Estimulación magnética transcraneal theta-burst intermitente para el tratamiento de la espasticidad en pacientes con esclerosis múltiple recurrente: resultados de un ensayo clínico aleatorizado doble ciego / Intermittent theta-burst transcranial magnetic stimulation for the treatment of spasticity in patients with recurring multiple sclerosis: the results of a double-blind randomised clinical trial

Objetivo. La estimulación magnética transcraneal repetitiva podría ser útil como tratamiento no farmacológico para la espasticidad. El objetivo de este estudio es reevaluar el efecto clínico y los cambios neurofisiológicos que produce la estimulación theta-burst intermitente (ETBi) sobre la espasticidad de las extremidades inferiores en pacientes con esclerosis múltiple recurrente en un ensayo aleatorizado, doble ciego, controlado con placebo. Pacientes y métodos. Diecisiete pacientes en la fase remitente de la enfermedad fueron aleatoriamente asignados al grupo placebo o al grupo de tratamiento activo mediante estimulación magnética transcraneal repetitiva con protocolo ETBi sobre la corteza motora contralateral de la pierna más afectada. El procedimiento consistió en 10 sesiones diarias durante dos semanas. Cada sesión consistió en 10 ráfagas que contenían tres pulsos a 50 Hz repetidos a intervalos de 200 ms (5 Hz) cada 10 s para un total de 600 estímulos. El efecto de ETBi se evaluó mediante el uso de parámetros clínicos (como la escala de Ashworth modificada) y neurofisiológicos (ratio de amplitud H/M y duración del período cortical silente). Resultados. Dos semanas de ETBi sobre la corteza motora de la pierna más afectada no produjeron ningún efecto clínico significativo sobre la espasticidad en pacientes con esclerosis múltiple recurrente. Sin embargo, aunque de forma no significativa, se observó disminución de la ratio de amplitud H/M y un aumento de la duración del período cortical silente. Conclusión. El protocolo de estimulación utilizado en este estudio no parece tener un efecto terapéutico significativo. Sin embargo, recomendamos estudios adicionales, ya que los cambios neurofisiológicos fueron evidentes

Aim. It has been suggested that the repetitive transcranial magnetic stimulation could be useful as a non-pharmacological treatment for spasticity. The aim of this study was to evaluate the clinical and neurophysiological effects of high-frequency intermittent theta burst stimulation (iTBS) on lower limb spasticity in patients with relapsing multiple sclerosis in a randomized, double-blind placebo controlled trial. Patients and methods. Seventeen patients in the remitting phase of the disease were randomly allocated to sham or magnetic therapy group and underwent iTBS over contralateral motor cortex of the most affected leg once a day for two weeks. Each session consisted of 10 bursts containing three pulses at 50 Hz repeated at 200 ms intervals (5 Hz) every 10 s for a total of 600 stimuli. The iTBS effect was assessed by using clinical (such as the Modified Ashworth Scale) and neurophysiological (H/M amplitude ratio and cortical silent period duration) parameters. Results. Two-week iTBS over motor cortex of the most affected leg did not produce any significant clinical effect on spasticity. However, it decreases the H/M amplitude ratio and increases duration of cortical silent period but not significantly, in patients with relapsing multiple sclerosis. CONCLUSION. The stimulation protocol used in this study does not have significant therapeutic effect. Therefore, we do recommend further studies as neurophysiological changes were evident

Revisión de las novedades del XXXII Congreso ECTRIMS 2016, presentadas en la IX Reunión Post-ECTRIMS (I) / Review of the novelties from the 32nd ECTRIMS Congress, 2016, presented at the 9th Post-ECTRIMS Meeting (I)

Por noveno año consecutivo se ha celebrado en Madrid (España) la Reunión Post-ECTRIMS con el objetivo de presentar y discutir los temas más debatidos en el congreso ECTRIMS de la mano de reconocidos especialistas en esclerosis múltiple de nuestro país. Fruto de esta actividad científica, avalada por la Sociedad Española de Neurología, se genera este artículo de revisión que sale publicado en dos partes. Esta primera parte aborda la planificación familiar en las mujeres con esclerosis múltiple, el manejo del embarazo y el papel de la lactancia. Se dirige la atención a la población pediátrica, a las características de la resonancia magnética y a los factores de riesgo geneticoambientales para el desarrollo de la enfermedad en niños, sin olvidar los factores de riesgo de progresión en los adultos. Se actualiza la epidemiología del deterioro cognitivo en los pacientes con esclerosis múltiple, las ventajas e inconvenientes de las herramientas de evaluación disponibles, y los enfoques actuales de manejo, y se insiste en la importancia de la afectación cognitiva en el curso de la enfermedad. Además, se introduce el concepto de medicina individualizada y de precisión, desde el diagnóstico de la enfermedad hasta el tratamiento, con las polémicas que inevitablemente surgen en el manejo de los pacientes, principalmente en lo relacionado con el cambio de tratamiento y el manejo de riesgos asociados (AU)

For the ninth year in a row the Post-ECTRIMS Meeting has been held in Madrid (Spain) with the aim of presenting and discussing the hottest issues debated at the ECTRIMS Congress by renowned specialists in multiple sclerosis in our country. One outcome of this scientific activity, endorsed by the Spanish Neurology Society, is this review article, which is published in two parts. This first part addresses family planning, pregnancy management and the role of breastfeeding in women with multiple sclerosis. Attention is drawn to the paediatric population, to magnetic resonance imaging features and to the genetic-environmental risk factors for developing the disease in children, without neglecting the risk factors for development in adults. The review updates the epidemiology of cognitive deterioration in patients with multiple sclerosis, the advantages and disadvantages of available assessment tools, and current management approaches, while also insisting on the importance of cognitive involvement during the course of the disease. Furthermore, the concept of individualised, precision medicine is introduced, from the diagnosis of the disease until its treatment, with the controversies that inevitably arise in patient management, above all with regard to the change of treatment and the handling of associated risks (AU)

Revisión de las novedades del XXXII Congreso ECTRIMS 2016, presentadas en la IX Reunión Post-ECTRIMS (II) / Review of the novelties from the 32nd ECTRIMS Congress, 2016, presented at the 9th Post-ECTRIMS Meeting (II)

Por noveno año consecutivo se ha celebrado en Madrid (España) la Reunión Post-ECTRIMS con el objetivo de presentar y discutir los temas más debatidos en el congreso ECTRIMS de la mano de reconocidos especialistas en esclerosis múltiple de nuestro país. Fruto de esta reunión científica, avalada por la Sociedad Española de Neurología, se genera este artículo de revisión que sale publicado en dos partes. En esta segunda parte se pone de manifiesto la controversia actual en el manejo de la esclerosis múltiple, especialmente en cuanto a formas progresivas y diagnóstico diferencial se refiere. Se presentan los últimos avances en remielinización, donde destaca el uso de la técnica con micropilares en el laboratorio, y en neuroprotección, la cual se revisa a través del estudio del nervio óptico. Los anticuerpos anti-CD20 ofrecen grandes expectativas, y estamos ante un nuevo mecanismo de acción y diana terapéutica en unas células a las que les habíamos prestado poca atención hasta la fecha. Otro hecho destacable es la elevada correlación entre los niveles de neurofilamentos en el líquido cefalorraquídeo y el suero, que podría evitar el uso del líquido cefalorraquídeo como muestra biológica en futuros estudios de biomarcadores. También se anticipan los avances en investigación clínica que en el futuro acabarán convergiendo en la práctica clínica, condicionando los pasos que se deberán seguir en el abordaje terapéutico de la esclerosis múltiple (AU)

For the ninth year in a row the Post-ECTRIMS Meeting has been held in Madrid (Spain) with the aim of presenting and discussing the hottest issues debated at the ECTRIMS Congress by renowned specialists in multiple sclerosis in our country. One outcome of this scientific activity, endorsed by the Spanish Neurology Society, is this review article, which is published in two parts. This second part reflects the current controversy over the management of multiple sclerosis, especially as regards the progressive forms and their differential diagnosis. The work presents the latest advances in remyelination, where the use of the micropillar technique in laboratory stands out, and in neuroprotection, which is reviewed through a study of the optic nerve. Anti-CD20 antibodies are a very promising development and we find ourselves before a new mechanism of action and therapeutic target in cells to which little attention has been paid to date. Another notable fact is the high correlation between the levels of neurofilaments in cerebrospinal fluid and in serum, which could make it possible to avoid the use of cerebrospinal fluid as a biological sample in future studies of biomarkers. The review also provides a preview of the advances in clinical research, which will converge in clinical practice in the future, thereby conditioning the steps that should be taken in the therapeutic management of multiple sclerosis (AU)

Patient preferences for treatment of multiple sclerosis with disease-modifying therapies: a discrete choice experiment.

OBJECTIVES: To assess disease-modifying therapy (DMT) preferences in a population of patients with multiple sclerosis (MS) and to estimate the association between sociodemographic and clinical factors and these preferences. METHODS: Preferences for DMTs attributes were measured using a discrete choice experiment. Analysis of preferences was assessed using mixed-logit hierarchical Bayes regression. A multilinear regression was used to evaluate the association between the preferences for each attribute and patients' demographic and clinical characteristics. A Student's t-test or Welch's t-test was used for subgroup comparisons. RESULTS: A total of 125 patients were included in the final analysis (62.9% female, mean age 44.5 years, 71.5% with relapsing-remitting MS diagnosis). The most important factor for patients was the possibility of suffering from the side effects of the treatment (relative importance [RI] =50%), followed by a delay in disease progression (RI =19.4%), and route and frequency of administration (RI =14.3%). According to maximum acceptable risk, patients were willing to accept an increase of 3.8% in severity of side effects, for a delay of 1 year in disease progression. Treatment duration was the most prevalent factor affecting preferences, followed by the age of patients, type of MS, level of education, and the type of current treatment. Patients treated orally were significantly more concerned about the route and frequency of administration (P=0.026) than patients on injectable therapy. Naïve patients stated significantly less importance to prevention of relapses (P=0.021) and deterioration of the capacity for performing usual daily life activities (P=0.015). Finally, patients with >5 years since diagnosis were significantly less concerned about preventing disease progression (P=0.021), and more concerned about treatment side effects (P=0.052) than compared with patients with <5 years of MS history. CONCLUSION: The most important attribute for MS patients was side effects of DMTs, followed by delay in disability progression. Experience with DMTs and time since MS diagnosis changed patients' preferences. These results give information to adjust new DMT treatment in order to satisfy patients' preferences and therefore, improve adherence to treatment.

Mes de nacimiento, HLA-DRB1 y riesgo de esclerosis múltiple en la descendencia / Month of birth, HLA-DRB1*15 locus and risk of multiple sclerosis in offspring

INTRODUCCIÓN: El haplotipo HLA-DRB1*1501 es el marcador genético que se ha asociado con un riesgo tres veces mayor de padecer esclerosis múltiple (EM) en caucásicos occidentales. Recientemente se ha sabido que hay una asociación entre el mes de nacimiento en abril, el genotipo HLA-DRB1 y el riesgo de EM en países del norte de Europa y Canadá. Esto apoya la teoría de que debe haber una interacción entre un factor de riesgo estacional con un locus cercano al HLA-DRB1*15 durante la gestación o cerca del posparto. Sujetos y MÉTODOS: Se realizó el genotipado de la presencia y subtipo de HLA-DRB1*1501 en 326 pacientes de dos centros españoles y en 226 controles sin patología neurológica. Se compararon los meses de nacimiento de la muestra de pacientes con los nacimientos mensuales locales en los mismos períodos. RESULTADOS: Comparados los pacientes con EM que eran portadores del alelo HLA-DRB1*15 (10,3%) frente a los pacientes no portadores (3,8%), significativamente más pacientes nacían en diciembre (p = 0,0185). También se confirmaba el mismo mes de nacimiento de diciembre entre sanos portadores frente a no portadores de HLA-DRB1*15 y entre pacientes portadores de HLA-DRB1*15 frente a sanos. CONCLUSIONES: El mes de nacimiento, el genotipo HLA-DRB1*15 y el riesgo de presentar EM están asociados. A diferencia de los resultados obtenidos en países del norte de Europa, donde esta asociación se ha encontrado en el mes de abril, en España es en diciembre. Se demuestra la interacción de un factor de riesgo estacional en invierno en el locus HLA-DRB1*15 o cercano a éste durante la gestación o tras el nacimiento (AU)

INTRODUCTION: A relationship among April births, HLA-DRB1*15:01 genotype and risk of multiple sclerosis (MS) has been described. We aim to determine this association in our cohort of Spanish MS PATIENTS: Subjects and METHODS: We genotyped HLA-DRB1*15:01 allele in 326 MS patients and 226 controls (non-neurological disease patients) by SSP-PCR and compared month of birth with local births during the same period. RESULTS: MS patients carrying HLA-DRB1*15 allele were more frequently born in December (10.3% HLA-DRB1*15+ vs.3.8% HLA-DRB1*15-; p = 0.019). Controls carrying HLA-DRB1*15 allele were less frequently born in December than non-carrier controls (0% HLA-DRB1*15+ vs.10.3% HLA-DRB1*15-; p = 0.028). Thus, December was confirmed as the common month of birth for HLA-DRB1*15-non-carrier controls and MS HLA-DRB1*15-carrier PATIENTS: CONCLUSIONS: Month of birth, HLA-DRB1 genotype and risk of MS are associated. In Spain, this association was found in December, supporting the potential interaction of a seasonal risk factor in winter, inside/close to HLA-DRB1*15 locus, during pregnancy or after birth

Fatigue Improvement after Switching Multiple Sclerosis Treatment from Interferon-ß to Glatiramer Acetate in Clinical Practice.

BACKGROUND/AIMS: The immunomodulatory effect of glatiramer acetate may help in reducing multiple sclerosis (MS)-related fatigue; however, evidence to prove this notion especially after switching from another immunomodulatory therapy is limited. We assessed the 6-month effect of glatiramer acetate on MS-related fatigue in patients switching from interferon-ß (IFN-ß) in clinical practice. METHODS: This was an observational study including 54 patients with relapsing-remitting MS that showed moderate/severe fatigue primarily caused by MS before switching from IFN-ß to glatiramer acetate and received glatiramer acetate for ≥6 months in daily practice. Study data were retrospectively collected through chart review at treatment switch and over the following 6 months on glatiramer acetate. RESULTS: Over the 6-month administration of glatiramer acetate, scores on the Modified Fatigue Impact Scale decreased: overall (p < 0.001), physical scale (p < 0.001), cognitive scale (p < 0.001), and psychosocial scale (p < 0.001). The Work Productivity and Activity Impairment Questionnaire showed improvements in work (p = 0.009) and other daily activity impairment (p < 0.001). Health-related quality of life as per the Multiple Sclerosis Impact Scale also improved: physical score (p < 0.001) and psychological score (p < 0.001). CONCLUSION: Patients with moderate/severe fatigue switching from IFN-ß to glatiramer acetate may benefit from fatigue improvements that contribute to reduce their work/activity impairment and improve their quality of life.

Clinical response and tolerability of fampridine in clinical practice.

BACKGROUND: Gait disorder is very prevalent in multiple sclerosis. After 15 years of disease progression, 50% of patients need assistive devices for walking. MATERIALS & METHODS: We performed a multicenter observational study, including multiple sclerosis patients with an Expanded Disability Status Scale score between 4.0 and 7.0, normal kidney function and no previous history of seizures. RESULTS: The study sample comprised 138 patients with average age of 50.3 years median Expanded Disability Status Scale of 6.0. After treatment, a significant reduction was observed in both the Timed 25-Foot Walk test (baseline, 20.3 s; 14 days, 13.2 s; p < 0.001; 3 months, 12.1 s; p < 0.001) and the 12-Item Multiple Sclerosis Walking Scale score (baseline, 82.3; 14 days, 59.4; p < 0.001; 3 months, 57.2; p < 0.001). Adverse events were recorded in 39.9% of patients.

Fingolimod: efectividad y seguridad en la práctica clínica habitual. Estudio observacional, retrospectivo y multicéntrico en Galicia / Fingolimod: effectiveness and safety in routine clinical practice. An observational, retrospective, multi-centre study in Galicia

INTRODUCCIÓN: La efectividad y seguridad del fingolimod en pacientes con esclerosis múltiple remitente recurrente (EMRR) se demostró en ensayos clínicos. Sin embargo, por las limitaciones de éstos, es importante saber cómo se comporta en condiciones de práctica clínica habitual. Así, el objetivo de este estudio es evaluar la efectividad y seguridad del fingolimod después de 12 meses de uso en la práctica clínica en Galicia. PACIENTES Y MÉTODOS: Estudio retrospectivo y multicéntrico (n = 8) de pacientes con EMRR y tratados con una o más dosis de fingolimod, 0,5 mg/día. Se evaluó la efectividad -tasa anualizada de brotes (TAB), cambio en la puntuación de la escala expandida del estado de discapacidad (EDSS), porcentaje de pacientes libres de brotes, libres de progresión de discapacidad y libres de actividad en resonancia- para el total de pacientes y según tratamiento previo. Se evaluó la seguridad a partir del porcentaje de pacientes que discontinuaron y que presentaron efectos adversos. RESULTADOS: Después de 12 meses de uso, el fingolimod redujo un 87% la TAB (de 1,7 a 0,23; p < 0,0001) y, en consecuencia, un 81% de pacientes estuvo libre de brotes. La puntuación de la EDSS disminuyó un 9%. Un 91% de pacientes estuvo libre de progresión de discapacidad y un 72%, libre de actividad en resonancia. En el 43% de los pacientes no se evidenciaron signos de la actividad de la enfermedad. La mayoría de los beneficios del fingolimod difirieron según el tratamiento previo. Alrededor de un tercio de los pacientes comunicaron efectos adversos, pero sólo el 2% discontinuó debido a ellos. CONCLUSIONES: La mayoría de los resultados de efectividad de los ensayos clínicos del fingolimod se observa durante los 12 primeros meses de tratamiento en la práctica clínica. Se observó un mejor perfil de seguridad al comunicado en los ensayos clínicos

INTRODUCTION: The effectiveness and safety of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS) have been proven in clinical trials. Yet, due to their limitations, it is important to know how it behaves under everyday clinical practice conditions. Hence, the aim of this study is to evaluate the effectiveness and safety of fingolimod after 12 months' usage in clinical practice in Galicia. PATIENTS AND METHODS: We conducted a retrospective, multi-centre study (n = 8) of patients with RRMS who were treated with one or more doses of fingolimod, 0.5 mg/day. Effectiveness was assessed -annualised relapse rate (ARR), changes in the score on the Expanded Disability Status Scale (EDSS), percentage of patients free from relapses, free from progression of disability and free from activity in resonance- for the total number of patients and according to previous treatment. Safety was assessed based on the percentage of patients who withdrew and presented adverse side effects. RESULTS: After 12 months' use, fingolimod reduced the ARR by 87% (1.7 to 0.23; p < 0.0001) and, consequently, 81% of patients were free from relapses. The score was reduced by 9%. In all, 91% of patients were free from progression of disability and 72% were free from resonance activity. No signs of disease activity were found in 43% of the PATIENTS: Most of the benefits of fingolimod differed depending on previous treatment. About a third of the patients reported adverse side effects, but only 2% of them withdrew for this reason. CONCLUSIONS: In clinical practice, most of the results on the effectiveness of the clinical trials conducted with fingolimod were observed during the first 12 months of treatment. A better safety profile was observed than that reported in the clinical trials (AU)

Effects of diazoxide in multiple sclerosis: A randomized, double-blind phase 2 clinical trial.

OBJECTIVE: The aim of this study was to test the safety of diazoxide and to search for signs of efficacy in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: In this multicenter, randomized, placebo-controlled, double-blind trial (treatment allocation was concealed), 102 patients with RRMS were randomized to receive a daily oral dose of diazoxide (0.3 and 4 mg/d) or placebo for 24 weeks (NCT01428726). The primary endpoint was the cumulative number of new T1 gadolinium-enhancing lesions per patient, recorded every 4 weeks from week 4 to week 24. Secondary endpoints included brain MRI variables such as the number of new/enlarging T2 lesions and the percentage brain volume change (PBVC); clinical variables such as the percentage of relapse-free patients, relapse rate, and change in the Expanded Disability Status Scale score; and safety and tolerability. RESULTS: Diazoxide was well-tolerated and it produced no serious adverse events other than 1 case of Hashimoto disease. At the 2 doses tested, diazoxide did not improve the primary endpoint or the MRI and clinical variables related to the presence of new lesions or relapses. Patients treated with diazoxide showed reduced PBVC compared with the placebo group, although such changes could be confounded by the higher disease activity of the treated group and the vascular effects of diazoxide. CONCLUSION: At the doses tested, oral diazoxide did not decrease the appearance of new lesions evident by MRI. The effects in slowing the progression of brain atrophy require further validation. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with RRMS, diazoxide (0.3 and 4 mg/d) does not significantly change the number of new MRI T1 gadolinium-enhancing lesions.

Adverse events during the titration phase of interferon-beta in remitting-relapsing multiple sclerosis are not predicted by body mass index nor by pharmacodynamic biomarkers.

BACKGROUND: This study aimed to correlate body mass index or biomarkers with the frequency of common adverse events (AEs) with subcutaneous IFN ß-1a during treatment titration in patients with relapsing-remitting multiple sclerosis previously naïve to IFN ß. METHODS: Eighty-four patients (66.3% females) were followed up during 8 weeks, 25.3% were overweight and 14.5% were obese. RESULTS: Biomarkers steadily increased during all study period by 45.3% for ß2-microglobulin, 262.8% for olygoadenylate synthetase-1, and 92.8% for neopterin. Overall AE reporting did not vary with the dose or treatment duration. CONCLUSIONS: BMI was not predictive of increased risk for AEs. Biomarkers did not discriminate on the frequency of any AE either.