Performance of McDonald 2017 multiple sclerosis diagnostic criteria and evaluation of genetic ancestry in patients with a first demyelinating event in Argentina.

BACKGROUND: Information on performance of multiple sclerosis (MS) diagnostic criteria is scarce for populations from Latin America, Asia, or the Caribbean. OBJECTIVE: To assess performance of revised 2017 McDonald criteria as well as evaluate genetic ancestry in a group of MS patients from Argentina experiencing a debut demyelinating event. METHODS: Demographic and clinical characteristics, cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI) findings and new T2 lesions were recorded at baseline and during relapses. Diagnostic accuracy in predicting conversion to clinically defined MS (CDMS) based on initial imaging applying revised 2017 criteria was evaluated and genetic ancestry-informative markers analyzed. RESULTS: Of 201 patients experiencing their first demyelinating event (median follow-up 60 months), CDMS was confirmed in 67. We found 2017 diagnostic criteria were more sensitive (84% vs 67%) and less specific (14% vs 33%) than 2010 criteria, especially in a group of patients revised separately, presenting positive oligoclonal bands (88% vs 8%). Genetic testing performed in 128 cases showed 72% of patients were of European ancestry and 27% presented genetic admixture. CONCLUSION: 2017 McDonald criteria showed higher sensitivity and lower specificity compared with 2010 criteria, shortening both time-to-diagnosis and time-to-treatment implementation.

Clinically relevant increases in serum neurofilament light chain and glial fibrillary acidic protein in patients with Susac syndrome.

BACKGROUND AND PURPOSE: Serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are promising neuro-axonal damage and astrocytic activation biomarkers. Susac syndrome (SS) is an increasingly recognized neurological condition and biomarkers that can help assess and monitor disease evolution are highly needed for the adequate management of these patients. sNfL and sGFAP levels were evaluated in patients with SS and their clinical relevance in the relapse and remission phase of the disease was assessed. METHODS: As part of a multicentre study that enrolled patients diagnosed with SS from six international centres, sNfL and sGFAP levels were assessed in 22 SS patients (nine during a relapse and 13 in remission) and 59 age- and sex-matched healthy controls using SimoaTM assay Neurology 2-Plex B Kit. RESULTS: Serum NfL levels were higher than those of healthy controls (p < 0.001) in SS patients and in both subgroups of patients in relapse and in remission (p < 0.001 for both), with significantly higher levels in relapse than in remission (p = 0.008). sNfL levels showed a negative correlation with time from the last relapse (r = -0.663; p = 0.001). sGFAP levels were slightly higher in the whole group of patients than in healthy controls (p = 0.046) and were more pronounced in relapse than in remission (p = 0.013). CONCLUSION: In SS patients, both sNFL and sGFAP levels increased compared with healthy controls. Both biomarkers had higher levels during clinical relapse and much lower levels in remission. sNFL was shown to be time sensitive to clinical changes and can be useful to monitor neuro-axonal damage in SS.

Susac syndrome: challenges in the diagnosis and treatment.

Susac syndrome is a disorder thought to be mediated by an autoimmune response towards endothelial cells, leading to a characteristic clinical triad of encephalopathy, visual disturbances due to branch arterial occlusions and sensorineural hearing impairment. Although it is a rare disease, three reasons make it important. First, given its variable presentation, Susac syndrome is underdiagnosed. Second, it is considered an important differential diagnosis in different neurological, psychiatric, ophthalmological and hearing disorders, and consequently is frequently misdiagnosed. Third, in many cases, Susac syndrome is diagnosed and treated late, with significant irreversible sequelae including dementia, blindness and hearing loss. Neuropathology findings derived from both Susac syndrome patient tissue and novel transgenic mouse models indicate cytotoxic CD8+ T cells adhere to microvessels, inducing endothelial cell swelling, vascular narrowing and occlusion, causing microinfarcts. Anti-endothelial cell antibodies are present in serum in 25% of Susac syndrome patients, but it is unclear whether they are aetiologically related to the disease, or an epiphenomenon. The clinical triad comprising encephalopathy, branch arterial occlusions, and sensorineural hearing impairment is considered pathognomonic, although great variability is found in presentation and natural course of disease. At first evaluation, only 13-30% of patients exhibit the full clinical triad, making diagnosis difficult. Retinal fluorescein angiography, optic coherence tomography, MRI and tonal audiometry are helpful methods for diagnosing and monitoring disease activity during treatment. By contrast, there are no reliable objective immune markers to monitor disease activity. Immunosuppression is the current treatment, with high-dose corticosteroid therapy as the mainstay, but additional therapies such as intravenous immunoglobulins, cyclophosphamide, rituximab and mycophenolate mofetil are often necessary, because the disease can be devastating, causing irreversible organ damage. Unfortunately, low rates of disease, variability in presentation and paucity of objective biomarkers make prospective controlled clinical trials for Susac syndrome treatment difficult. Current immunosuppressive treatments are therefore based on empirical evidence, mainly from retrospective case series and expert opinion. In this review, we draw attention to the need to take consider Susac syndrome in the differential diagnosis of different neurological, psychiatric, ophthalmological and hearing disorders. Furthermore, we summarize our current knowledge of this syndrome, in reference to its pathophysiology, diagnosis and management, emphasizing the need for prospective and controlled studies that allow a better therapeutic approach.

Disability outcomes in NMOSD and MOGAD patients: data from a nationwide registry in Argentina.

The objective was to evaluate time to reach an EDSS of 4, 6, and 7 in NMOSD and MOGAD patients included in the Argentinean MS and NMOSD registry (RelevarEM, NCT 03,375,177). METHODS: NMOSD patients diagnosed according to 2015 criteria and with MOGAD were identified. Patients with at least 3 years of follow-up and periodic clinical evaluations with EDSS outcomes were included. AQP4-antibody and MOG-antibody status was recorded, and patients were stratified as seropositive and seronegative for AQP4-antibody. EDSS of 4, 6, and 7 were defined as dependent variables. Log rank test was used to identify differences between groups. RESULTS: Registry data was provided for a total of 137 patients. Of these, seventy-five presented AQP4-ab-positive NMOSD, 45 AQP4-ab-negative NMOSD, and 11 MOGAD. AQP4-ab status was determined by cell-based assay (CBA) in 72% of NMOSD patients. MOG-ab status was tested by CBA in all cases. Mean time to EDSS of 4 was 53.6 ± 24.5 vs. 63.1 ± 32.2 vs. 44.7 ± 32 months in seropositive, seronegative NMOSD, and MOGAD, respectively (p = 0.76). Mean time to EDSS of 6 was 79.2 ± 44.3 vs. 75.7 ± 48.6 vs. 54.7 ± 50 months in seropositive, seronegative NMOSD, and MOGAD (p = 0.23), while mean time to EDSS of 7 was 86.8 ± 54 vs. 80.4 ± 51 vs. 58.5 ± 47 months in seropositive, seronegative NMOSD, and MOGAD (p = 0.39). CONCLUSION: No differences were observed between NMOSD (seropositive and seronegative) and MOGAD in survival curves.

The frequency and characteristics of multiple sclerosis misdiagnosis in Latin America: A referral center study in Buenos Aires, Argentina.

OBJECTIVE: Most contemporary data concerning the frequency and causes of multiple sclerosis (MS) misdiagnosis are from North America and Europe with different healthcare system structure and resources than countries in Latin America. We sought to determine the frequency, and potential contributors to MS misdiagnosis in patients evaluated at an MS referral center in Argentina. METHODS: The study was a retrospective medical record review. We included patients evaluated at the MS Clinic at Fleni between April 2013 and March 2021. Diagnoses prior to consultation, final diagnoses after consultation, demographic, clinical and paraclinical data, and treatment were extracted and classified. RESULTS: Seven hundred thirty-six patients were identified. Five hundred seventy-two presented with an established diagnosis of MS and after evaluation, misdiagnosis was identified in 89 (16%). Women were at 83% greater risk of misdiagnosis (p = 0.034). The most frequent alternative diagnoses were cerebrovascular disease, radiological isolated syndrome (RIS), and headache. Seventy-four (83%) of misdiagnosed patients presented with a syndrome atypical for demyelination, 62 (70%) had an atypical brain magnetic resonance imaging (MRI), and 54 (61%) were prescribed disease-modifying therapy. CONCLUSION: Sixteen percent of patients with established MS were subsequently found to have been misdiagnosed. Women were at higher risk for misdiagnosis. Expert application of the McDonald criteria may prevent misdiagnosis and its associated morbidity and healthcare system cost.

Multiple sclerosis and neuromyelitis optica spectrum disorders in Argentina: comparing baseline data from the Argentinean MS Registry (RelevarEM).

The objective of this study was to describe and compare the baseline epidemiological data of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) patients included in RelevarEM (Clinical Trials registry number NCT03375177). METHODS: RelevarEM is a longitudinal, strictly observational MS and NMOSD registry in Argentina. Epidemiological and comorbidity data from MS and NMOSD patients were described and compared. For comorbidities, the Charlson comorbidity index (CCI) was used to calculate the burden at entry. CCI was stratified in 0 and ≥ 1 and described for the entire cohort. RESULTS: A total of 1588 and 75 MS and NMOSD patients (respectively) were included. For MS patients, the mean age was 42 ± 7 years, female sex 65.3%, mean EDSS 2, and mean disease duration 8 ± 6 years. In NMOSD, the mean age was 40 ± 7 years, female sex 78.7%, mean disease duration 5 ± 3.5 years, and mean EDSS 2.5. The most frequent MS phenotype was RRMS in 82.4%. In MS, the CCI was 0 in 85.8.2% while ≥ 1 was in 14.2% of patients. Regarding phenotype stratification, CCI ≥ 1 was 3.9% in CIS, 13.5% in RRMS, 28.7% in SPMS, and 17.4% in PPMS (p < 0.001 between groups). In NMOSD, the CCI was 0 in 64% while ≥ 1 was in 36%. The MS/NMOSD ratio found was 21/1. CONCLUSIONS: This is the first analysis of the longitudinal Argentinean registry of MS and NMOSD describing and comparing conditions that contributes to provide reliable real-world data in the country.

Adaptation and validation of a Spanish version of the treatment burden questionnaire in patients with multiple sclerosis.

BACKGROUND: The Treatment Burden Questionnaire (TBQ) is a self-reported measure of the effect of treatment workload on patient wellbeing. We sought to validate the TBQ in Spanish and use it to estimate the burden of treatment in Argentinian patients with multiple sclerosis (MS). METHODS: The TBQ was forward-backward translated into Spanish. Two focus groups and 25 semi-structured interviews focused on wording and possible item exclusion. Validation was performed in 2 steps. First, 162 patients across a range of MS severity completed the questionnaire. Confirmatory factor analysis assessed the dimensional structure of the TBQ. Construct validity was assessed by studying correlations with fatigue and quality of life (QoL). Then, in a second cohort of 171 patients, we evaluated the association between TBQ scores and patients' sex, age, education level, employment status, type of MS, disease duration, comorbidities, EDSS, pharmacological treatment and medication adherence. RESULTS: The questionnaire presented a 3-factor structure in which burden was related to pharmacological treatment; comprehensive health assistance; and psycho-social-economic context. Composite reliability was > 0.8 for all factors. TBQ showed positive correlation with fatigue (rs = 0.467, p = 0.006), negative correlation with QoL (rs - 0.446, p = 0.009). For the second cohort, total TBQ score was 43 (SD 29). Lowest scores were observed on self-monitoring (0.53, SD 1.3) and highest for administrative load (4.2, SD 3.4). Inverse association was found between the TBQ score and medication adherence (r 0.243 p = 0.001). TBQ scores also correlated with daily patient pill/injection requirements (r 0.175 p = 0.020). Individuals receiving injectable treatment scored higher than patients on oral drugs (total TBQ 51 (SD 32) vs 39 (SD 27) p = 0.002). CONCLUSIONS: The TBQ in Spanish is a reliable instrument and showed adequate correlation with QoL and adherence scales in MS patients. TBQ may benefit health resources allocation and provide tailor therapeutic interventions to construct a minimally disruptive care.

Progressive multiple sclerosis: from pathogenic mechanisms to treatment.

During the past decades, better understanding of relapsing-remitting multiple sclerosis disease mechanisms have led to the development of several disease-modifying therapies, reducing relapse rates and severity, through immune system modulation or suppression. In contrast, current therapeutic options for progressive multiple sclerosis remain comparatively disappointing and challenging. One possible explanation is a lack of understanding of pathogenic mechanisms driving progressive multiple sclerosis. Furthermore, diagnosis is usually retrospective, based on history of gradual neurological worsening with or without occasional relapses, minor remissions or plateaus. In addition, imaging methods as well as biomarkers are not well established. Magnetic resonance imaging studies in progressive multiple sclerosis show decreased blood-brain barrier permeability, probably reflecting compartmentalization of inflammation behind a relatively intact blood-brain barrier. Interestingly, a spectrum of inflammatory cell types infiltrates the leptomeninges during subpial cortical demyelination. Indeed, recent magnetic resonance imaging studies show leptomeningeal contrast enhancement in subjects with progressive multiple sclerosis, possibly representing an in vivo marker of inflammation associated to subpial demyelination. Treatments for progressive disease depend on underlying mechanisms causing central nervous system damage. Immunity sheltered behind an intact blood-brain barrier, energy failure, and membrane channel dysfunction may be key processes in progressive disease. Interfering with these mechanisms may provide neuroprotection and prevent disability progression, while potentially restoring activity and conduction along damaged axons by repairing myelin. Although most previous clinical trials in progressive multiple sclerosis have yielded disappointing results, important lessons have been learnt, improving the design of novel ones. This review discusses mechanisms involved in progressive multiple sclerosis, correlations between histopathology and magnetic resonance imaging studies, along with possible new therapeutic approaches.

Quantifying risk of early relapse in patients with first demyelinating events: Prediction in clinical practice.

BACKGROUND: Characteristics at clinically isolated syndrome (CIS) examination assist in identification of patient at highest risk of early second attack and could benefit the most from early disease-modifying drugs (DMDs). OBJECTIVE: To examine determinants of second attack and validate a prognostic nomogram for individualised risk assessment of clinical conversion. METHODS: Patients with CIS were prospectively followed up in the MSBase Incident Study. Predictors of clinical conversion were analysed using Cox proportional hazards regression. Prognostic nomograms were derived to calculate conversion probability and validated using concordance indices. RESULTS: A total of 3296 patients from 50 clinics in 22 countries were followed up for a median (inter-quartile range (IQR)) of 1.92 years (0.90, 3.71). In all, 1953 (59.3%) patients recorded a second attack. Higher Expanded Disability Status Scale (EDSS) at baseline, first symptom location, oligoclonal bands and various brain and spinal magnetic resonance imaging (MRI) metrics were all predictors of conversion. Conversely, older age and DMD exposure post-CIS were associated with reduced rates. Prognostic nomograms demonstrated high concordance between estimated and observed conversion probabilities. CONCLUSION: This multinational study shows that age at CIS onset, DMD exposure, EDSS, multiple brain and spinal MRI criteria and oligoclonal bands are associated with shorter time to relapse. Nomogram assessment may be useful in clinical practice for estimating future clinical conversion.

Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis.

BACKGROUND: Age at onset (AAO) in multiple sclerosis (MS) is an important marker of disease severity and may have prognostic significance. Understanding what factors can influence AAO may shed light on the aetiology of this complex disease, and have applications in the diagnostic process. METHODS: The study cohort of 22 162 eligible patients from 21 countries was extracted from the MSBase registry. Only patients with MS aged ≥16 years were included. To reduce heterogeneity, only centres of largely European descent were included for analysis. AAO was defined as the year of the first symptom suggestive of inflammatory central nervous system demyelination. Predictors of AAO were evaluated by linear regression. RESULTS: Compared with those living in lower latitudes (19.0-39.9°), onset of symptoms was 1.9 years earlier for those at higher latitudes (50.0-56.0°) (p=3.83×10-23). A reciprocal relationship was seen for ambient ultraviolet radiation (UVR), with a significantly increasing AAO for patients with MS per each quartile increment of ambient UVR (p=1.56×10-17). We found that the AAO of female patients was ∼5 months earlier than male patients (p=0.002). AAO of progressive-onset patients with MS were ∼9 years later than relapsing-onset patients (p=1.40×10-265). CONCLUSIONS: An earlier AAO in higher latitude regions was found in this worldwide European-descent cohort and correlated inversely with variation in latitudinal UVR. These results suggest that environmental factors which act at the population level may significantly influence disease severity characteristics in genetically susceptible populations.

The effect of oral immunomodulatory therapy on treatment uptake and persistence in multiple sclerosis.

OBJECTIVE: We aimed to analyse the effect of the introduction of fingolimod, the first oral disease-modifying therapy, on treatment utilisation and persistence in an international cohort of patients with multiple sclerosis (MS). METHODS: MSBASIS, a prospective, observational sub-study of the MSBase registry, collects demographic, clinical and paraclinical data on patients followed from MS onset (n=4718). We conducted a multivariable conditional risk set survival analysis to identify predictors of treatment discontinuation, and to assess if the introduction of fingolimod has altered treatment persistence. RESULTS: A total of 2640 patients commenced immunomodulatory therapy. Following the introduction of fingolimod, patients were more likely to discontinue all other treatments (hazard ratio 1.64, p<0.001) while more patients switched to fingolimod than any other therapy (42.3% of switches). Patients switched to fingolimod due to convenience. Patients treated with fingolimod were less likely to discontinue treatment compared with other therapies (p<0.001). Female sex, country of residence, younger age, a high Expanded Disability Status Scale score and relapse activity were all independently associated with higher rates of treatment discontinuation. CONCLUSION: Following the availability of fingolimod, patients were more likely to discontinue injectable treatments. Those who switched to fingolimod were more likely to do so for convenience. Persistence was improved on fingolimod compared to other medications.

Defining reliable disability outcomes in multiple sclerosis.

Prevention of irreversible disability is currently the most important goal of disease modifying therapy for multiple sclerosis. The disability outcomes used in most clinical trials rely on progression of Expanded Disability Status Scale score confirmed over 3 or 6 months. However, sensitivity and stability of this metric has not been extensively evaluated. Using the global MSBase cohort study, we evaluated 48 criteria of disability progression, testing three definitions of baseline disability, two definitions of progression magnitude, two definitions of long-term irreversibility and four definitions of event confirmation period. The study outcomes comprised the rates of detected progression events per 10 years and the proportions of the recorded events persistent at later time points. To evaluate the ratio of progression frequency and stability for each criterion, we calculated the proportion of events persistent over the five subsequent years once progression was achieved. Finally, we evaluated the clinical and demographic determinants characterising progression events and, for those that regressed back to baseline, determinants of their subsequent regression. The study population consisted of 16 636 patients with the minimum of three recorded disability scores, totalling 112 584 patient-years. The progression rates varied between 0.41 and 1.14 events per 10 years, with the length of required confirmation interval as the most important determinant of the observed variance. The concordance among all tested progression criteria was only 17.3%. Regression of disability occurred in 11-34% of the progression events over the five subsequent years. The most important determinant of progression stability was the length of the confirmation period. For the most accurate set of the progression criteria, the proportions of 3-, 6-, 12- or 24-month confirmed events persistent over 5 years reached 70%, 74%, 80% and 89%, respectively. Regression post progression was more common in younger patients, relapsing-remitting disease course, and after a smaller change in disability, and was inflated by higher visit frequency. These results suggest that the disability outcomes based on 3-6-month confirmed disability progression overestimate the accumulation of permanent disability by up to 30%. This could lead to spurious results in short-term clinical trials, and the issue may be magnified further in cohorts consisting predominantly of younger patients and patients with relapsing-remitting disease. Extension of the required confirmation period increases the persistence of progression events.

Sodium intake is associated with increased disease activity in multiple sclerosis.

BACKGROUND: Recently, salt has been shown to modulate the differentiation of human and mouse Th17 cells and mice that were fed a high-sodium diet were described to develop more aggressive courses of experimental autoimmune encephalomyelitis. However, the role of sodium intake in multiple sclerosis (MS) has not been addressed. We aimed to investigate the relationship between salt consumption and clinical and radiological disease activity in MS. METHODS: We conducted an observational study in which sodium intake was estimated from sodium excretion in urine samples from a cohort of 70 relapsing-remitting patients with MS who were followed for 2 years. The effect of sodium intake in MS disease activity was estimated using regression analysis. We then replicated our findings in a separate group of 52 patients with MS. RESULTS: We found a positive correlation between exacerbation rates and sodium intake in a multivariate model adjusted for age, gender, disease duration, smoking status, vitamin D levels, body mass index and treatment. We found an exacerbation rate that was 2.75-fold (95% CI 1.3 to 5.8) or 3.95-fold (95% CI 1.4 to 11.2) higher in patients with medium or high sodium intakes compared with the low-intake group. Additionally, individuals with high-sodium intake had a 3.4-fold greater chance of developing a new lesion on the MRI and on average had eight more T2 lesions on MRI. A similar relationship was found in the independent replication group. CONCLUSIONS: Our results suggest that a higher sodium intake is associated with increased clinical and radiological disease activity in patients with MS.

Risk of relapse phenotype recurrence in multiple sclerosis.

OBJECTIVES: The aim was to analyse risk of relapse phenotype recurrence in multiple sclerosis and to characterise the effect of demographic and clinical features on this phenotype. METHODS: Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis. RESULTS: Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR = 1.8-5, p = 10(-14)). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease. CONCLUSION: Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance.

Sex as a determinant of relapse incidence and progressive course of multiple sclerosis.

The aim of this work was to evaluate sex differences in the incidence of multiple sclerosis relapses; assess the relationship between sex and primary progressive disease course; and compare effects of age and disease duration on relapse incidence. Annualized relapse rates were calculated using the MSBase registry. Patients with incomplete data or <1 year of follow-up were excluded. Patients with primary progressive multiple sclerosis were only included in the sex ratio analysis. Relapse incidences over 40 years of multiple sclerosis or 70 years of age were compared between females and males with Andersen-Gill and Tweedie models. Female-to-male ratios stratified by annual relapse count were evaluated across disease duration and patient age and compared between relapse-onset and primary progressive multiple sclerosis. The study cohort consisted of 11 570 eligible patients with relapse-onset and 881 patients with primary progressive multiple sclerosis. Among the relapse-onset patients (82 552 patient-years), 48,362 relapses were recorded. Relapse frequency was 17.7% higher in females compared with males. Within the initial 5 years, the female-to-male ratio increased from 2.3:1 to 3.3:1 in patients with 0 versus ≥4 relapses per year, respectively. The magnitude of this sex effect increased at longer disease duration and older age (P < 10(-12)). However, the female-to-male ratio in patients with relapse-onset multiple sclerosis and zero relapses in any given year was double that of the patients with primary progressive multiple sclerosis. Patient age was a more important determinant of decline in relapse incidence than disease duration (P < 10(-12)). Females are predisposed to higher relapse activity than males. However, this difference does not explain the markedly lower female-to-male sex ratio in primary progressive multiple sclerosis. Decline in relapse activity over time is more closely related to patient age than disease duration.

Clinical characterization of long-term multiple sclerosis (COLuMbus) patients in Argentina: A cross-sectional non-interventional study.

BACKGROUND: Most Multiple Sclerosis (MS) clinical trials fail to assess the long-term effects of disease-modifying therapies (DMT) or disability. METHODS: COLuMbus was a single-visit, cross-sectional study in Argentina in adult patients with ≥10 years of MS since first diagnosis. The primary endpoint was to determine patient disability using the Expanded Disability Status Scale (EDSS). The secondary endpoints were to evaluate the distribution of diagnoses between relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS), patient demographics, disease history, and the risk of disability progression. The relationship between baseline characteristics and the current disability state and the risk of disability progression was assessed. RESULTS: Out of the 210 patients included, 76.7 % had a diagnosis of RRMS and 23.3 % had been diagnosed with SPMS, with a mean disease duration of 17.9 years and 20.5 years, respectively. The mean delay in the initial MS diagnosis was 2.6 years for the RRMS subgroup and 2.8 years for the SPMS subgroups. At the time of cut-off (28May2020), 90.1 % (RRMS) and 75.5 % (SPMS) of patients were receiving a DMT, with a mean of 1.5 and 2.0 prior DMTs, respectively. The median EDSS scores were 2.5 (RRMS) and 6.5 (SPMS). In the RRMS and SPMS subgroups, 23 % and 95.9 % of patients were at high risk of disability, respectively; the time since first diagnosis showed a significant correlation with the degree of disability. CONCLUSIONS: This is the first local real-world study in patients with long-term MS that highlights the importance of recognizing early disease progression to treat the disease on time and delay disability.

Selection of disease modifying therapies in multiple sclerosis based on patient's age and disease activity: Data from a nationwide registry.

BACKGROUND: Knowledge of the safety and efficacy of disease-modifying therapies (DMTs) in older patients with Multiple Sclerosis (pwMS) is limited due to their exclusion from clinical trials. Our purpose is to evaluate the choice of DMTs in pwMS older than 50 years old in a real-world setting. METHODS: Cross-sectional study of pwMS from the Argentine MS and NMOSD Registry. We included patients under 35 and above 50 years old prescribed DMTs. Disease activity was categorized as highly active (HA) or not highly active (NHA), and DMTs were classified as low efficacy therapies (LET) or high efficacy therapies (HET). RESULTS: 1460 patients (65% females) were enrolled. The HA group comprised 241 patients, 198 young (82.2%) and 43 older (17.8%). The NHA group included 1219 patients, 893 young (73%) and 326 older (27%). In the NHA group, older patients received LET more frequently than younger patients (66% versus 44%; p < 0.01). In the HA group, older patients received LET in 61% of cases, whereas younger patients received HET in 71% (p = 0.01). CONCLUSION: The study shows the preference of LET in older patients regardless of disease activity. However it does not demonstrate a difference in disability in older patients based on low vs high efficacy DMTs used, probably due to the design of the study. Further longitudinal studies are warranted to address this issue.

The Kurtzke EDSS rank stability increases 4 years after the onset of multiple sclerosis: results from the MSBase Registry.

BACKGROUND: The Expanded Disability Status Scale (EDSS) is widely used to rate multiple sclerosis (MS) disability, but lack of disease duration information limits utility in assessing severity. EDSS ranking at specific disease durations was used to devise the MS Severity Score, which is gaining popularity for predicting outcomes. As this requires validation in longitudinal cohorts, we aimed to assess the utility of EDSS ranking as a predictor of 5-year outcome in the MSBase Registry. METHODS: Rank stability of EDSS over time was examined in the MSBase Registry, a large multicentre MS cohort. Scores were ranked for 5-year intervals, and correlation of rank across intervals was assessed using Spearman's rank correlation. EDSS progression outcomes at 10 years were disaggregated by 5-year EDSS scores. RESULTS: Correlation coefficients for EDSS rank over 5-year intervals increased with MS duration: years 1-6=0.55, years 4-9=0.74, years 7-12=0.80 and years 10-15=0.83. EDSS progression risk at 10 years after onset was highly dependent on EDSS at 5 years; one-point progression risk was greater for EDSS score of >2 than ≤2. Two-point progression was uncommon for EDSS score of <2 and more common at EDSS score of 4. CONCLUSIONS: EDSS rank stability increases with disease duration, probably due to reduced relapses and less random variation in later disease. After 4 years duration, EDSS rank was highly predictive of EDSS rank 5 years later. Risk of progression by 10 years was highly dependent on EDSS score at 5 years duration. We confirm the utility of EDSS ranking to predict 5-year outcome in individuals 4 years after disease onset.

Alerting network dysfunction in early multiple sclerosis.

The objective of this study is to assess attention in recently diagnosed relapsing-remitting multiple sclerosis patients. Twenty-seven patients with early multiple sclerosis and low clinical disability scores (EDSS<2) and 27 sex-, age-, and education-matched healthy controls underwent attention assessment using the Attentional Network Test, a computerized task designed to measure efficiency independently in 3 attentional networks (Alerting, Orienting and Executive Control). MS patients had significantly less efficiency in the Alerting network (p = .006). In contrast, in the Orienting and Executive Control networks, they did not differ from controls. A significant interaction between Alerting and Executive Control was also found in the MS patients (p = .007). Early relapsing-remitting multiple sclerosis particularly affects the Alerting domain of attention, whereas the Orienting and Executive Control domains are not affected.

Benign multiple sclerosis: does it exist?

Although the definition of benign multiple sclerosis (BMS) remains controversial, it is generally applied to a subgroup of MS patients showing little disease progression, with minimal disability decades after disease onset, and is based mainly on changes in motor function. Recent studies, however, reveal that deterioration of cognitive function, fatigue, pain, and depression also occur in BMS patients, causing negative impact on work and social activities, despite complete preservation of motor function. Using conventional MRI techniques, lesion load observed in BMS is similar to levels in other disease subtypes; however, newer quantitative MRI techniques show less tissue damage, as well as greater repair and compensatory efficiency following MS injury. Currently accepted criteria for BMS diagnosis may cause overestimation of true prevalence, underscoring the need for routine monitoring of nonmotor symptoms and imaging studies. Clearly, the definition of BMS currently applied in clinical practice requires reassessment.