Clinical impact of gender and age at onset on disease trajectory in primary progressive multiple sclerosis patients.

BACKGROUND AND OBJECTIVES: Primary-progressive multiple sclerosis (PPMS) is characterized by gradual neurological deterioration without relapses. This study aimed to investigate the clinical impact of gender and age at disease onset on disease progression and disability accumulation in patients with this disease phenotype. METHODS: Secondary data from the RelevarEM registry, a longitudinal database in Argentina, were analyzed. The cohort comprised patients with PPMS who met inclusion criteria. Statistical analysis with multilevel Bayesian robust regression modeling was conducted to assess the associations between gender, age at onset, and Expanded Disability Status Scale (EDSS) score trajectories. RESULTS: We identified 125 patients with a confirmed diagnosis of PPMS encompassing a total of 464 observations. We found no significant differences in EDSS scores after 10 years of disease progression between genders (-0.08; credible interval (CI): -0.60, 0.42). A 20-year difference in age at onset did not show significant differences in EDSS score after 10 years of disease progression (0.281; CI: -0.251, 0.814). Finally, we also did not find any clinically relevant difference between gender EDSS score with a difference of 20 years in age at onset (-0.021; CI: -0.371, 0.319). CONCLUSION: Biological plausibility of gender and age effects does not correlate with clinical impact measured by EDSS score.

Analysis of potential microRNA biomarkers for multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating autoimmune neurodegenerative disorder for which no specific blood biomarker is available. MicroRNAs (miRNAs) have been investigated for their diagnostic potential in MS. However, MS-associated miRNAs are rarely replicated in different MS populations, thus impeding their use in clinical testing. Here, we evaluated the fold expression of seven reported MS miRNAs associated with MS incidence and clinical characteristics in 76 MS patients and 75 healthy control plasma samples. We found miR-23a-3p to be upregulated in relapsing-remitting MS (RRMS), while miR-326 was downregulated. MiR-150-5p and -320a-3p were significantly downregulated in secondary progressive MS (SPMS) patients compared to RRMS. High disability was associated with low miR-320a-3p, whereas low BDNF levels were associated with upregulation of miR-150-5p and downregulation of miR-326 expression in the total cohort. MiR-23a-3p and miR-326 showed significant diagnostic sensitivity, specificity, and accuracy for RRMS diagnosis. In addition, miR-150-5p and miR-320a-3p had comparable significant diagnostic test performance metrics distinguishing SPMS from RRMS. Therefore, there is potential for including miR-23a-3p and miR-326 in an RRMS diagnostic miRNA panel. Moreover, we have shown that miR-150-5p and miR-320a-3p could be novel RRMS conversion to SPMS biomarkers. The use of these miRNAs in MS diagnosis and prognosis warrants further investigation.

Multiple Sclerosis: An Emergency Medicine-Focused Narrative Review.

BACKGROUND: Multiple sclerosis (MS) is a rare but serious condition associated with significant morbidity. OBJECTIVE: This review provides a focused assessment of MS for emergency clinicians, including the presentation, evaluation, and emergency department (ED) management based on current evidence. DISCUSSION: MS is an autoimmune disorder targeting the central nervous system (CNS), characterized by clinical relapses and radiological lesions disseminated in time and location. Patients with MS most commonly present with long tract signs (e.g., myelopathy, asymmetric spastic paraplegia, urinary dysfunction, Lhermitte's sign), optic neuritis, or brainstem syndromes (bilateral internuclear ophthalmoplegia). Cortical syndromes or multifocal presentations are less common. Radiologically isolated syndrome and clinically isolated syndrome (CIS) may or may not progress to chronic forms of MS, including relapsing remitting MS, primary progressive MS, and secondary progressive MS. The foundation of outpatient management involves disease-modifying therapy, which is typically initiated with the first signs of disease onset. Management of CIS and acute flares of MS in the ED includes corticosteroid therapy, ideally after diagnostic testing with imaging and lumbar puncture for cerebrospinal fluid analysis. Emergency clinicians should evaluate whether patients with MS are presenting with new-onset debilitating neurological symptoms to avoid unnecessary testing and admissions, but failure to appropriately diagnose CIS or MS flare is associated with increased morbidity. CONCLUSIONS: An understanding of MS can assist emergency clinicians in better diagnosing and managing this neurologically devastating disease.

Primary Progressive Multiple Sclerosis-A Key to Understanding and Managing Disease Progression.

Primary progressive multiple sclerosis (PPMS), the least frequent type of multiple sclerosis (MS), is characterized by a specific course and clinical symptoms, and it is associated with a poor prognosis. It requires extensive differential diagnosis and often a long-term follow-up before its correct recognition. Despite recent progress in research into and treatment for progressive MS, the diagnosis and management of this type of disease still poses a challenge. Considering the modern concept of progression "smoldering" throughout all the stages of disease, a thorough exploration of PPMS may provide a better insight into mechanisms of progression in MS, with potential clinical implications. The goal of this study was to review the current evidence from investigations of PPMS, including its background, clinical characteristics, potential biomarkers and therapeutic opportunities. Processes underlying CNS damage in PPMS are discussed, including chronic immune-mediated inflammation, neurodegeneration, and remyelination failure. A review of potential clinical, biochemical and radiological biomarkers is presented, which is useful in monitoring and predicting the progression of PPMS. Therapeutic options for PPMS are summarized, with approved therapies, ongoing clinical trials and future directions of investigations. The clinical implications of findings from PPMS research would be associated with reliable assessments of disease outcomes, improvements in individualized therapeutic approaches and, hopefully, novel therapeutic targets, relevant for the management of progression.

Granzyme B + CD8 + T cells with terminal differentiated effector signature determine multiple sclerosis progression.

BACKGROUND: Multiple sclerosis (MS) leads to demyelination and neurodegeneration with autoimmune responses in central nervous system. Patients begin with a relapsing-remitting (RR) course, and more than 80% of them may advance to secondary progressive MS (SPMS), which is characteristic for the gradual decline of neurological functions without demonstrated treating method to prevent. This study aims to investigate the contribution of peripheral CD8 + T cells during the conversion from RRMS to SPMS, as well as reveal potential diagnostic signature in distinguishing SPMS. METHODS: Single-cell RNA sequencing was employed to reveal the heterogeneity of CD8 + T cells between SPMS and RRMS. In addition, flow cytometry was used to further characterized CD8 + T cell dynamic changes in patients. T cell receptor sequencing was performed to detect the clonal expansion of MS. Using Tbx21 siRNA, T-bet was confirmed to manipulate GzmB expression. The correlation between GzmB + CD8 + T cell subsets and clinical characteristics of MS and their potential diagnostic value for SPMS were evaluated by generalized linear regression models and receiver operating characteristic (ROC) curve respectively. RESULTS: Other than diminished naïve CD8 + T cell, elevating of activated CD8 + T cell subsets were observed in SPMS patients. Meanwhile, this aberrant amplified peripheral CD8 + T cells not only exhibited terminal differentiated effector (EMRA) phenotype with GzmB expression, but also possessed distinct trajectory from clonal expansion. In addition, T-bet acted as a key transcriptional factor that elicited GzmB expression in CD8 + TEMRA cells of patients with SPMS. Finally, the expression of GzmB in CD8 + T cells was positively correlated with disability and progression of MS, and could effectively distinguish SPMS from RRMS with a high accuracy. CONCLUSIONS: Our study mapped peripheral immune cells of RRMS and SPMS patients and provided an evidence for the involvement of GzmB + CD8 + TEMRA cells in the progression of MS, which could be used as a diagnostic biomarker for distinguishing SPMS from RRMS.

Early Predictors of Clinical and MRI Outcomes Using Least Absolute Shrinkage and Selection Operator (LASSO) in Multiple Sclerosis.

OBJECTIVE: The objective of this study was to identify predictors in common between different clinical and magnetic resonance imaging (MRI) outcomes in multiple sclerosis (MS) by comparing predictive models. METHODS: We analyzed 704 patients from our center seen at MS onset, measuring 37 baseline demographic, clinical, treatment, and MRI predictors, and 10-year outcomes. Our primary aim was identifying predictors in common among clinical outcomes: aggressive MS, benign MS, and secondary-progressive (SP)MS. We also investigated MRI outcomes: T2 lesion volume (T2LV) and brain parenchymal fraction (BPF). The performance of the full 37-predictor model was compared with a least absolute shrinkage and selection operator (LASSO)-selected model of predictors in common between each outcome by the area under the receiver operating characteristic curves (AUCs). RESULTS: The full 37-predictor model was highly predictive of clinical outcomes: in-sample AUC was 0.91 for aggressive MS, 0.81 for benign MS, and 0.81 for SPMS. After variable selection, 10 LASSO-selected predictors were in common between each clinical outcome: age, Expanded Disability Status Scale, pyramidal, cerebellar, sensory and bowel/bladder signs, timed 25-foot walk ≥6 seconds, poor attack recovery, no sensory attacks, and time-to-treatment. This reduced model had comparable cross-validation AUC as the full 37-predictor model: 0.84 versus 0.81 for aggressive MS, 0.75 versus 0.73 for benign MS, and 0.76 versus 0.75 for SPMS, respectively. In contrast, 10-year MRI outcomes were more strongly influenced by initial T2LV and BPF than clinical outcomes. INTERPRETATION: Early prognostication of MS is possible using LASSO modeling to identify a limited set of accessible clinical features. These predictive models can be clinically usable in treatment decision making once implemented into web-based calculators. ANN NEUROL 2022;92:87-96.

Threshold definitions for significant change on the timed 25-foot walk and nine-hole peg test in primary progressive multiple sclerosis.

BACKGROUND AND PURPOSE: The timed 25-foot walk (T25FW) and nine-hole peg test (NHPT) exhibit random variability in the short term. A threshold of ≥20% change from baseline has been used to indicate true disability change, but other threshold definitions may be better suited to exclude false and include true change events. The aim of this study was to use patient-level original trial data to investigate the short-term variation in T25FW and NHPT, and to compare its extent with disability change at 12-month follow-up in people with primary progressive multiple sclerosis (PPMS). METHODS: We used original patient-level data from PROMISE, a large PPMS trial. In this trial, three separate T25FW and NHPT measurements were performed 1 week apart during screening. We used these repeated measures to describe the extent of short-term variation. We used binary logistic regression models to investigate the association between screening characteristics and unacceptable short-term variation. RESULTS: The traditional 20% threshold excluded a reasonable number of false change events, while also yielding a large number of change events at follow-up. Increasing index values on the T25FW and NHPT were associated with higher short-term variation. CONCLUSIONS: The traditional ≥20% change threshold for the T25FW and NHPT represents a reasonable compromise between reducing the number of false change events and achieving the largest number of change events in people with PPMS. Our analyses inform the design of clinical trials in PPMS.

Real-world challenges in the diagnosis of primary progressive multiple sclerosis.

BACKGROUND AND PURPOSE: Despite the 2017 revisions to the McDonald criteria, diagnosing primary progressive multiple sclerosis (PPMS) remains challenging. To improve clinical practice, the aim was to identify frequent diagnostic challenges in a real-world setting and associate these with the performance of the 2010 and 2017 PPMS diagnostic McDonald criteria. METHODS: Clinical, radiological and laboratory characteristics at the time of diagnosis were retrospectively recorded from designated PPMS patient files. Possible complicating factors were recorded such as confounding comorbidity, signs indicative of alternative diagnoses, possible earlier relapses and/or incomplete diagnostic work-up (no cerebrospinal fluid examination and/or magnetic resonance imaging brain and spinal cord). The percentages of patients fulfilling the 2010 and 2017 McDonald criteria were calculated after censoring patients with these complicating factors. RESULTS: A total of 322 designated PPMS patients were included. Of all participants, it was found that n = 28/322 had confounding comorbidity and/or signs indicative of alternative diagnoses, n = 103/294 had possible initial relapsing and/or uncertainly progressive phenotypes and n = 73/191 received an incomplete diagnostic work-up. When applying the 2010 and 2017 diagnostic PPMS McDonald criteria on n = 118 cases with a full diagnostic work-up and a primary progressive disease course without a better alternative explanation, these were met by 104/118 (88.1%) and 98/118 remaining patients (83.1%), respectively (p = 0.15). CONCLUSION: Accurate interpretation of the initial clinical course, consideration of alternative diagnoses and a full diagnostic work-up are the cornerstones of a PPMS diagnosis. When these conditions are met, the 2010 and 2017 McDonald criteria for PPMS perform similarly, emphasizing the importance of their appropriate application in clinical practice.

Rapid, non-contact multifocal visual assessment in multiple sclerosis.

OBJECTIVE: Previous work on temporally sparse multifocal methods suggests that the results are correlated with disability and progression in people with multiple sclerosis (PwMS). Here, we assess the diagnostic power of three cortically mediated sparse multifocal pupillographic objective perimetry (mfPOP) methods that quantified response-delay and light-sensitivity at up to 44 regions of both visual fields concurrently. METHODS: One high-spatial-resolution mfPOP method, P129, and two rapid medium-resolution methods, W12 and W20, were tested on 44 PwMS and controls. W12 and W20 took 82 s to test both visual fields concurrently, providing response delay and sensitivity at each field location, while P129 took 7 min. Diagnostic power was assessed using areas under the receiver operating characteristic (AUROC) curves and effect-size (Hedges' g). Linear models examined significance. Concurrent testing of both eyes permitted assessment of between-eye asymmetries. RESULTS: Per-region response delays and asymmetries achieved AUROCs of 86.6% ± 4.72% (mean ± SE) in relapsing-remitting MS, and 96.5% ± 2.30% in progressive MS. Performance increased with increasing disability scores, with even moderate EDSS 2 to 4.5 PwMS producing AUROCs of 82.1 to 89.8%, Hedge's g values up to 2.06, and p = 4.0e - 13. All tests performed well regardless of any history of optic neuritis. W12 and W20 performed as well or better than P129. CONCLUSION: Overall, the 82-s tests (W12 and W20) performed better than P129. The results suggest that mfPOP assesses a correlate of disease severity rather than a history of inflammation, and that it may be useful in the clinical management of PwMS.

Unmet needs and gaps in the identification of secondary progression in multiple sclerosis: a Southern Italy healthcare professionals' perspective.

OBJECTIVE: Multiple sclerosis (MS) is a chronic disease with different clinical courses and a tendency to worsening. The relapsing-remitting MS presents acute onset and relapses of neurological symptoms, followed by their remission. This form can convert to secondary progressive MS (SPMS) with irreversible neurological worsening and disability. The identification of signs, symptoms, markers of progression, and strategies to manage MS patients is mandatory to allow early identification of those at higher risk of conversion to SPMS, for prompt intervention to cope with the progression of the disease. METHODS: A panel of Italian experts from Southern Italy have reviewed the current knowledge on MS and its management and identified the crucial tools for SPMS recognition. RESULTS: More effective communication between patients and clinicians should be established, with the support of digital tools. Moreover, the improvement in the clinical use of biomarkers for progression (cellular structures and tissue organization, such as neurofilaments and chitinase 3-like 1, axonal and neurons density) and of instrumental analyses for recognition of whole-brain atrophy, chronic active lesions, spinal cord lesions and atrophy, and the improvement the combination of the Expanded Disability Status Scale and the evaluation of cognitive dysfunction are discussed. CONCLUSION: Given the availability of a pharmacological option, adequate education both for patients, regarding the evolution of the disease and the specific treatment, and for professionals, to allow more effective and sensitive communication and the best use of diagnostic and management tools, could represent a strategy to improve patient management and their quality of life.

Prognostic uncertainty in multiple sclerosis: A concept analysis.

AIM: To report an analysis of the concept of prognostic uncertainty in patients with multiple sclerosis (MS). BACKGROUND: The complexity and ambiguity involved in a diagnosis of MS lead to the occurrence of prognostic uncertainty among patients. A concept analysis is presented that analyses what prognostic uncertainty means to those experiencing the transition between relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis. DESIGN: Concept analysis. DATA SOURCES: PubMed, Ovid Medline, Cumulative Index for Nursing and Allied Health Literature databases were searched for literature published within the last 10 years using combinations of the terms prognostic and diagnostic uncertainty, and multiple sclerosis along with archival referencing. METHODS: The Walker and Avant method was used to analyse the concept of prognostic uncertainty in patients with MS. RESULTS: The defining attributes identified that provide additional context to prognostic uncertainty are illness uncertainty, intolerance of uncertainty and progressive dwindling. Related, contrary, model and borderline cases are presented to further discuss the application of the key attributes to the concept. CONCLUSION: There are limited data on prognostic uncertainty and multiple sclerosis; however, patients and physicians express uncertainty in understanding one's disease trajectory and determining when a patient with relapsing-remitting multiple sclerosis has entered the secondary progressive multiple sclerosis disease course leading to ineffective communication and frustration. RELEVANCE TO CLINICAL PRACTICE: Genetics and genomics have the potential to provide a prognostic factor for addressing the concept of uncertainty as it relates to persons with multiple sclerosis. Moving beyond the concept analysis, a case is made for nurse involvement in genetic and genomic research to conduct trials, translate, and apply these findings to clinical practice and nursing curricula, addressing the uncertainty experienced by those afflicted with chronic illnesses, such as multiple sclerosis.

Recent Progress in the Identification of Early Transition Biomarkers from Relapsing-Remitting to Progressive Multiple Sclerosis.

Despite extensive research into the pathophysiology of multiple sclerosis (MS) and recent developments in potent disease-modifying therapies (DMTs), two-thirds of relapsing-remitting MS patients transition to progressive MS (PMS). The main pathogenic mechanism in PMS is represented not by inflammation but by neurodegeneration, which leads to irreversible neurological disability. For this reason, this transition represents a critical factor for the long-term prognosis. Currently, the diagnosis of PMS can only be established retrospectively based on the progressive worsening of the disability over a period of at least 6 months. In some cases, the diagnosis of PMS is delayed for up to 3 years. With the approval of highly effective DMTs, some with proven effects on neurodegeneration, there is an urgent need for reliable biomarkers to identify this transition phase early and to select patients at a high risk of conversion to PMS. The purpose of this review is to discuss the progress made in the last decade in an attempt to find such a biomarker in the molecular field (serum and cerebrospinal fluid) between the magnetic resonance imaging parameters and optical coherence tomography measures.

Myelin Basic Protein in Oligodendrocyte-Derived Extracellular Vesicles as a Diagnostic and Prognostic Biomarker in Multiple Sclerosis: A Pilot Study.

Approximately 15% of multiple sclerosis (MS) patients develop a progressive form of disease from onset; this condition (primary progressive-PP) MS is difficult to diagnose and treat, and is associated with a poor prognosis. Extracellular vesicles (EVs) of brain origin isolated from blood and their protein cargoes could function as a biomarker of pathological conditions. We verified whether MBP and MOG content in oligodendrocytes-derived EVs (ODEVs) could be biomarkers of MS and could help in the differential diagnosis of clinical MS phenotypes. A total of 136 individuals (7 clinically isolated syndrome (CIS), 18 PPMS, 49 relapsing remitting (RRMS)) and 70 matched healthy controls (HC) were enrolled. ODEVs were enriched from serum by immune-capture with anti-MOG antibody; MBP and MOG protein cargoes were measured by ELISA. MBP concentration in ODEVs was significantly increased in CIS (p < 0.001), RRMS (p < 0.001) and PPMS (p < 0.001) compared to HC and was correlated with disease severity measured by EDSS and MSSS. Notably, MBP concentration in ODEVs was also significantly augmented in PPMS compared to RRMS (p = 0.004) and CIS (p = 0.03). Logistic regression and ROC analyses confirmed these results. A minimally invasive blood test measuring the concentration of MBP in ODEVs is a promising tool that could facilitate MS diagnosis.

Brain volume loss in multiple sclerosis is independent of disease activity and might be prevented by early disease-modifying therapy.

INTRODUCTION: Neurodegeneration is likely to be present from the earliest stages of multiple sclerosis (MS). MS responds poorly to disease-modifying treatments (DMTs) and leads to irreversible brain volume loss (BVL), which is a reliable predictor of future physical and cognitive disability. Our study aimed to discover the relationship between BVL, disease activity, and DMTs in a cohort of patients with MS. MATERIAL AND METHODS: A total of 147 patients fulfilled our inclusion criteria. Relevant demographic and clinical data (age, gender, time of MS onset, time of treatment initiation, DMT characteristics, Expanded Disability Status Scale (EDSS), number of relapses in the last two years prior to MRI examination) were correlated with MRI findings. RESULTS: Patients with progressive MS had significantly lower total brain and grey matter volumes (p = 0.003; p < 0.001), and higher EDSS scores (p < 0.001), compared to relapsing-remitting patients matched by disease duration and age. There was no association between MRI atrophy and MRI activity (c2 = 0.013, p = 0.910). Total EDSS negatively correlated with the whole brain (rs = -0.368, p < 0.001) and grey matter volumes (rs = -0.308, p < 0.001), but was not associated with the number of relapses in the last two years (p = 0.278). Delay in DMT negatively correlated with whole brain (rs = -0.387, p < 0.001) and grey matter volumes (rs = -0.377, p < 0.001). Treatment delay was connected with a higher risk for lower brain volume (b = -3.973, p < 0.001), and also predicted a higher EDSS score (b = 0.067, p < 0.001). CONCLUSIONS: Brain volume loss is a major contributor to disability progression, independent of disease activity. Delay in DMT leads to higher BVL and increased disability. Brain atrophy assessment should be translated into daily clinical practice to monitor disease course and response to DMTs. The assessment of BVL itself should be considered a suitable marker for treatment escalation.

THE RELATIONSHIP BETWEEN THE DURATION OF REMISSIONS AFTER THE ONSET, THE SEVERITY OF THE RELAPSES AGAINST THE BACKGROUND OF DIFFERENT DURATION OF THE RELAPSING STAGE AND THE NATURE OF THE PROGNOSIS IN SECONDARY-PROGRESSIVE MULTIPLE SCLEROSIS.

Work objective - to study the relationship between the duration of remission after the onset, the severity of relapses against the background of different duration of the relapsing stage (RS) and the nature of the prognosis in the secondary progressive multiple sclerosis (SPMS) using clinical and mathematical analysis. Patients with different prognosis for SPMS; neurological examination using The Expanded Disability Status Scale (EDSS); a survey method. Mathematical methods: 'contingency tables 2x2' (determining the significance of the connection between a pair of two indicators - different duration of remission after the onset and RS in four groups of patients), Yule's Coefficient of Association (determining the magnitude of differences between the group and the studied indicator), a permutation test (defining clinical indicators on RS, which significantly differed in mild and severe relapses). Pairwise comparison in four groups of patients with different duration of remission after the onset and RS in SPMS showed that long-term remission after the onset and prolonged RS delay the transition of RS into secondary progression (SP). Short duration of these indicators revealed the opposite prognostic tendencies, indicating the further progression of the disease. The presence of severe relapses on RS in SPMS is predominantly associated with unfavorable prognostic indicators on RS and indicates the initiation of the transition into SP. Accordingly, the duration of remission after the onset, the severity of relapses against the background of different durations of RS should be regarded as prognostic clinical markers that play a key role in the switch of RS to SPS in SPMS. The results obtained should be used to assess the current clinical situation and timely prescribe an appropriate pathogenetic therapy on RS.

Towards a validated definition of the clinical transition to secondary progressive multiple sclerosis: A study from the Italian MS Register.

BACKGROUND: Definitions for reliable identification of transition from relapsing-remitting multiple sclerosis (MS) to secondary progressive (SP)MS in clinical cohorts are not available. OBJECTIVES: To compare diagnostic performances of two different data-driven SPMS definitions. METHODS: Data-driven SPMS definitions based on a version of Lorscheider's algorithm (DDA) and on the EXPAND trial inclusion criteria were compared, using the neurologist's definition (ND) as gold standard, in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), Akaike information criterion (AIC) and area under the curve (AUC). RESULTS: A cohort of 10,240 MS patients with ⩾5 years of follow-up was extracted from the Italian MS Registry; 880 (8.5%) patients were classified as SPMS according to the neurologist definition, 1806 (17.6%) applying the DDA and 1134 (11.0%) with the EXPAND definition. The DDA showed greater discrimination power (AUC: 0.8 vs 0.6) and a higher sensitivity (77.1% vs 38.0%) than the EXPAND definition, with similar specificity (88.0% vs 91.5%). PPV and NPV were higher using the DDA than considering EXPAND definition (37.5% vs 29.5%; 97.6% vs 94.0%). CONCLUSION: Data-driven definitions demonstrated greater ability to capture SP transition than neurologist's definition and the global accuracy of DDA seems to be higher than the EXPAND definition.

Grey-matter sodium concentration as an individual marker of multiple sclerosis severity.

OBJECTIVE: Quantification of brain injury in patients with variable disability despite similar disease duration may be relevant to identify the mechanisms underlying disability in multiple sclerosis (MS). We aimed to compare grey-matter sodium abnormalities (GMSAs), a parameter reflecting neuronal and astrocyte dysfunction, in MS patients with benign multiple sclerosis (BMS) and non-benign multiple sclerosis (NBMS). METHODS: We identified never-treated BMS patients in our local MS database of 1352 patients. A group with NBMS was identified with same disease duration. All participants underwent 23Na magnetic resonance imaging (MRI). The existence of GMSA was detected by statistical analysis. RESULTS: In total, 102 individuals were included (21 BMS, 25 NBMS and 56 controls). GMSA was detected in 10 BMS and 19 NBMS (11/16 relapsing-remitting multiple sclerosis (RRMS) and 8/9 secondary progressive multiple sclerosis (SPMS) patients) (p = 0.05). On logistic regression including the presence or absence of GMSA, thalamic volume, cortical grey-matter volume and T2-weighted lesion load, thalamic volume was independently associated with BMS status (odds ratio (OR) = 0.64 for each unit). Nonetheless, the absence of GMSA was independently associated when excluding patients with significant cognitive alteration (n = 7) from the BMS group (OR = 4.6). CONCLUSION: Detection of GMSA in individuals and thalamic volume are promising to differentiate BMS from NBMS as compared with cortical or whole grey-matter atrophy and T2-weighted lesions.

Secondary progressive multiple sclerosis: A national consensus paper on diagnostic criteria.

BACKGROUND: In clinical practice, the diagnosis of secondary progressive multiple sclerosis (SPMS) is often delayed, retrospective and non-reproducible, as there are no consensus criteria that define the advent of SPMS. Early identification of SPMS is essential to improve patient care. METHODS: Eight regional board meetings in France involving 56 multiple sclerosis (MS) experts (neurologists) were convened to discuss diagnostic criteria for SPMS. Subsequently, a national board meeting of 13 neurologists (with an expert representing each geographical region) was held to review points of convergence or divergence between regions and to develop a national consensus document. RESULTS: Based on the discussions from the regional boards, the MS experts at the national board retained the worsening of the EDSS score, with compatible clinical features, as the only consensus criterion for the diagnosis of SPMS in clinical practice. The patient should have experienced during at least the previous 6 months and in the absence of any relapse, a worsening in the EDSS score of +1.0 point (if the previous EDSS was≤5.0) or of +0.5 point (if the previous EDSS was≥5.5), with a pyramidal or cerebellar functional system score≥2 and without setting a minimum EDSS score; or, in case of a stable EDSS score≥4.0, a worsening of a functional score. This worsening should be confirmed within 3 to 6 months. According to the MS experts, the patient's age, duration of illness and a minimal threshold EDSS score are only risk factors for transition to SPMS. Patient reports during consultation and cognitive impairment are important warning signs, which should trigger an objective assessment with specific tests or closer monitoring. Clinical relapse and/or MRI activities are non-discriminatory for making the diagnosis of SPMS. CONCLUSIONS: The experts defined precise diagnostic criteria adapted to clinical practice for earlier identification of SPMS, paving the way for better management of this stage of the disease.

N6-Methyladenosine RNA modification in cerebrospinal fluid as a novel potential diagnostic biomarker for progressive multiple sclerosis.

BACKGROUND: Progressive multiple sclerosis (PMS) is an uncommon and severe subtype of MS that worsens gradually and leads to irreversible disabilities in young adults. Currently, there are no applicable or reliable biomarkers to distinguish PMS from relapsing-remitting multiple sclerosis (RRMS). Previous studies have demonstrated that dysfunction of N6-methyladenosine (m6A) RNA modification is relevant to many neurological disorders. Thus, the aim of this study was to explore the diagnostic biomarkers for PMS based on m6A regulatory genes in the cerebrospinal fluid (CSF). METHODS: Gene expression matrices were downloaded from the ArrayExpress database. Then, we identified differentially expressed m6A regulatory genes between MS and non-MS patients. MS clusters were identified by consensus clustering analysis. Next, we analyzed the correlation between clusters and clinical characteristics. The random forest (RF) algorithm was applied to select key m6A-related genes. The support vector machine (SVM) was then used to construct a diagnostic gene signature. Receiver operating characteristic (ROC) curves were plotted to evaluate the accuracy of the diagnostic model. In addition, CSF samples from MS and non-MS patients were collected and used for external validation, as evaluated by an m6A RNA Methylation Quantification Kit and by real-time quantitative polymerase chain reaction. RESULTS: The 13 central m6A RNA methylation regulators were all upregulated in MS patients when compared with non-MS patients. Consensus clustering analysis identified two clusters, both of which were significantly associated with MS subtypes. Next, we divided 61 MS patients into a training set (n = 41) and a test set (n = 20). The RF algorithm identified eight feature genes, and the SVM method was successfully applied to construct a diagnostic model. ROC curves revealed good performance. Finally, the analysis of 11 CSF samples demonstrated that RRMS samples exhibited significantly higher levels of m6A RNA methylation and higher gene expression levels of m6A-related genes than PMS samples. CONCLUSIONS: The dynamic modification of m6A RNA methylation is involved in the progression of MS and could potentially represent a novel CSF biomarker for diagnosing MS and distinguishing PMS from RRMS in the early stages of the disease.

Identifying Progression in Multiple Sclerosis: New Perspectives.

The identification of progression in multiple sclerosis is typically retrospective. Given the profound burden of progressive multiple sclerosis, and the recent development of effective treatments for these patients, there is a need to establish measures capable of identifying progressive multiple sclerosis early in the disease course. Starting from recent pathological findings, this review assesses the state of the art of potential measures able to predict progressive multiple sclerosis. Future promising biomarkers that might shed light on mechanisms of progression are also discussed. Finally, expansion of the concept of progressive multiple sclerosis, by including an assessment of cognition, patient-reported outcomes, and comorbidities, is considered. ANN NEUROL 2020;88:438-452.