked immunosorbent assay (ELISA), while chitotriosidase (CHIT1) was analyzed by spectrofluorometry., Results: The levels of NFL, CXCL13, and CHI3L1 decreased ( p < 0.05) after fingolimod treatment. Subgroup analysis revealed a reduction in NFL ( p < 0.001), CXCL13 ( p = 0.001), CHI3L1 ( p < 0.001), and CHIT1 ( p = 0.002) in patients previously treated with first-line therapies. In contrast, the levels of all analyzed biomarkers were essentially unchanged in patients switching from natalizumab., Conclusion: We found reduced inflammatory activity (CXCL13, CHI3L1, and CHIT1) and reduced axonal damage (NFL) in patients switching from first-line DMTs to fingolimod. Biomarker levels in patients switching from natalizumab indicate similar effects on inflammatory and degenerative processes. The CSF biomarkers provide an additional measure of treatment efficacy.

Background: Microglia-mediated proteolysis of the triggering receptor expressed on myeloid cells-2 (TREM-2) produces soluble TREM-2 (sTREM-2) that can be measured in cerebrospinal fluid (CSF) samples. Loss-of-function mutations in TREM2 or in the gene encoding its adaptor protein cause the rare Nasu-Hakola disease (NHD). Multiple sclerosis (MS) is an autoimmune disease that in common with NHD is characterized by demyelination and microglial activation., Objective: To investigate the potential utility of sTREM-2 as a biomarker for MS and to follow treatment effects., Methods: sTREM-2 was analyzed in CSF samples from subjects with MS (N = 59); relapsing-remitting MS (RRMS) (N = 36), secondary progressive MS (SPMS) (N = 20) and primary progressive MS (PPMS) (N = 3), and controls (N = 27). CSF levels of sTREM-2 were also assessed before and after treatment of patients with natalizumab or mitoxantrone., Results: CSF levels of sTREM-2 were significantly increased in patients with RRMS, SPMS, and PPMS compared with controls. After natalizumab treatment, the levels of sTREM-2 were normalized to control levels. The levels of sTREM-2 were also reduced after mitoxantrone treatment., Conclusion: Increased CSF levels of sTREM-2, a new marker of microglial activation, in MS and normalization upon treatment with either natalizumab or mitoxantrone support a role for microglial activation in active MS., (© The Author(s), 2016.)

The proportion of patients with clinically isolated syndrome (CIS) reported to convert to clinically definite multiple sclerosis varied between 30 and 75%. We studied the lifetime probability of remaining in the "CIS only" condition. The study was based on the longitudinally followed Gothenburg 1950-1964 incidence cohort (n = 306). Survival analysis revealed that 17.8% of 236 attack onset patients remained "CIS only". Patients with afferent (optic and sensory) symptoms had a better prognosis with approximately 30% of these patients remaining "CIS only". Patients who had experienced no relapse during the first 25 years remained "CIS only" for the subsequent 25 years of follow-up.

Stenosis is the most frequent vascular access complication and is responsible for access thrombosis and thus long-term patency limitation. Regular arteriovenous graft (AVG) examination by ultrasonography and preemptive balloon angioplasty prolong AVG cumulative patency according to some, but by far not all trials. This was why the routine use of ultrasound surveillance is not recommended recently.In this review we show huge differences in the definition of stenosis significance among the trials and other probable factors, which may have caused the contradiction of the results. Without precise definition of stenosis significance, many AVGs have been undergoing unnecessary balloon interventions with high morbidity, high cost and low benefit.