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| 2. |
- Kuhle, J., et al.
(author)
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Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study
- 2015
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In: Multiple Sclerosis Journal. - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 21:8, s. 1013-1024
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Journal article (peer-reviewed)abstract
- Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.
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- Coles, AJ, et al.
(author)
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Autoimmunity and long-term safety and efficacy of alemtuzumab for multiple sclerosis: Benefit/risk following review of trial and post-marketing data
- 2022
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In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 28:5, s. 842-846
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Journal article (peer-reviewed)abstract
- Does preexisting or treatment-emergent autoimmunity increase the risk of subsequent autoimmune disease in individuals with relapsing-remitting multiple sclerosis (MS) after alemtuzumab? In the extended phase 2/3 trials, 34/96 (35.4%) patients with and 395/1120 (35.3%) without preexisting autoimmunity developed non-MS autoimmunity. Thyroid autoimmunity after alemtuzumab courses 1 or 2 did not increase subsequent non-thyroid autoimmune adverse events. Therefore, autoimmune disease before or after alemtuzumab treatment does not predict autoimmunity after further courses, so should not preclude adequate alemtuzumab dosing to control MS. Finally, post-marketing safety data contribute toward a full record of the alemtuzumab benefit/risk profile for the MS field.
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- Giovannoni, G., et al.
(author)
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Smouldering multiple sclerosis: the ‘real MS’
- 2022
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In: Therapeutic Advances in Neurological Disorders. - : SAGE Publications. - 1756-2856 .- 1756-2864. ; 15
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Journal article (peer-reviewed)abstract
- Using a philosophical approach or deductive reasoning, we challenge the dominant clinico-radiological worldview that defines multiple sclerosis (MS) as a focal inflammatory disease of the central nervous system (CNS). We provide a range of evidence to argue that the ‘real MS’ is in fact driven primarily by a smouldering pathological disease process. In natural history studies and clinical trials, relapses and focal activity revealed by magnetic resonance imaging (MRI) in MS patients on placebo or on disease-modifying therapies (DMTs) were found to be poor predictors of long-term disease evolution and were dissociated from disability outcomes. In addition, the progressive accumulation of disability in MS can occur independently of relapse activity from early in the disease course. This scenario is underpinned by a more diffuse smouldering pathological process that may affect the entire CNS. Many putative pathological drivers of smouldering MS can be potentially modified by specific therapeutic strategies, an approach that may have major implications for the management of MS patients. We hypothesise that therapeutically targeting a state of ‘no evident inflammatory disease activity’ (NEIDA) cannot sufficiently prevent disability accumulation in MS, meaning that treatment should also focus on other brain and spinal cord pathological processes contributing to the slow loss of neurological function. This should also be complemented with a holistic approach to the management of other systemic disease processes that have been shown to worsen MS outcomes. © The Author(s), 2022.
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| 13. |
- Hobart, J, et al.
(author)
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International consensus on quality standards for brain health-focused care in multiple sclerosis
- 2019
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In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 25:13, s. 1809-1818
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Journal article (peer-reviewed)abstract
- Time matters in multiple sclerosis (MS). Irreversible neural damage and cell loss occur from disease onset. The MS community has endorsed a management strategy of prompt diagnosis, timely intervention and regular proactive monitoring of treatment effectiveness and disease activity to improve outcomes in people with MS. Objectives: We sought to develop internationally applicable quality standards for timely, brain health–focused MS care. Methods: A panel of MS specialist neurologists participated in an iterative, online, modified Delphi process to define ‘core’, ‘achievable’ and ‘aspirational’ time frames reflecting minimum, good and high care standards, respectively. A multidisciplinary Reviewing Group (MS nurses, people with MS, allied healthcare professionals) provided insights ensuring recommendations reflected perspectives from multiple stakeholders. Results: Twenty-one MS neurologists from 19 countries reached consensus on most core (25/27), achievable (25/27) and aspirational (22/27) time frames at the end of five rounds. Agreed standards cover six aspects of the care pathway: symptom onset, referral and diagnosis, treatment decisions, lifestyle, disease monitoring and managing new symptoms. Conclusion: These quality standards for core, achievable and aspirational care provide MS teams with a three-level framework for service evaluation, benchmarking and improvement. They have the potential to produce a profound change in the care of people with MS.
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- Lim, ET, et al.
(author)
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Cerebrospinal fluid levels of brain specific proteins in optic neuritis
- 2004
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In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 10:3, s. 261-265
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Journal article (peer-reviewed)abstract
- This study evaluates levels of cerebrospinal fluid (C SF) brain-specific proteins (BSP) in subjects with optic neuritis (O N) who are at high risk of progression to multiple sclerosis (MS). Forty-one subjects had acute O N and 17 subjects with other neurological diseases (OND) served as controls. Twenty-o ne subjects with O N had white matter lesions on magnetic resonance imaging (MRI) and intrathecal synthesis of oligoclonal IgG bands (OB) consistent with being at high risk of progression to MS; eight of whom later were diagnosed with clinically definite MS (C DMS). Levels of S100B, ferritin and two neurofilament heavy chain phosphoforms (NfHSMI34 and NfHSMI35) were analysed using ELISA technique. A putative index of ‘axonal health’ was expressed as a ratio of NfHSMI34 to NfHSMI35. NfHSMI34 and the NfHSMI34:SMI35 were significantly elevated in subjects with O N compared to controls. No significant differences in levels of C SF BSP were seen between O N subjects with C DMS plus those at high risk of progression to MS and O N subjects with normal MRI and negative C SF analysis. In conclusion, there is evidence of axonal damage in subjects who present with O N, which is independent of the diagnosis of C DMS.
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| 16. |
- Sorensen, PS, et al.
(author)
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Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab
- 2012
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In: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 18:2, s. 143-152
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Journal article (peer-reviewed)abstract
- Natalizumab is a highly effective immunomodulator in the treatment of multiple sclerosis (MS). Treatment with natalizumab has been associated with progressive multifocal leukoencephalopathy (PML), an infection of the central nervous system (CNS) caused by a pathogenic form of the normally benign JC virus (JCV). We searched PubMed and used current data from the natalizumab global safety database to assess risk factors and quantify the risk of PML. Natalizumab treatment duration and prior use of immunosuppressive therapies are established risk factors for development of PML in natalizumab-treated patients. With the development of a reliable and validated assay for detection of antibodies in patients with MS directed against JCV, it is now possible to identify persons who are carriers of JCV. The availability of this assay provides an additional option for risk stratification of PML in patients using or considering natalizumab therapy. Recommendations for clinical management of patients with MS and use of natalizumab are provided based on the presence of these three risk factors. The identification of risk factors that increase the likelihood of PML in natalizumab-treated patients can facilitate benefit–risk discussions between health care professionals and patients. Continued research and data collection will further develop our understanding of PML and the mechanisms by which these risk factors contribute to its development.
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| 18. |
- Wilson, D., et al.
(author)
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Development and multi-center validation of a fully automated digital immunoassay for neurofilament light chain: toward a clinical blood test for neuronal injury
- 2024
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In: Clinical Chemistry and Laboratory Medicine. - 1434-6621 .- 1437-4331. ; 62:2, s. 322-331
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Journal article (peer-reviewed)abstract
- Objectives Neurofilament light chain (NfL) has emerged as a promising biomarker for detecting and monitoring axonal injury. Until recently, NfL could only be reliably measured in cerebrospinal fluid, but digital single molecule array (Simoa) technology has enabled its precise measurement in blood samples where it is typically 50-100 times less abundant. We report development and multi-center validation of a novel fully automated digital immunoassay for NfL in serum for informing axonal injury status.Methods A 45-min immunoassay for serum NfL was developed for use on an automated digital analyzer based on Simoa technology. The analytical performance (sensitivity, precision, reproducibility, linearity, sample type) was characterized and then cross validated across 17 laboratories in 10 countries. Analytical performance for clinical NfL measurement was examined in individual patients with relapsing remitting multiple sclerosis (RRMS) after 3 months of disease modifying treatment (DMT) with fingolimod.Results The assay exhibited a lower limit of detection (LLoD) of 0.05 ng/L, a lower limit of quantification (LLoQ) of 0.8 ng/L, and between-laboratory imprecision <10 % across 17 validation sites. All tested samples had measurable NfL concentrations well above the LLoQ. In matched pre-post treatment samples, decreases in NfL were observed in 26/29 RRMS patients three months after DMT start, with significant decreases detected in a majority of patients.Conclusions The sensitivity characteristics and reproducible performance across laboratories combined with full automation make this assay suitable for clinical use for NfL assessment, monitoring in individual patients, and cross-comparisons of results across multiple sites.
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| 19. |
- Axelsson, Markus, 1975, et al.
(author)
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Cerebrospinal fluid NCAM levels are modulated by disease-modifying therapies
- 2019
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In: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 139:5, s. 411-427
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Journal article (peer-reviewed)abstract
- Background: Little is known about what leads to recovery between relapses in multiple sclerosis (MS), particularly following treatment. In the past, it has been demonstrated that soluble neural cell adhesion molecule (sNCAM), a putative biomarker of neuroplasticity, increased following steroid treatment in the Cerebrospinal fluid (CSF) of MS subjects undergoing acute relapses. Taking this a step further, we have evaluated the effect of disease-modifying treatment (DMTs) on CSF sNCAM levels in various subtypes of MS. Methods: We measured CSF sNCAM levels at baseline and after 12-24months of DMT in 69 patients, 49 relapsing-remitting MS (RRMS), 20 progressive MS(PMS), and 24 healthy controls (HC) using an in-house ELISA. Of this, 31 patients had received natalizumab, 17 mitoxantrone, and 21 fingolimod. Changes in disability were measured using EDSS and disease severity by MSSS. In conjunction, CSF NfL levels were also measured. Results: At baseline, the mean sNCAM level was 268.7ng/mL (SD: 109ng/mL) in MS patients compared with 340.6ng/ml (SD: 139ng/mL) in HC, and PMS had significantly lower sNCAM (239.2ng/mL, SD: 123.0, P=0.019) compared to RRMS (269.4, SD: 127.4, P=0.043). After natalizumab and mitoxantrone treatments, we observed an increase in mean sNCAM. However, in the fingolimod-treated group, mean sNCAM decreased. There was no correlation found with EDSS or MSSS, or NfL levels as a whole. Conclusions: Cerebrospinal fluid sNCAM levels were found to be lower in MS than in HC and the lowest sNCAM levels were found in PMS. Following natalizumab and mitoxantrone treatments, we observed an elevation in sNCAM levels, an effect that was not observed following fingolimod treatment. These changes, however, did not appear to correlate with disability in the short-term or NfL levels. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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| 22. |
- Jiang, X. T., et al.
(author)
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Glial fibrillary acidic protein and multiple sclerosis progression independent of acute inflammation
- 2023
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In: Multiple Sclerosis Journal. - 1352-4585. ; 29:9
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Journal article (peer-reviewed)abstract
- Background: The clinical relevance of serum glial fibrillary acidic protein (sGFAP) concentration as a biomarker of MS disability progression independent of acute inflammation has yet to be quantified. Objective: To test whether baseline values and longitudinal changes in sGFAP concentration are associated with disability progression without detectable relapse of magnetic resonance imaging (MRI) inflammatory activity in participants with secondary-progressive multiple sclerosis (SPMS). Methods: We retrospectively analyzed longitudinal sGFAP concentration and clinical outcome data from the Phase 3 ASCEND trial of participants with SPMS, with no detectable relapse or MRI signs of inflammatory activity at baseline nor during the study (n = 264). Serum neurofilament (sNfL), sGFAP, T2 lesion volume, Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), and composite confirmed disability progression (CDP) were measured. Linear and logistic regressions and generalized estimating equations were used in the prognostic and dynamic analyses. Results: We found a significant cross-sectional association between baseline sGFAP and sNfL concentrations and T2 lesion volume. No or weak correlations between sGFAP concentration and changes in EDSS, T25FW, and 9HPT, or CDP were observed. Conclusion: Without inflammatory activity, changes in sGFAP concentration in participants with SPMS were neither associated with current nor predictive of future disability progression.
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| 23. |
- Kuhle, J, et al.
(author)
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Neurofilament light and heavy subunits compared as therapeutic biomarkers in multiple sclerosis
- 2013
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In: Acta neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 128:6
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Journal article (peer-reviewed)abstract
- Neurofilaments are promising biomarkers in multiple sclerosis (MS) and increased levels in cerebrospinal fluid (CSF) indicate axonal damage or degeneration. In a previous study, neurofilament light chain (NfL) levels in CSF of relapsing remitting (RR) patients with MS were normalized by natalizumab treatment.We compared the coherence between NfL and neurofilament heavy chain (NfH(SMI) (35) ) levels in longitudinal CSF samples in a subset of these patients.In 30 patients with RRMS, CSF was obtained prior to and following 12months of natalizumab treatment. NfH(SMI) (35) was measured by an electrochemiluminescence-based immunoassay. NfL levels were determined previously by the UmanDiagnostics NF-light(®) assay.NfH(SMI) (35) decreased in 73.3% and NfL in 90% of the patients following natalizumab treatment (32.4 vs 27.4pg/ml, P=0.002 and 820 vs 375pg/ml, P<0.0001). Patients experiencing a relapse showed higher NfH(SMI) (35) levels compared with patients in remission (47.7 vs 27.6pg/ml, n=8, P=0.001). This difference was less obvious for NfL (1055 vs 725pg/ml, P=0.256). In patients in remission, NfL levels were lower following natalizumab treatment (830 vs 365pg/ml, n=20, P=0.0002), whereas the same comparison failed significance for NfH(SMI) (35) (28.3 vs 26.9pg/ml, P=0.086).We confirm previous findings, indicating reduced axonal damage under natalizumab treatment by measuring NfH(SMI) (35) , using an assay with independent methodology. In comparison with NfH(SMI) (35) , NfL changes were more pronounced and the treatment effect also included patients in remission. Our results suggest that NfL is superior over NfH(SMI) (35) as therapeutic biomarker and is a promising candidate to measure neuroaxonal damage in MS treatment trials.
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| 24. |
- Raftopoulos, R., et al.
(author)
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Neurofilament results for the phase II neuroprotection study of phenytoin in optic neuritis
- 2021
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In: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 28:2, s. 587-594
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Journal article (peer-reviewed)abstract
- Background A randomized trial of phenytoin in acute optic neuritis (ON) demonstrated a 30% reduction in retinal nerve fiber layer (RNFL) loss with phenytoin versus placebo. Here we present the corresponding serum neurofilament analyses. Methods Eighty-six acute ON cases were randomized to receive phenytoin (4-6 mg/kg/day) or placebo for 3 months, and followed up for 6 months. Serum was collected at baseline, 3 and 6 months for analysis of neurofilament heavy chain (NfH) and neurofilament light chain (NfL). Results Sixty-four patients had blood sampling. Of these, 58 and 56 were available at 3 months, and 55 and 54 were available at 6 months for NfH and NfL, respectively. There was no significant correlation between serum NfH and NfL at the time points tested. For NfH, the difference in mean placebo - phenytoin was -44 pg/ml at 3 months (P = 0.019) and -27 pg/ml at 6 months (P = 0.234). For NfL, the difference was 1.4 pg/ml at 3 months (P = 0.726) and -1.6 pg/ml at 6 months (P = 0.766). Conclusions At 3 months, there was a reduction in NfH, but not NFL, in the phenytoin versus placebo group, while differences at 6 months were not statistically significant. This suggests a potential neuroprotective role for phenytoin in acute ON, with the lower NfH at 3 months, when levels secondary to degeneration of the anterior visual pathway are still elevated, but not at 6 months, when levels have normalized.
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