Seasonality and clinical characteristics of MS in an equatorial country.

BACKGROUND: Month and season of birth have been associated with risk of multiple sclerosis (MS), but there is relatively little evidence regarding their influence on the timing and severity of disease at onset. OBJECTIVE: To assess whether month and season of birth influence the age and phenotype at onset of MS as well as its severity in a cohort of Colombian patients. METHODS: This study is an analysis on MS cases only, drawn from a previously published case-control study. MS cases confirmed with current diagnostic criteria cared for at least once in our center were included. We assessed the influence of the month and season of birth in the age at MS onset, MS severity score, and age-related MS severity score using multiple and pairwise comparisons. Age at onset was also studied using Kaplan-Meier survival estimates compared with the log-rank test. The likelihood of progressive MS onset was evaluated with OR estimated from logistic regression models adjusted for age at onset and sex. RESULTS: 668 MS cases were included. No significant differences were found in the age at MS onset according to month of birth or season of birth. Neither month of birth nor season of birth conferred significant differences in MS severity score or age-related MS severity score. No significant association was found between month (ORs ranging from 0.62 to 3.11, none significant) or season of birth (OR 0.91; 95 %CI: 0.46-1.84) with primary progressive MS. CONCLUSION: The month or season of birth do not appear to influence the age onset and phenotype of MS in our country.

Quantitative T1 brain mapping in early relapsing-remitting multiple sclerosis: longitudinal changes, lesion heterogeneity and disability.

OBJECTIVES: To quantify brain microstructural changes in recently diagnosed relapsing-remitting multiple sclerosis (RRMS) using longitudinal T1 measures, and determine their associations with clinical disability. METHODS: Seventy-nine people with recently diagnosed (< 6 months) RRMS were recruited from a single-centre cohort sub-study, and underwent baseline and 1-year brain MRI, including variable flip angle T1 mapping. Median T1 was measured in white matter lesions (WML), normal-appearing white matter (NAWM), cortical/deep grey matter (GM), thalami, basal ganglia and medial temporal regions. Prolonged T1 (≥ 2.00 s) and supramedian T1 (relative to cohort WML values) WML voxel counts were also measured. Longitudinal change was assessed with paired t-tests and compared with Bland-Altman limits of agreement from healthy control test-retest data. Regression analyses determined relationships with Expanded Disability Status Scale (EDSS) score and dichotomised EDSS outcomes (worsening or stable/improving). RESULTS: Sixty-two people with RRMS (mean age 37.2 ± 10.9 [standard deviation], 48 female) and 11 healthy controls (age 44 ± 11, 7 female) contributed data. Prolonged and supramedian T1 WML components increased longitudinally (176 and 463 voxels, respectively; p < .001), and were associated with EDSS score at baseline (p < .05) and follow-up (supramedian: p < .01; prolonged: p < .05). No cohort-wide median T1 changes were found; however, increasing T1 in WML, NAWM, cortical/deep GM, basal ganglia and thalami was positively associated with EDSS worsening (p < .05). CONCLUSION: T1 is sensitive to brain microstructure changes in early RRMS. Prolonged WML T1 components and subtle changes in NAWM and GM structures are associated with disability. CLINICAL RELEVANCE STATEMENT: MRI T1 brain mapping quantifies disability-associated white matter lesion heterogeneity and subtle microstructural damage in normal-appearing brain parenchyma in recently diagnosed RRMS, and shows promise for early objective disease characterisation and stratification. KEY POINTS: • Quantitative T1 mapping detects brain microstructural damage and lesion heterogeneity in recently diagnosed relapsing-remitting multiple sclerosis. • T1 increases in lesions and normal-appearing parenchyma, indicating microstructural damage, are associated with worsening disability. • Brain T1 measures are objective markers of disability-relevant pathology in early multiple sclerosis.

Implementing Shared Decision-Making for Multiple Sclerosis: The MS-SUPPORT Tool.

BACKGROUND: Disease modifying therapies (DMTs) offer opportunities to improve the course of multiple sclerosis (MS), but decisions about treatment are difficult. People with multiple sclerosis (pwMS) want more involvement in decisions about DMTs, but new approaches are needed to support shared decision-making (SDM) because of the number of treatment options and the range of outcomes affected by treatment. We designed a patient-centered tool, MS-SUPPORT, to facilitate SDM for pwMS. We sought to evaluate the feasibility and impact of MS-SUPPORT on decisions about disease modifying treatments (DMTs), SDM processes, and quality-of-life. METHODS: This multisite randomized controlled trial compared the SDM intervention (MS-SUPPORT) to control (usual care) over a 12-month period. English-speaking adults with relapsing MS were eligible if they had an upcoming MS appointment and an email address. To evaluate clinician perspectives, participants' MS clinicians were invited to participate. Patients were referred between November 11, 2019 and October 23, 2020 by their MS clinician or a patient advocacy organization (the Multiple Sclerosis Association of America). MS-SUPPORT is an online, interactive, evidence-based decision aid that was co-created with pwMS. It clarifies patient treatment goals and values and provides tailored information about MS, DMTs, and adherence. Viewed by patients before their clinic appointment, MS-SUPPORT generates a personalized summary of the patient's treatment goals and preferences, adherence, DMT use, and clinical situation to share with their MS clinician. Outcomes (DMT utilization, adherence, quality-of-life, and SDM) were assessed at enrollment, post-MS-SUPPORT, post-appointment, and quarterly for 1 year. RESULTS: Participants included 501 adults with MS from across the USA (84.6% female, 83% white) and 34 of their MS clinicians (47% neurologists, 41% Nurse Practitioners, 12% Physician Assistants). Among the 203 patients who completed MS-SUPPORT, most (88.2%) reported they would recommend it to others and that it helped them talk to their doctor (85.2%), understand their options (82.3%) and the importance of taking DMTs as prescribed (82.3%). Among non-users of DMTs at baseline, the probability ratio of current DMT use consistently trended higher over one-year follow-up in the MS-SUPPORT group (1.30 [0.86-1.96]), as did the cumulative probability of starting a DMT within 6-months, with shorter time-to-start (46 vs 90 days, p=0.24). Among the 222 responses from 34 participating clinicians, more clinicians in the MS-SUPPORT group (vs control) trended towards recommending their patient start a DMT (9 of 108 (8%) vs 5 of 109 (5%), respectively, p=0.26). Adherence (no missed doses) to daily-dosed DMTs was higher in the MS-SUPPORT group (81.25% vs 56.41%, p=.026). Fewer patients forgot their doses (p=.046). The MS-SUPPORT group (vs control) reported 1.7 fewer days/month of poor mental health (p=0.02). CONCLUSIONS: MS-SUPPORT was strongly endorsed by patients and is feasible to use in clinical settings. MS-SUPPORT increased the short-term probability of taking and adhering to a DMT, and improved long-term mental health. Study limitations include selection bias, response bias, social desirability bias, and recall bias. Exploring approaches to reinforcement and monitoring its implementation in real-world settings should provide further insights into the value and utility of this new SDM tool.

Caracterización clínica de pacientes con esclerosis múltiple

Introducción: La esclerosis múltiple es una enfermedad autoinmune, inflamatoria, desmielinizante, crónica, del sistema nervioso central. Supone la primera causa de discapacidad no traumática en adultos jóvenes; afecta de forma significativa la calidad de vida de los pacientes, con alteraciones físicas, sociales y emocionales. Objetivo: Caracterizar desde el punto de vista clínico, a pacientes con diagnóstico de esclerosis múltiple. Método: Se realizó un estudio descriptivo transversal en una serie de casos de 40 pacientes, según las variables edad, sexo, comorbilidad, síntomas iniciales, formas clínicas y grado de discapacidad. Se realizó un análisis de frecuencias. Resultados: Predominaron los pacientes con edades comprendidas entre 30 y 39 años (57,5 %). Los pacientes del sexo femenino representaron el 58,8 % de los casos estudiados y el 85,5% presentó manifestaciones motoras, como síntomas iniciales de la enfermedad. La forma clínica de esclerosis múltiple más frecuente fue la recurrente remitente y el grado de discapacidad mínima. Conclusiones: Las manifestaciones motoras son los síntomas iniciales más frecuentes, así como la forma clínica recurrente remitente y el grado de discapacidad mínima. Los pacientes son fundamentalmente del sexo femenino, en la cuarta década de la vida.

Introduction: Multiple sclerosis is a chronic, inflammatory, demyelinating, autoimmune disease of the central nervous system. It is the first cause of non-traumatic disability in young adults, significantly affecting the quality of life, with physical, social and emotional alterations. Objective: To characterize from the clinical point of view, patients diagnosed with multiple sclerosis. Method: A descriptive and cross-sectional observational study was carried out in a case series of 40 patients, with variables age, sex, comorbidity, initial symptoms, clinical forms and degree of disability. A frequency analysis was carried out. Results: Patients aged between 30 and 39 years (57.5%) predominated. Female patients represented 58.8% of the cases studied and 85.5% presented motor manifestations, as initial symptoms of the disease. Motor symptoms were predominant during the onset of the disease. The most frequent clinical form of multiple sclerosis was relapsing-remitting and the degree of minimal disability. Conclusions: Motor manifestations are the most frequent initial symptoms, as well as the relapsing-remitting clinical form and the minimum degree of disability. The patients are fundamentally female, in the fourth decade of life.

Cost-Utility Analysis Comparing Ocrelizumab Versus Rituximab in the Treatment of Relapsing-Remitting Multiple Sclerosis: The Colombian Perspective.

OBJECTIVES: This study aimed to determine the cost-utility of ocrelizumab versus rituximab in patients with RRMS, from the perspective of the Colombian healthcare system. METHODOLOGY: Cost-utility study based on a Markov model, with a 50-year horizon and payer perspective. The currency was the US dollar for the year 2019, with a cost-effectiveness threshold of $5180 defined for Colombian health system. The model used annual cycles according to the health status determined by the disability scale. Direct costs were considered, and the incremental cost-effectiveness ratio per 1 quality-adjusted life-year (QALY) gained was used as the outcome measure. A discount rate of 5% was applied to costs and outcomes. Multiple one-way deterministic sensitivity analyses and 10 000 Monte Carlo simulation were conducted. RESULTS: For the treatment of patients with RRMS, ocrelizumab versus rituximab had an incremental cost-effectiveness ratio of $73 652 for each QALY gained. After 50 years, 1 subject treated with ocrelizumab earns 4.8 QALYs >1 subject treated with rituximab, but at a higher cost of $521 759 versus $168 752, respectively. Ocrelizumab becomes a cost-effective therapy if its price is discounted > 86% or if there is a high willingness to pay. CONCLUSIONS: Ocrelizumab was not a cost-effective drug as compared with rituximab in treating patients with RRMS in Colombia.

[Multiple sclerosis: interventions to halt disease : Which patients can be considered for autologous stem cell transplantation]. / Multiple Sklerose: Stillstand durch Interventionen : Welche Patienten für eine autologe Stammzelltransplantation infrage kommen.

BACKGROUND: Autologous hematopoietic stem cell transplantation (aHSCT) for treatment of multiple sclerosis (MS) is gaining increasing prominence in the therapeutic landscape. This review article focuses on describing the evidence and European guidelines for aHSCT so that neurologists in Germany can consider this treatment option for appropriate MS patients. In this context, it must be taken into consideration that in every case a cost transfer must be individually applied for. AIM: To provide information for neurologists considering aHSCT for patients with MS. MATERIAL AND METHODS: In this narrative review articles from PubMed were pooled and analyzed. RESULTS AND DISCUSSION: High quality data from randomized, controlled clinical trials are required to compare the efficacy of aHSCT to the currently available highly effective disease-modifying therapies (DMT) so that reliable conclusions can be drawn regarding the relationship between the risks and benefits of aHSCT in MS; however, the studies discussed in this review provide important points of reference for patient selection and the transplantation protocol. Further advice is available from the European Society for Blood and Marrow Transplantation (EBMT) for experienced centers considering aHSCT. The available data and the European guidelines suggest that patients aged less than 45 years, an expanded disability status scale (EDSS) ≤ 5.5, highly active MS, a disease duration of less than 10 years, an ineffective course of DMT or rapidly progressive MS may be eligible for aHSCT and should be referred to an experienced center for further assessment.

Multi-lesion radiomics model for discrimination of relapsing-remitting multiple sclerosis and neuropsychiatric systemic lupus erythematosus.

OBJECTIVES: To develop an MRI-based multi-lesion radiomics model for discrimination of relapsing-remitting multiple sclerosis (RRMS) and its mimicker neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: A total of 112 patients with RRMS (n = 63) or NPSLE (n = 49) were assigned to training and test sets with a ratio of 3:1. All lesions across the whole brain were manually segmented on T2-weighted fluid-attenuated inversion recovery images. For each single lesion, 371 radiomics features were extracted and trained using machine learning algorithms, producing Radiomics Index for Lesion (RIL) for each lesion and a single-lesion radiomics model. Then, for each subject, single lesions were assigned to one of two disease courts based on their distance to decision threshold, and a Radiomics Index for Subject (RIS) was calculated as the mean RIL value of lesions on the higher-weighted court. Accordingly, a subject-level discrimination model was constructed and compared with performances of two radiologists. RESULTS: The subject-based discrimination model satisfactorily differentiated RRMS and NPSLE in both training (AUC = 0.967, accuracy = 0.892, sensitivity = 0.917, and specificity = 0.872) and test sets (AUC = 0.962, accuracy = 0.931, sensitivity = 1.000, and specificity = 0.875), significantly better than the single-lesion radiomics method (training: p < 0.001; test: p = 0.001) Besides, the discrimination model significantly outperformed the senior radiologist in the training set (training: p = 0.018; test: p = 0.077) and the junior radiologist in both the training and test sets (training: p = 0.008; test: p = 0.023). CONCLUSIONS: The multi-lesion radiomics model could effectively discriminate between RRMS and NPSLE, providing a supplementary tool for accurate differential diagnosis of the two diseases. KEY POINTS: • Radiomic features of brain lesions in RRMS and NPSLE were different. • The multi-lesion radiomics model constructed using a merging strategy was comprehensively superior to the single-lesion-based model for discrimination of RRMS and NPSLE. • The RRMS-NPSLE discrimination model showed a significantly better performance or a trend toward significance than the radiologists.

Serum YKL-40 levels in patients with multiple sclerosis / Níveis séricos de YKL-40 em pacientes com esclerose múltipla

ABSTRACT Background: Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system. The YKL-40 protein, which is secreted from various cells that contribute to inflammation and infection, plays a role in immune regulation. Objective: This study investigated the serum YKL-40 levels of patients with clinically isolated syndrome (CIS) and MS. Methods: The participants was divided into three groups: 1) patients with CIS (n = 20); 2) patients with relapsing-remitting MS (RRMS; n = 39); and 3) healthy individuals (n = 35). The YKL-40 levels in serum samples obtained from the participants were measured using enzyme-linked immunoassays. Results: The median serum YKL-40 level was 20.2 ng/mL (range 9.8-75.9 ng/mL) in the patients with CIS, 22.7 ng/mL (range 13.4-57.9 ng/mL) in the patients with RRMS and 11.0 ng/mL (range 10.0-17.3 ng/mL) in the control group (p < 0.001). The serum YKL-40 levels in the patients with RRMS were correlated with the patients' expanded disability status scale scores and ages (p < 0.05). No relationships were determined between the serum YKL-40 levels and the other variables (p > 0.05). The serum YKL-40 levels were higher in the CIS group than in the MS group. These findings show that the serum YKL-40 levels were high even at the beginning of the disease. The serum YKL-40 levels were also not involved in the progression to clinically definite MS. Conclusions: The findings from this study suggested that YKL-40 may be a useful marker for the inflammatory process of MS.

RESUMO Contexto: A Esclerose Múltipla (EM) é uma doença inflamatória crônica que afeta o sistema nervoso central. A proteína UKL-40, secretada de várias células que participam de processos inflamatórios e infecciosos, desempenha um importante papel na regulação imunológica. Objetivo: Este estudo investigou níveis séricos de YKL-40 em pacientes com Síndrome Clinicamente Isolada (SCI) e EM. Métodos: Os participantes foram divididos em três grupos: 1) pacientes com SCI (n = 20); 2) pacientes com EM recorrente-remitente (EMRR; n = 39); e 3) indivíduos saudáveis (n = 35). Os níveis de YKL-40 em amostras séricas obtidas dos participantes foram medidos usando-se imunoensaios ligados a enzimas. Resultados: O nível sérico médio de YKL-40 foi 20.2 ng/mL (range 9.8-75.9 ng/mL) em pacientes com CIS, 22.7 ng/mL (intervalo entre 13.4-57.9 ng/mL) em pacientes com EMRR e 11.0 ng/mL (intervalo entre 10.0-17.3 ng/mL) no grupo controle (p < 0.001). Os níveis séricos de YKL-40 em pacientes com EMRR estavam correlacionados às pontuações e idades dos pacientes na EDSS (p < 0.05). Não foram determinadas relações entre os níveis séricos de YKL-40 e outras variáveis (p > 0.05). Os níveis séricos de YKL-40 no grupo SCI estavam mais elevados do que no grupo EM. Estes resultados demonstram que os níveis séricos de YKL-40 estavam mais elevados até mesmo no início da doença. Os níveis séricos de YKL-40 também não estavam associados à progressão da EM clinicamente definida. Conclusões: A partir deste estudo, os resultados sugeriram que a proteína YKL-40 pode ser um indicador útil no processo inflamatório da EM.

Brain microstructural and metabolic alterations detected in vivo at onset of the first demyelinating event.

In early multiple sclerosis, a clearer understanding of normal-brain tissue microstructural and metabolic abnormalities will provide valuable insights into its pathophysiology. We used multi-parametric quantitative MRI to detect alterations in brain tissues of patients with their first demyelinating episode. We acquired neurite orientation dispersion and density imaging [to investigate morphology of neurites (dendrites and axons)] and 23Na MRI (to estimate total sodium concentration, a reflection of underlying changes in metabolic function). In this cross-sectional study, we enrolled 42 patients diagnosed with clinically isolated syndrome or multiple sclerosis within 3 months of their first demyelinating event and 16 healthy controls. Physical and cognitive scales were assessed. At 3 T, we acquired brain and spinal cord structural scans, and neurite orientation dispersion and density imaging. Thirty-two patients and 13 healthy controls also underwent brain 23Na MRI. We measured neurite density and orientation dispersion indices and total sodium concentration in brain normal-appearing white matter, white matter lesions, and grey matter. We used linear regression models (adjusting for brain parenchymal fraction and lesion load) and Spearman correlation tests (significance level P ≤ 0.01). Patients showed higher orientation dispersion index in normal-appearing white matter, including the corpus callosum, where they also showed lower neurite density index and higher total sodium concentration, compared with healthy controls. In grey matter, compared with healthy controls, patients demonstrated: lower orientation dispersion index in frontal, parietal and temporal cortices; lower neurite density index in parietal, temporal and occipital cortices; and higher total sodium concentration in limbic and frontal cortices. Brain volumes did not differ between patients and controls. In patients, higher orientation dispersion index in corpus callosum was associated with worse performance on timed walk test (P = 0.009, B = 0.01, 99% confidence interval = 0.0001 to 0.02), independent of brain and lesion volumes. Higher total sodium concentration in left frontal middle gyrus was associated with higher disability on Expanded Disability Status Scale (rs = 0.5, P = 0.005). Increased axonal dispersion was found in normal-appearing white matter, particularly corpus callosum, where there was also axonal degeneration and total sodium accumulation. The association between increased axonal dispersion in the corpus callosum and worse walking performance implies that morphological and metabolic alterations in this structure could mechanistically contribute to disability in multiple sclerosis. As brain volumes were neither altered nor related to disability in patients, our findings suggest that these two advanced MRI techniques are more sensitive at detecting clinically relevant pathology in early multiple sclerosis.

Abnormalcortical thickness in relapsing-remitting multiple sclerosis, correlations with cognition impairment, and effect of modified Bushenyisui decoction on cognitive function of multiple sclerosis.

OBJECTIVE: To investigate the changes of subcortical gray matter volume and cortical thickness, andexplorethe correlations between regional abnormalities of cortical thickness and cognitive impairment and the effect of modified Bushenyisui decoction ( BSYSD) on the cognitive function of multiple sclerosis (MS). METHODS: This prospective study was approved by the institutional review board. 92 subjects were recruited, including 46 relapsing-remitting multiple sclerosis (RRMS) patients and 46 healthy controls (HC). Of the 46 patients, 22 patients experienced the treatment of BSYSD for half a year. A conventional three-dimensional T1-weighted sequence were acquired for all participants on a 3.0 tesla magnetic resonance system. Basic information, detailed cognitive scales Montreal Cognitive Assessment (MoCA), symbol digit modalities test (SDMT), immediate memory, delayed recall, and long-term recognition were evaluated. Subcortical gray matter volume and cortical thickness weremeasured by FreeSurfer. The correlations between cortical thickness which MS patients showed reduced with respect to HC and cognitive scales wereanalyzed by Pearson correlation in RRMS patients. The influence of modified BSYSD on MS patients' cognition was analyzed by paired T Test. RESULTS: MoCA, immediate memory, delayed recall, and long-term delayed recognition in RRMS were significantly decreased than those of HC. Gray matter atrophy measured by FreeSurfer showed mainly in thalamus and hippocampus of RRMS patients. Compared with HC, the cortical thickness of several regions in frontal lobe, parietal lobe, temporal lobe, hippocampal, cingulate gyrus, and fusiform gyrus of RRMS patients were decreased with significant difference. The regions of cortical thickness thinning related to MoCA, immediate memory, delayed recall, and long-term delayed recognition were temporal lobe and fusiform gyrus. Modified BSYSD could improve MoCA, SDMT, immediate memory, delayed recall, and long-term delayed recognition of MS patients, and it could promote the recovery of cognitive function in MS patients. CONCLUSIONS: Gray matter atrophy and cortical thickness thinning were validated in RRMS. Cortical thickness thinning of temporal lobe and fusiform gyrus strongly related to cognitive deficits in RRMS. The modified BSYSD could promote the recovery of cognitive function in MS.

Cerebellar-cerebral resting-state functional connectivity alterations in relapsing-remitting multiple sclerosis / 中华放射学杂志

Objective:To investigate the alterations of cerebellar and cerebral functional connectivity (FC) in patients with relapsing-remitting multiple sclerosis (RRMS) and associations with clinical parameters.Methods:Eighteen acute RRMS patients, 25 remitting RRMS patients and 20 healthy controls (HC) who underwent 3.0 T brain MRI using resting-state functional protocols were collected retrospectively from September 2012 to June 2019 at the First Hospital of Nanchang University. After data preprocessing, the functional connectivity coefficients were calculated between each seed of the cerebellum and every other voxel in the cerebrum for comparison of the inter-groups difference and correlation analysis with clinical variables.Results:Compared with HC, the acute RRMS patients showed significant decreased FC of left cerebellar lobule Ⅵ, the right cerebellar lobule Ⅵ and the left vermis ( P<0.001, Gaussian Random Field theory correction at cluster level P<0.05), the remitting RRMS patients showed the decreased FC of the right cerebellar Crus I, the left cerebellar Crus Ⅰ, the left cerebellar lobule Ⅴ and right cerebellar lobule Ⅴ ( P<0.001, Gaussian Random Field theory correction at cluster level P<0.05). In the acute RRMS patients, FC between the left cerebellar lobule Ⅵ and the right precentral/postcentral gyrus was negatively correlated with illness duration ( r=-0.492, P=0.038). FC between the right cerebellar lobule Ⅵ and the right postcentral gyrus/right superior parietal gyrus was negatively correlated with the expanded disability status scale scores ( r=-0.611, P=0.007). FC between the left vermis and the left calcarine gyrus was negatively correlated with illness duration ( r=-0.534, P=0.02). In the remitting RRMS patients, FC between the right Crus Ⅰ and the left anterior insula was negatively correlated with normalized total white matter lesion load ( r=-0.453, P=0.023). FC between the right Crus Ⅰ and the right anterior insula was negatively correlated with modified fatigue impact scale ( r=-0.450, P=0.024). Conclusions:The cerebello-cerebral connection of cognitive related networks is decreased in both acute attack and remission stages of RRMS patients. In addition, the cerebello-cerebral connection in sensorimotor network can also be significantly impacted in acute attack stage, while the cerebello-cerebral connection of emotional network may be decreased in remission stage.

Differentiation of relapsing-remitting and secondary progressive multiple sclerosis: a magnetic resonance spectroscopy study based on machine learning / Diferenciação de esclerose múltipla recorrente-remitente e progressiva secundária: um estudo de ressonância magnética com espectroscopia baseado em aprendizado de máquina

ABSTRACT Introduction: Magnetic resonance imaging (MRI) is the most important tool for diagnosis and follow-up in multiple sclerosis (MS). The discrimination of relapsing-remitting MS (RRMS) from secondary progressive MS (SPMS) is clinically difficult, and developing the proposal presented in this study would contribute to the process. Objective: This study aimed to ensure the automatic classification of healthy controls, RRMS, and SPMS by using MR spectroscopy and machine learning methods. Methods: MR spectroscopy (MRS) was performed on a total of 91 participants, distributed into healthy controls (n=30), RRMS (n=36), and SPMS (n=25). Firstly, MRS metabolites were identified using signal processing techniques. Secondly, feature extraction was performed based on MRS Spectra. N-acetylaspartate (NAA) was the most significant metabolite in differentiating MS types. Lastly, binary classifications (healthy controls-RRMS and RRMS-SPMS) were carried out according to features obtained by the Support Vector Machine algorithm. Results: RRMS cases were differentiated from healthy controls with 85% accuracy, 90.91% sensitivity, and 77.78% specificity. RRMS and SPMS were classified with 83.33% accuracy, 81.81% sensitivity, and 85.71% specificity. Conclusions: A combined analysis of MRS and computer-aided diagnosis may be useful as a complementary imaging technique to determine MS types.

RESUMO Introdução: A ressonância magnética é a ferramenta mais importante para o diagnóstico e acompanhamento na EM. A transição da EM recorrente-remitente (EMRR) para a EM progressiva secundária (EMPS) é clinicamente difícil e seria importante desenvolver a proposta apresentada neste estudo a fim de contribuir com o processo. Objetivo: o objetivo deste estudo foi garantir a classificação automática de grupo controle saudável, EMRR e EMPS usando a RM com espectroscopia e métodos de aprendizado de máquina. Métodos: Os exames de RM com espectroscopia foram realizados em um total de 91 amostras com grupo controle saudável (n=30), EMRR (n=36) e EMPS (n=25). Em primeiro lugar, os metabólitos da RM com espectroscopia foram identificados usando técnicas de processamento de sinal. Em segundo lugar, a extração de recursos foi realizada a partir do MRS Spectra. O NAA foi determinado como o metabólito mais significativo na diferenciação dos tipos de MS. Por fim, as classificações binárias (Healthy Control Group-RRMS e RRMS-SPMS) foram realizadas de acordo com as características obtidas por meio do algoritmo Support Vector Machine. Resultados: Os casos de EMRR e do grupo de controle saudável foram diferenciados entre si com 85% de acerto, 90,91% de sensibilidade e 77,78% de especificidade, respectivamente. A EMRR e a EMPS foram classificadas com 83,33% de acurácia, 81,81% de sensibilidade e 85,71% de especificidade, respectivamente. Conclusões: Uma análise combinada de RM com espectroscopia e abordagem de diagnóstico auxiliado por computador pode ser útil como uma técnica de imagem complementar na determinação dos tipos de EM.

A Novel, Integrative Approach for Evaluating Progression in Multiple Sclerosis: Development of a Scoring Algorithm.

BACKGROUND: There is an unmet need for a tool that helps to evaluate patients who are at risk of progressing from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis (SPMS). A new tool supporting the evaluation of early signs suggestive of progression in multiple sclerosis (MS) has been developed. In the initial stage, concepts relevant to progression were identified using a mixed method approach involving regression on data from a real-world observational study and qualitative research with patients and physicians. The tool was drafted in a questionnaire format to assess these variables. OBJECTIVE: This study aimed to develop the scoring algorithm for the tool, using both quantitative and qualitative research methods. METHODS: The draft scoring algorithm was developed using two approaches: quantitative analysis of real-world data and qualitative analysis based on physician interviews and ranking and weighting exercises. Variables that were included in the draft tool and regarded as most clinically relevant were selected for inclusion in a multiple logistic regression. The analyses were run using physician-reported data and patient-reported data. Subsequently, a ranking and weighting exercise was conducted with 8 experienced neurologists as part of semistructured interviews. Physicians were presented with the variables included in the draft tool and were asked to rank them in order of strength of contribution to progression and assign a weight by providing a percentage of the overall contribution. Physicians were also asked to explain their ranking and weighting choices. Concordance between physicians was explored. RESULTS: Multiple logistic regression identified age, MS disease activity, and Expanded Disability Status Scale score as the most significant physician-reported predictors of progression to SPMS. Patient age, mobility, and self-care were identified as the strongest patient-reported predictors of progression to SPMS. In physician interviews, the variables ranked and weighted as most important were stability or worsening of symptoms, intermittent or persistent symptoms, and presence of ambulatory and cognitive symptoms. Across all physicians, the level of concordance was 0.278 (P<.001), indicating a low to moderate, but statistically significant, level of agreement. Variables were categorized as high (n=8), moderate (n=8), or low (n=10) importance based on the findings from the different approaches described above. Accordingly, the respective questions in the tool were assigned a weight of "three," "two," or "one" to inform the draft scoring algorithm. CONCLUSIONS: This study further confirms the need for a tool to provide a consistent, comprehensive approach across physicians to support the early evaluation of signs indicative of progression to SPMS. The novel and comprehensive approach to develop the draft scoring algorithm triangulates data obtained from ranking and weighting exercises, qualitative interviews, and a real-world observational study. Variables that go beyond the clinically most obvious impairment in lower limbs have been identified as relevant subtle/sensitive signs suggestive of progressive disease.

Factors influencing multiple sclerosis disease-modifying treatment prescribing decisions in the United Kingdom: A qualitative interview study.

BACKGROUND: The proportion of people with relapsing-remitting multiple sclerosis prescribed disease modifying treatments (DMTs) in the United Kingdom (UK) is considered low compared with other countries. There are differences in DMT prescription rates between UK nations (England, Wales, Scotland, Northern Ireland). Despite this, there has been little research into decision-making processes and prescribing practices. OBJECTIVE: To investigate views and experiences of neurologists prescribing DMTs and MS specialist nurses to identify factors influencing prescribing. METHODS: Semi-structured interviews with 18 consultant neurologists and 16 specialist nurses from diverse settings across the four UK nations. Data were analysed using thematic framework analysis. RESULTS: Prescribing practices are influenced by organisational prescribing "cultures", informal "benchmarking" within peer networks, and prior experience with different DMTs. Health professionals differ in their perceptions of benefits and risks of DMTs and personal "thresholds" for discerning relapses and determining eligibility for DMTs. Prescribers in England felt most constrained by guidelines. CONCLUSION: To achieve equity in access to DMTs for people with MS eligible for treatment, there is a need for public discussion acknowledging differences in health professionals' interpretations of "relapses" and guidelines and perceptions of DMTs, variation in organisational prescribing "cultures", and whether the prevailing culture sufficiently meets patients' needs.

Uncovering the association between fatigue and fatigability in multiple sclerosis using cognitive control.

BACKGROUND: Fatigue and cognitive dysfunction are two common symptoms experienced by patients with multiple sclerosis (MS). The relationship between subjective and objective fatigue (fatigability) in MS is poorly understood. Cognitive control tasks might be more conducive to fatigability and more likely to show associations between subjective and objective cognitive fatigue in MS. OBJECTIVE: To study the association between objective fatigability, as induced by a cognitive control task called the Blocked Cyclic Naming Task (BCNT), subjective fatigue and baseline cognitive functioning in patients with MS. METHODS: Twenty-one patients with MS completed baseline questions about their disease, the Montreal Cognitive Assessment (MoCA) battery and self-reported questionnaires on trait fatigue, sleep and depression. Disability was captured using the expanded disability status scale (EDSS). Participants then performed the BCNT and were asked about their level of state momentary fatigue before and after the BCNT. The BCNT consists of several blocks of either related or unrelated pictures that participants name as quickly as possible. The pictures cycled 4 times in each block and the difference in the response times (RTs) between related and unrelated blocks was captured. Data were analyzed using repeated measures analysis of variance and Pearson correlations. RESULTS: MS participants' performance declined for the related, but not unrelated blocks. The difference in RTs between related and unrelated conditions increased with repetition across cycles (p < 0.001). Participants also showed objective fatigability with less repetition priming (p = 0.02) in the 4th quarter and with greater differences between related and unrelated conditions in the later part of the task. Objective fatigability was strongly associated with participants' assessment of their level of momentary state fatigue (r = 0.612, p = 0.007). CONCLUSION: Using the appropriate tools, this study showed an association between subjective and objective cognitive fatigue in people with MS. The BCNT and cognitive control are useful tools in assessing patients with MS and should be explored in future, larger studies in this population.

Evaluation of patients with relapsing-remitting multiple sclerosis using tract-based spatial statistics analysis: diffusion kurtosis imaging.

BACKGROUND: Diffusion kurtosis imaging (DKI) has the potential to provide microstructural insights into myelin and axonal pathology with additional kurtosis parameters. To our knowledge, few studies are available in the current literature using DKI by tract-based spatial statistics (TBSS) analysis in patients with multiple sclerosis (MS). The aim of this study is to assess the performance of commonly used parameters derived from DKI and diffusion tensor imaging (DTI) in detecting microstructural changes and associated pathology in relapsing remitting MS (RRMS). METHODS: Thirty-six patients with RRMS and 49 age and sex matched healthy controls underwent DKI. The brain tissue integrity was assessed by fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da), radial diffusivity (Dr), mean kurtosis (MK), axial kurtosis (Ka) and radial kurtosis (Kr) of DKI and FA, MD, Da and Dr of DTI. Group differences in these parameters were compared using TBSS (P < 0.01, corrected). To compare the sensitivity of these parameters in detecting white matter (WM) damage, the percentage of the abnormal voxels based on TBSS analysis, relative to the whole skeleton voxels for each parameter was calculated. RESULTS: The sensitivities in detecting WM abnormality in RRMS were MK (78.2%) > Kr (76.7%) > Ka (53.5%) and Dr (78.8%) > MD (76.7%) > FA (74.1%) > Da (28.3%) for DKI, and Dr (79.8%) > MD (79.5%) > FA (68.6%) > Da (40.1%) for DTI. DKI-derived diffusion parameters (FA, MD, and Dr) were sensitive for detecting abnormality in WM regions with coherent fiber arrangement; however, the kurtosis parameters (MK and Kr) were sensitive to discern abnormalities in WM regions with complex fiber arrangement. CONCLUSIONS: The diffusion and kurtosis parameters could provide complementary information for revealing brain microstructural damage in RRMS. Dr and DKI_Kr may be regarded as useful surrogate markers for reflecting pathological changes in RRMS.

The changing multiple sclerosis treatment landscape: impact of new drugs and treatment recommendations.

PURPOSE: The purpose of this study is to describe the utilization of disease-modifying treatments (DMTs) in relapsing-remitting multiple sclerosis (MS) and assess the impact of both the introduction of new drugs and treatment recommendations (local recommendation on rituximab use issued at the largest MS clinic in Stockholm and regional Drug and Therapeutics Committee (DTC) recommendation on how dimethyl fumarate should be used). METHODS: Interrupted time series analyses using monthly data on all MS patients treated with DMTs in the Stockholm County, Sweden, from January 2011 to December 2017. RESULTS: There were 4765 individuals diagnosed with MS residing in the Stockholm County from 2011 to 2017. Of these, 2934 (62%) were treated with an MS DMT. Since 2011, fingolimod, alemtuzumab, teriflunomide, dimethyl fumarate, peginterferon beta-1a, and daclizumab were introduced. Only fingolimod and dimethyl fumarate significantly impacted MS DMT utilization. In parallel, the use of rituximab off-label increased steadily, reaching 58% of all DMT-treated MS patients by the end of the study period. The local recommendation on rituximab was associated with an increase in rituximab use. The regional DTC recommendation on dimethyl fumarate was associated with a decrease in dimethyl fumarate use. CONCLUSIONS: Three MS DMTs-fingolimod, dimethyl fumarate, and rituximab off-label-impacted MS DMT utilization in the Stockholm County. The associations between the treatment recommendations and the subsequent changes in MS DMT utilization indicate that such interventions can influence the uptake and utilization of new drugs used in the specialized care setting.

Persistence with dimethyl fumarate in relapsing-remitting multiple sclerosis: a population-based cohort study.

PURPOSE: To describe patients initiating dimethyl fumarate (DMF) and measure persistence with DMF, discontinuation, and switching in treatment-naïve DMF patients and patients switching to DMF from other multiple sclerosis disease-modifying treatments (DMTs). METHODS: A population-based cohort study of all Stockholm County residents initiating DMF from 9 May 2014 until 31 May 2017. All data were derived from a regional database that collects individual-level data on healthcare and drug utilization of all residents. The study outcomes were persistence with DMF and DMF discontinuation and switching to other DMTs. Persistence was measured as the number of days until either DMF discontinuation (treatment gap ≥ 60 days) or switching to another DMT. RESULTS: The study included 400 patients (median follow-up = 2.5 years). The majority had previously been treated with other DMTs (61%). Throughout the follow-up period, 124 patients (31%) discontinued DMF and 114 patients (29%) switched treatment. Overall, 34% of patients initiating DMF stopped treatment within 1 year and only 43% of patients remained on DMF at 2 years from treatment initiation. CONCLUSIONS: DMF had a rapid market uptake likely due to high expectations held by both patients and clinicians. However, persistence with DMF in routine clinical practice was found to be low.

[Relapsing-remitting multiple sclerosis at remission stage treated with acupuncture:a randomized controlled trial].

OBJECTIVE: To evaluate the differences in the therapeutic effects on relapsing-remitting multiple sclerosis (RRMS) at remission stage between acupuncture at acupoints and shallow needling therapy at the nearby points. METHODS: Forty-two patients of RRMS were randomized into an observation group and a control group, 21 cases in each one. In the observation group, besides the basic treatment, acupuncture was applied according to WANG Leting's empirical prescriptions as "the empirical ten needles" "thirteen needles of the governor vessel" "twelve needles of hand and foot" as well as the symptomatic points. In the control group, the basic treatment was given. Additionally, the shallow needling therapy was given at the sites 0.2 to 0.3 cun lateral to the acupoints, and the arrival of qi was not required. In the two groups, acupuncture was given once a day for 5 days a week, continuously for 2 weeks. At the intervals of 2 weeks, totally the treatment of 3 months was required. The follow-up visit was conducted for 2 years. Separately, the scores of the expanded disability status scale (EDSS) before and in follow-up after treatment, the annual recurrent rate before and after treatment and recurrent interval after treatment were observed in the patients of the two groups. RESULTS: In the observation group, EDSS scores in 3-month and 6-month follow-up were reduced as compared with those before treatment (both P<0.05) and those in the 12-month and 24-month follow-up were increased (both P<0.05). In the control group, EDSS scores were increased in tendency continuously in 3-month, 6-month, 12-month and 24-month follow-up (all P<0.05). In each time point of follow-up, the different value of EDSS scores in the observation group was lower than that in the control group (P<0.05, P<0.01). The annual recurrent rates after treatment were reduced as compared with those before treatment in the two groups (both P<0.01) and the value in the observation group was lower than that in the control group (P<0.01). The recurrent interval in the observation group was longer than that in the control group[(441.56±65.37) d vs (382.78±59.33) d, P<0.01]. CONCLUSIONS: Acupuncture achieves the significant therapeutic effects on RRMS at the remission stage. This therapy relieves the symptoms of neural functional deficits, delays the time of occurrence and reduces the annual recurrent rate.

Peginterferon beta-1a reduces the evolution of MRI lesions to black holes in patients with RRMS: a post hoc analysis from the ADVANCE study.

The presence of chronic black holes, i.e., chronic lesions that are hypointense on T1-weighted images and are indicative of more severe tissue injury, has been increasingly utilized as a surrogate marker of therapeutic outcome in multiple sclerosis. The ADVANCE study was a 2-year, double-blind, pivotal trial evaluating the safety and efficacy of subcutaneous peginterferon beta-1a 125 mcg in 1512 patients with relapsing-remitting multiple sclerosis (RRMS). This report describes the correlation of clinical outcomes with the evolution of acute lesions into chronic black holes in ADVANCE, and the efficacy of peginterferon beta-1a in reducing this evolution. Treatment with peginterferon beta-1a significantly reduced the mean number of new/enlarging T2-weighted (NET2) lesions (0.76 vs. 1.03 from week 24, p = 0.0037; 0.44 vs. 0.99 from week 48, p < 0.0001) and new gadolinium-enhancing (Gd+) lesions (0.15 vs. 0.32 from week 24, p < 0.0001; 0.09 vs. 0.19 from week 48) that evolved into chronic black holes by 2 years. Patients with NET2 or Gd+ lesions at 24 weeks that evolved into chronic black holes showed significantly worse clinical outcomes, including a greater proportion with 12-week (14.9 vs. 8.4%; p = 0.0167) and 24-week (12.3 vs. 7.0%; p = 0.0333) confirmed disability worsening and higher mean annualized relapse rate (0.62 vs. 0.43; p = 0.0118), compared with patients with lesions that did not evolve into black holes. The correlation was independent of treatment. Reduced risk of evolution of new lesions into chronic black holes with peginterferon beta-1a treatment suggests potential to reduce long-term disability in RRMS by preventing irreversible tissue damage.