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Introduction: Effective treatments that reduce relapses can diminish the impact on MS costs in the long-term. This study aims to estimate direct costs of RRMS relapses in Catalonia (Spanish region). Methods: Multi-centre, prospective, cross-sectional observational study with retrospective data collection. Estimated costs: disease-modifying therapies (DMTs) and symptoms treatments, use of hospital and ambulatory resources, technical aids, transport and paid caregivers from the National Health System (NHS) and global perspectives. Results: One hundered and forty (140) suitable patients were included to estimate direct costs (mean [SD] age: 40.7 [10] years; females: 71.5%; low EDSS score at relapse start: 77.5%). Mean total direct costs of relapse/patient were €4,541 (NHS) and €4,626 (global). A subanalysis was performed in patients with relapses lasting ≤90 days (100 patients), relapse total direct costs/patient were €4,989 (NHS) and €5,115 (global). Motor relapses presented a higher cost (a mean of €9,345/patient). Mean total direct cost/patient was higher when there was a DMT switch due to the relapse (€14,370 compared to €1,149), from a global perspective. Conclusion: Mean direct costs of RRMS relapse/patient in Catalonia were €4,989 and €5,115 for NHS and global perspectives, respectively. The type of relapse and switching the DMT due to the relapse were associated with an increase in direct costs. Resumen: Introducción: Los tratamientos que logran reducir los brotes en la esclerosis múltiple (EM) también pueden disminuir el coste de la enfermedad a largo plazo. El propósito de este estudio es realizar una estimación de los costes directos relacionados con la EM remitente-recurrente (EMRR) en Cataluña. Métodos: Hemos realizado un estudio observacional, transversal, prospectivo y multicéntrico en el que hemos recogido los datos de forma retrospectiva. Para calcular los costes directos, consideramos los costes derivados del uso de fármacos modificadores de la enfermedad (FME) y tratamientos sintomáticos, recursos hospitalarios y ambulatorios, ayudas técnicas, transporte y cuidadores remunerados, tanto desde la perspectiva del sistema nacional de salud (SNS) como desde una perspectiva global. Resultados: Recogimos datos de 140 pacientes cuya edad media (DE) era de 40,7 (10) años; de ellos, el 71,5% eran mujeres y 77,5% presentaron una puntuación baja en la EDSS al comienzo de los brotes. Los costes directos medios de los brotes fueron de 4541€ (SNS) y de 4626€ (costes globales) por paciente. Se realizó un subanálisis de los pacientes que sufrieron brotes de al menos 90 días de duración (100 pacientes), en los que los costes directos medios del brote fueron de 4989€ (SNS) y 5115€ (costes globales) por paciente. Las recaídas de las manifestaciones motoras supusieron un coste mayor (media de 9345€ por paciente). En términos globales, los costes directos medios por paciente fueron mayores cuando hubo que cambiar de FME debido a un brote (14 370€ frente a 1149€). Conclusión: Los brotes de la EMRR en Cataluña tuvieron un coste directo medio de 4989€ por paciente para el SNS y de 5115€ por paciente a nivel global. El tipo de brote y el cambio de FME debido a un brote se relacionaron con un aumento de los costes directos.

Introduction: Gait impairment, a frequent sign in multiple sclerosis (MS), places a major burden on patients since it results in progressive loss of personal and social autonomy, along with work productivity. This guide aims to provide recommendations on how to evaluate gait impairment and use prolonged-release fampridine (PR-fampridine) as treatment for MS patients with gait impairment in Spain. Development: PR-fampridine dosed at 10 mg every 12 hours is currently the only drug approved to treat gait impairment in adults with MS. Additionally, PR-fampridine has been shown in clinical practice to significantly improve quality of life (QoL) in patients who respond to treatment. Treatment response can be assessed with the Timed 25-Foot Walk (T25FW) or the 12-item MS Walking Scale (MSWS-12); tests should be completed before and after starting treatment. The minimum time recommended for evaluating treatment response is 2 weeks after treatment onset. Patients are considered responders and permitted to continue the treatment when they demonstrate a decrease in their T25FW time or an increase in MSWS-12 scores. A re-evaluation is recommended at least every 6 months. The SF-36 (Short Form-36) and the MSIS-29 (MS Impact Scale-29) tests are recommended for clinicians interested in performing a detailed QoL assessment. This drug is generally well-tolerated and has a good safety profile. It should be taken on an empty stomach and renal function must be monitored regularly. Conclusions: These recommendations will help ensure safer and more efficient prescription practices and easier management of PR-fampridine as treatment for gait impairment in Spanish adults with MS. Resumen: Introducción: La alteración de la marcha es frecuente en la esclerosis múltiple (EM) y tiene un gran impacto negativo en los pacientes pues conlleva a la pérdida progresiva de autonomía personal y social, y de productividad laboral. Esta guía pretende establecer recomendaciones para la evaluación del deterioro de la marcha y el uso de fampridina de liberación prolongada (fampridina-LP) como tratamiento de pacientes con EM y deterioro de la marcha en España. Desarrollo: Fampridina-LP a dosis de 10 mg cada 12 h es actualmente el único fármaco autorizado para mejorar el trastorno de la marcha en adultos con EM. En la práctica clínica, el fármaco ha demostrado además que mejora de forma significativa la calidad de vida de los pacientes que responden al tratamiento. La respuesta se puede evaluar mediante la prueba cronometrada de la marcha de 25 pies (T25FW) o el cuestionario MSWS-12 que deben realizarse antes y después del inicio del tratamiento. El tiempo mínimo recomendado para evaluar la respuesta inicial es de 2 semanas. Para considerar a un paciente como respondedor y continuar el tratamiento debe presentar, según indica la ficha técnica, una disminución en el tiempo T25FW o mejoría en el MSWS-12. Se recomienda realizar las revaluaciones al menos cada 6 meses. En los casos en que se considere la valoración de la calidad de vida, se recomienda la utilización del cuestionario de salud Short Form-36 (SF-36) o la escala MS Impact Scale-29 (MSIS-29). Es un fármaco en general bien tolerado y con buen perfil de seguridad. Se recomienda su administración en ayunas y control periódico de la función renal. Conclusiones: Estas recomendaciones permiten garantizar una prescripción eficiente y más segura, y ayudan al manejo de fampridina-LP como tratamiento del deterioro de la marcha en pacientes adultos con EM en España. Keywords: Fampridine, Gait impairment, Quality of life, Multiple sclerosis, T25FW, MSWS-12, Palabras clave: Fampridina, Marcha, Calidad de vida, Esclerosis múltiple, Timed 25-Foot Walk Test, The 12-item multiple sclerosis walking scale

Resumen: Introducción: La alteración de la marcha es frecuente en la esclerosis múltiple (EM) y tiene un gran impacto negativo en los pacientes pues conlleva a la pérdida progresiva de autonomía personal y social, y de productividad laboral. Esta guía pretende establecer recomendaciones para la evaluación del deterioro de la marcha y el uso de fampridina de liberación prolongada (fampridina-LP) como tratamiento de pacientes con EM y deterioro de la marcha en España. Desarrollo: Fampridina-LP a dosis de 10 mg cada 12 h es actualmente el único fármaco autorizado para mejorar el trastorno de la marcha en adultos con EM. En la práctica clínica, el fármaco ha demostrado además que mejora de forma significativa la calidad de vida de los pacientes que responden al tratamiento. La respuesta se puede evaluar mediante la prueba cronometrada de la marcha de 25 pies (T25FW) o el cuestionario MSWS-12 que deben realizarse antes y después del inicio del tratamiento. El tiempo mínimo recomendado para evaluar la respuesta inicial es de 2 semanas. Para considerar a un paciente como respondedor y continuar el tratamiento debe presentar, según indica la ficha técnica, una disminución en el tiempo T25FW o mejoría en el MSWS-12. Se recomienda realizar las revaluaciones al menos cada 6 meses. En los casos en que se considere la valoración de la calidad de vida, se recomienda la utilización del cuestionario de salud Short Form-36 (SF-36) o la escala MS Impact Scale-29 (MSIS-29). Es un fármaco en general bien tolerado y con buen perfil de seguridad. Se recomienda su administración en ayunas y control periódico de la función renal. Conclusiones: Estas recomendaciones permiten garantizar una prescripción eficiente y más segura, y ayudan al manejo de fampridina-LP como tratamiento del deterioro de la marcha en pacientes adultos con EM en España. Abstract: Introduction: Gait impairment, a frequent sign in multiple sclerosis (MS), places a major burden on patients since it results in progressive loss of personal and social autonomy, along with work productivity. This guide aims to provide recommendations on how to evaluate gait impairment and use prolonged-release fampridine (PR-fampridine) as treatment for MS patients with gait impairment in Spain. Development: PR-fampridine dosed at 10 mg every 12 hours is currently the only drug approved to treat gait impairment in adults with MS. Additionally, PR-fampridine has been shown in clinical practice to significantly improve quality of life (QoL) in patients who respond to treatment. Treatment response can be assessed with the Timed 25-Foot Walk (T25FW) or the 12-item MS Walking Scale (MSWS-12); tests should be completed before and after starting treatment. The minimum time recommended for evaluating treatment response is 2 weeks after treatment onset. Patients are considered responders and permitted to continue the treatment when they demonstrate a decrease in their T25FW time or an increase in MSWS-12 scores. A re-evaluation is recommended at least every 6 months. The SF-36 (Short Form-36) and the MSIS-29 (MS Impact Scale-29) tests are recommended for clinicians interested in performing a detailed QoL assessment. This drug is generally well-tolerated and has a good safety profile. It should be taken on an empty stomach and renal function must be monitored regularly. Conclusions: These recommendations will help ensure safer and more efficient prescription practices and easier management of PR-fampridine as treatment for gait impairment in Spanish adults with MS. Palabras clave: Fampridina, Marcha, Calidad de vida, Esclerosis múltiple, Timed 25-Foot Walk Test, The 12-item multiple sclerosis walking scale, Keywords: Fampridine, Gait impairment, Quality of life, Multiple sclerosis, T25FW, MSWS-12

Resumen: Introducción: La encefalopatía de Wernicke (EW) es una entidad infradiagnosticada, generalmente asociada a alcoholismo, que tiene peor pronóstico si existe retraso diagnóstico. Se presenta una serie de 8 pacientes no alcohólicos con EW y se evalúa si el retraso en el diagnóstico implica un peor pronóstico. Pacientes y métodos: Revisión retrospectiva de las historias clínicas de pacientes ingresados en dos hospitales universitarios entre 2004 y 2009 con diagnóstico de EW, excluidos aquéllos con historia de alcoholismo. Resultados: Se incluyó a 4 varones y 4 mujeres, con edades comprendidas entre los 35 y los 82 años; 7 tenían antecedentes patológicos gastrointestinales y los vómitos persistentes fueron el desencadenante en 7 casos. La encefalopatía fue la forma de inicio más frecuente (4 casos). La tríada clásica llegó a estar presente en 7 pacientes. Los niveles de tiamina fueron bajos en 3/6 y normales en 3/6 pacientes. La RM fue patológica en 7 pacientes, con hiperintensidad en diencéfalo y cuerpos mamilares (7), sustancia gris periacueductal (6), corteza (3) y cerebelo (1). Siete pacientes mejoraron tras el tratamiento con tiamina. Las secuelas fueron leves en 5 casos y graves en 3 pacientes. Todos los pacientes con un retraso diagnóstico inferior a 18 días tuvieron secuelas leves. Conclusiones: En la EW no alcohólica son frecuentes los antecedentes gastrointestinales que podrían condicionar una menor absorción de tiamina. Mientras que los niveles de tiamina pueden ser normales en muchos casos, la RM casi siempre muestra alteración de señal en localizaciones típicas. El retraso en el diagnóstico y, por tanto, en el tratamiento podría implicar un peor pronóstico. Abstract: Introduction: Wernicke's encephalopathy (WE) is an underdiagnosed condition, usually associated with alcoholism, and has a worse prognosis if there is a delay in diagnosis. A series of 8 non-alcoholic patients with WE is presented and an assessment is made on whether a delay in diagnosis leads to a worse prognosis. Patients and methods: The clinical records of patients admitted to 2 university hospitals between 2004 and 2009 with the diagnosis of WE, excluding those with a history of alcoholism, were retrospectively reviewed. Results: The study included 4 men and 4 women aged 35-82 of whom 7 had a history of gastrointestinal pathology, and persistent vomiting was the precipitating factor in 7. Encephalopathy was the most frequent onset symptom (4). The classical triad was present in seven patients. Thiamine levels were low in 3/6 and normal in 3/6 cases. MRI was abnormal in seven patients, with high signal intensity in the diencephalon and mammillary bodies (7), periaqueductal grey matter (6), cortex (3) and cerebellum (1). Seven improved with thiamine. Sequelae were mild in 6, and severe in 2 after 6-12 months of follow-up. All patients with a diagnostic delay less than 18 days had mild sequelae. Conclusions: Non-alcoholic WE frequently occurs after gastrointestinal disturbances that could result in lower thiamine absorption. Whereas thiamine levels can be normal in many cases, in almost all cases the MRI shows signal alterations in typical locations. A delay in the diagnosis, and therefore, in treatment leads to a worse prognosis. Palabras clave: Encefalopatía de Wernicke, Encefalopatía de Wernicke no alcohólica, Gastrointestinal, Tiamina, Resonancia magnética, Pronóstico, Keywords: Wernicke's encephalopathy, Non-alcoholic Wernicke's encephalopathy, Gastrointestinal, Thiamine, Magnetic resonante, Prognosis

Introduction: Wernicke's encephalopathy (WE) is an underdiagnosed condition, usually associated with alcoholism, and has a worse prognosis if there is a delay in diagnosis. A series of 8 non-alcoholic patients with WE is presented and an assessment is made on whether a delay in diagnosis leads to a worse prognosis. Patients and methods: The clinical records of patients admitted to 2 university hospitals between 2004 and 2009 with the diagnosis of WE, excluding those with a history of alcoholism, were retrospectively reviewed. Results: The study included 4 men and 4 women aged 35–82 of whom 7 had a history of gastrointestinal pathology, and persistent vomiting was the precipitating factor in 7. Encephalopathy was the most frequent onset symptom (4). The classical triad was present in seven patients. Thiamine levels were low in 3/6 and normal in 3/6 cases. MRI was abnormal in seven patients, with high signal intensity in the diencephalon and mammillary bodies (7), periaqueductal grey matter (6), cortex (3) and cerebellum (1). Seven improved with thiamine. Sequelae were mild in 6, and severe in 2 after 6–12 months of follow-up. All patients with a diagnostic delay less than 18 days had mild sequelae. Conclusions: Non-alcoholic WE frequently occurs after gastrointestinal disturbances that could result in lower thiamine absorption. Whereas thiamine levels can be normal in many cases, in almost all cases the MRI shows signal alterations in typical locations. A delay in the diagnosis, and therefore, in treatment leads to a worse prognosis. Resumen: Introducción: La encefalopatía de Wernicke (EW) es una entidad infradiagnosticada, generalmente asociada a alcoholismo, que tiene peor pronóstico si existe retraso diagnóstico. Se presenta una serie de 8 pacientes no alcohólicos con EW y se evalúa si el retraso en el diagnóstico implica un peor pronóstico. Pacientes y métodos: Revisión retrospectiva de las historias clínicas de pacientes ingresados en dos hospitales universitarios entre 2004 y 2009 con diagnóstico de EW, excluidos aquéllos con historia de alcoholismo. Resultados: Se incluyó a 4 varones y 4 mujeres, con edades comprendidas entre los 35 y los 82 años; 7 tenían antecedentes patológicos gastrointestinales y los vómitos persistentes fueron el desencadenante en 7 casos. La encefalopatía fue la forma de inicio más frecuente (4 casos). La tríada clásica llegó a estar presente en 7 pacientes. Los niveles de tiamina fueron bajos en 3/6 y normales en 3/6 pacientes. La RM fue patológica en 7 pacientes, con hiperintensidad en diencéfalo y cuerpos mamilares (7), sustancia gris periacueductal (6), corteza (3) y cerebelo (1). Siete pacientes mejoraron tras el tratamiento con tiamina. Las secuelas fueron leves en 5 casos y graves en 3 pacientes. Todos los pacientes con un retraso diagnóstico inferior a 18 días tuvieron secuelas leves. Conclusiones: En la EW no alcohólica son frecuentes los antecedentes gastrointestinales que podrían condicionar una menor absorción de tiamina. Mientras que los niveles de tiamina pueden ser normales en muchos casos, la RM casi siempre muestra alteración de señal en localizaciones típicas. El retraso en el diagnóstico y, por tanto, en el tratamiento podría implicar un peor pronóstico. Keywords: Wernicke's encephalopathy, Non-alcoholic Wernicke's encephalopathy, Gastrointestinal, Thiamine, Magnetic resonant, Prognosis, Palabras clave: Encefalopatía de Wernicke, Encefalopatía de Wernicke no alcohólica, Gastrointestinal, Tiamina, Resonancia magnética, Pronóstico

Resumen: El último documento de consenso del Grupo de Estudio de Enfermedades Desmielinizantes de la Sociedad Española de Neurología sobre el tratamiento de la esclerosis múltiple (EM) data del año 2016. Aunque muchas consideraciones continúan todavía vigentes, desde entonces se han producido cambios significativos en el manejo y tratamiento de esta enfermedad, motivados no solo por la aprobación de nuevos fármacos con diferentes mecanismos de acción, sino también por la evolución de conceptos otrora consolidados. Esto ha permitido abordar situaciones especiales como el embarazo y la vacunación desde otra perspectiva, e incluir nuevas variables en la toma de decisiones en práctica clínica, como plantear tratamiento modificador de la enfermedad (TME) de alta eficacia en fases tempranas, considerar la perspectiva del paciente y utilizar nuevas tecnologías como monitorización remota.Estos cambios han motivado la presente actualización del consenso mediante metodología Delphi, con el objetivo de reflejar el nuevo paradigma de manejo del paciente con EM basándose en la evidencia científica y la experiencia clínica de los participantes.Entre las principales conclusiones destacan como recomendaciones: iniciar TME inmunomodulador en el síndrome radiológico aislado con actividad radiológica persistente, evaluar la perspectiva del paciente y abandonar la terminología «líneas de tratamiento» en la clasificación de los TME (consenso mayor del 90%). Tras el diagnóstico de EM la elección del primer TME debería considerar la presencia/ausencia de factores de mal pronóstico (epidemiológicos, clínicos, radiológicos y biomarcadores) para la aparición de nuevos brotes o progresión de discapacidad, pudiendo plantear desde el inicio TME de alta eficacia. Abstract: The last consensus statement of the Spanish Society of Neurology's Demyelinating Diseases Study Group on the treatment of multiple sclerosis (MS) was issued in 2016. Although many of the positions taken remain valid, there have been significant changes in the management and treatment of MS, both due to the approval of new drugs with different action mechanisms and due to the evolution of previously fixed concepts. This has enabled new approaches to specific situations such as pregnancy and vaccination, and the inclusion of new variables in clinical decision-making, such as the early use of high-efficacy disease-modifying therapies (DMT), consideration of the patient's perspective, and the use of such novel technologies as remote monitoring.In the light of these changes, this updated consensus statement, developed according to the Delphi method, seeks to reflect the new paradigm in the management of patients with MS, based on the available scientific evidence and the clinical expertise of the participants.The most significant recommendations are that immunomodulatory DMT be started in patients with radiologically isolated syndrome with persistent radiological activity, that patient perspectives be considered, and that the term “lines of therapy” no longer be used in the classification of DMTs (> 90% consensus). Following diagnosis of MS, the first DMT should be selected according to the presence/absence of factors of poor prognosis (whether epidemiological, clinical, radiological, or biomarkers) for the occurrence of new relapses or progression of disability; high-efficacy DMTs may be considered from disease onset.

The last consensus statement of the Spanish Society of Neurology’s Demyelinating Diseases Study Group on the treatment of multiple sclerosis (MS) was issued in 2016. Although many of the positions taken remain valid, there have been significant changes in the management and treatment of MS, both due to the approval of new drugs with different action mechanisms and due to the evolution of previously fixed concepts. This has enabled new approaches to specific situations such as pregnancy and vaccination, and the inclusion of new variables in clinical decision-making, such as the early use of high-efficacy disease-modifying therapies (DMT), consideration of the patient’s perspective, and the use of such novel technologies as remote monitoring.In the light of these changes, this updated consensus statement, developed according to the Delphi method, seeks to reflect the new paradigm in the management of patients with MS, based on the available scientific evidence and the clinical expertise of the participants.The most significant recommendations are that immunomodulatory DMT be started in patients with radiologically isolated syndrome with persistent radiological activity, that patient perspectives be considered, and that the term “lines of therapy” no longer be used in the classification of DMTs (> 90% consensus). Following diagnosis of MS, the first DMT should be selected according to the presence/absence of factors of poor prognosis (whether epidemiological, clinical, radiological, or biomarkers) for the occurrence of new relapses or progression of disability; high-efficacy DMTs may be considered from disease onset. Resumen: El último documento de consenso del Grupo de Estudio de Enfermedades Desmielinizantes de la Sociedad Española de Neurología sobre el tratamiento de la esclerosis múltiple (EM) data del año 2016. Aunque muchas consideraciones continúan todavía vigentes, desde entonces se han producido significativos cambios en el manejo y tratamiento de esta enfermedad motivados no sólo por la aprobación de nuevos fármacos con diferentes mecanismos de acción, sino también por la evolución de conceptos otrora consolidados. Esto ha permitido abordar situaciones especiales como el embarazo y la vacunación desde otra perspectiva e incluir nuevas variables en la toma de decisiones en práctica clínica, como plantear tratamiento modificador de la enfermedad (TME) de alta eficacia en fases tempranas, considerar la perspectiva del paciente y utilizar nuevas tecnologías como monitorización remota.Estos cambios han motivado la presente actualización del consenso mediante metodología Delphi, con el objetivo de reflejar el nuevo paradigma de manejo del paciente con EM basándose en la evidencia científica y experiencia clínica de los participantes.Entre las principales conclusiones destacan como recomendaciones: iniciar TME inmunomodulador en el síndrome radiológico aislado con actividad radiológica persistente, evaluar la perspectiva del paciente y abandonar la terminología “líneas de tratamiento” en la clasificación de los TME (consenso mayor del 90%). Tras el diagnóstico de EM, la elección del primer TME debería considerar la presencia/ausencia de factores de mal pronóstico (epidemiológicos, clínicos, radiológicos y biomarcadores) para la aparición de nuevos brotes o progresión de discapacidad, pudiendo plantear desde el inicio TME de alta eficacia.

Background: People with multiple sclerosis (MS) present varying degrees of disability throughout their disease course. The Multiple Sclerosis Severity Score (MSSS) and the Age-Related Multiple Sclerosis Severity Score (ARMSSS) adjust the Expanded Disability Status Scale (EDSS) according to disease duration and age, respectively. These measures could be useful for quantifying MS severity and as health outcome indicators for benchmarking in population-based settings. The aim of this study was to describe the severity of MS in our health district using the MSSS and ARMSSS and to assess their consistency over time., Methods: This population-based study included patients from our health district who were diagnosed with MS according to the 2010 McDonald criteria, had a disease duration of at least one year and were followed up in our MS unit. Sex, age at onset, disease duration, clinical course, age and irreversible EDSS at the last follow-up visit were collected, and the MSSS and ARMSSS were calculated at two time points: 2017 and 2020., Results: One hundred seventy-seven patients were included in 2017, and 208 in 2020. The prevalence of MS was 90 and 104 per 100,000 inhabitants, respectively. The median MSSS was 1.77 (IQR 0.76-4.28) in 2017 and 2.03 (IQR 0.82-4.36) in 2020. The median ARMSSS was 2.90 (IQR 1.47-5.72) in 2017 and 2.93 (IQR 1.51-5.56) in 2020. No significant differences were found., Conclusions: According to the MSSS and ARMSSS, the severity of MS in our area is mild, and these instruments are consistent. These measures could be reliable health outcome measures., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Hospital Universitari de Bellvitge Research Ethics Committee. The patients signed informed consent forms, and the data were collected anonymously. Competing interests: In the last three years, LB has received funding for travel and congress expenses and honoraria for lectures from Biogen, Bristol Myers Squibb, Merck, Novartis and Roche. EM has received funding for travel and congress expenses and honoraria for lectures from Biogen, Bristol Myers Squibb, Merck and Janssen. LRP has received funding for travel and congress expenses and honoraria for lectures from Biogen, Bristol Myers Squibb, Novartis, Merck, Roche and Teva. IL has received funding for travel and congress expenses from Biogen, Merck, Novartis and Roche. AMV has received honoraria or funding for travel and congress expenses from Teva, Lilly, Lundbeck, Organon, UCB, Bial, Chiesi, Allergan, Kern Pharma, Pfizer, Biogen, Novartis, Merck, Janssen, Sanofi and/or Bristol Myers Squibb. PAP has received funding for travel and congress expenses from Novartis, Roche and Sanofi. AMY has received support for congress attendance from Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Roche and Sandoz. SMY has received support for congress attendance from Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Roche and Sandoz. The institution where the authors work (Hospital Universitari de Bellvitge/ Institut d’Investigació Biomèdica de Bellvitge) has received in the last three years and dedicated exclusively to support the research of the Unit, fees for advisory council, collaborations, donations and advice from Almirall, Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Horizon/Amgen, Janssen, Kern Pharma, Lilly, Merck, Neuraxpharm, Novartis, Roche, Sandoz and Sanofi., (© 2024. The Author(s).)

The potential for combining serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels to predict worsening disability in multiple sclerosis remains underexplored. We aimed to investigate whether sNfL and sGFAP values identify distinct subgroups of patients according to the risk of disability worsening and their response to disease-modifying treatments (DMTs). This multicentre study, conducted across 13 European hospitals, spanned from 15 July 1994 to 18 August 2022, with follow-up until 26 September 2023. We enrolled patients with multiple sclerosis who had serum samples collected within 12 months from disease onset and before initiating DMTs. Multivariable regression models were used to estimate the risk of relapse-associated worsening (RAW), progression independent of relapse activity (PIRA) and Expanded Disability Status Scale (EDSS) score of 3. Of the 725 patients included, the median age was 34.2 (interquartile range, 27.6-42.4) years, and 509 patients (70.2%) were female. The median follow-up duration was 6.43 (interquartile range, 4.65-9.81) years. Higher sNfL values were associated with an elevated risk of RAW [hazard ratio (HR) of 1.45; 95% confidence interval (CI) 1.19-1.76; P < 0.001], PIRA (HR of 1.43; 95% CI 1.13-1.81; P = 0.003) and reaching an EDSS of 3 (HR of 1.55; 95% CI 1.29-1.85; P < 0.001). Moreover, higher sGFAP levels were linked to a higher risk of achieving an EDSS score of 3 (HR of 1.36; 95% CI 1.06-1.74; P = 0.02) and, in patients with low sNfL values, to PIRA (HR of 1.86; 95% CI 1.01-3.45; P = 0.04). We also examined the combined effect of sNfL and sGFAP levels. Patients with low sNfL and sGFAP values exhibited a low risk of all outcomes and served as a reference. Untreated patients with high sNfL levels showed a higher risk of RAW, PIRA and reaching an EDSS of 3. Injectable or oral DMTs reduced the risk of RAW in these patients but failed to mitigate the risk of PIRA and reaching an EDSS of 3. Conversely, high-efficacy DMTs counteracted the heightened risk of these outcomes, except for the risk of PIRA in patients with high sNfL and sGFAP levels. Patients with low sNfL and high sGFAP values showed an increased risk of PIRA and achieving an EDSS of 3, which remained unchanged with either high-efficacy or other DMTs. In conclusion, evaluating sNfL and sGFAP levels at disease onset in multiple sclerosis might identify distinct phenotypes associated with diverse immunological pathways of disability acquisition and therapeutic response., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objectives: To characterize the serum cytokine profile in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) at onset and during follow-up and assess their utility for predicting relapses and disability., Methods: This retrospective multicentric cohort study included patients aged 16 years and older meeting MOGAD 2023 criteria, with serum samples collected at baseline (≤3 months from disease onset) and follow-up (≥6 months from the baseline), and age-matched and time to sampling-matched patients with multiple sclerosis (MS). Eleven cytokines were assessed using the ELLA system. Data comparisons and statistical analyses between cytokine levels and clinical outcomes were performed., Results: Eighty-eight patients with MOGAD and 32 patients with MS were included. Patients with MOGAD showed higher IL6 ( p = 0.036), IL8 ( p = 0.012), and IL18 ( p = 0.026) baseline levels compared with those with MS, in non-optic neuritis (ON) presentations. BAFF values increased over time, especially in patients with MOGAD treated with anti-CD20 ( p = 0.002). Baseline BAFF, CXCL10, IL10, and IL8 levels correlated with disease severity at MOGAD onset (all p < 0.05). Finally, higher baseline BAFF levels predicted lower risk of relapses (hazard ratio 0.41 [0.19; 0.89], p = 0.024)., Discussion: This study suggests a proinflammatory Th17-dominant profile in non-ON MOGAD patients, with a novel finding of a potential protective role of BAFF on relapses. These results shed new light on the pathogenesis of MOGAD, potentially guiding therapeutic decisions.

Objective: To ascertain the changes of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) values in relapsing-remitting multiple sclerosis (RRMS) patients treated with ocrelizumab and their association with treatment response., Methods: Multicenter prospective study including 115 RRMS patients initiating ocrelizumab treatment between February 2020 and March 2022 followed during a year. Serum samples were collected at baseline and every 3 months to measure sNfL and sGFAP levels using single-molecule array (SIMOA) technology. Based on age and body mass index, sNfL values were standardized using z-score. NEDA (non-evidence of disease activity)-3 status was defined for patients free of disease activity after a year of follow-up. Inflammation (INFL) was considered when new relapses occurred during follow-up or new MRI lesions were found at 1-year exploration. PIRA (progression independent of relapse activity) was defined as disability progression occurring in the absence of relapses or new MRI activity., Results: After a year on ocrelizumab, 85 patients (73.9%) achieved NEDA-3. Thirty patients did not achieve NEDA: 20 (17.4%) because of INFL and 10 (8.7%) because of PIRA. Of INFL patients, 6 (30.0%) had relapses, and 17 (85.0%) had at least one new MRI lesion at the 12-month examination. At baseline, INFL patients had higher sNfL (p = 0.0003) and sGFAP (p = 0.03) than the NEDA-3 group. PIRA patients mostly exhibited low sNfL and heterogeneous sGFAP levels. After a year, NEDA-3 and INFL patients showed similar decreases in sNfL (p < 0.0001) and sGFAP (p < 0.0001 for NEDA-3 and p = 0.001 for INFL ones). However, the decrease occurred earlier in NEDA-3 patients. Accordingly, sNfL > 1.5 z-score 3 months after ocrelizumab initiation indicated a higher risk of inflammation (OR = 13.6; p < 0.0001). Decrease in sGFAP values occurred later in both groups, with significant reductions observed at 12 months for INFL and 6 and 12 months for NEDA-3. No significant changes in sNfL or sGFAP were observed in PIRA patients., Conclusion: Ocrelizumab induced normalization of sNfL and sGFAP in the majority of NEDA-3 and inflammatory patients but did not cause changes in the PIRA group. Our data suggest that normalization of sNfL and sGFAP is associated with the lack of inflammatory-associated disease progression but it may not affect non-inflammatory PIRA., Competing Interests: FR-J received research grants and travel support for speaking engagements from Janssen, Biogen, Novartis, Roche, Sanofi-Genzyme, Bristol-Myers-Squibb and Merck. JG-G received research support, compensation for participating on advisory boards, lecture fees, and/or travel support from Almirall, Bayer, Biogen, Genzyme‐Sanofi, Novartis, Roche, and Teva. EF received research support, compensation for participating on advisory boards, speaking fees, and/or funding for travel from Almirall, Bayer, Biogen, Genzyme‐Sanofi, Merck, Novartis, and Roche. VM-L received consulting and speaking fees from Almirall, Biogen, Genzyme, Janssen, Merck, Novartis, Roche, Terumo, Sanofi, Teva, and Bristol Myers Squibb. CD-P received funding for training and scientific meetings from Sanofi, Merck, Novartis and Roche. SS received research grants, travel support or honoraria for speaking engagements from Almirall, Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. AQ is funded by a grant from the Fundación Francisco Soria y Melguizo and has received funding from Merck, Novartis, and Horizon Therapeutics to attend conferences. LR-T received compensation for consulting services and speaking fees from Biogen, Novartis, Bayer, Merck, Sanofi, Genzyme, Roche, Bristol-Myers-Squibb, TEVA, and Horizon. SM-Y received honoraria for participating on advisory boards and for collaborations as consultant and scientific communications and also received research support as well as funding for travel and congress expenses from Roche, Biogen Idec, Novartis, TEVA, Merck, Genzyme, Sanofi, Bayer, Almirall, and Bristol Myers Squibb. EM received research grants, travel support, or honoraria for speaking engagements from Almirall, Merck, Roche, Sanofi, Bristol Myers Squibbb, Biogen, Janssen, and Novartis. AL-R received speaker and consultation fees from Biogen, Janssen, Novartis, Roche and Sanofi, and congress travel support from Roche. LBo received research grants and travel support from Merck, Roche, Novartis, Sanofi, Horizon and Bristol Myer Squibb. JC-G received speaker fees, travel support, and/or served on advisory boards by Biogen, Sanofi, Bayer, Janssen, BMS, and Bial. FB received compensation for consulting services and speaking honoraria from Almirall, Biogen, Bristol Myer Squibb, Genzyme, Johnson & Johnson, Merck, Novartis, Roche, Sanofi, Teva. MM-G received compensation for consulting services and speaking fees from Merck, Biogen, Novartis, Sanofi-Genzyme, Almirall, BMS, Janssen, Roche, Horizon, and Viatris. JG-D received honoraria as speaker, advisor and researcher from Almirall, Bristol Myers Squibb, Biogen, Janssen, Merck, Novartis, Roche, Teva, and Sanofi. MM-M received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries Ltd., Sanofi-Aventis, Merck Serono, Novartis, Bayer Schering Pharma, Bristol Myers Squibb and Roche. JM-L received honoraria as a consultant, lecturer in meetings and has participated in clinical trials and other research projects promoted by Alexion, Almirall, Biogen, Bristol-Meyers-Squibb, Horizon, Johnson & Johnson, Merck, Neuraxpharm, Novartis, Roche, Sandoz, Sanofi and UCB. LC-F received speaker fees, travel support, and/or served on advisory boards by Biogen, Sanofi, Merck, Bayer, Novartis, Roche, Teva, Celgene, Ipsen, Biopas, Almirall. LV received research grants and personal fees from Merck, Roche, Sanofi, Bristol Myers Squibb, Biogen, and Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Rodríguez-Jorge, Fernández-Velasco, Villarrubia, Gracia-Gil, Fernández, Meca-Lallana, Díaz-Pérez, Sainz de la Maza, Pacheco, Quiroga, Ramió-Torrentà, Martínez-Yélamos, Bau, Monreal, López-Real, Rodero-Romero, Borrega, Díaz, Eguía, Espiño, Chico-García, Barrero, Martínez-Ginés, García-Domínguez, De la Fuente, Moreno, Sainz-Amo, Mañé-Martínez, Caminero, Castellanos, Gómez López, Labiano-Fontcuberta, Ayuso, Abreu, Hernández, Meca-Lallana, Martín-Aguilar, Muriel García, Masjuan, Costa-Frossard and Villar.)

Recent advances in multiple sclerosis (MS) management have shifted perspectives on treatment strategies, advocating for the early initiation of high-efficacy disease-modifying therapies (heDMTs). This perspective review discusses the rationale, benefits, and challenges associated with early heDMT initiation, reflecting on the obsolescence of the traditional "first-line" and "second-line" treatment classifications. The article emerges from the last update of the consensus document of the Spanish Society of Neurology on the treatment of MS. During its development, there was a recognized need to further discuss the concept of treatment lines and the early use of heDMTs. Evidence from randomized controlled trials and real-world studies suggests that early heDMT initiation leads to improved clinical outcomes, including reduced relapse rates, slowed disease progression, and decreased radiological activity, especially in younger patients or those in early disease stages. Despite the historical belief that heDMTs involve more risks and adverse events compared to moderate-efficacy DMTs (meDMTs), some studies have reported comparable safety profiles between early heDMTs and meDMTs, though long-term safety data are still lacking. The review also addresses the need for a personalized approach based on patient characteristics, prognostic factors, and preferences, explores the importance of therapeutic inertia, and highlights the evolving landscape of international and national guidelines that increasingly advocate for early intensive treatment approaches. The article also addresses the challenges of ensuring access to these therapies and the importance of further research to establish long-term safety and effectiveness of DMTs in MS., (© The Author(s), 2024.)

Background: The assessment of serum neurofilament light chain (sNfL) concentration in multiple sclerosis (MS) is a useful tool for predicting clinical outcomes and assessing treatment response. However, its use in clinical practice is still limited. We aimed to assess how measurement of sNfL influences neurologists' treatment decisions in MS., Methods: We conducted a cross-sectional, web-based study in collaboration with the Spanish Society of Neurology. Neurologists involved in MS care were presented with different simulated case scenarios of patients experiencing either their first demyelinating MS event or a relapsing-remitting MS. The primary outcome was therapeutic inertia (TI), defined as the absence of treatment initiation or intensification despite elevated sNfL levels. Nine cases were included to estimate the TI score (range 0-9, where higher values represented a higher degree of TI)., Results: A total of 116 participants were studied. Mean age (standard deviation-SD) was 41.9 (10.1) years, 53.4 % male. Seventy-eight (67.2 %) were neurologists fully dedicated to the care of demyelinating disorders. Mean (SD) TI score was 3.65 (1.01). Overall, 92.2 % of participants (n = 107) presented TI in at least 2/9 case scenarios. The lack of full dedication to MS care (p = 0.014), preference for taking risks (p = 0.008), and low willingness to adopt evidence-based innovations (p = 0.009) were associated with higher TI scores in the multivariate analysis after adjustment for confounders., Conclusion: TI was a common phenomenon among neurologists managing MS patients when faced with the decision to initiate or escalate treatment based on elevated sNfL levels. Identifying factors associated with this phenomenon may help optimize treatment decisions in MS care., Competing Interests: Declaration of competing interest Gustavo Saposnik received consulting fees from Roche Farma Spain and is supported by the University of Toronto Scientific Merit award. He also receives a modest stipend from the World Stroke Organization as the Editor in Chief of the World Stroke Academy. Enric Monreal reported receiving research grants, travel support, or honoraria for speaking engagements from Almirall, Merck, Roche, Sanofi, Bristol Myers Squibbb, Biogen, Janssen, and Novartis. Jose M García-Domínguez received honoraria as speaker, advisor and researcher from Almirall, Bristol Myers Squibb, Biogen, Janssen, Merck, Novartis, Roche, Teva, and Sanofi. Jose E Meca-Lallana received honoraria as a consultant, chairman and lecturer in meetings and participated in clinical trials and other research projects promoted by Alexion, Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Roche, and Sanofi. Lamberto Landete received honoraria for participating in advisory boards and scientific and educational activities from Almirall, Bayer, Biogen, Bristol Myers Squibb, Sanofi, Merck, Novartis, UCB, Roche, and Teva. Virginia Meca-Lallana received consulting and speaking fees from Almirall, Biogen, Genzyme, Janssen, Merck, Novartis, Roche, Terumo, Sanofi, Teva, and Bristol Myers Squibb. Luis Querol received speaker honoraria from Merck, Sanofi, Roche, Biogen, Grifols and CSL Behring; provided expert testimony for Grifols, Johnson & Johnson, Annexon Pharmaceuticals, Sanofi, Novartis, Takeda, and CSL-Behring; and received research funds from Roche, UCB, and Grifols. Eduardo Agüera received speaking honoraria from Roche, Novartis, Merck, Sanofi, and Biogen. Sergio Martínez-Yélamos received honoraria for participating on advisory boards and for collaborations as consultant and scientific communications; they also received research support as well as funding for travel and congress expenses from Roche, Biogen Idec, Novartis, TEVA, Merck, Genzyme, Sanofi, Bayer, Almirall, and Bristol Myers Squibb. Luisa M Villar reported receiving research grants and personal fees from Merck, Roche, Sanofi, Bristol Myers Squibb, Biogen, and Novartis. Ana B Caminero received courses and honoraria for her participation as speaker/meeting moderator/symposia organizer from Alter, Almirall, Bayer, Bial, Biogen, Bristol Myers Squibb, Lilly, Merck, Mylan, Novartis, Roche, Sanofi-Genzyme, Teva, and UCB; and support to attend scientific meetings from Biogen, Bial, Merck-Serono, Novartis, Roche, Sanofi, and Teva. Rocío Gómez-Ballesteros, Elisa Salas, Nicolas Medrano, Elena García-Arcelay, and Jorge Maurino are employees of Roche Farma Spain., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: People with secondary progressive multiple sclerosis (pwSPMS) experience increasing disability, which impacts negatively on their health-related quality of life (HRQoL). Our aims were to assess the impact of secondary progressive multiple sclerosis (SPMS) on functional status and HRQoL and describe the clinical profile in this population., Methods: DISCOVER is an observational, cross-sectional, multicenter study with retrospective data collection in real-world clinical practice in Spain. Sociodemographic and clinical variables, functional and cognitive scales, patient-reported outcomes (PROs), and direct healthcare, and non-healthcare and indirect costs were collected., Results: A total of 297 evaluable pwSPMS with a EDSS score between 3-6.5 participated: 62.3 % were female and 18.9 % had active SPMS. At the study visit, 77 % of them presented an Expanded Disability Scale Score (EDSS) of 6-6.5. Nearly 40 % did not receive any disease-modifying treatment. Regarding the working situation, 61.6 % were inactive due to disability. PROs: 99.3 % showed mobility impairment in EuroQoL-5 Dimensions-5 Levels, and about 60 % reported physical impact on the Multiple Sclerosis Impact Scale-29. Fatigue was present in 76.1 %, and almost 40 % reported anxiety or depression. The Symbol Digit Modalities Test was used to assess cognitive impairment; 80 % of the patients were below the mean score. Participants who presented relapses two years before and had high EDSS scores had a more negative impact on HRQoL. PwSPMS with a negative impact on HRQoL presented a higher cost burden, primarily due to indirect costs., Conclusions: PwSPMS experience a negative impact on their HRQoL, with a high physical impact, fatigue, cognitive impairment, and a high burden of indirect costs., Competing Interests: Declaration of competing interest None, (Copyright © 2024. Published by Elsevier B.V.)

Amyotrophic lateral sclerosis is a debilitating and lethal neurodegenerative disorder marked by the gradual deterioration of motor neurons. Diagnosing amyotrophic lateral sclerosis is challenging due to the lack of reliable diagnostic tools, with clinical assessment being the primary criterion. Recently, increased levels of neurofilament light chain in CSF have been considered a useful biomarker in disease, correlating with disease progression but not specific for diagnosis. This study utilized enzyme-linked immunosorbent assay to measure CSF C-X-C motif chemokine ligand 12 levels in healthy controls, amyotrophic lateral sclerosis patients and patients with amyotrophic lateral sclerosis-mimic disorders, assessing its potential as a diagnostic biomarker and comparing it with neurofilament light chain levels. Our results confirmed previous findings, showing increased C-X-C motif chemokine ligand 12 levels in amyotrophic lateral sclerosis patients compared to healthy control (797.07 ± 31.84 pg/mL versus 316.15 ± 16.6 pg/mL; P = 0.000) and increased CSF neurofilament light chain levels in amyotrophic lateral sclerosis (4565.63 ± 263.77 pg/mL) compared to healthy control (847.86 ± 214.37 pg/mL; P = 0.000). Increased C-X-C motif chemokine ligand levels were specific to amyotrophic lateral sclerosis, not seen in amyotrophic lateral sclerosis-mimic conditions like myelopathies (252.20 ± 23.16 pg/mL; P = 0.000), inflammatory polyneuropathies (270.24 ± 32.23 pg/mL; P = 0.000) and other mimic diseases (228.91 ± 29.20 pg/mL; P = 0.000). In contrast, CSF neurofilament light chain levels in amyotrophic lateral sclerosis overlapped with those in myelopathies (2900.11 ± 872.20 pg/mL; P = 0.821) and other mimic diseases (3169.75 ± 1096.65 pg/mL; P = 0.63), but not with inflammatory polyneuropathies (1156.4 ± 356.6 pg/mL; P = 0.000). Receiver operating characteristic curve analysis indicated significant differences between the area under the curve values of C-X-C motif chemokine ligand and neurofilament light chain in their diagnostic capacities. C-X-C motif chemokine ligand could differentiate between amyotrophic lateral sclerosis and myelopathies (area under the curve 0.99 ± 0.005), inflammatory polyneuropathies (area under the curve 0.962 ± 0.027) and other mimic diseases (area under the curve 1.00 ± 0.00), whereas neurofilament light chain was only effective in inflammatory polyneuropathies cases (area under the curve 0.92 ± 0.048), not in myelopathies (area under the curve 0.71 ± 0.09) or other mimic diseases (area under the curve 0.69 ± 0.14). We also evaluated C-X-C motif chemokine ligand levels in plasma [amyotrophic lateral sclerosis (2022 ± 81.8 pg/mL) versus healthy control (1739.43 ± 77.3 pg/mL; P = 0.015)] but found CSF determination (area under the curve 0.97 ± 0.012) to be more accurate than plasma determination (area under the curve 0.65 ± 0.063). In plasma, single molecule array (SIMOA) neurofilament light chain determination [amyotrophic lateral sclerosis (86.00 ± 12.23 pg/mL) versus healthy control (12.69 ± 1.15 pg/mL); P = 0.000] was more accurate than plasma C-X-C motif chemokine ligand 12 (area under the curve 0.98 ± 0.01405). These findings suggest that CSF C-X-C motif chemokine ligand 12 levels can enhance diagnostic specificity in distinguishing amyotrophic lateral sclerosis from amyotrophic lateral sclerosis-mimic disorders, compared to neurofilament light chain. Larger studies are needed to validate these results, but C-X-C motif chemokine ligand 12 determination shows promising diagnostic potential., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: The complement system is known to play a role in multiple sclerosis (MS) pathogenesis. However, its contribution to disease progression remains elusive. The study investigated the role of the complement system in disability progression of patients with primary progressive MS (PPMS)., Methods: Sixty-eight patients with PPMS from 12 European MS centers were included in the study. Serum and CSF levels of a panel of complement components (CCs) were measured by multiplex enzyme-linked immunosorbent assay at a baseline time point (i.e., sampling). Mean (SD) follow-up time from baseline was 9.6 (4.8) years. Only one patient (1.5%) was treated during follow-up. Univariable and multivariable logistic regressions adjusted for age, sex, and albumin quotient were performed to assess the association between baseline CC levels and disability progression in short term (2 years), medium term (6 years), and long term (at the time of the last follow-up)., Results: In short term, CC played little or no role in disability progression. In medium term, an elevated serum C3a/C3 ratio was associated with a higher risk of disability progression (adjusted OR 2.30; 95% CI 1.17-6.03; p = 0.040). By contrast, increased CSF C1q levels were associated with a trend toward reduced risk of disability progression (adjusted OR 0.43; 95% CI 0.17-0.98; p = 0.054). Similarly, in long term, an elevated serum C3a/C3 ratio was associated with higher risk of disability progression (adjusted OR 1.81; 95% CI 1.09-3.40; p = 0.037), and increased CSF C1q levels predicted lower disability progression (adjusted OR 0.41; 95% CI 0.17-0.86; p = 0.025)., Discussion: Proteins involved in the activation of early complement cascades play a role in disability progression as risk (elevated serum C3a/C3 ratio) or protective (elevated CSF C1q) factors after 6 or more years of follow-up in patients with PPMS. The protective effects associated with C1q levels in CSF may be related to its neuroprotective and anti-inflammatory properties.

Background: We aimed to investigate the potential of serum biomarker levels to predict disability progression in a multicentric real-world cohort of patients with primary progressive multiple sclerosis (PPMS)., Methods: A total of 141 patients with PPMS from 18 European MS centres were included. Disability progression was investigated using change in Expanded Disability Status Scale (EDSS) score over three time intervals: baseline to 2 years, 6 years and to the last follow-up. Serum levels of neurofilament light chain (sNfL), glial fibrillar acidic protein (sGFAP) and chitinase 3-like 1 (sCHI3L1) were measured using single-molecule array assays at baseline. Correlations between biomarker levels, and between biomarkers and age were quantified using Spearman's r. Univariable and multivariable linear models were performed to assess associations between biomarker levels and EDSS change over the different time periods., Results: Median (IQR) age of patients was 52.9 (46.4-58.5) years, and 58 (41.1%) were men. Median follow-up time was 9.1 (7.0-12.6) years. Only 8 (5.7%) patients received treatment during follow-up. sNfL and sGFAP levels were moderately correlated (r=0.43) and both weakly correlated with sCHI3L1 levels (r=0.19 and r=0.17, respectively). In multivariable analyses, levels of the three biomarkers were associated with EDSS changes across all time periods. However, when analysis was restricted to non-inflammatory patients according to clinical and radiological parameters (n=64), only sCHI3L1 levels remained associated with future EDSS change., Conclusions: Levels of sNfL, sGFAP and sCHI3L1 are prognostic biomarkers associated with disability progression in patients with PPMS, being CHI3L1 findings less dependent on the inflammatory component associated with disease progression., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Neurosarcoidosis is an uncommon but potentially serious disease of the central nervous system that can cause major sequelae. We analyzed the presence and diagnostic usefulness of specific cutaneous lesions in 58 patients with neurosarcoidosis. Sixteen patients (27.6%) had specific cutaneous lesions (14 men and 2 women; mean age, 50 years [range, 20-84 years]). Twenty-four types of neurological lesions were observed: cranial neuropathy (n=7), parenchymal lesions (n=4), meningeal lesions (n=3), myelopathy (n=3), pituitary lesions (n=1), hydrocephalus (n=2), and peripheral neuropathy (n=4). Twenty types of specific cutaneous lesions were observed: maculopapular lesions (n=6), plaques (n=9), lupus pernio (n=1), and scar sarcoidosis (n=4). These last lesions coexisted with maculopapular lesions in 2 patients and plaques in another 2. Specific cutaneous lesions were present at diagnosis of neurosarcoidosis in 13 patients. Recognition of specific cutaneous lesions in a patient with suspected neurosarcoidosis is important as biopsy can accelerate diagnosis., (Copyright © 2023 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: Paramagnetic rim lesions (PRLs), usually identified in susceptibility-weighted imaging (SWI), are a promising prognostic biomarker of disability progression in multiple sclerosis (MS). However, SWI is not routinely performed in clinical practice. The objective of this study is to define a novel imaging sign, the T1-dark rim, identifiable in a standard 3DT1 gradient-echo inversion-recovery sequence, such as 3D T1 turbo field echo (3DT1FE) and explore its performance as a SWI surrogate to define PRLs., Methods: This observational cross-sectional study analyzed MS patients who underwent 3T magnetic resonance imaging (MRI) including 3DT1TFE and SWI. Rim lesions were evaluated in 3DT1TFE, processed SWI, and SWI phase and categorized as true positive, false positive, or false negative based on the value of the T1-dark rim in predicting SWI phase PRLs. Sensitivity and positive predictive values of the T1-dark rim for detecting PRLs were calculated., Results: Overall, 80 rim lesions were identified in 63 patients (60 in the SWI phase and 78 in 3DT1TFE; 58 true positives, 20 false positives, and two false negatives). The T1-dark rim demonstrated 97% sensitivity and 74% positive predictive value for detecting PRLs. More PRLs were detected in the SWI phase than in processed SWI (60 and 57, respectively)., Conclusion: The T1-dark rim sign is a promising and accessible novel imaging marker to detect PRLs whose high sensitivity may enable earlier detection of chronic active lesions to guide MS treatment escalation. The relevance of T1-dark rim lesions that are negative on SWI opens up a new field for analysis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)