Effectiveness and Safety of Teriflunomide in Relapsing-Remitting Multiple Sclerosis and Improvements in Quality of Life: Results from the Real-World TERICARE Study.

INTRODUCTION: Teriflunomide is a once-daily oral immunomodulator approved for relapsing forms of multiple sclerosis (MS) or relapsing-remitting multiple sclerosis (RRMS; depending on the local label), based on extensive evidence from clinical trials and a real-world setting on efficacy, tolerability and patient-reported benefits. The TERICARE study assessed the impact of teriflunomide treatment over 2 years on health-related quality of life (HRQoL) and some of the most common and disabling symptoms of MS, such as fatigue and depression. METHODS: This prospective observational study in Spain included RRMS patients treated with teriflunomide for ≤ 4 weeks. The following patient-reported outcomes (PROs) were collected at baseline and every 6 months for 2 years: the 29-item Multiple Sclerosis Impact Scale version 2 (MSIS-29), the 21-item Modified Fatigue Impact Scale (MFIS-21), the Beck Depression Inventory (BDI-II), the Short Form (SF)-Qualiveen and the Treatment Satisfaction Questionnaire for Medication v1.4 (TSQM). Annualised relapse rate (ARR), disability progression according to the Expanded Disability Status Scale (EDSS), and no evidence of disease activity (NEDA-3) were also assessed. RESULTS: A total of 325 patients were analysed. Patients had a mean (SD) age of 43.2 years (10.4), a mean baseline EDSS score of 1.75 (1.5), a mean number of relapses in the past 2 years of 1.5 (0.7), and 64% had received prior disease-modifying therapy (DMT). Patients showed significant improvements in the psychological domain of MSIS-29 from 35.9 (26.6) at baseline to 29.4 (25.5) at 18 months (p = 0.004) and 29.0 (24.6) at 24 months (p = 0.002). Levels of fatigue and depression were also reduced. After 2 years of treatment with teriflunomide, ARR was reduced to 0.17 (95% CI 0.14-0.21) from the baseline of 0.42 (95% CI 0.38-0.48), representing a 60.1% reduction. Mean EDSS scores remained stable during the study, and 79.9% of patients showed no disability progression. 54.7% of patients achieved NEDA-3 in the first 12 months, which increased to 61.4% during months 12-24. Patients reported increased satisfaction with treatment over the course of the study, regardless of whether they were DMT naive or not. CONCLUSION: Teriflunomide improves psychological aspects of HRQoL and maintains low levels of fatigue and depression. Treatment with teriflunomide over 2 years is effective in reducing ARR and disability progression.

New Algorithms Improving PML Risk Stratification in MS Patients Treated With Natalizumab.

Overview: We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression. Results: Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from <1/3,300 in patients with anti-John Cunninghan virus antibody indices <0.9 and relapse rate >0.5, to 1/50 in the opposite case. In patients with lipid-specific IgM oligoclonal bands assessment, age at natalizumab onset, anti-John Cunninghan virus antibody indices, and lipid-specific IgM oligoclonal band status predicted progressive multifocal leucoencephalopathy risk (AUC = 0.92). The absence of lipid-specific IgM oligoclonal bands was the best individual predictor (OR = 40.94). The individual risk ranged from <1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices <0.9 and lipid-specific IgM oligoclonal bands to 1/33 in the opposite case. Conclusions: In a perspective of personalized medicine, disease activity, anti-lipid specific IgM oligoclonal bands, anti Jonh Cunninghan virus antibody levels, and age can help tailor natalizumab therapy in multiple sclerosis patients, as predictors of progressive multifocal leucoencephalopathy.

Cambios estructurales y funcionales del hipocampo en pacientes con esclerosis múltiple y su relación con procesos de memoria / Structural and functional changes of the hippocampus in patients with multiple sclerosis and their relationship with memory processes

Introducción. Una de las alteraciones cognitivas más prevalentes en los pacientes con esclerosis múltiple son los problemas de codificación de la información (tanto verbal como visual), proceso relacionado con el hipocampo. Objetivo. Estudiar la relación entre los procesos de aprendizaje y retención de la información a largo plazo con el volumen hipocampal y la conectividad funcional (CF) en pacientes con esclerosis múltiple comparados con un grupo control. Sujetos y métodos. Ambos grupos fueron evaluados con la batería neuropsicológica breve, que incluye pruebas de memoria verbal y visual. Se realizó el estudio de volumetría de la sustancia gris mediante la técnica de morfometría basada en el vóxel y un estudio de CF de vóxel de semilla centrado en la zona de interés (hipocampo). Se realizaron análisis de asociación entre rendimiento en memoria y cambios volumétricos y de CF. Resultados. Los resultados mostraron atrofia en la sustancia gris en el hipocampo izquierdo y una menor CF entre el hipocampo izquierdo y el troncoencéfalo, el cerebelo, el giro fusiforme y el giro temporal superior en los pacientes respecto al grupo control. En el grupo de pacientes se observa una correlación positiva entre la sustancia gris en ambos hipocampos y el rendimiento en memoria verbal, así como una correlación positiva entre el rendimiento en memoria visual y la CF entre el hipocampo izquierdo y diversas regiones temporales. Conclusiones. Los resultados muestran una relación entre el rendimiento de memoria verbal y visual, y cambios estructurales y funcionales en el hipocampo en pacientes con esclerosis múltiple (AU)

Introduction. One of the most prevalent cognitive deficits in multiple sclerosis (MS) patients relates to (both verbal and visual) information encoding, a process related the hippocampus. Aim. To assess the relationship between information learning and long-term retention processes and hippocampal volume and functional connectivity (FC) in MS patients. Subjects and methods. MS patients and a control group of healthy volunteers were assessed using the brief neuropsychological battery, which includes tests of verbal and visual memory. Gray matter volume was assessed through the voxel based morphometry technique, and a study of seed-based FC focused on the region of interest (hippocampus) was also conducted. Results. Results revealed that, as compared to the control group, MS patients display gray matter atrophy at the left hippocampus gray matter and smaller FC between left hippocampus and brainstem, cerebellum, fusiform gyrus and superior temporal gyrus. Association analyses were performed between memory tests performance and both volumetric and FC changes. Results showed a positive correlation between gray matter hippocampal (bilateral) volume and verbal memory performance of the MS group. Further, in MS patients, a positive correlation between visual memory performance and FC between the left hippocampus and several temporal regions was also found. Conclusions. The results of the present study reveal a relationship between structural and functional changes in the hippocampus of MS patients and their performance on verbal and visual memory tests (AU)

[Structural and functional changes of the hippocampus in patients with multiple sclerosis and their relationship with memory processes]. / Cambios estructurales y funcionales del hipocampo en pacientes con esclerosis múltiple y su relación con procesos de memoria.

INTRODUCTION: One of the most prevalent cognitive deficits in multiple sclerosis (MS) patients relates to (both verbal and visual) information encoding, a process related the hippocampus. AIM: To assess the relationship between information learning and long-term retention processes and hippocampal volume and functional connectivity (FC) in MS patients. SUBJECTS AND METHODS: MS patients and a control group of healthy volunteers were assessed using the brief neuro-psychological battery, which includes tests of verbal and visual memory. Gray matter volume was assessed through the voxel based morphometry technique, and a study of seed-based FC focused on the region of ??interest (hippocampus) was also conducted. RESULTS: Results revealed that, as compared to the control group, MS patients display gray matter atrophy at the left hippocampus gray matter and smaller FC between left hippocampus and brainstem, cerebellum, fusiform gyrus and superior temporal gyrus. Association analyses were performed between memory tests performance and both volumetric and FC changes. Results showed a positive correlation between gray matter hippocampal (bilateral) volume and verbal memory performance of the MS group. Further, in MS patients, a positive correlation between visual memory performance and FC between the left hippocampus and several temporal regions was also found. CONCLUSIONS: The results of the present study reveal a relationship between structural and functional changes in the hippocampus of MS patients and their performance on verbal and visual memory tests.

TITLE: Cambios estructurales y funcionales del hipocampo en pacientes con esclerosis multiple y su relacion con procesos de memoria.Introduccion. Una de las alteraciones cognitivas mas prevalentes en los pacientes con esclerosis multiple son los problemas de codificacion de la informacion (tanto verbal como visual), proceso relacionado con el hipocampo. Objetivo. Estudiar la relacion entre los procesos de aprendizaje y retencion de la informacion a largo plazo con el volumen hipocampal y la conectividad funcional (CF) en pacientes con esclerosis multiple comparados con un grupo control. Sujetos y metodos. Ambos grupos fueron evaluados con la bateria neuropsicologica breve, que incluye pruebas de memoria verbal y visual. Se realizo el estudio de volumetria de la sustancia gris mediante la tecnica de morfometria basada en el voxel y un estudio de CF de voxel de semilla centrado en la zona de interes (hipocampo). Se realizaron analisis de asociacion entre rendimiento en memoria y cambios volumetricos y de CF. Resultados. Los resultados mostraron atrofia en la sustancia gris en el hipocampo izquierdo y una menor CF entre el hipocampo izquierdo y el troncoencefalo, el cerebelo, el giro fusiforme y el giro temporal superior en los pacientes respecto al grupo control. En el grupo de pacientes se observa una correlacion positiva entre la sustancia gris en ambos hipocampos y el rendimiento en memoria verbal, asi como una correlacion positiva entre el rendimiento en memoria visual y la CF entre el hipocampo izquierdo y diversas regiones temporales. Conclusiones. Los resultados muestran una relacion entre el rendimiento de memoria verbal y visual, y cambios estructurales y funcionales en el hipocampo en pacientes con esclerosis multiple.

Análisis crítico de los estudios de neuroimagen en relación con el rendimiento cognitivo en pacientes con esclerosis múltiple / A critical analysis of neuroimaging studies in relation to cognitive performance in multiple sclerosis patients

El estudio y comprensión del deterioro cognitivo en los pacientes de esclerosis múltiple (EM) resulta esencial para entender esta enfermedad. El uso de las técnicas de neuroimagen puede aportar datos a la comprensión de la naturaleza de dichos déficits, así como a su evolución. Durante los últimos años, se ha producido un marcado incremento de trabajos que evalúan la relación entre el deterioro cognitivo de esta población clínica y diversas variables patológicas obtenidas mediante técnicas de neuroimagen clásicas, así como mediante el uso de otros procedimientos de desarrollo más reciente. Los resultados de los estudios que usan técnicas de neuroimagen estructural han revelado la importancia de procesos atróficos en el deterioro cognitivo de la EM. Sin embargo, esta información debe complementarse con la aportada por otros procedimientos más novedosos acerca de alteraciones en la sustancia blanca y en la sustancia gris de ‘apariencia normal’. Por otra parte, los estudios que han empleado técnicas de resonancia magnética funcional han mostrado la existencia de distintos procesos de neuroplasticidad que pueden enmascarar la relación entre los índices morfológicos de daño cerebral y el rendimiento cognitivo de los pacientes con EM. Estos procesos no deben ignorarse, en tanto que pueden compensar las alteraciones cognitivas de esta población clínica. El presente trabajo de revisión intenta aportar una visión crítica e integradora de los estudios dedicados a evaluar la relación entre el deterioro cognitivo de la EM y diferentes tipos de información aportados por las técnicas de neuroimagen (AU)

Studying the cognitive impairment of multiple sclerosis (MS) patients is fundamental for a global understanding of this disease. Neuroimaging techniques might provide crucial data about the nature of this deficit and their progression. Accordingly to this idea, over the last years there has been a marked increase in the number of studies devoted to explore the possible relationship between the cognitive alterations of this clinical population and different sorts of neuropathological indexes provided by both, classical as well as by more recently developed techniques. The results of the studies using structural information provided by structural techniques, have revealed the important role of atrophic processes in the aethiology of cognitive decline in MS patients. However, this information needs to be complemented with newer indexes of neuropathological alterations in ‘apparently normal’ gray and white matter. On the other hand, functional magnetic resonance imaging studies have provided clear evidence of the existence and functional significance of neuroplastic processes that can mask the relationship between morphological markers of tissue damage and cognitive performance of MS patients. Those neuroplastic processes need to be taken into account as they might compensate the cognitive decline of this clinical population. In summary, the present review tries to provide a critic and integrative view of different studies assessing the relationship between cognitive impairment in MS patients and different kinds of information provided by neuroimaging techniques (AU)

Código ictus provincial: características e impacto asistencial / Provincial stroke code: characteristics and impact on health care

Introducción. La trombólisis endovenosa en el infarto cerebral es el tratamiento de elección en las primeras horas y el retraso es la principal barrera para su empleo. El código ictus (CI) es un sistema que permite una rápida identificación y traslado del paciente con ictus al hospital adecuado para realizarla. Objetivo. Conocer el impacto de extender el CI intrahospitalario (CII) a CI provincial (CIP). Pacientes y métodos. Registro prospectivo de CI atendidos en un centro de ictus provincial. Se recogieron los infartos cerebrales ingresados de forma consecutiva el año previo y posterior al inicio del CIP (1 de noviembre de 2008). Resultados. En un año se atendieron 318 CI: el 61,2% fueron CI extrahospitalarios (CIE). Se trombolizaron 45 pacientes: el 14,2% de las activaciones y el 25,7% de los infartos cerebrales con código activado. La tasa bruta anual de trombólisis fue de 7,7 × 100.000 habitantes (intervalo de confianza del 95%, IC 95% = 5,7-10,4). Medicina primaria activó el 34% de los códigos. No hay diferencias significativas en el porcentaje de activaciones correctas y trombólisis entre CIE y CII. El retraso puerta-aguja es menor en los CIE (59,7 ± 24 frente a 74,4 ± 20 min; p = 0,012). La franja horaria de 22:00 a 08:00 h incluye el 23,6% de los CI y el 22,2% de los trombolizados. Del primer al segundo período, la activación del CI pasa del 11,1 al 37,9% de infartos cerebrales, y la trombólisis aumenta del 3,8 al 12,7% (p < 0,0001; odds ratio = 4,1; IC 95% = 1,9-8,6). Conclusión. El CIP permitió cuadruplicar la trombólisis del infarto cerebral, mejorar la cadena asistencial y extenderla a toda la provincia (AU)

Introduction. Endovenous thrombolysis is the preferred treatment in the early hours following cerebral infarction and delays are the main obstacle preventing it from being used on a more widespread basis. The stroke code (SC) is a system that allows stroke patients to be identified quickly and taken to the most suitable hospital for such treatment to be implemented. Aim. To determine the impact of extending the intra-hospital SC (ISC) to a provincial SC (PSC). Patients and methods. The system consists in a prospective register of cases of SC treated in a provincial stroke centre. Data on the cases of cerebral infarction admitted consecutively the year prior to and after beginning the PSC (1st November 2008) were collected. Results. In one year 318 SC were handled: 61.2% were extra-hospital SC (ESC). A total of 45 patients were thrombolysed: 14.2% of the activations and 25.7% of cerebral infarctions with the code activated. The gross annual rate of thrombolysis was 7.7/100,000 inhabitants (95% confidence interval, 95% CI = 5.7-10.4). Primary medicine activated 34% of the codes. There are no significant differences between ESC and ISC as regards the percentage of correct activations and thrombolysis. The door-to-needle delay is shorter in ESC (59.7 ± 24 versus 74.4 ± 20 minutes; p = 0.012). The time slot from 22 pm to 8 am covers 23.6% of the SC and 22.2% of cases of thrombolysed patients. From the first to the second period, SC activation rises from 11.1% to 37.9% of cerebral infarctions and thrombolysis increases from 3.8 to 12.7% (p < 0.0001; odds ratio = 4.1; 95% CI = 1.9-8.6). Conclusions. The PSC allowed thrombolysis of cerebral infarction to be carried out in four times as many cases, as well as improving the health care chain and extending it throughout the whole province (AU)

[Provincial stroke code: characteristics and impact on health care]. / Código ictus provincial: características e impacto asistencial.

INTRODUCTION: Endovenous thrombolysis is the preferred treatment in the early hours following cerebral infarction and delays are the main obstacle preventing it from being used on a more widespread basis. The stroke code (SC) is a system that allows stroke patients to be identified quickly and taken to the most suitable hospital for such treatment to be implemented. AIM. To determine the impact of extending the intra-hospital SC (ISC) to a provincial SC (PSC). PATIENTS AND METHODS: The system consists in a prospective register of cases of SC treated in a provincial stroke centre. Data on the cases of cerebral infarction admitted consecutively the year prior to and after beginning the PSC (1st November 2008) were collected. RESULTS: In one year 318 SC were handled: 61.2% were extra-hospital SC (ESC). A total of 45 patients were thrombolysed: 14.2% of the activations and 25.7% of cerebral infarctions with the code activated. The gross annual rate of thrombolysis was 7.7/100,000 inhabitants (95% confidence interval, 95% CI = 5.7-10.4). Primary medicine activated 34% of the codes. There are no significant differences between ESC and ISC as regards the percentage of correct activations and thrombolysis. The door-to-needle delay is shorter in ESC (59.7 ± 24 versus 74.4 ± 20 minutes; p = 0.012). The time slot from 22 pm to 8 am covers 23.6% of the SC and 22.2% of cases of thrombolysed patients. From the first to the second period, SC activation rises from 11.1% to 37.9% of cerebral infarctions and thrombolysis increases from 3.8 to 12.7% (p < 0.0001; odds ratio = 4.1; 95% CI = 1.9-8.6). CONCLUSIONS: The PSC allowed thrombolysis of cerebral infarction to be carried out in four times as many cases, as well as improving the health care chain and extending it throughout the whole province.