Early beginning of alemtuzumab: Changing the multiple sclerosis treatment paradigm. Interim analysis of the LEMVIDA study.

INTRODUCTION: LEMVIDA is a real-world prospective study of 3-year follow-up on quality of life of patients with multiple sclerosis (MS) receiving alemtuzumab in Spain. METHODS: This is an interim analysis evaluating the baseline characteristics of patients who started alemtuzumab between October 2016-September 2018. For 3 additional subanalysis patients were categorised by baseline EDSS score; time of alemtuzumab initiation during the recruitment period (cohort 1: October 2016-March 2017, cohort 2: April-September 2017, cohort 3: October 2017-March 2018 and cohort 4: April-September 2018); and the presence of highly active MS criteria. RESULTS: 161 patients were analysed: 67.1% female, age 38.7 ± 9.4 years, MS duration 8.5 ± 6.0 years, EDSS 3.3 ± 1.7 and number of relapses in the previous 2 years 1.8 ± 1.3. 48.3% of patients presented gadolinium-enhanced (Gd+) lesions (mean: 5.2 ± 6.9) and 63.1% had received prior treatment with fingolimod or natalizumab. Baseline EDSS scores and number of Gd+ lesions were higher in cohort 1 than in cohort 4 (4.1 ± 1.8 vs 3.2 ± 1.7; P = .040 and 10.9 ± 11.9 vs 4.5 ± 5.7; P = .020). The frequency of prior treatment with fingolimod and natalizumab was lower in cohort 4 (60.6%) than in cohort 1 (70.6%) (comparison between groups not analysed). CONCLUSIONS: Unlike phase 3 studies of alemtuzumab, the patients included in LEMVIDA are older, have a longer duration of MS, higher disability and have received previous immunosuppressants. However, throughout the recruitment period, there is a tendency towards an early beginning of treatment with alemtuzumab, probably due to the evidence of higher effectiveness in the early stages of MS.

A guide to treating gait impairment with prolonged-release fampridine (Fampyra®) in patients with multiple sclerosis. / Guía de tratamiento del deterioro de la marcha con fampridina de liberación prolongada (Fampyra®) en pacientes con esclerosis múltiple.

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 10mg every 12hours 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.

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

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.

TITLE: Revision de las novedades del XXXII Congreso ECTRIMS 2016, presentadas en la IX Reunion Post-ECTRIMS (II).Por noveno año consecutivo se ha celebrado en Madrid (España) la Reunion Post-ECTRIMS con el objetivo de presentar y discutir los temas mas debatidos en el congreso ECTRIMS de la mano de reconocidos especialistas en esclerosis multiple de nuestro pais. Fruto de esta reunion cientifica, avalada por la Sociedad Española de Neurologia, se genera este articulo de revision que sale publicado en dos partes. En esta segunda parte se pone de manifiesto la controversia actual en el manejo de la esclerosis multiple, especialmente en cuanto a formas progresivas y diagnostico diferencial se refiere. Se presentan los ultimos avances en remielinizacion, donde destaca el uso de la tecnica con micropilares en el laboratorio, y en neuroproteccion, la cual se revisa a traves del estudio del nervio optico. Los anticuerpos anti-CD20 ofrecen grandes expectativas, y estamos ante un nuevo mecanismo de accion y diana terapeutica en unas celulas a las que les habiamos prestado poca atencion hasta la fecha. Otro hecho destacable es la elevada correlacion entre los niveles de neurofilamentos en el liquido cefalorraquideo y el suero, que podria evitar el uso del liquido cefalorraquideo como muestra biologica en futuros estudios de biomarcadores. Tambien se anticipan los avances en investigacion clinica que en el futuro acabaran convergiendo en la practica clinica, condicionando los pasos que se deberan seguir en el abordaje terapeutico de la esclerosis multiple.

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

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.

TITLE: Revision de las novedades del XXXII Congreso ECTRIMS 2016, presentadas en la IX Reunion Post-ECTRIMS (I).Por noveno año consecutivo se ha celebrado en Madrid (España) la Reunion Post-ECTRIMS con el objetivo de presentar y discutir los temas mas debatidos en el congreso ECTRIMS de la mano de reconocidos especialistas en esclerosis multiple de nuestro pais. Fruto de esta actividad cientifica, avalada por la Sociedad Española de Neurologia, se genera este articulo de revision que sale publicado en dos partes. Esta primera parte aborda la planificacion familiar en las mujeres con esclerosis multiple, el manejo del embarazo y el papel de la lactancia. Se dirige la atencion a la poblacion pediatrica, a las caracteristicas de la resonancia magnetica y a los factores de riesgo geneticoambientales para el desarrollo de la enfermedad en niños, sin olvidar los factores de riesgo de progresion en los adultos. Se actualiza la epidemiologia del deterioro cognitivo en los pacientes con esclerosis multiple, las ventajas e inconvenientes de las herramientas de evaluacion disponibles, y los enfoques actuales de manejo, y se insiste en la importancia de la afectacion cognitiva en el curso de la enfermedad. Ademas, se introduce el concepto de medicina individualizada y de precision, desde el diagnostico de la enfermedad hasta el tratamiento, con las polemicas que inevitablemente surgen en el manejo de los pacientes, principalmente en lo relacionado con el cambio de tratamiento y el manejo de riesgos asociados.

[Treatment of relapsing-remitting multiple sclerosis with fingolimod in routine clinical practice]. / Tratamiento de la esclerosis multiple remitente recurrente con fingolimod en la practica clinica habitual.

INTRODUCTION: Fingolimod is a selective immunosuppressant that targets the S1P receptor, and is indicated in the treatment of aggressive relapsing-remitting multiple sclerosis (RRMS) and following treatment failure with first-order drugs. AIM: To investigate the safety and effectiveness of fingolimod under the conditions of routine clinical practice. PATIENTS AND METHODS: We conducted an observational study with prospective follow-up of patients with RRMS who received fingolimod from January 2011 until February 2014. Data assessed were the annualised relapse rate (ARR), disability measured by the Expanded Disability Status Scale (EDSS), magnetic resonance activity and the appearance of side effects. RESULTS: Our sample consisted of 122 patients, 79.5% of them females and with a mean age of 26.8 years. They were classified, according to the last treatment received, as being: naive (aggressive RRMS; n = 17), previous treatment failure (n = 67) and withdrawal of natalizumab due to risk of progressive multifocal leukoencephalopathy (n = 38). After a mean follow-up of 29.9 ± 15.9 months, the ARR and the appearance of new lesions with gadolinium enhancement were reduced in both the naive and the previous treatment failure groups. There were no differences between the various subgroups as regards the progression of EDSS or the time elapsed until the first attack or treatment failure. The risk of treatment failure is higher with a baseline EDSS > 3 (hazard ratio: 4.24; p = 0.001) and presence of IgM oligoclonal bands (hazard ratio: 2.45; p < 0.022). CONCLUSIONS: Fingolimod is an effective and well-tolerated drug under conditions of routine clinical practice. Having a baseline EDSS > 3 and IgM oligoclonal bands is predictive of a poor response to fingolimod.

TITLE: Tratamiento de la esclerosis multiple remitente recurrente con fingolimod en la practica clinica habitual.Introduccion. El fingolimod es un inmunosupresor selectivo dirigido contra el receptor SP-1, indicado en el tratamiento de la esclerosis multiple remitente recurrente (EMRR) agresiva y tras el fracaso del tratamiento con farmacos de primera linea. Objetivo. Investigar la seguridad y efectividad del fingolimod en condiciones de practica clinica habitual. Pacientes y metodos. Estudio observacional con seguimiento prospectivo de pacientes con EMRR que recibieron fingolimod desde enero de 2011 hasta febrero de 2014. Se evaluo la tasa anual de brotes (TAB), la discapacidad medida por la escala expandida del estado de discapacidad (EDSS), la actividad en la resonancia magnetica y la aparicion de efectos adversos. Resultados. Incluimos 122 pacientes, el 79,5% mujeres y con una edad media de 26,8 antilde;os. Se clasificaron segun el ultimo tratamiento recibido en: naive (EMRR agresiva; n = 17), fracaso a terapias previas (n = 67) y retirada de natalizumab por riesgo de leucoencefalopatia multifocal progresiva (n = 38). Tras un seguimiento medio de 29,9 ± 15,9 meses, se redujo de forma significativa la TAB y la aparicion de nuevas lesiones con realce de gadolinio en el grupo naive y el de fracaso a terapias previas. No ha habido diferencias en la evolucion de la EDSS ni en el tiempo hasta el primer brote o el fracaso terapeutico entre los diferentes subgrupos. El riesgo a fracaso terapeutico es mayor con la EDSS basal > 3 (hazard ratio: 4,24; p = 0,001) y presencia de bandas oligoclonales IgM (hazard ratio: 2,45; p < 0,022). Conclusiones. El fingolimod es un farmaco eficaz y seguro en la EMRR en condiciones de practica clinica habitual. Tener una EDSS basal > 3 y bandas oligoclonales IgM predice una mala respuesta al fingolimod.

Review of the novelties from the 2014 ECTRIMS-ACTRIMS Joint Congress, presented at the 7th Post-ECTRIMS Meeting (II).

For the seventh year in a row the Post-ECTRIMS Meeting has been held in Madrid (Spain). Renowned specialists in multiple sclerosis and national leaders in this area have gathered once again to discuss the novelties presented at the 2014 ECTRIM-ACTRIMS World Congress. That meeting gave rise to this review, which is published in two parts. This second part shows that immunological phenomena are increasingly more present in the pathogenesis of the disease, and that the interaction between inflammation and neurodegeneration is becoming more apparent. Metabolic, mitochondrial dysfunction and oxidative stress phenomena are also involved in axonal degeneration and the experimental models open up the way to promising new therapeutic approaches for regenerative strategies. Although ambitious, inducible neural progenitor cells have become a promising alternative to the conventional treatments with stem cells, and the identification of new genetic variants of susceptibility to multiple sclerosis opens up the way to the discovery of new drugs. Reconsidering the value of old drugs and procedures would be another alternative therapeutic development.

TITLE: Revision de las novedades del congreso conjunto ECTRIMS-ACTRIMS 2014, presentadas en la VII Reunion Post-ECTRIMS (II).Por septimo año consecutivo se ha celebrado en Madrid (España) la Reunion Post-ECTRIMS. Reconocidos especialistas en esclerosis multiple y lideres de opinion nacionales se han reunido un año mas para exponer las novedades presentadas en el Congreso Mundial ECTRIMS-ACTRIMS 2014, y fruto de esa reunion se genera esta revision que se publica en dos partes. En esta segunda parte se pone de manifiesto que los fenomenos inmunologicos cada vez estan mas presentes en la patogenia de la enfermedad, y que la interaccion entre inflamacion y neurodegeneracion es mas evidente. Fenomenos metabolicos, de disfuncion mitocondrial y de estres oxidativo tambien se implican en la degeneracion axonal, y los modelos experimentales abren paso a nuevos enfoques terapeuticos con esperanza para las estrategias regenerativas. Aunque resulte ambicioso, los progenitores neurales inducibles se convierten en una prometedora alternativa a los tratamientos convencionales con celulas madre, y la identificacion de nuevas variantes geneticas de susceptibilidad a la esclerosis multiple abre camino al descubrimiento de nuevos farmacos. Replantear el valor de antiguos farmacos y procedimientos seria otra alternativa de desarrollo terapeutico.

[Review of the novelties from the 2014 ECTRIMS-ACTRIMS Joint Congress, presented at the 7th Post-ECTRIMS meeting (I)]. / Revision de las novedades del congreso conjunto ECTRIMS-ACTRIMS 2014, presentadas en la VII Reunion Post-ECTRIMS (I).

For the seventh year in a row the Post-ECTRIMS Meeting has been held in Madrid (Spain). Renowned specialists in multiple sclerosis and national leaders in this area have gathered once again to discuss the novelties presented at the 2014 ECTRIM-ACTRIMS World Congress. That meeting gave rise to this review, which will be published in two parts. One of the main conclusions in this first part is the deeper understanding of the genetic component of multiple sclerosis that we are acquiring, although it is still insufficient unless we bear in mind its interaction with the environmental risk factors of the disease or the impact of comorbidity and healthy habits on the patients' susceptibility and prognosis. In this respect, the authors insist on the fact that, in clinical practice, the cognitive and psychiatric disorders remain under-diagnosed and are rarely taken into account in clinical research. Yet, although scarce, the evidence we have points to the possible benefits of disease-modifying drugs and alternatives to treatment with selective serotonin reuptake inhibitors. Addressing the sub-populations in multiple sclerosis and variants of the disease enhances the importance of an early accurate diagnosis in order to offer patients a safer and more personalised prognosis and treatment. Paediatric multiple sclerosis is ideal for studying the risk factors of the disease but, given its low prevalence, the use of prospective studies raises a number of doubts and there is a preference for conducting collaborative studies.

TITLE: Revision de las novedades del congreso conjunto ECTRIMS-ACTRIMS 2014, presentadas en la VII Reunion Post-ECTRIMS (I).Por septimo año consecutivo se ha celebrado en Madrid (España) la Reunion Post-ECTRIMS. Reconocidos especialistas en esclerosis multiple y lideres de opinion nacionales se han reunido un año mas para exponer las novedades presentadas en el Congreso Mundial ECTRIMS-ACTRIMS 2014, y fruto de esa reunion se genera esta revision que sale publicada en dos partes. Como principales conclusiones de esta primera parte se destaca el mayor entendimiento del componente genetico de la esclerosis multiple al que estamos asistiendo, el cual no resulta suficiente si no se considera su interaccion con los factores ambientales de riesgo de la enfermedad, ni el impacto de la comorbilidad y de las conductas saludables en la susceptibilidad y pronostico de los pacientes. Al respecto, los autores insisten en que, en la practica clinica, las alteraciones cognitivas y psiquiatricas estan infradiagnosticadas y son poco consideradas en la investigacion clinica; no obstante, la evidencia, aunque escasa, apunta hacia posibles beneficios de los farmacos modificadores de la enfermedad y alternativas al tratamiento inhibidor selectivo de la recaptacion de serotonina. El abordaje de las subpoblaciones en esclerosis multiple y variantes de la enfermedad refuerza la importancia del diagnostico precoz y preciso para ofrecer a los pacientes un pronostico y un tratamiento mas seguros y personalizados. La esclerosis multiple pediatrica es idonea para estudiar factores de riesgo de la enfermedad, pero dada su baja prevalencia, se cuestionan los estudios prospectivos y se aboga por los estudios colaborativos.

Clinical evaluation of rituximab treatment for neuromyelitis optica.

INTRODUCTION: Neuromyelitis optica is an inflammatory and usually relapsing demyelinating autoimmune disease of the central nervous system that targets the optic nerves and spinal cord. Rituximab has been used for different neurological diseases that are probably immune-mediated or involving humoural immunity. The objective of this study is to evaluate the efficacy and safety of rituximab as treatment for neuromyelitis optica in a tertiary hospital. METHODS: Retrospective study of patients with neuromyelitis optica treated with rituximab 1000mg on days 1 and 15, repeated every 6 to 8 months. We recorded EDSS score, relapse rate, overall condition, CD19+ count, presence of anti-NMO antibodies, and possible adverse reactions. RESULTS: Six patients were treated; all were women with a median age of 46 years (range, 38-58). Anti-NMO antibodies were detected in 3 patients (50%). Baseline EDSS was 4 (range 2.0-5.5). Two patients had previously been treated with an immunomodulatory drug. Median time from the first rituximab infusion to first relapse was 3.7 years (range 1.7-6.9). Two patients had infusion reactions after the first dose of rituximab. Four patients remained relapse-free and their EDSS score did not progress during rituximab treatment, one patient showed no clinical improvement, and one patient could not be evaluated. CONCLUSION: Rituximab can be considered an attractive therapeutic alternative for patients with neuromyelitis optica as there are no approved treatments for this disease. Further studies with rituximab are needed to establish the role of this drug in treating neuromyelitis optica.

Review of the novelties presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (I).

The most relevant data presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in October 2013 in Denmark, were summarised at the sixth edition of the Post-ECTRIMS Expert Meeting, held in Madrid in October 2013, resulting in this review, to be published in three parts. This first part of the Post-ECTRIMS review presents an update on gender differences in multiple sclerosis (MS) as well as new evidence on the impact of sex hormones on the disease. We should consider that there is still much to discover with regard to the genetic components of the disease. Similarly, possible infections and lifestyle habits are added as triggers of the known environmental risk factors for MS. The interaction between genetics and the environment has been increasingly implicated as a cause of susceptibility to MS. With regard to the mechanisms of inflammation, axo-glial proteins, instead of myelin proteins, may be the early antigenic targets, and B cells have been implicated in the production of cytokines toxic to oligodendrocytes. Chitinase 3-like 1 (CHI3L1) is validated as a prognostic marker of conversion to MS, and immunoglobulin M oligoclonal bands and L-selectin could be incorporated as possible measures of the risk stratification strategy in patients treated with natalizumab.

TITLE: Revision de las novedades presentadas en el XXIX Congreso del Comite Europeo para el Tratamiento e Investigacion en Esclerosis Multiple (ECTRIMS) (I).Los datos mas relevantes presentados en la XXIX edicion del Congreso del Comite Europeo para el Tratamiento e Investigacion en Esclerosis Multiple (ECTRIMS), celebrado en octubre de 2013 en Dinamarca, se han resumido en la sexta edicion de la Reunion de Expertos Post-ECTRIMS celebrada en Madrid en octubre de 2013, fruto de la cual nace esta revision, que se publica en tres partes. Esta primera parte de la revision Post-ECTRIMS presenta una vision actualizada de las diferencias de genero en la esclerosis multiple (EM), asi como las nuevas evidencias sobre el impacto de las hormonas sexuales en la enfermedad. Podemos asumir que aun queda mucho por descubrir con relacion al componente genetico de la enfermedad. De la misma manera, a los ya conocidos factores ambientales de riesgo para la EM se unen posibles infecciones y habitos de vida como desencadenantes. La interaccion entre la genetica y el ambiente cada vez cobra mas fuerza como causa de susceptibilidad a la EM. En cuanto a los mecanismos de inflamacion, las proteinas del complejo axoglial pueden ser las dianas antigenicas iniciales en lugar de las proteinas de mielina, y las celulas B se han visto implicadas en la produccion de citocinas toxicas para los oligodendrocitos. La quitinasa 3-like 1 se valida como marcador pronostico de conversion a EM, y las bandas oligoclonales de inmunoglobulina M y la L-selectina podrian incorporarse como posibles medidas dentro de la estrategia de estratificacion del riesgo en pacientes tratados con natalizumab.

Clinical experiences with cannabinoids in spasticity management in multiple sclerosis.

INTRODUCTION: Spasticity is a common symptom among patients with multiple sclerosis (MS). This study aims to assess the effectiveness and safety of the combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in clinical practice for the treatment of spasticity in MS. METHODS: Retrospective observational study with patients treated with inhaled THC/CBD between April 2008 and March 2012. Descriptive patient and treatment variables were collected. Therapeutic response was evaluated based on the doctor's analysis and overall impression. RESULTS: Of the 56 patients who started treatment with THC/CBD, 6 were excluded because of missing data. We evaluated 50 patients (42% male) with a median age 47.8 years (25.6-76.8); 38% were diagnosed with primary progressive MS, 44% with secondary progressive MS, and 18% with relapsing-remitting MS. The reason for prescribing the drug was spasticity (44%), pain (10%), or both (46%). Treatment was discontinued in 16 patients because of ineffectiveness (7 patients), withdrawal (4), and adverse effects (5). The median exposure time in patients whose treatment was discontinued was 30 days vs 174 days in those whose treatment continued at the end of the study. THC/CBD was effective in 80% of patients at a median dose of 5 (2-10) inhalations/day. The adverse event profile consisted of dizziness (11 patients), somnolence (6), muscle weakness (7), oral discomfort (2), diarrhoea (3), dry mouth (2), blurred vision (2), agitation (1), nausea (1), and paranoid ideation (1). CONCLUSIONS: THC/CBD appears to be a good alternative to standard treatment as it improves refractory spasticity in MS and has an acceptable toxicity profile.

Review of the novelties presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (II).

The most relevant data presented at the 28th edition of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) held in October 2012 in France have been summarised in the fifth edition of the Post-ECTRIMS Expert Meeting held in Madrid in October 2012. This review is the result of the meeting, which is being published in three parts. This second part of the Post-ECTRIMS review discusses the biology of recovery and remyelination in multiple sclerosis (MS) as well as the different repair and endogenous and exogenous remyelination strategies currently being evaluated based on the fact that resident microglia and oligodendroglial progenitor cells have been implicated in the remyelination process. This review also discusses the current state and future use of biomarkers in MS and proposes as markers of neurodegeneration the following: T2 lesion volume and brain atrophy using MRI and the loss of the ganglion cell layer as assessed by optical coherence tomography. A greater future utility for double inversion recovery (DIR) sequences is proposed to correlate cognitive impairment with MS impairment, given its higher diagnostic yield in locating and defining cortical lesions. The availability of novel biomarkers in the future requires strict validation. In this context, this paper proposes possible areas of action to improve the current situation and also presents the latest research results in identifying potential candidates with useful diagnostic characteristics, prognostic characteristics, treatment responses, and safety procedures.

TITLE: Revision de las novedades presentadas en el XXVIII Congreso del Comite Europeo para el Tratamiento e Investigacion en Esclerosis Multiple (ECTRIMS) (II).Los datos mas relevantes presentados en la XXVIII edicion del Congreso del Comite Europeo para el Tratamiento e Investigacion en Esclerosis Multiple (ECTRIMS), celebrado en octubre de 2012 en Francia, han sido resumidos en la quinta edicion de la Reunion de Expertos Post-ECTRIMS celebrada en Madrid en octubre de 2012, fruto de la cual nace esta revision que se publica en tres partes. En esta segunda parte de la revision Post-ECTRIMS se analiza la biologia de la recuperacion y remielinizacion en la esclerosis multiple (EM), y se discuten las diferentes estrategias de reparacion y remielinizacion endogena y exogena que actualmente estan siendo evaluadas, sobre la base de que la microglia residente y las celulas precursoras de oligodendrocitos se han visto implicadas en el proceso de remielinizacion. Asimismo, se expone el estado actual y uso futuro de los biomarcadores en EM, y se proponen como marcadores de neurodegeneracion el volumen lesional en T2 y la atrofia cerebral mediante resonancia magnetica, asi como la perdida de capa de celulas ganglionares mediante tomografia de coherencia optica. Se plantea una mayor utilidad futura de las secuencias DIR para correlacionar las alteraciones cognitivas con las alteraciones de la EM, dado su mayor rendimiento diagnostico en localizar y definir lesiones corticales. La disponibilidad de nuevos biomarcadores en un futuro requiere una validacion estricta. En este sentido, se plantean posibles areas de actuacion dirigidas a mejorar la situacion actual, y ademas se presentan los resultados de las investigaciones mas recientes en la identificacion de posibles candidatos con utilidad diagnostica, pronostica, de respuesta al tratamiento y de seguridad.

Safety profile and practical considerations of monoclonal antibody treatment.

INTRODUCTION: Monoclonal antibodies are immunoglobulins specially designed to act against specific targets, in such a way that their administration stops a specific pathogenic process, stimulates a particular cellular action, or changes a cell mechanism to another pathway of interest. Their production is based on the establishment of modified immortal B lymphocytes to produce a specific immunoglobulin. Depending on the level of purity, this immunoglobulin may be murine complement (ending in "o", for example muromonab); chimeric, in which all the immunoglobulin is human, except in the variable region which is murine (ending in "xi", for example, rituximab); humanised, in which all the immunoglobulin is human, except in the variable complement region which remains murine (ending in "zu", for example, natalizumab); and human complement (ending in "u", for example, adalimumab). Therefore, there will be two types of secondary effects: those arising from the action of the antibody, such as opportunistic infections due to immunosuppression, and those arising from the administration of a protein, such as anaphylactic reactions. The sources used for the present articles were articles published in PubMed, located by searching for "Monoclonal antibodies and Secondary effects", and the web pages of the European Medicines Agency (EMEA) and the US Food and Drus Administration (FDA). DEVELOPMENT: The secondary effects arising from the mechanisms of action were opportunistic infections, common infections, development of tumours and autoimmune phenomena, and those arising from the administration of proteins: anaphylactic reaction, cytokine release syndrome, and the development of neutralising antibodies. Finally, the management of monoclonal antibodies in clinical practice and in special situations is discussed, including administering vaccines, pregnancy and paediatric use. Reference will be made to immune recovery syndrome. CONCLUSIONS: Monoclonal antibodies are highly effective drugs when specifically indicated, but they also may incur serious secondary effects, which although incidence is low, require close monitoring of the patients receiving these treatments.

[HLA-DRB1 typing in Caucasians patients with neuromyelitis optica]. / HLA-DRB1 en pacientes caucasicos con neuromielitis optica.

INTRODUCTION: The existence of antibodies to aquaporin-4 (AQP-4-ab) has identified neuromyelitis optica (NMO) and multiple sclerosis (MS) as different diseases. Although HLA-DRB1 alleles contribute to MS risk, recent studies suggest that HLA back-ground differs between patients with NMO or MS in non-Caucasians populations. Our study was aimed to analyze HLA-DRB1 distribution in Caucasians NMO patients. SUBJECTS AND METHODS: We recruited a cohort of 22 NMO patients (73% were AQP-4-ab positive), 228 MS patients and 225 healthy controls from Spain and we genotyped the HLA-DRB1 locus. Then, we performed a pool analysis using reported data from 45 NMO patients (53% were AQP-4-ab positive), 156 MS patients and 310 healthy controls from Caucasian French population. RESULTS: In the Spanish cohort, NMO was associated with increased frequency of DRB1*10 allele compared with MS (odds ratio, OR = 15.1; 95% confidence interval, 95% CI = 3.26-69.84; p = 0.012). In the pooled analysis, by comparison with healthy controls, NMO was associated with increased frequency of DRB1*03 allele (OR = 2.27; 95% CI = 1.44-3.58; p < 0.0008) which was related to AQP-4-ab seropositivity (OR = 2.74; 95% CI = 1.58-4.77; p < 0.0008). By contrast, MS was associated with increased frequency of DRB1*15 allele (OR = 2.09; 95% CI = 1.62-2.68; p < 0.0008) and decreased frequency of DRB1*07 allele (OR = 0.58; 95% CI = 0.44-0.78; p < 0.0008). CONCLUSIONS: Caucasian patients with NMO and MS have a different HLA-DRB1 allelic distribution. DRB1*03 allele seems to contribute to NMO seropositivity. Multicenter collaborative efforts are needed to adequately address the genetic contribution to NMO susceptibility.

[Review of the novelties presented at the 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (II)]. / Revision de las novedades presentadas en el XXVI Congreso del Comite Europeo para el Tratamiento e Investigacion en Esclerosis Multiple (ECTRIMS) (II).

The new insights presented at European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in the city of Gothenburg, Sweden, in October 2010, have been summarized at the third edition of Post-ECTRIMS meeting held in Madrid in November 2010. Encouraging findings from the 5-years follow up extension from PreCISe study confirm the benefit of early treatment with glatiramer acetate in patients with clinically isolated syndromes (CIS) against the conversion to clinically definitive multiple sclerosis and cerebral atrophy with an adequate safety and tolerability. Regarding treatment decision with escalation or induction therapy, different strategies have been proposed depending on to the characteristics of the individual patient with CIS. Findings from several of the reported studies have revealed the favorable role of combined therapy on relapse rate but not on magnetic resonance parameters in patients with recurrent-remittent multiple sclerosis. Novel therapies such as alemtuzumab, daclizumab ofatutumab or ocrelizumab have shown promising findings regarding efficacy. Nevertheless, safety findings for these emerging therapies have detected some severe adverse events, the main ones being potentially fatal opportunistic infections such as progressive multifocal leukoencephalopathy (PML) caused by JC virus, mainly linked to natalizumab treatment. In this regard, clinicians will face the assessment of he benefit-risk ratio when deciding on the adequate treatment for each patient in the clinical setting. In this regard, determination of antibodies to JC virus by a novel two-step enzyme-linked immunosorbent assay (ELISA) could provide clinicians with a useful tool to stratify PML risk in patients. Regarding non pharmacologic therapies, behavioral intervention has emerged as an effective therapy in the treatment of depression in multiple sclerosis, showing additional benefits on fatigue, disability and adherence to treatment.

[Compromise of the cognitive functions in progressive secondary multiple sclerosis]. / Afectación de las funciones cognitivas en la esclerosis múltiple secundaria progresiva.

AIM: To define the patterns of cognitive impairment in a homogeneous group of secondary progressive multiple sclerosis (SPMS) patients. PATIENTS AND METHODS: Forty-two SPMS patients were included with a similar degree of disability; all had been treated with interferon beta-1b for a minimum of 3 months. They voluntarily complimented a battery of 10 neuropsychological tests selected for this study, distributed in two sessions of one hour. In addition, the emotional state was evaluated with the Beck Depression Inventory and the Hamilton Anxiety Scale. We considered cognitive impairment as more than two tests altered, according with previously reported studies. RESULTS: 73.8% of patients were women; mean age was 45 years (range: 25-62); mean EDSS was 5.4 (range: 3.0-7.5); mean evolution time was 34.5 months (range: 24-80); mean treatment duration was 13.5 months (range: 3-38). Cognitive impairment was present in 78.5% of patients. The most frequently impaired functions were: attentional capacity, visuospatial perception, verbal fluency, short-term and long-term logic memory and abstract reasoning. The presence of cognitive impairment was related to the time of evolution of the disease (r = 0.31; p < 0.05) but not with the age, the degree of disability or the treatment duration. CONCLUSION: Cognitive impairment in the SPMS patients is a frequent finding, being the alteration in the speed for the acquisition and processing of new information, and the abstract reasoning the most frequent and severe altered functions. The also frequent impairment of visuospatial information was a differential finding in our study that could contribute to diagnosis of clinical progression.

[Total brain T2-hyperintense lesion-volume and the axonal damage in the normal-appearing white matter of brainstem in early lapsing-remitting multiple sclerosis]. / Relación entre el volumen lesional cerebral total en resonancia magnética secuencia T2 y el daño neuroaxonal en la sustancia blanca aparentemente normal del tronco del encéfalo en la esclerosis múltiple remitente-recurrente.

AIM: To evaluate the relationship between the total brain T2-hyperintense lesion volume (TBT2LV) and the axonal damage in the normal-appearing white matter of brainstem measured by 1H-MRS in a group of early relapsing-remitting multiple sclerosis patients. SUBJECTS AND METHODS: 40 relapsing-remitting multiple sclerosis patients and ten sex- and age-matched healthy subjects were prospectively studied for two years. T2-weighted MR and 1H-MRS imaging were acquired at time of recruitment and at year two. The TBT2LV was calculated with a semiautomatic program; N-acetylaspartate (NAA), creatine (Cr) and choline (Cho) resonances areas were integrated with jMRUI program and the ratios were calculated for four volume elements that represented the brainstem. RESULTS: At basal study we obtained an axonal loss (as a decrement of NAA/ Cho ratio) in the group of patients compared with controls (p = 0.017); this axonal loss increased at the second year of the follow-up for patients (NAA/Cho decrease, p = 0.004, and NAA/Cr decrease, p = 0.002) meanwhile control subjects had no significant metabolic changes. Higher lesion load was correlated with a poor clinical outcome, being the correlation between the basal TBT2LV and the Expanded Disability Status Scale at second year (r = 0.299; p = 0.05). Besides, axonal loss was not homogeneous for all multiple sclerosis patients, being stronger in the subgroup of patients with high basal TBT2LV (p = 0.043; ANOVA). CONCLUSION: Our data suggest that axonal damage is early in multiple sclerosis and higher in patients high basal TBT2LV, suggesting a possible relationship between these two phenomena.

[Pseudopolyneuritic symptoms with a medullary origin as the presenting symptom of multiple sclerosis]. / Patrón pseudopolineurítico de origen medular como forma de presentación de una esclerosis múltiple.

INTRODUCTION: Myelopathy is, frequently, the first manifestation of a multiple sclerosis (MS), being the acute transverse mielitis, partial or incomplete, the habitual clinical syndrome. Other sensitive symptoms with an origin in the spinal cord as 'steroanesthesia', 'pseudo-athetosis' or 'pseudo-radiculopathy' have been described as unusual form of presentation in MS, but not the 'pseudo-polyneuropathy', perhaps in relation with its rapid progression in an acute transverse mielitis or other sensory pattern. CASE REPORTS: We presented two patients with a 'pseudo-polyneuropathy' pattern as the first manifestation of MS. In the two cases magnetic resonance imaging showed a cervical lesion of spinal cord with a probably inflammatory origin and other similar lesions in the brain. Neurophysiological studies were normal. We think that the 'pseudo-polyneuropathy' could be caused by an antero-lateral demyelinating process in the cervical spinal cord, with affectation of the anterior comissure and the ventral portion of lateral spinothalamic pathway. CONCLUSION: The 'pseudo-polyneuropathic' syndrome is uncommon form of presentation of MS in young people. We may be capable of recognize the 'pseudo-polyneuropathy' with spinal origin and early choose the appropriate complementary examinations for a correct diagnosis and therapy.

[Differences in the spectroscopy of the lesions of the remitting relapsing form of multiple sclerosis shown by magnetic resonance]. / Diferencias en la espectroscopía de las lesiones de esclerosis múltiple en su forma remitente recurrente mediante resonancia magnética.

INTRODUCTION: Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system, characterized by the presence of inflammatory lesions. OBJECTIVE: To analyze the biochemical profile of the demyelinating lesions of the initial forms of MS (remitting relapsing) by analyzing the proton magnetic resonance spectra (1H MRS) to characterize the process of demyelination and relate it to the metabolites and clinical variables analyzed. PATIENTS AND METHODS: We analyzed the largest demyelinating lesions in eight patients with remitting relapsing MS (RRMS) using the technique of single volume 1H MRS (VOI) with short echo time. The spectra of the white matter of two healthy control were used as reference. RESULTS: NAA/Cr and NAA/Cho value ratios decrease and mI/Cr one increase in all spectra lesions as compared to healthy controls. In four of the eight patients, the Cho/Cr was higher than in the controls. Qualitative and quantitative differences in the resonances of macromolecules were observed, related to the biochemistry of the process of demyelination. These differences in NAA/Cr, Cho/Cr, mI/Cr and macromolecules probably represent different stages in the evolution of the plaques. CONCLUSIONS: MRS is a non invasive technique able to observe biochemical variations related to the evolution process of demyelination. Activity of the lesion is shown by the increment of resonances around 0.9 1.3 ppm. An increase in mI seems to occur at an early stage of demyelination and later the NAA is reduced. The initial forms of MS show metabolic alterations in the plaques which are similar to the most advanced forms of MS.

[Axonal involvement in multiple sclerosis. Current concepts]. / Afectación axonal en la esclerosis múltiple. Conceptos actuales.

INTRODUCTION: Axon pathology in multiple sclerosis is an emerging concept, not because it is unknown but because it has been forgotten. However, clinical, functional and pathological aspects have clearly shown that it is damaged at a very early stage in development of the plaque of demyelination. There is sufficient clinical, radiological and pathological evidence to permit definition of axonal damage as the central element of the pathology and clinical features of multiple sclerosis. DEVELOPMENT AND CONCLUSIONS: Throughout this article we will see how the axon is affected in multiple sclerosis, how this affects the inflammatory response and which parameters allow us to measure axonal damage and its relation to disability. Finally we will see how a new physiopathogenic concept of multiple sclerosis appears, based on the axonal lesion, and how this fits current clinico-pathological concepts better.