Rituximab en el tratamiento de esclerosis múltiple. Experiencia de un hospital de tercer nivel en México / Rituximab in the treatment of multiple sclerosis. Experience of a tertiary care hospital in Mexico

Resumen Antecedentes: La esclerosis múltiple es una enfermedad crónica, autoinmune y degenerativa. Las terapias blanco contra los linfocitos B han probado ser efectivas en su tratamiento; sin embargo, existen pocos estudios que evalúen su eficacia en población mexicana. Objetivo: Evaluar el impacto clínico del rituximab en pacientes con esclerosis múltiple remitente recurrente (EMRR) de reciente diagnóstico. Material y métodos: Estudio de vida real, descriptivo, en el que se evalúa rituximab como tratamiento de EMRR durante un periodo de 24 meses. Se analizaron variables clínicas pre y postratamiento; se realizó la comparación entre pacientes naïve y no naïve. Resultados: Se incluyeron 28 pacientes con EMRR. La edad media al diagnóstico fue de 30.7 años y 22 pacientes fueron naïve (78.5 %). Después de 24 meses, se observó una reducción media de 1.8 puntos en EDSS y en el número de lesiones activas por resonancia magnética. Aunque se logró establecer una diferencia significativa en ambas variables con p < 0.05, el modelo de regresión logística no mostró una relación entre las variables para alcanzar un NEDA-3. No se observaron eventos adversos graves. Conclusiones: El tratamiento con rituximab resultó en mejoría significativa clínica y radiológica en pacientes mexicanos con EMRR naïve y no-naïve.

Abstract Background: Multiple sclerosis is a chronic, autoimmune, degenerative disease. Therapies targeting B-cells have been shown to be effective in its treatment; however, there are few studies evaluating their efficacy in the Mexican population. Objective: To evaluate the clinical impact of rituximab in patients with newly-diagnosed relapsing-remitting multiple sclerosis (RRMS). Material and methods: Real life, descriptive study, in which rituximab was evaluated as treatment for RRMS over a 24-month period. Pre- and post-treatment clinical variables were analyzed; a comparison was made between treatment-naïve and non-treatment-naïve patients. Results: Twenty-eight patients with RRMS were included. Mean age at diagnosis was 30.7 years, and 22 patients were treatment-naïve (78.5 %). After 24 months, there was a mean reduction of 1.8 points in the EDSS scale and a decrease in the number of active lesions on magnetic resonance imaging; a significant difference in both variables could be established (p < 0.05). However, the logistic regression model did not show a relationship between the variables for achieving NEDA-3 criteria. No serious adverse events were observed. Conclusions: Treatment with rituximab resulted in significant clinical and radiological improvement in treatment-naïve and non-treatment-naïve Mexican patients with RRMS.

Postural Control in Relapsing-Remitting Multiple Sclerosis

Abstract Introduction Postural instability is considered one of the most disabling symptoms of relapsing-remitting multiple sclerosis (RRMS). Objective To evaluate postural control in patients with RRMS. Method A total of 79 individuals between 18 and 65 years old, of both genders, were distributed into an experimental group composed of patients with RRMS (n = 51) and in a control group composed by healthy individuals (n = 28). The evaluation consisted of anamnesis, Dizziness Handicap Inventory (DHI), visual vertigo analog scale (WAS), and static posturography (Tetrax IBS). Results Patients with RRMS presented mild degree in the DHI and in the VVAS; in Tetrax IBS, they presented higher or lower values of the indices of general stability, weight distribution, synchronization of postural oscillation, fall risk, and frequency bands of postural oscillation in two, five or all eight sensory conditions, in relation to the control group. Vestibular, visual and/or somatosensory dysfunction of peripheral type (51.0%) prevailed over the central type. The RRMS group, with an expanded scale of disability status > 3 points, presented a higher fall risk than with a score ≤ 3 points (p = 0.003). There was a positive correlation of the Fall Risk Index with the total DHI Score (s = 0.380; p = 0.006) and with the VVAS score (s = 0.348; p = 0.012). Conclusion Patients with RRMS may present with inability to maintain postural control due to general instability, desynchronization and increased postural oscillation at frequencies that suggest deficiencies in the vestibular, visual, and somatosensory systems; as well as fall risk related to the state and intensity of functional disability and self-perception of the influence of dizziness on quality of life.

Respuesta al tratamiento con Interferón beta-1a en pacientes con esclerosis múltiple remitente-recurrente / Response to treatment with Interferon beta-1a in patients with relapsing-remitting multiple sclerosis

RESUMEN Fundamento: los fármacos modificadores, en la esclerosis múltiple, tienen la finalidad de reducir la frecuencia de recaídas, retardar la progresión de la discapacidad, así como la aparición de nuevas lesiones en el Sistema Nervioso Central. Objetivo determinar los indicadores precoces de respuesta al tratamiento con IFNb-1ª en pacientes con esclerosis múltiple remitente-recurrente. Métodos: estudio observacional, analítico de cohorte con prospectiva longitudinal en los pacientes con diagnóstico de esclerosis múltiple. Se conformaron dos cohortes de estudio, cada una con 39 pacientes. Resultados: la media y desviación estándar de la escala ampliada del estado de discapacidad a los 36 meses fue de 2.37 ± 1.86 en el grupo estudio y en el control de 3.15 ± 2.1. En los brotes de .13 ± .33 en el grupo estudio y en el grupo control de .41 ± .59. Las lesiones nuevas en T2 tras los 12 primeros meses de tratamiento fue de 0.90 ± 1.16 para el grupo estudio y para el control de 1 ± 1.10. La progresión por escala ampliada del estado de discapacidad, la tasa anualizada de brotes antes del tratamiento, la edad de inicio de la enfermedad, tiempo de evolución de la enfermedad y lesiones que realzan gadolinio se asociaron de forma significativa con la razón de ventaja de mayor probabilidad de no progresión para el grupo estudio con respecto al grupo control por la variable combinada progresión por escala ampliada del estado de discapacidad y brotes. Conclusiones: se identificaron indicadores precoces de respuesta al tratamiento con el interferón beta-1a, que ayudan a valorar la respuesta al tratamiento de forma precoz, lo que repercute de forma positiva en la evolución de la enfermedad.

ABSTRACT Background: multiple sclerosis modifying drugs are intended to reduce the frequency of relapses, delay the progression of disability, as well as the appearance of new lesions in the Central Nervous System. Objective: to determine the early indicators of response to treatment with IFNb-1a. Methods: Observational, analytical longitudinal prospective cohort study in patients diagnosed with multiple sclerosis. Two study cohorts were formed, each with 39 patients. Results the mean and standard deviation of the expanded disability status scale at 36 months was 2.37 ± 1.86 in the study group and 3.15 ± 2.1 in the control group. In the outbreaks of .13 ± .33 in the study group and in the control group of .41 ± .59. New lesions in T2 after the first 12 months of treatment was 0.90 ± 1.16 for the study group and 1 ± 1.10 for the control. Extended-scale progression of disability status, pretreatment annualized relapse rate, age of disease onset, time since disease progression, and gadolinium-enhancing lesions were significantly associated with the odds ratio of older Probability of non-progression for the study group with respect to the control group for the combined variable progression by extended disability status scale and relapses. Conclusions: early indicators of response to treatment with interferon beta-1a were identified; that help assess the response to treatment early, which has a positive impact on the evolution of the disease.

Neurorrestauración integral en pacientes con esclerosis múltiple remitente-recurrente: estudio piloto / Comprehensive neurorestoration in patients with relapsing-remitting multiple sclerosis: a pilot study

Introducción: La neurorrestauración integral en la esclerosis múltiple mejora los déficits funcionales. Dentro de la atención de las personas con la enfermedad, se ha incluido la valoración de la calidad de vida relacionada con la salud, que es un elemento clave para la evaluación subjetiva de las influencias del estado de salud actual. Objetivo: Determinar la influencia de la neurorrestauración integral en la calidad de vida relacionada con la salud de los pacientes con esclerosis múltiple remitente-recurrente. Material y Métodos: Se realizó un estudio cuasi-experimental en 78 pacientes con esclerosis múltiple remitente-recurrente, tratados en el Hospital Universitario Clínico-quirúrgico Arnaldo Milián Castro de Santa Clara, en el periodo comprendido entre enero de 2014 a diciembre de 2020. Los pacientes se distribuyeron aleatoriamente en un grupo estudio y un grupo control, asignados por sorteo. Resultados: En cuanto a las actividades de la vida diaria mostró una media al final de la intervención de 95,89 para el grupo estudio; y para el grupo control de 81,28. Posterior a la intervención se evidenció una mejoría del funcionamiento de la calidad de vida relacionada con la salud del grupo estudio en los componentes de la escala en comparación con los controles. Conclusiones: se determinó como el desarrollo de intervenciones promueven el mayor bienestar posible de los pacientes con esclerosis múltiple remitente-recurrente a través de la neurorrestauración integral(AU)

Introduction: Comprehensive neurorestoration in Multiple Sclerosis improves functional deficits. The assessment of health-related quality of life, which is a key element for the subjective evaluation of the influences of the current state of health, has been included in the care of people with the disease. Objective: To determine the influence of comprehensive neurorestoration on the health-related quality of life of patients with relapsing-remitting multiple sclerosis. Material and Methods: A quasi-experimental study was carried out in 78 patients with relapsing-remitting multiple sclerosis treated at the "Arnaldo Milián Castro" Clinical-Surgical University Hospital in Santa Clara, in the period between January 2014 and December 2020. The patients were randomly assigned to a study group and a control group. Results: Regarding activities of daily living, the study group showed a mean of 95.89 at the end of the intervention, while the control group showed a mean of 81.28. After the intervention, an improvement in the functioning of the health-related quality of life of the study group was evidenced in the components of the scale, compared with the controls. Conclusions: It was determined that the development of interventions through comprehensive neurorestoration promote the best possible well-being of patients with relapsing-remitting multiple sclerosis(AU)

Efectividad del tratamiento neurorrehabilitador integral en la función cognitiva de los pacientes con esclerosis múltiple remitente recurrente

RESUMEN Fundamento: las alternativas terapéuticas en pacientes con esclerosis múltiple no deben centrar sus esfuerzos en la rehabilitación de dominios cognitivos específicos, sino valorar el empleo de estrategias de intervención multimodal, con el propósito de minimizar los factores negativos que intervienen en la salud cognitiva de estos. Objetivo: determinar la efectividad del tratamiento neurorrehabilitador integral en la función cognitiva de los pacientes con esclerosis múltiple remitente recurrente. Métodos: se realizó un estudio cuasiexperimental con dos grupos (un grupo estudio y un grupo control) en pacientes con diagnóstico de esclerosis múltiple remitente recurrente. Cada grupo quedó conformado por 39 pacientes. Los métodos estadísticos exigieron la utilización de un estudio de pruebas repetidas, variante de ANOVA. Para las pruebas de dos momentos se utilizó el concepto de ANOVA de un factor. Resultados: después de la intervención se obtuvo en el grupo de estudio, un aumento de las puntuaciones en las pruebas de velocidad de procesamiento, memoria de trabajo-flexibilidad cognitiva, fluidez verbal y el control inhibitorio; así como disminución en los niveles de fatiga. Se comprobó una mejoría significativa en el estado emocional del grupo de estudio, pues hubo disminución del estado de ansiedad y depresión. Conclusiones: el proceso de neurorrehabilitación integral resultó efectivo al disminuir en los pacientes los niveles de depresión y ansiedad, además de mejorar el funcionamiento cognitivo en el grupo de pacientes que completó el proceso, lo que muestra la viabilidad de un enfoque de neurorrehabilitación integral y su utilidad para mejorar la calidad de vida en adultos con esclerosis múltiple.

ABSTRACT Background: Therapeutic alternatives should not focus their efforts on the rehabilitation of specific cognitive domains, but value the use of multimodal intervention strategies, with the purpose of minimizing the negative factors that intervene in the cognitive health of patients with multiple sclerosis. Objective: to determine the effectiveness of comprehensive neurorehabilitation treatment on the cognitive function of patients with relapsing-remitting multiple sclerosis. Methods: a quasi-experimental study was carried out with two groups (a study group and a control group) in patients diagnosed with relapsing-remitting multiple sclerosis. Each group was made up of 39 patients. Statistical methods required the use of a repeated test study, variant of ANOVA. For the two-moment tests, the one-way ANOVA concept was used. Results: after the intervention, in the study group, an increase in the scores in the tests of processing speed, working memory-cognitive flexibility, verbal fluency and inhibitory control was obtained; as well as decreased levels of fatigue. A significant improvement in the emotional state of the study group was verified, showing a decrease in the state of anxiety and depression. Conclusions: the comprehensive neurorehabilitation process was effective in reducing depression and anxiety levels in patients, in addition to improving cognitive functioning in the group of patients who completed the process, which shows the viability of a comprehensive neurorehabilitation approach and its effectiveness utility to improve quality of life in adults with multiple sclerosis.

Evolución clínica de pacientes con esclerosis múltiple remitente- recurrente tratados con interferón beta-1a / Clinical evolution of patients with relapsing-remitting multiple sclerosis treated with interferon beta-1a

RESUMEN Introducción: El inicio de la terapia con interferón ha sido y es el primer paso en el tratamiento de muchos pacientes con esclerosis múltiple, con el propósito de retrasar la progresión de la enfermedad. Objetivo: Identificar los marcadores clínicos de respuesta al tratamiento con interferón beta-1a de pacientes con esclerosis múltiple remitente-recurrente. Métodos: Se realizó un estudio observacional, descriptivo, longitudinal, prospectivo, de una serie de casos de pacientes con diagnóstico de esclerosis múltiple remitente-recurrente, que recibían tratamiento con interferón beta-1a, en el periodo comprendido entre enero del 2014 a diciembre del 2020. Se incluyeron los 39 pacientes. Resultados: La media de edad fue de 34,54 años. La media del nivel de discapacidad en la línea base, 12, 24 y a los 36 meses fue de 1,76; 1,91; 2,1 y 2,37 respectivamente. La media de los brotes en la línea base, 12, 24 y a los 36 meses fue de 1,13; 0,26; 0,38 y 0,13 respectivamente. Se muestra la cifra de progresiones inferior en un 51 % a los 36 meses. La razón de ventajas (odds ratio) para la no presencia de brotes se muestra entre 2 y 4 veces en estos pacientes. Conclusiones: Se identifican marcadores clínicos de respuesta al tratamiento con interferón beta-1a que ayudan a valorar la respuesta al tratamiento, lo cual repercute de forma positiva en la evolución de la enfermedad.

ABSTRACT Introduction: The initiation of interferon therapy has been and is the first step in the treatment of many patients with multiple sclerosis, with the aim of delaying the progression of the disease. Objective: To identify the clinical markers of response to treatment with Interferon beta-1a in patients with relapsing-remitting multiple sclerosis. Methods: An observational, descriptive, longitudinal, prospective study was carried out of a series of cases of patients diagnosed with relapsing-remitting multiple sclerosis, who received treatment with interferon beta-1a, in the period between January 2014 and December 2020. All 39 patients were included. Results: The mean age was 34.54 years. The mean disability level at baseline, 12, 24, and 36 months was 1.76; 1.91; 2.1 and 2.37 respectively. The mean number of flares at baseline, 12, 24, and 36 months was 1.13; 0.26; 0.38 and 0.13 respectively. The number of progressions lower by 51% at 36 months is shown. The odds ratio for the absence of relapses is between 2 and 4 times in these patients. Conclusions: Clinical markers of response to treatment with Interferon beta-1a are identified that help assess the response to treatment, which has a positive impact on the evolution of the disease.

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.

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.

Cladribina oral para o tratamento da esclerose múltipla remitente-recorrente altamente ativa: análise de impacto orçamentário sob a perspectiva do sistema brasileiro de saúde suplementar / Cladribine tablets for the treatment of highly active recurrent multiple sclerosis: budget impact analysis from the perspective of the Brazilian supplementary health system

Objetivo: Avaliar o impacto orçamentário da inclusão da cladribina oral no tratamento de esclerose múltipla remitente-recorrente em alta atividade da doença (EMRR HDA) no Sistema de Saúde Suplementar (SSS). Métodos: Foi conduzida uma análise de impacto orçamentário, sob a perspectiva do SSS, com horizonte temporal de quatro anos, considerando a abordagem de coorte aberta na qual o número de pacientes elegíveis para tratamento varia em cada ano com a introdução de novos pacientes diagnosticados de EMRR HDA e a retirada de indivíduos prevalentes devido a morte ou progressão secundária. Foram considerados custos médicos diretos, incluindo a aquisição e administração de medicamentos, monitoramento, eventos adversos e surtos. Os comparadores utilizados na análise foram: alentuzumabe, fingolimode, natalizumabe e ocrelizumabe. Os custos foram apresentados em real brasileiro (BRL). Resultados: O custo incremental da inclusão da cladribina oral para o SSS foi estimado em 463.265 BRL, 739.691 BRL, -1.414.963 BRL, -3.719.007 BRL, nos anos 1, 2, 3 e 4, respectivamente. Isso resultou em um custo incremental total de -3.931.015 BRL no período analisado, representando 1,5% da redução orçamentária total no tratamento de EMRR HDA. Conclusão: A inclusão da cladribina oral para o tratamento de pacientes com diagnóstico de EMRR HDA poderia gerar uma economia substancial para o sistema brasileiro de saúde suplementar, atingindo um valor de cerca de 3,9 milhões de BRL em um período de quatro anos

Objective: To evaluate the budget impact of adopting cladribine tablets as a treatment strategy for relapsing remitting multiple sclerosis with high disease activity (RRMS HDA), from the Brazilian private healthcare system perspective. Methods: A budget impact analysis, under private healthcare system perspective, with a 4-years time horizon was conducted, considering the open cohort approach in which the number of patients eligible for treatment varies each year with the introduction of newly diagnosed RRMS HDA patients and the drop out of prevalent individuals due to death or secondary progression. Direct medical costs, including acquisition, drug administration, monitoring, adverse events and relapses were considered. Comparators used in the analysis were: alentuzumab, fingolimod, natalizumab and ocrelizumab. Costs were presented in Brazilian real (BRL). Results: The incremental cost of incorporating cladribine tablets into the private healthcare system was estimated at 463,265BRL, 739,961BRL, -1,414,963 BRL, -3,716,007 BRL, in years 1, 2, 3 and 4, respectively. This resulted in a total incremental cost of -3,931,015 BRL over the period analyzed, representing 1.5% of the total budget reduction in the treatment of RRMS HDA. Conclusion: Incorporation of cladribine tablets for the management of RRMS HDA could generate substantial savings for the private healthcare system, reaching a value of approximately 3.9 million BRL in a 4-years period

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.

Medicamentos modificadores en esclerosis múltiple: esquemas terapéuticos actuales / Disease-Modifying drugs in multiple sclerosis: current therapeutic schemes

La esclerosis múltiple (EM) es una enfermedad crónica, autoinmune y neurodegenerativa; que tiene como principal característica la desmielinización de los axones en el sistema nervioso. Los medicamentos modificadores de la enfermedad (MME) logran retrasar la aparición de los síntomas y modificar parcialmente el progreso de la desmielinización y daño neuronal, resultando cada vez más complejo determinar un esquema terapéutico estandarizado según la condición particular de cada paciente. En este artículo se presenta una revisión actualizada de la evidencia clínica que ha llevado al uso de los esquemas terapéuticos en EM. La mayoría de los medicamentos aprobados actualmente son utilizados para la EM remitente-recurrente y se pueden dividir de acuerdo a la eficacia y seguridad. Los medicamentos de primera línea han mostrado una baja o moderada eficacia y alta seguridad; después de usar estos fármacos sin lograr una buena respuesta o ante una enfermedad avanzada se usan medicamentos de segunda y tercera línea que tienen una alta eficacia, pero son menos seguros, presentando mayores efectos secundarios y riesgos asociados para los pacientes. El ocrelizumab es el único fármaco aceptado para la EM primaria progresiva y el siponimod fue aprobado como una alternativa para la EM secundaria progresiva. El desarrollo de nuevos medicamentos y el seguimiento clínico de los ya aprobados permitirá establecer un mejor abordaje terapéutico logrando así mejorar la calidad de vida de cada paciente.

Multiple sclerosis (MS) is a chronic, autoimmune and neurodegenerative disease; whose main characteristic is the demyelination of axons in the nervous system. Disease-modifying drugs (DMD) can delay the onset of symptoms and partially modify the progression of demyelination and neuronal damage, making it increasingly complex to determine a standardized therapeutic scheme that is individualized to each patient. This article presents an updated review on the clinical evidence that has led to the use of current therapeutic schemes in MS with focus on DMD. Current medications in treating relapsing-remitting MS can be divided according to efficacy and safety. First-line drugs have shown low or moderate efficacy and high safety. Second- and third-line drugs are used after a poor response or in cases of advanced disease. These drugs are highly effective, but less safe, presenting greater side effects and associated risks for patients. Ocrelizumab is the only accepted drug for primary progressive MS and siponimod is accepted as an alternative for secondary progressive MS. The development of new medications and the clinical follow-up of those already approved will allow establishing a better therapeutic approach, thus improving the quality of life of each patient.

Evaluation of plasma soluble CD137 level in relapsing-remitting multiple sclerosis patients in comparison with healthy controls in Isfahan Province, Iran

@#Objective: Multiple sclerosis (MS) is a chronic neuroinflammatory disease, characterizes by demyelination in the central nervous system (CNS). Co-stimulatory molecules such as CD137 (4-1 BB) play a major role in the activation of lymphocytes in CNS. The exact immunopathogenesis of MS is unknown. Hence, detection of specific biomarkers in the process of MS disease can lead to new therapeutic approaches. This study aimed to compare plasma sCD137 levels in relapsing-remitting multiple sclerosis (RRMS) patients with healthy controls in Isfahan province. Methods: Plasma sCD137 level was measured by enzyme-linked immune sorbent assays (ELISA) in 36 RRMS patients as well as 52 (age and sex-matched) healthy controls and the results were compared. Results: The plasma sCD137 level in studied RRMS patients was significantly higher in the patient group compared to the healthy controls (P- value=0.027). In addition, there was no significant association between age, sex, job and education level, with plasma sCD137 level in both the control and the case groups (P value>0.05). There was no correlation between mean of sCD137 and EDSS score, age of onset, duration of disease as well as serum 25 (OH) D concentrations of the patients. Conclusion: High plasma sCD137 level was detected in RRMS patients when compared with the controls, which may indicate the possible role of this biomarker in the immunopathogenesis of MS. Since CD137 can affect T lymphocytes activation and apoptosis, further studies are needed to elucidate its exact role in the pathogenesis of MS.

Facial emotion recognition in patients with relapsing-remitting multiple sclerosis

@#Objective: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system and the most common cause of disability among young adults. In addition to physical and cognitive disturbances, MS patients also have emotional processing deficits. Despite the rich knowledge available about cognitive impairments, little is known about emotion recognition in patients with relapsing-remitting MS (RRMS), despite the fact that it plays a key role in social behavior. The aim of our study was to investigate facial emotion recognition in patients with RRMS, compared with healthy controls. Methods: Facial emotion recognition abilities were studied in a homogeneous group of 51 RRMS patients and 51 healthy controls, using the Persian version of the Florida Affect Battery. We controlled both groups for physical symptoms, anxiety, depression and social dysfunction, using general health questionnaire (GHQ-28). Patients and healthy controls were matched according to age and gender. Early stage of the disease was defined as being diagnosed with RRMS and having an EDSS of 4 or lower. Results: MS patients performed as well as healthy controls in facial identity discrimination and facial emotion discrimination tasks, but showed significantly less performance in other subtests that required emotion recognition in comparison with healthy controls. Conclusions: Facial emotion recognition is impaired at early stages of MS. MS patients have problems in their emotional processing system. Deficits in facial emotion recognition merit attention because they might negatively influence interpersonal relationships and quality of life in MS patients.

Prospective memory in patients with relapsing remitting Multiple Sclerosis

La Memoria Prospectiva (MP) es un conjunto de habilidades cognitivas que permite recordar y realizar acciones planeadas o intenciones demoradas. El objetivo de este estudio fue investigar la MP en pacientes con Esclerosis Múltiple Recaídas y Remisiones (EMRR) con dos pruebas experimentales que evalúan distintos aspectos de la MP. Se evaluaron 36 pacientes con EMRR y un grupo control de 35 voluntarios sanos (GC), apareados por edad y escolaridad. Se administró una batería de tests neuropsicológicos que incluye dos técnicas que evalúan la MP: El Cóndor y el Test de Memoria Prospectiva de Tareas Múltiples (MTPM). Los pacientes obtuvieron un puntaje más bajo que el GC (en puntaje total de El Cóndor, p = .007, d = 0.7). En el MTPM, el GC obtuvo significativamente más puntos en la Fase de Formación de la intención (p = .027, d = .5). El 63% de los pacientes versus el 88.5% del GC, autoiniciaron la intención (p = .014). Los pacientes que obtuvieron mejor puntaje en Formación, autoiniciaron más la acción proyectada (p = .012). La educación, la duración de la enfermedad y la depresión correlacionaron leve y significativamente con el Cóndor y el MTPM. La discapacidad física se relacionó sólo con la capacidad de autoiniciar del MTPM. Se concluye que la MP parece estar afectada negativamente en pacientes con EMRR. Se encontró un deterioro de la planificación y la autoiniciación de la intención. La autoniciación fue influenciada por la calidad de la planificación. Los resultados destacan la necesidad de evaluar objetivamente la MP en pacientes con EMRR para poder detectar cualquier alteración en las etapas iniciales de la enfermedad y comenzar una rehabilitación apropiada.

Prospective Memory (PM) is a set of cognitive abilities that allow us to remember to perform planned actions or delayed intentions. It requires the recall of the content of the planned task in the form of an intention to be able to execute it at the appropriate moment. Previous studies have yielded conflicting results as some show that MS patients have difficulty in remembering the content of intentions and others in the process of self-initiation of delayed intentions. Moreover, the relationship between PM and clinical variables also remains unclear. The aim of this study was to investigate PM in Relapsing-Remitting Multiple Sclerosis (RRMS) with two experimental tests that evaluate different aspects of the MP. Another aim of the current study was to analyse the relationship between PM and demographic variables and clinical variables. 36 outpatients with a diagnosis of RRMS attending to two centers specialized in multiple sclerosis clinics, were recruited. Thirty five healthy volunteers formed the contrast group (CG), matched for age, gender and education with the MS patients. A neuropsychological test battery that included two techniques for measuring PM was administered. The Condor Test consists of reading a text whilst simultaneously executing many actions. In the Multitask Prospective Memory (MTPM), the participant must remember to initiate a complex intention, which was previously planned. The test yields formation scores of the intention, initiation, plan retention capacity and finally two execution scores. A depression scale (Beck Depression Inventory, BDI-II) was administered and physical disability was revealed using the Expanded Disability Status Scale. In the RRMS group, the majority of patients (80.6%) had none or minimal signs of depression according to BDI-II classification criteria. Seventy five % of patients were in full- or half-time employment, 13.9% were unemployed or in occasional employment and 11.1% were house wives or retired on grounds of age. With respect to cognitive performance 47.2% of MS patients presented cognitive impairment. RRMS patients and the CG did not differ significantly on age and years of formal education. Groups showed no significant differences in distribution of Gender. Patients scored significantly lower than the CG on the Condor's total score, p = .007, d = .7. On the MTPM, the CG obtained significantly more points for intention formation than patients, p = .027, d = .5. Sixty-three percent of patients versus 88.5% of the CG self-initiated the intention, p = .014. Patients who obtained a higher score on Formation, self-initiated more often, p = .012. Education, disease progression and depression measure with the Beck Depression Inventory, significantly and mildly correlated with the Condor and the MTPM. Physical disability was only associated with the intention planning phase of MTPM. PM appears to be impaired in patients with RRMS. A deficit was found in planning and self-initiation of planned actions. Self-initiation was influenced by planning quality. Education, disease progression and depression were shown to influence recall and execution of future intentions. Physical disability was only associated with the intention planning phase. Some previous studies have not found a significant relationship between physical disability and cognitive measures. This study suggests that PM can be affected in patients with a low level of physical impairment. Results highlight the need for objective assessment of PM in RRMS patients to be able to detect any disorder in the initial stages of the disease and start appropriate rehabilitation. Amongst the limitations of this study, the observational, non-blind design must be acknowledged, as well as the small sample size. Also, the instruments used to assess PM are relatively new and studies of their psychometric properties are lacking. Nevertheless, the use of an instrument like The Condor is notable, given that it was developed for local population.

Relapsing-remitting multiple sclerosis at remission stage treated with acupuncture:a randomized controlled trial / 中国针灸

<p><b>OBJECTIVE</b>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.</p><p><b>METHODS</b>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'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 0.3lateral to the acupoints, and the arrival ofwas 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.</p><p><b>RESULTS</b>In the observation group, EDSS scores in 3-month and 6-month follow-up were reduced as compared with those before treatment (both<0.05) and those in the 12-month and 24-month follow-up were increased (both<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<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 (<0.05,<0.01). The annual recurrent rates after treatment were reduced as compared with those before treatment in the two groups (both<0.01) and the value in the observation group was lower than that in the control group (<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,<0.01].</p><p><b>CONCLUSIONS</b>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.</p>

Studies of the perfusion and permeability characteristic in the brain lesions of patients with relapsing-remitting multiple sclerosis using dynamic contrast-enhanced MRI / 中华放射学杂志

Objective To evaluate dynamic contrast-enhanced MRI (DCE-MRI) with Patlak model for depicting the perfusion and permeability characteristics of lesions and normal-appearing white matter (NAWM) regions in patients with relapsing-remitting multiple sclerosis (RRMS). Methods Twenty-three patients with clinical confirmed RRMS were retrospectively analyzed, who had underwent conventional MRI and DCE-MRI using a 3.0 T MR scanner . The clinical characteristics and imaging data were collected. Post-processing was performed using the Patlak model. Volume transfer constant (Ktrans), fractional plasma volume (Vp) and perfusion parameters including cerebral blood flow (CBF) and cerebral blood volume (CBV) were represented as median and interquartile range(IQR). The four parameters of non-enhanced(NE) lesions, NAWM regions located close to NE lesions(NAWM close) and NAWM regions located far from NE lesions (NAWM far) were compared using the Kruskal-Wallis H rank sum test. Artificial color mappings were also proceeded. Results MR imaging biomarkers Ktrans was 0.132(0.064, 0.233) min-1 for NE lesions, 0.111 (0.060, 0.233) min-1 for NAWM close and 0.077(0.044, 0.185) min-1 for NAWM far, respectively. CBV was 10.660(5.555, 22.193) ml · 100 g-1 for NE lesions, 9.359(4.883, 16.290) ml · 100 g-1 for NAWM close, 6.814 (4.699, 13.623) ml·100 g-1 for NAWM far, respectively. Ktrans and CBV of NE lesions was significantly higher than that of NAWM far(χ2=7.582,P0.05). Conclusion DCE-MRI with Patlak model can measure perfusion and permeability characteristics and hemodynamic abnormalities of NE lesions and NAWM regions in patients with multiple sclerosis.

Effect of methylprednisolone on T helper 17 cell related cytokines in patients with relapsing remitting multiple sclerosis / 中华神经科杂志

Objective To investigate the effect of methylprednisolone on T helper 17 cell (Th17 cells) related cytokines (interleukin (IL)-23,17A,21,22,6,and tansforming growth factor (TGF)-β) in serum and cerebrospinal fluid from patients with relapsing remitting multiple sclerosis and their effects on the pathogenesis.Methods We recruited relapsing remitting multiple sclerosis group (38 patients)and noninflammatory neurological disease group (20 controls),and detected the levels of IL-23,IL-17A,IL-21,IL-22,TGF-β and IL-6 in serum and cerebrospinal fluid (CSF) with ELISA kit in both controls and patients before and after treatment by methylprednisolone.Results After treatment in relapsing remitting multiple sclerosis patients,IL-17A,IL-23,IL-21,and IL-22 levels in cerebrospinal fluid and serum were significantly decreased,however,they were still higher than that in the non-inflammatory neurological disease patients.TGF-β levels was significantly increased (serum:(17.2 ± 5.9) pg/ml vs (34.1 ± 6.5) pg/ml,t =14.351,P =0.000 ; CSF:(26.4 ± 4.7) pg/ml vs (73.2 ± 19.7) pg/ml,t =16.352,P =0.000).The levels of TGF-β in serum and CSF in patients before treatment were lower than those of in non-inflammatory neurological disease patients (serum:(30.2 ± 8.9) pg/ml,t =6.769,P =0.012 ; CSF:(3 1.4 ± 7.5) pg/ml,t =9.368,P =0.017).However,the levels of TGF-β in CSF in patients after treatment were significantly higher than those in non-inflammatory neurological disease patients (t =9.138,P =0.000).Correlation analysis showed that IL-23 and IL-17A were positive correlation in the serum of relapsing remitting multiple sclerosis patients before treatment.Moreover,positive correlations among IL-23,IL-17A and IL-21 were detected in the CSF of relapsing remitting multiple sclerosis patients before treatment.Conclusions Decreased levels of IL-23,IL-17A,IL-21 and IL-22,and elevated levels of TGF-β were detected in serum and CSF of patients with relapsing remitting multiple sclerosis after methylprednisolone treatment.IL-23,IL-17A,IL-21,IL-22 and TGF-β might involve in the pathogenesis of relapsing remitting multiple sclerosis.

"The ""small-world"" property of default mode network in relapsing-remitting multiple sclerosis:a graph theory resting-state functional network analysis" / 中华行为医学与脑科学杂志

Objective To investigate the small-world property of default mode network in relapsingremitting multiple sclerosis (RRMS) compared with the (matched) healthy control subjects,using a graph theory for resting-state functional network analysis.Methods Twenty four patients with RRMS and 24 age-,and sexmatched healthy controls were exanined with resting-state functional MRI (R-fMRI) and 3D-T1WI on Trio 3.0 Tesla.The R-fMRI data were preprocessed,then 20 regions of interest (ROIs) was defined and extracted from the default mode network.The functional connectivity between a pair of regions was defined as the Pearson's correlation coefficient in the time courses.Graph theoretical analysis was implemented and compared with the property of binary functional network.Further,the relationships were examined between the topological property of functional networks and the clinical parameters.Results In this study,functional network in the default mode network was conducted,and the small-world characteristics were observed in both RRMS and healthy control group.In the range of densities (Dmin:0.01∶0.48 ;Dmin =0.42),compared with healthy control group,RRMS groups had a slightly smaller normalized clustering coefficient (P＞0.05),a slightly larger normalized path length (P＞0.05),and a slightly decrease small-world index (P＞0.05).The left posterior cingulated cortex showed a significantly larger clustering coefficient in RRMS group (P=0.031) on the network threshold at Dmin.The area under a curve (AUC) for clustering coefficient measure curves of the left posterior cingulated cortex (density range of 0.42:0.01:0.48) between two groups were compared.The AUC result was similar to the Dmin result (P=0.031).Negative correlation was observed between the clustering coefficient of left posterior cingulated cortex and the Paced Auditory Serial Addition Test (PASAT) in both the Dmin(P=0.023) and the AUC (P=0.020).Conclusion The default mode network has small-world property in RRMS group.The significantly increased clustering coefficience is observed in the left posterior cingulated cortex,which may be a side effect.

Contingent Negative Variation Is Associated with Cognitive Dysfunction and Secondary Progressive Disease Course in Multiple Sclerosis

BACKGROUND AND PURPOSE: The relationship between contingent negative variation (CNV), which is an event-related potential, and cognition in multiple sclerosis (MS) has not been examined previously. The primary objective of the present study was thus to determine the association between CNV and cognition in a sample of MS patients. METHODS: The subjects of this study comprised 66 MS patients [50 with relapsing-remitting MS (RRMS) and 16 with secondary progressive MS (SPMS)] and 40 matched healthy volunteers. A neuropsychological battery was administered to all of the subjects; CNV recordings were made from the Cz, Fz, and Pz electrodes, and the amplitude and area under the curve (AUC) were measured at each electrode. RESULTS: RRMS patients exhibited CNVs with lower amplitudes and smaller AUCs than the controls at Pz. SPMS patients exhibited CNVs with lower amplitudes and smaller AUCs than the controls, and CNVs with a smaller amplitude than the RRMS patients at both Cz and Pz. After correcting for multiple comparisons, a lower CNV amplitude at Pz was significantly associated with worse performance on measures of speed of information processing, verbal fluency, verbal learning, and verbal recall. CONCLUSIONS: CNV may serve as a marker for disease progression and cognitive dysfunction in MS. Further studies with larger samples and wider electrode coverage are required to fully assess the value of CNV in these areas.

Medication withdrawal may be an option for a select group of patients in relapsing-remitting multiple sclerosis / Retirada de medicacao pode ser uma opcao para um grupo selecionado de pacientes com esclerose multipla remitente-recorrente

This article describes the clinical and radiological evolution of a stable group of patients with relapsing-remitting multiple sclerosis that had their disease-modifying therapy (DMT) withdrawn. Forty patients, which had made continuous use of one immunomodulator and had remained free of disease for at least 5 years, had their DMT withdrawn and were observed from 13 to 86 months. Out of the followed patients, 4 (10%) patients presented with new attacks. In addition to these patients, 2 (5%) patients had new lesions revealed by magnetic resonance imaging that did not correspond to clinical attacks. Despite these results, the difficult decision to withdraw medication requires careful analysis. Withdrawal, however, should not be viewed as simply the suspension of treatment because these patients should be evaluated periodically, and the immunomodulators should be readily reintroduced if new attacks occur. Nonetheless, medication withdrawal is an option for a select group of patients.

Esse artigo descreve a evolução clínica e radiológica de um grupo de pacientes com esclerose múltipla estável, forma recorrente-remitente, nos quais foi retirada a terapia modificadora da doença (DMT). Quarenta pacientes, que faziam uso contínuo de um imunomodulador e permaneceram livres da doença pelo menos por 5 anos, tiveram sua DMT retirada e foram observados de 13 a 86 meses. Dos pacientes seguidos, 4 (10%) apresentaram novos surtos. Além destes, 2 (5%) pacientes apresentavam novas lesões na ressonância magnética, sem sintomas clínicos. Apesar destes resultados, a retirada da medicação é uma decisão difícil, requer análise cuidadosa e não deve ser considerada como sinônimo de suspender o tratamento, já que estes pacientes devem ser avaliados periodicamente e o uso de imunomoduladores tem de ser prontamente reiniciado no caso do aparecimento de novos surtos. Não obstante, a retirada do medicamento é uma opção para um grupo selecionado de pacientes.