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Background Despite progresses in autoimmune encephalitis and related disorders (AERD), they remain a major challenge in daily clinical practice. Objectives To describe a tertiary hospital's longitudinal experience in AERD between 2005 and 2020. Methods Single-centre retrospective analysis of 43 patients. Results 43 patients were included, 55.8% with positive antibodies (10 antiGAD, 4 antiNMDAR, 2 antiGABABR, 2 antiLGI1, 2 antiCASPR2, 1 antiIgLON5, 1 antiHu, 1 antiYo, 1 antiCV2 and 1 antiMa2, detecting coexisting antibodies in one patient: antiNMDAR + antiGABABR); 28% with negative antibodies; and 16.2% with steroid responsive encephalitis associated to antithyroid antibodies (SREAT). The median age was 62 years-old [14–88]. Females (62.8%) outnumbered males (37.2%). Limbic encephalitis was the most common clinical syndrome (60.5%), followed by SREAT (16.2%), autoimmune cerebellitis (9.3%), stiff-person syndrome (7%), antiNMDAR-encephalitis (5%) and antiIgLON5 encephalopathy (2%). CSF showed pleocytosis and/or hyperproteinorrhachia in 54.2%. MRI was unremarkable in 60%. Brain SPECT/PET showed hyperperfusion/hypermetabolism of limbic areas in 60% of patients to whom it was performed. Antibody-positivity was significantly associated with satisfaction of diagnostic criteria at high levels of certainty (p Conclusions AERD's diagnosis and treatment have significantly improved over the last years. However, several limitations remain, particularly concerning antibody-negative AERD. The proposed diagnostic criteria might be still too reliant on antibody-positivity. Antibody-status seems to condition treatment escalation. The creation of a Neuroimmunology Unit optimized AERD's management in clinical practice.

Relapsing multiple sclerosis (RMS) presents a highly variable clinical evolution among patients, and its management should be personalized. Although there is no cure at present, effective disease-modifying therapies (DMTs) are available. Selection of the most appropriate DMT for each patient is influenced by several clinical, radiological and demographic aspects as well as personal preferences that, at times, are not covered in the regulatory criteria. This may be a source of difficulty, especially in certain situations where so-called ‘high-efficacy DMTs’ (usually considered second-line) could be of greater benefit to the patient. In this narrative review, we discuss evidence and experience, and propose a pragmatic guidance on decision-making with respect to the indication and management of high-efficacy DMT in adult patients with RMS based on expert opinion.

Botulism is a life-threatening presynaptic disorder of the neuromuscular transmission produced by the neurotoxin elaborated by the botulinum neurotoxin-producing clostridia. We describe the management of a case series of 14 patients, members of 5 different families that were exposed to home-canned tuna and developed symptoms compatible with a mild clinical presentation of foodborne botulism. The electrophysiological study of the index case represented a reliable diagnostic test as it demonstrated a slight presynaptic dysfunction of the neuromuscular junction. Definite diagnosis was later confirmed by microbiological tests. Out of 14, only 3 patients presenting with a shorter period from symptom onset and with signs of multiple cranial neuropathies received botulinum antitoxin. All the patients remained stable and recovered progressively. Treatment with antitoxin may not be necessary in patients with late-presenting disease and mild and stable clinical picture.

Background: The recent development of highly effective treatments for multiple sclerosis (MS) and the potential risk of infectious complications require the development of prevention and risk minimisation strategies. Vaccination is an essential element of the management of these patients. This consensus statement includes a series of recommendations and practical scenarios for the vaccination of adult patients with MS who are eligible for highly effective immunosuppressive treatments. Methodology: A formal consensus procedure was followed. Having defined the scope of the statement, we conducted a literature search on recommendations for the vaccination of patients with MS and specific vaccination guidelines for immunosuppressed patients receiving biological therapy for other conditions. The modified nominal group technique methodology was used to formulate the recommendations. Development: Vaccination in patients who are candidates for immunosuppressive therapy should be considered before starting immunosuppressive treatment providing the patient's clinical situation allows. Vaccines included in the routine adult vaccination schedule, as well as some specific ones, are recommended depending on the pre-existing immunity status. If immunosuppressive treatment is already established, live attenuated vaccines are contraindicated. For vaccines with a correlate of protection, it is recommended to monitor the serological response in an optimal interval of 1-2 months from the last dose. Antecedentes: La reciente aparición de terapias de alta efectividad para el tratamiento de la esclerosis múltiple (EM), con potencial riesgo de complicaciones infecciosas, obliga plantear estrategias de prevención y minimización de riesgos. La vacunación constituye una parte esencial del manejo de estos pacientes. Este consenso recoge una serie de pautasy escenarios prácticos de vacunación en pacientes adultos con EM candidatos a tratamiento inmunosupresor. Metodología: Se llevó a cabo un consenso de tipo formal. Tras definir el alcance del documento, se realizó una búsqueda bibliográfica de vacunación en pacientes con EM, así como guías de vacunación específicas de pacientes inmunosuprimidosy en tratamiento biológico con otras enfermedades.Para la formulación de las recomendaciones se empleó la metodología de Modified Nominal Group Technique. Desarrollo: La vacunación en pacientes candidatos a tratamiento inmunosupresor se debe plantear antes de iniciar un tratamiento inmunosupresor siempre que la situación clínica del paciente lo permita. Se recomendarán tanto aquellas indicadas en el calendario vacunal del adulto, como algunas específicas, en función de la inmunidad previa. Si ya está instaurado el tratamiento inmunosupresor las vacunas vivas atenuadas estarán contraindicadas.Para aquellas vacunas que dispongan de un correlato de protección se recomienda monitorizar la respuesta serológica transcurridos de uno a2 meses de la última dosis

[EN] Background: Decisions based on erroneous assessments may result in unrealistic patient and family expectations, suboptimal advice, incorrect treatment, or costlymedical errors. Regret is a common emotion in daily life that involves counterfactual thinking when considering alternative choices. Limited information is available on care-related regret affecting healthcare professionals managing patients with multiple sclerosis (MS). Methods: We reviewed identified gaps in the literature by searching for the combination of the following keywords in Pubmed: “regret and decision,” “regret and physicians,” and “regret and nurses.” An expert panel of neurologists, a nurse, a psychiatrist, a pharmacist, and a psychometrics specialist participated in the study design. Care-related regret will be assessed by a behavioral battery including the standardized questionnaire Regret Intensity Scale (RIS-10) and 15 new specific items. Six items will evaluate regret in the most common social domains affecting individuals (financial, driving, sports—recreation, work, own health, and confidence in people). Another nine items will explore past and recent regret experiences in common situations experienced by healthcare professionals caring for patients with MS. We will also assess concomitant behavioral characteristics of healthcare professionals that could be associated with regret: coping strategies, life satisfaction, mood, positive social behaviors, occupational burnout, and tolerance to uncertainty. Planned Outcomes: This is the first comprehensive and standardized protocol to assess care-related regret and associated behavioral factors among healthcare professionals managing MS. These results will allow to understand and ameliorate regret in healthcare professionals. This study protocol was funded by the Medical Department of Roche Farma Spain (SL42129). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

Esclerosis múltiple; Reacciones adversas; Infecciones respiratorias Esclerosi múltiple; Reaccions adverses; Infeccions respiratòries Multiple sclerosis; Adverse reactions; Respiratory infections Objective To describe the profile of patients with multiple sclerosis (MS) treated with fingolimod in Spain and to assess the effectiveness and safety of fingolimod after 4 years of inclusion in the Spanish Gilenya Registry. Methods An observational, retrospective/prospective, multicenter case registry, including all patients with relapsing-remitting MS (RRMS) starting treatment with fingolimod in 43 centers in Spain. Analyses were performed in the overall population and in subgroups according to prior disease-modifying therapy (DMT): glatiramer acetate/interferon beta-1 (BRACE), natalizumab, other treatment, or naïve. Results Six hundred and sixty-six evaluable patients were included (91.1% previously treated with at least one DMT). The mean annualized relapse rate (ARR) prior to fingolimod was 1.12, and the mean EDSS at fingolimod initiation was 3.03. Fingolimod reduced the ARR by 71.4%, 75%, 75.5%, and 80.3%, after 1, 2, 3 and 4 years, respectively (p

Summary Background Opicinumab is a human monoclonal antibody against LINGO-1, an inhibitor of oligodendrocyte differentiation and axonal regeneration. Previous findings suggested that opicinumab treatment might enhance remyelination in patients with CNS demyelinating diseases. We aimed to assess the safety and efficacy of opicinumab in patients with relapsing multiple sclerosis. Methods We did a randomised, double-blind, placebo-controlled, dose-ranging, phase 2 study (SYNERGY) at 72 sites in 12 countries. Participants (aged 18–58 years) with relapsing multiple sclerosis (relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis with relapses) were randomised in a 1:2:2:2:2 ratio by an interactive voice and web response system to opicinumab 3 mg/kg, 10 mg/kg, 30 mg/kg, or 100 mg/kg, or placebo. An identical volume of study drug was administered intravenously once every 4 weeks. All participants self-administered intramuscular interferon beta-1a as background anti-inflammatory treatment once a week. The primary endpoint was the percentage of participants achieving confirmed disability improvement over 72 weeks, which was a multicomponent endpoint measured by the Expanded Disability Status Scale, the Timed 25-Foot Walk, the Nine-Hole Peg Test, and the 3 s Paced Auditory Serial Addition Test. The primary endpoint was analysed under intention-to-treat principles. This study is registered at ClinicalTrials.gov , number NCT01864148 . Findings Between Aug 13, 2013, and July 31, 2014, 419 patients were enrolled and randomly assigned either placebo (n=93) or opicinumab 3 mg/kg (n=45), 10 mg/kg (n=95), 30 mg/kg (n=94; one patient did not receive the assigned treatment), or 100 mg/kg (n=92). The last patient visit was on March 29, 2016. Confirmed disability improvement over 72 weeks was seen in 45 (49%) of 91 patients assigned to placebo, 21 (47%) of 45 assigned to opicinumab 3 mg/kg, 59 (63%) of 94 assigned to opicinumab 10 mg/kg, 59 (65%) of 91 assigned to opicinumab 30 mg/kg, and 36 (40%) of 91 assigned to opicinumab 100 mg/kg. A linear dose-response in the probability of confirmed disability improvement was not seen (linear trend test p=0·89). Adverse events occurred in 79 (85%) patients assigned placebo and in 275 (85%) assigned any dose of opicinumab. The most common adverse events of any grade in patients assigned any dose of opicinumab included influenza-like illness (140 [43%] with any dose of opicinumab vs 37 [40%] with placebo), multiple sclerosis relapses (117 [36%] vs 30 [32%]), and headache (51 [16%] vs 23 [25%]). Serious adverse events reported as related to treatment were urinary tract infection in one (1%) participant in the the placebo group, suicidal ideation and intentional overdose in one (1%) participant in the 30 mg/kg opicinumab group, bipolar disorder in one (1%) participant in the 100 mg/kg opicinumab group, and hypersensitivity in four (4%) participants in the 100 mg/kg opicinumab group. One patient in the opicinumab 30 mg/kg group died during the study due to a traffic accident, which was not considered related to study treatment. Interpretation Our findings did not show a significant dose-linear improvement in disability compared with placebo in patients with relapsing multiple sclerosis. Further studies are needed to investigate whether some subpopulations identified in the study might benefit from opicinumab treatment at an optimum dose. Funding Biogen.

An 82-year-old man developed a sudden onset headache with nausea and vomiting. The pain was severe and diffuse, reaching its maximum intensity in less than 1 min, and was refractory to simple analgesia. There was no history of headache. He was already in hospital following a pulmonary embolism and had a history of hypertension, coronary artery disease and atrial flutter. He had previously taken dual antiplatelet therapy but had recently switched to single antiplatelet therapy and unfractionated heparin because of the pulmonary embolism. His initial CT scan of head was reported as normal (figure 1). Figure 1 CT scan of head (initially reported as normal). (A and B) Initial image: Sellar mass with patchy hyperdensity. (C and D) Repeated image with CT angiography. This excluded an aneurysm; there is …

Opercular myoclonic-anarthric status epilepticus (OMASE) is a rare form of epilepsia partialis continua presenting as fluctuating dysarthria, or even anarthria. The condition is caused by an epileptogenic lesion involving the opercular cortex of either hemisphere. Speech impairment is secondary to bilateral epileptic activity affecting the glossopharyngeal muscles. This bilateral nature of the condition is due to the fact that innervation of cranial nerves V, VII, IX, X and XII from the opercular area of the primary motor cortex is bilateral. The aetiology of the condition varies, and includes vascular lesions, tumours, and encephalitis, among other causes. A low threshold for clinical suspicion is necessary in order to ensure the timely initiation of antiepileptic treatment, thereby preventing the condition from becoming drug resistant. We present two cases of OMASE which differ in terms of aetiology, clinical course, and treatment response. [Published with video sequences on www.epilepticdisorders.com].

Cerebral venous thrombosis (CVT) is characterized by its variety of neurological manifestations and difficulty in diagnosis. In subacute cases, the main symptoms are secondary to increased intracranial pressure. This condition is associated with an extensive range of medical disorders, but only 2% are caused by a CNS infection in recent series. We report a 45-year-old patient, with no previous medical history, who developed a syndrome of increased intracranial pressure as the presentation of a cryptococcal meningoencephalitis (CM) complicated with a CVT. The patient was first diagnosed of a CVT, and later on, the VIH infection and the CM diagnosis were made. Despite being treated with anticoagulation, liposomal amphotericin B, and a therapeutic lumbar puncture, the patient continued to deteriorate and suffered a respiratory arrest secondary to the increased intracranial pressure, with subsequent brain death. Cryptococcus is an infrequent cause of CNS infection in developed countries, despite being the most frequent cause of meningits in adults in several countries with high rates of HIV infection. CVT is a very rare complication of CM which can contribute to worsen the increased intracranial pressure and in consequence, its prognosis and outcome. A high level of suspicion is needed for diagnosing CM as the underlying cause of CVT and the subsequent increased intracranial pressure should be managed exhaustively.

The autoimmune GFAP astrocytopathy has been associated with meningoencephalomyelitis that usually responds to glucocorticoids. We report a 20-year-old man that developed an acute and severe meningoencephalomyelitis with remarkable CNS hyperexcitability and oculogyric crises. CSF analysis showed hypoglycorrhachia, pleocytosis, elevated ADA, and CSF-immunofluorescence characteristic of autoimmune GFAP astrocytopathy. MRI showed lesions at thalamus, corpus-callosum, dorsal pons and dentate nucleus with associated myelitis. Immunotherapy led to a full recovery, although MRI activity was observed at follow-up. CNS hyperexcitability, typically seen in other immune-mediated syndromes, represents a novel presenting form to be included as part of the clinical spectrum of this entity.

With the advent of new disease-modifying drugs, the treatment of multiple sclerosis is becoming increasingly complex. Using consensus statements is therefore advisable. The present consensus statement, which was drawn up by the Spanish Society of Neurology's study group for demyelinating diseases, updates previous consensus statements on the disease.The present study lists the medications currently approved for multiple sclerosis and their official indications, and analyses such treatment-related aspects as activity, early treatment, maintenance, follow-up, treatment failure, changes in medication, and special therapeutic situations.This consensus statement includes treatment recommendations for a wide range of demyelinating diseases, from isolated demyelinating syndromes to the different forms of multiple sclerosis, as well as recommendations for initial therapy and changes in drug medication, and additional comments on induction and combined therapy and practical aspects of the use of these drugs. Resumen: La incorporación de nuevos medicamentos para modificar el curso de la esclerosis múltiple y la complejidad de su uso plantea la conveniencia de utilizar consensos terapéuticos. El consenso actual ha sido elaborado por el grupo de enfermedades desmielinizantes de la Sociedad Española de Neurología y actualiza consensos previamente publicados.Se enumeran los medicamentos aprobados para la esclerosis múltiple con sus indicaciones oficiales. Se analizan aspectos relacionados con el tratamiento, como la presencia de actividad, la precocidad, el mantenimiento terapéutico, el seguimiento, el fallo terapéutico, los cambios de medicación y el tratamiento en situaciones especiales.Se elaboran indicaciones de tratamiento desde el síndrome desmielinizante aislado a las distintas formas de esclerosis múltiple detallando recomendaciones de tratamiento inicial, cambios de medicación, con consideraciones sobre terapia combinada e inducción y aspectos prácticos del uso de medicamentos. Keywords: Multiple sclerosis, Consensus statement, Disease-modifying drugs, Lines of therapy, Changes in medication, Algorithm, Palabras clave: Esclerosis múltiple, Consenso, Medicamentos para el curso de la enfermedad, Líneas terapéuticas, Cambios de medicación, Algoritmo

The endocannabinoid system is associated with protective effects in multiple sclerosis (MS) that involve attenuated innate immune cell responses. Astrocytes and microglia are modulated by endocannabinoids and participate in the biosynthesis and metabolism of these compounds. However, the role of neuroglial cells as targets and mediators of endocannabinoid signaling in MS is poorly understood. Here we used a microfluidic RT-qPCR screen to assess changes in the expression of the main endocannabinoid signaling genes in astrocytes and microglia purified from female mice during the time-course of experimental autoimmune encephalomyelitis (EAE). We show that astrocytes and microglia upregulate the expression of genes encoding neurotoxic A1 and pro-inflammatory molecules at the acute disease with many of these transcripts remaining elevated during the recovery phase. Both cell populations exhibited an early onset decrease in the gene expression levels of 2-arachidonoylglycerol (2-AG) hydrolytic enzymes that persisted during EAE progression as well as cell-type-specific changes in the transcript levels for genes encoding cannabinoid receptors and molecules involved in anandamide (AEA) signaling. Our results demonstrate that astrocytes and microglia responses to autoimmune demyelination involve alterations in the expression of multiple endocannabinoid signaling-associated genes and suggest that this system may regulate the induction of neurotoxic and pro-inflammatory transcriptional programs in both cell types during MS. This research was funded by FEDER and ISCIII (AES 2018—PI18/00513 to S.M. and A.R.-A.), the Basque Government (PIBA19-0059 to S.M. and IT1203-19 to C.M.), the Spanish Ministry of Economy and Competitiveness (SAF2016-75292-R to C.M.) and CIBERNED (CB06/0005/0076 to C.M.). A.M.-G. and A.B.-C. held fellowships from the UPV/EHU and the Basque Government, respectively.

Background and Purpose: To assess whether neuroimaging markers of chronic cerebral small vessel disease (cSVDm) influence early recovery after acute ischemic stroke (AIS). Methods: Retrospective analysis of patients diagnosed with AIS and included in the Spanish Neurological Society Stroke Database. Inclusion criteria: (1) Brain MRI performed after acute stroke and (2) Premorbid modified Rankin scale (mRS) = 0. Exclusion criteria: (1) Uncommon stroke etiologies, (2) AIS not confirmed on neuroimaging, or (3) Old territorial infarcts on neuroimaging. Patients scored from 0 to 2 according to the amount of cSVDm. Patients were divided into lacunar ischemic stroke (LIS) and nonlacunar ischemic stroke (NLIS) groups according to TOAST classification. Primary outcome: Distribution of mRS at discharge. Secondary outcomes: NIHSS improvement more than or equal to 3 at 24 hours and at discharge, NIHSS worsening more than or equal to 3 points at 24 hours. Results: We studied 4424 patients (3457 NLIS, 967 LIS). The presence of cSVDm increased the risk of worsening 1 category on the mRS at discharge in the LIS group ([1] cSVDm: OR 1.89 CI 95% 1.29-2.75, P = .001. [2] cSVDm: OR 1.87, CI 95% 1.37-2.56 P = .001) and was an independent factor for not achieving an improvement more than or equal to 3 points on the NIHSS at discharge for all the patients and the LIS group (all stroke patients: [1] cSVDm: OR 0.81 CI 95% .68-.97 P = .022. [2] cSVD: OR 0.58 CI95% .45-.77, P = .001./LIS: [1] cSVDm: OR 0.64, CI 95% .41-.98, P = .038. [2] cSVDm: OR 0.43, CI 95% .24-.75 P = .003). Conclusions: Pre-existing SVD limits early functional and neurological recovery after AIS, especially in LIS patients.

In the last 15 years, considerable improvements have been made in acute stroke care in Guipuzkoa, including the implementation of a centralised care model at Hospital Universitario Donostia (HUD), improved coordination between professionals, early detection campaigns, new treatments, a stroke unit, and specific rehabilitation. The aim of this work is to describe the results of a reference hospital (HUD) in a centralised care model.We performed a retrospective observational study of a sample of patients discharged between August and December 2015 from the HUD with a diagnosis of acute stroke (ICD-9-CM codes 430-436, except 433.10). We review patients' baseline characteristics, acute-phase care, and functional outcomes and mortality at discharge and at one year.We identified 536 patients, with a mean age of 73.6 years and a high comorbidity rate. Ischaemic stroke accounted for 64.8% of patients, followed by haemorrhagic stroke (20%) and transient ischaemic attack (14.8%). A total of 53% of patients were attended in6 hours, with code stroke being activated in 37.1%; 52.2% of patients were admitted to the stroke unit. Intravenous therapy was administered to 8.3% of patients with ischaemic stroke, and 9.5% underwent mechanical thrombectomy. Surgery was performed in 12.1% patients with haemorrhagic stroke. Rehabilitation was started at hospital in 56% of patients, and 39.6% continued with this treatment at discharge. Mortality was 13.8% at discharge and 25.9% at one year (ischaemic stroke, 25.3%; haemorrhagic stroke, 47.5%); these figures are lower than those previously reported in Guipuzkoa. At one year, 62.5% of patients had a Barthel Index score of 95-100, and 50% a modified Rankin Scale score of 0-2.After the strategic changes implemented in acute stroke care in Guipuzkoa, including the centralisation of the acute stroke care model, mortality rates at discharge and at one year are lower in 2015 than the previously reported rates, with similar rates of independence. These results are consistent with those published by other Spanish and European centres.

[Background]: It remains unclear whether disease course in multiple sclerosis (MS) is influenced by genetic polymorphisms. Here, we aimed to identify genetic variants associated with benign and aggressive disease courses in MS patients., [Methods]: MS patients were classified into benign and aggressive phenotypes according to clinical criteria. We performed exome sequencing in a discovery cohort, which included 20 MS patients, 10 with benign and 10 with aggressive disease course, and genotyping in 2 independent validation cohorts. The first validation cohort encompassed 194 MS patients, 107 with benign and 87 with aggressive phenotypes. The second validation cohort comprised 257 patients, of whom 224 patients had benign phenotypes and 33 aggressive disease courses. Brain immunohistochemistries were performed using disease course associated genes antibodies., [Results]: By means of single-nucleotide polymorphism (SNP) detection and comparison of allele frequencies between patients with benign and aggressive phenotypes, a total of 16 SNPs were selected for validation from the exome sequencing data in the discovery cohort. Meta-analysis of genotyping results in two validation cohorts revealed two polymorphisms, rs28469012 and rs10894768, significantly associated with disease course. SNP rs28469012 is located in CPXM2 (carboxypeptidase X, M14 family, member 2) and was associated with aggressive disease course (uncorrected p value, [Conclusions]: Genetic variants located in CPXM2, IGSF9B, and NLRP9 have the potential to modulate disease course in MS patients and may be used as disease activity biomarkers to identify patients with divergent disease courses. Altogether, the reported results from this study support the influence of genetic factors in MS disease course and may help to better understand the complex molecular mechanisms underlying disease pathogenesis., This work was supported by (a) grants PI10/02099, FIS PI13/0879, PI15/00513, PI15/00587, PI16/01259, RD16/0015/0001, RD16/0015/0002, RD16/0015/0004 integrated in the Plan Estatal de Investigación Científica y Técnica de Innovación I+D+I and co-funded by the Instituto de Salud Carlos IIISubdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER), and Red Española de Esclerosis Múltiple (REEM); (b) Junta de Andalucía (JA)-FEDER grant CTS2704, Ministerio de Economía y Competitividad (grant number SAF 2016-80595-C2-1-P); (c) MS Society of Canada Scientific Research Foundation as part of the CCPGSMS, and research undertaken thanks to funding from the Canada Research Chair (950-228408) program, Michael Smith Foundation for Health Research (16827) and Canadian Institutes of Health Research (MOP-137051).

Introduction: Natalizumab treatment has been shown to be very efficacious in clinical trials and very effective in clinical practice in patients with relapsing-remitting multiple sclerosis, by reducing relapses, slowing disease progression, and improving magnetic resonance imaging patterns. However, the drug has also been associated with a risk of progressive multifocal leukoencephalopathy (PML). The first consensus statement on natalizumab use, published in 2011, has been updated to include new data on diagnostic procedures, monitoring for patients undergoing treatment, PML management, and other topics of interest including the management of patients discontinuing natalizumab. Materials and methods: This updated version followed the method used in the first consensus. A group of Spanish experts in multiple sclerosis (the authors of the present document) reviewed all currently available literature on natalizumab and identified the relevant topics that would need updating based on their clinical experience. The initial draft passed through review cycles until the final version was completed. Results and conclusions: Studies in clinical practice have demonstrated that changing to natalizumab is more effective than switching between immunomodulators. They favour early treatment with natalizumab rather than using natalizumab in a later stage as a rescue therapy. Although the drug is very effective, its potential adverse effects need to be considered, with particular attention to the patient's likelihood of developing PML. The neurologist should carefully explain the risks and benefits of the treatment, comparing them to the risks of multiple sclerosis in terms the patient can understand. Before treatment is started, laboratory tests and magnetic resonance images should be available to permit proper follow-up. The risk of PML should be stratified as high, medium, or low according to presence or absence of anti-JC virus antibodies, history of immunosuppressive therapy, and treatment duration. Although the presence of anti-JC virus antibodies is a significant finding, it should not be considered an absolute contraindication for natalizumab. This update provides general recommendations, but neurologists must use their clinical expertise to provide personalised follow-up for each patient. Resumen: Introducción: Natalizumab es un tratamiento que ha demostrado ser muy eficaz en los ensayos clínicos y muy efectivo en la práctica clínica en los pacientes con esclerosis múltiple recurrente-remitente, en cuanto a la reducción del número de brotes, enlentecimiento de la progresión de la enfermedad y variables de resonancia magnética. Sin embargo, el fármaco se ha asociado con el riesgo de desarrollar leucoencefalopatía multifocal progresiva (LMP). Los nuevos datos aparecidos sobre la monitorización de los pacientes en tratamiento, el diagnóstico, y manejo de la LMP y otros temas de interés como la actuación ante la suspensión del natalizumab se han incorporado en esta actualización del primer consenso sobre el uso del natalizumab publicado en el 2011. Material y métodos: En esta actualización se procedió con la misma metodología que la del primer consenso. Un grupo de expertos españoles en esclerosis múltiple (los autores de esta actualización) revisaron toda la bibliografía disponible sobre natalizumab hasta la fecha, y basándose en su experiencia clínica definieron los temas relevantes a actualizar. Un primer borrador se sometió a ciclos de revisión hasta llegar a la versión final. Resultados y conclusiones: Los estudios de práctica clínica han demostrado que el cambio a natalizumab es más efectivo que el cambio entre inmunomoduladores, y apoyan una mayor conveniencia del tratamiento temprano con natalizumab frente a una utilización más tardía como terapia de rescate. A pesar de ser un fármaco muy eficaz, se deben tener en cuenta los posibles efectos adversos y, en particular, la probabilidad de desarrollar LMP. El neurólogo debe explicar al paciente en detalle los riesgos y beneficios del tratamiento frente al riesgo de la esclerosis múltiple usando términos comprensibles. Antes de empezar el tratamiento, deben estar disponibles las pruebas de laboratorio y las imágenes de resonancia magnética que permitan hacer un seguimiento adecuado. El riesgo de LMP debe estratificarse en alto, medio y bajo de acuerdo con la presencia o ausencia de anticuerpos frente al virus JC, antecedente de tratamiento inmunosupresor y duración del tratamiento. La presencia de anticuerpos antivirus JC, aunque significativa, no se puede tomar como una contraindicación absoluta para el natalizumab. La presente actualización establece unas recomendaciones generales, pero los neurólogos deben aplicar su experiencia clínica para hacer un seguimiento individualizado de los pacientes. Keywords: Multiple sclerosis, Natalizumab, Risk, Consensus, Spain, Palabras clave: Esclerosis múltiple, Natalizumab, Riesgo, Consenso, España

Background: The injury of visual pathway and abnormalities of visual processing speed (VPS) are frequent in MS, but their association remains unexplored. Objective: To evaluate the impact of posterior visual pathway structural and functional integrity on VPS of MS patients. Methods: Cross-sectional study of 30 MS patients and 28 controls, evaluating the association of a VPS tests composite (Salthouse Perceptual Comparison test, Trail Making Test A and Symbol Digit Modalities Test) with 3T MRI visual cortex thickness, optic radiations (OR) diffusion tensor imaging indexes, and medial visual component (MVC) functional connectivity (FC) (MVC-MVC FC (iFC) and MVC-brain FC (eFC)) by linear regression, removing the effect of premorbid IQ, fatigue, and depression. Results: V2 atrophy, lower OR fractional anisotropy (FA) and MVC FC significantly influenced VPS in MS (at none or lesser extent in controls), even after removing the effect of Expanded Disability Status Scale and previous optic neuritis (V2 ( r2 = 0.210): β = +0.366, p = 0.046; OR FA ( r2 = 0.243): β = +0.378, p = 0.034; MVC iFC, for example, left cuneus ( r2 = 0.450): β = −0.613, p 2 = 0.368): β = −0.466, p = 0.002). Conclusion: Posterior visual pathway integrity, structural (V2 thickness and OR FA) and functional (MVC FC), may explain respectively up to 24% and 45% of VPS variability in MS.

INTRODUCTION: Like every year, after the ECTRIMS Congress, renowned Spanish neurologists who are experts in multiple sclerosis presented the main novelties in research in this field at the Post-ECTRIMS Meeting. AIM: To summarise the content presented at the 12th edition of the Post-ECTRIMS Meeting, which took place in September 2019 in Sevilla and is presented in two parts. DEVELOPMENT: This first part addresses the latest studies on vitamin D deficiency and the discrepancies that currently exist regarding its treatment. The advances made in epigenetics allow us to present this approach as a possible biomarker of multiple sclerosis. An account is provided to explain the growing importance of imaging techniques to detect atrophy and other phenomena that occur during the disease, such as changes in iron concentration or remyelination processes, which allow us to further our understanding of the mechanisms of cortical pathology, and the dimensionality of neurodegeneration during its course. Findings related to immunological mechanisms and advances in potential antigen-specific therapies are discussed. The contribution presents the latest studies on the assessment of cognitive impairment and its rehabilitation, which are becoming increasingly important due to the high prevalence of these disorders and the absence of their systematic assessment in clinical practice. Finally, the unmet social and health needs of multiple sclerosis patients in our country are presented, with emphasis on the current deficits in the system of social protection.

INTRODUCTION Like every year, after the ECTRIMS Congress, renowned Spanish neurologists who are experts in multiple sclerosis presented the main novelties in research in this field at the Post-ECTRIMS Meeting. AIM To summarise the content presented at the 12th edition of the Post-ECTRIMS Meeting, which took place in September 2019 in Sevilla and is presented in two parts. DEVELOPMENT In this second part, the most recent evidence on the use of disease-modifying treatments during pregnancy is presented. Details are provided concerning the results of phase 3 clinical trials conducted to evaluate the efficacy and safety of two potential disease-modifying treatments for relapsing-remitting multiple sclerosis: ponesimod and ofatumumab. For the progressive forms, both available disease modifying treatments and others still in the research phase are reviewed. In the field of stem cell therapies, the article includes the results of the only clinical trial carried out to date comparing patients with relapsing-remitting multiple sclerosis treated with autologous haematopoietic stem cell transplantation and those treated with disease-modifying therapies. There are no important developments as regards symptomatic treatments, although the European Academy of Neurology has published a guide on palliative care. The various sources of information that collect pharmacovigilance data in the post-marketing setting are reviewed. CONCLUSIONS Patients diagnosed in recent years tend to have less severe multiple sclerosis, probably due to the fact that it is diagnosed in its milder stages together with the steady increase in the number of treatments available.

Treatments for multiple sclerosis therapy are rapidly evolving. It is believed that new drugs will be approved in the near future, thereby changing current indications for treatment. In this context, the Spanish Society of Neurology's study group on demyelinating diseases, which evaluates medication use in MS, has decided to draw up a consensus statement on the current indications and guidelines for multiple sclerosis treatment. Resumen: La terapia de la esclerosis múltiple está en rápida evolución. En un plazo próximo, se prevé la incorporación de nuevos fármacos que pueden modificar las pautas actuales de tratamiento. Mientras tanto, el Grupo de Enfermedades Desmielinizantes de la Sociedad Española de Neurología encargado del consenso sobre la utilización de medicamentos para la EM, ha considerado necesaria una puesta al día de las indicaciones actuales y de los principios de tratamiento de esta enfermedad. Keywords: Multiple sclerosis, Treatment, Drugs, Lines of therapy, Drug failure, Palabras clave: Esclerosis múltiple, Tratamiento, Fármacos, Líneas de tratamiento, Fracaso terapéutico

Introduction: Natalizumab is very effective at reducing relapses and delaying disease progression in patients with relapsing-remitting multiple sclerosis (RRMS). However, treatment has also been associated with a risk of progressive multifocal leukoencephalopathy (PML). The aim of this article is to provide a consensus view on the assessment and stratification of these risks, and to improve the management of natalizumab-treated patients. Development: At an initial meeting of experts on multiple sclerosis (MS) (the authors of this consensus), the relevant topics of the consensus were decided and assigned for development. Topics included how to establish benefit and risk in general, stratification for risk of PML, informing patients of benefit/risk, monitoring treatment, and treatment withdrawal and follow-up. During the drafting phase, all available information published or presented at international meetings was reviewed. After a series of review rounds and meetings, the final draft was produced. Conclusions: Although natalizumab is a very effective drug, its use needs to be considered carefully in view of possible adverse effects and the risk of PML in particular. The neurologist should carefully explain the risks and benefits of treatment in terms the patient can best understand. Before starting treatment, baseline laboratory test and magnetic resonance imaging (MRI) should be available for comparison purposes in the event of suspected PML. The risk of PML should be stratified into high, medium and low risk groups according to antibodies against JC virus status, prior immunosuppressive therapy, and treatment duration. The follow-up, in particular, the frequency of MRI scans, should depend on the risk group to which patient belongs. As our understanding of the risk factors for PML develops, it should be possible to offer patients increasingly individualised therapy. This is a consensus that establishes general recommendations, but neurologists must use their clinical expertise to treat and follow individual patients. Resumen: Introducción: Natalizumab es un tratamiento que ha demostrado ser muy eficaz en los pacientes con esclerosis múltiple recurrente-remitente (EMRR) en cuanto a la reducción del número de brotes y al enlentecimiento de la progresión de la enfermedad. Sin embargo, el fármaco se ha asociado con el riesgo de desarrollar leucoencefalopatía multifocal progresiva (LMP). El objetivo de este artículo es proporcionar una posición consensuada sobre la valoración y estratificación de este riesgo y mejorar el manejo de los pacientes tratados con natalizumab. Desarrollo: En una reunión inicial de expertos en EM (los autores de este consenso), se perfilaron los temas de interés que fueron asignados a los asistentes para su desarrollo ulterior. Los temas incluían cómo establecer el beneficio y el riesgo en general, la estratificación para el riesgo de LMP, cómo informar a los pacientes de los beneficios y riesgos, cómo realizar el seguimiento del paciente en tratamiento y tras la suspensión del fármaco. Durante la fase de redacción, se revisó toda la información disponible, publicada o presentada en reuniones internacionales. Después de varios ciclos de revisión y de reuniones, se produjo el borrador final. Conclusiones: A pesar de ser un fármaco muy eficaz, la decisión de prescribir natalizumab debe ser tomada con cuidado por los posibles efectos adversos y en particular, el riesgo de LMP. El neurólogo debe explicar al paciente en detalle los riesgos y beneficios del tratamiento, en términos comprensibles para el paciente. Antes de empezar el tratamiento, deben estar disponibles las pruebas de laboratorio y las imágenes de resonancia magnética (RM) que permitan comparaciones en el futuro, en caso de sospecha de LMP. El riesgo de LMP debe estratificarse en alto, medio y bajo de acuerdo con la presencia o ausencia de anticuerpos frente al virus JC, antecedente de tratamiento inmunosupresor y duración del tratamiento. El seguimiento clínico y la frecuencia de la RM dependerá del grupo de riesgo al que pertenece el paciente. A medida que mejore nuestra comprensión de los factores de riesgo, será posible ofrecer a los pacientes una terapia cada vez más personalizada. El presente consenso establece unas recomendaciones generales, pero los neurólogos deben aplicar su experiencia clínica para hacer un seguimiento individualizado de los pacientes. Keywords: Multiple sclerosis, Treatment, Natalizumab, Risk, Consensus, Spain, Palabras clave: Esclerosis múltiple, Tratamiento, Natalizumab, Riesgo, Consenso, España

We have previously shown that P2X7 receptor blockade prevents ATP excitotoxicity in oligodendrocytes and ameliorates chronic experimental autoimmune encephalomyelitis. Here, we have explored the putative association of functionally relevant single nucleotide polymorphisms of the P2X7 receptor gene with multiple sclerosis. We found that T allele of rs17525809 polymorphism, which yields an Ala-76 to Val change in the extracellular domain, is more frequent in multiple sclerosis patients than in controls. Importantly, P2X7 variants with Val show a gain-of-function consisting in higher calcium permeability, larger electrophysiological responses and higher ethidium uptake, and enhance the effect of the also gain-of-function His-155 to Tyr substitution (rs208294) in the haplotype formed by these two variants. These findings may contribute to define the genetic background predisposing for multiple sclerosis and its pathophysiology.

An early and accurate diagnosis of multiple sclerosis (MS) is very important, since it allows early treatment initiation, which reduces the activity of the disease. Oligoclonal IgG band (OCGB) detection is a good ancillary tool for MS diagnosis. However, it was argued that its usefulness was limited by the high interlaboratory variability. In the last years, different techniques for OCGB detection have appeared. We performed a blinded aleatorized multicenter study in 19 Spanish hospitals to assess the accuracy and reproducibility of OCGB detection in this new scenario. We studied cerebrospinal fluid (CSF) and serum samples from 114 neurological patients. Every hospital contributed to the study with triplicated pairs of CSF and serum samples of six patients and analyzed 18 different samples. Global analysis rendered a sensitivity of 92.1%, a specificity of 95.1% and a Kappa value of 0.81. This shows that current techniques for OCGB detection have good accuracy and a high interlaboratory reproducibility and thus, represent a good tool for MS diagnosis. When we analyzed separately the different techniques used for OCGB detection, the highest concordance was observed in western blot with alkaline phosphatase detection (kappa=0.91). This indicates that high sensitivity techniques improve the reproducibility of this assay.

Introduction Cladribine is a prodrug, a synthetic analogue of deoxyadenosine, approved for use as selective immune reconstitution therapy in very active recurring multiple sclerosis in adults. Aims To review the development of the drug, its mechanism of action and the efficacy and safety data obtained to date, as well as to establish recommendations of Spanish experts for its use in clinical practice. Development The treatment of multiple sclerosis has been simplified with cladribine tablets, and two short courses of administration for two consecutive years (maximum 20 days) are needed to maintain an efficacy of up to four years after the first dose. Results of clinical trials have demonstrated the safety, tolerability and long-term efficacy of cladribine tablets in patients with recurring multiple sclerosis. Thus, patients treated with cladribine presented a significant reduction in the rate of flare-ups, in the risk of disability progression and in the development of new lesions in magnetic resonance imaging compared to those treated with placebo. In terms of safety, the treated patients had a higher frequency of lymphopenia, in relation to its mechanism of action, and of infections by herpes zoster virus. Long-term results with eight years' follow-up have shown that treated patients are not at greater risk of developing serious events, such as malignant neoplasms or opportunistic infections. Conclusions Cladribine is the first short-course oral therapy that has been shown to be effective and safe in patients with very active recurring multiple sclerosis, and with a sustained effect over time. The recommendations of Spanish experts on its usage are a fundamental complement to the considerations described by the regulatory agencies.

Introduction: Training in emergency neurological illness is very important for the neurologist today. The Neurology National Commission has decided to obtain information on the work duties of neurologist residents in the different neurology units of the hospitals of our country and the supervision of the training in urgent pathology. Method: A survey of adult neurology program directors to find out if their hospital fulfils the program criteria for the residents duty work. Results: A response rate of 98.5% was obtained. In 47% of the neurology training units a neurologist supervised resident duty work 24hours a day. In the rest of the neurology training units they did not fulfil all the training program criteria. We analysed the differences between the neurologist training units, and there are great differences between the hospitals and all regions and communities in our country. Only 65% of neurology residents do their education in neurology units who fullfill the national program criteria on training on urgent neurology pathology. Conclusions: There is too much diversity in resident duty work in neurologist training units and not all the units meet the national training program requirements. Resumen: Introducción: La formación en urgencias neurológicas es fundamental en el programa formativo de los residentes de Neurología. La Comisión Nacional de Neurología (CNN) decidió obtener información sobre el grado en que la Unidades Docentes de Neurología acreditadas posibilitan la realización de guardias específicas de Neurología y su grado de tutorización. Métodos: Realización de una encuesta a los tutores de las Unidades Docentes de Neurología para comprobar que se cumplen los criterios de la formación en guardias de neurología indicados en el programa oficial de formación. Resultados: Se obtuvo respuesta del 98,5% de las unidades docentes de Neurología que existen. En el 47% el médico de plantilla de Neurología tiene guardias de presencia física de 24 horas supervisando directamente al médico residente de Neurología. En el resto existe una diversidad de modelos que no cumplen de manera completa los criterios establecidos por el programa de especialidad. La distribución de los distintos modelos de guardias de Neurología varía mucho entre las distintas unidades docentes y entre las distintas Comunidades Autónomas. Sólo el 65% de los médicos residentes de Neurología realizan su formación en unidades docentes de Neurología que tienen guardias de Neurología autorizadas de manera correcta. Conclusiones: Hay una variabilidad injustificada en el cumplimiento de los criterios de formación en guardias de Neurología en las distintas unidades docentes distribuidas por todo nuestro país, habiendo diferencias de formación entre unos médicos residentes en Neurología y otros. Keywords: Training, Residents, Training program, Duty work, Duty work supervision, Palabras clave: Formación, Guardias, Guardias tutorizadas, Programa residencia, Residentes

Glutamate excitotoxicity contributes to oligodendrocyte and tissue damage in multiple sclerosis (MS). Here, we have examined if glutamate homeostasis is altered in plasma from MS patients. We initially observed that plasma glutamate levels are elevated in MS patients as compared to control subjects. In addition, we have studied the presence of a polymorphism sited in the promoter of the glutamate transporter EAAT2 whose mutant genotype results in lower transporter expression. We found that the polymorphism is not associated with the risk to develop MS. However, it is associated with higher glutamate plasma levels during the course of a relapse. These findings suggest that glutamate homeostasis is compromised in MS and that carrying this mutation may contribute to this alteration in relapsing MS.

Background FTY720 (fingolimod, Gilenya™), a structural analog of sphingosine-1-phosphate (S1P), is the first oral drug approved for treatment the relapsing-remitting form of multiple sclerosis (MS), and its efficacy has been related to induced lymphopenia and consequent immunosuppression via modulation of S1P1 receptors (S1P1R). However, due to its lipophilic nature, FTY720 crosses the blood brain barrier (BBB) and could act directly on neural cells. In this study, we investigated the effectiveness of FTY720 as a neuroprotective agent using in vitro and in vivo models of excitotoxic neuronal death and examined if FTY720 exerts a direct action on neurons, or/and an indirect modulation of inflammation-mediated neurodegeneration as a possible mechanism of neuroprotection. Methods Primary neuronal and organotypic cortical cultures were treated with N-methyl-D-aspartic acid (NMDA) to induce excitotoxic cell death (measured by lactate dehydrogenase (LDH) assay or propidium iodide uptake, respectively). The effects of FTY720 treatment (10, 100 and 1,000 nM) on neuronal survival were examined. As an in vivo model of neuronal death and inflammation, we used intracerebroventricular (icv) administration of kainic acid (KA; 0.5 μg/2 μl) in Sprague–Dawley rats. FTY720 was applied icv (1 μg/2 μl), together with KA, plus intraperitoneally (ip; 1 mg/kg) 24 h before, and daily, until sacrifice 3 days after icv. Rats were evaluated for neurological score, neuronal loss in CA3 hippocampal region and activation of microglia at the lesion site. In addition, we tested FTY720 as a modulator of microglia responses using microglial cell cultures activated with lipopolysaccharide (LPS) and its effects in stress signalling pathways using western blotting for p38 and JNK1/2 mitogen-activated protein kinases (MAPKs). Results FTY720 was able to reduce excitotoxic neuronal death in vitro. Moreover, in vivo repeated FTY720 administration attenuated KA-induced neurodegeneration and microgliosis at the CA3 lesion site. Furthermore, FTY720 negatively modulates p38 MAPK in LPS-activated microglia, whereas it had no effect on JNK1/2 activation. Conclusions These data support a role for FTY720 as a neuroprotective agent against excitotoxin-induced neuronal death and as a negative modulator of neuroinflammation by targeting the p38 MAPK stress signalling pathway in microglia. Electronic supplementary material The online version of this article (doi:10.1186/s12974-015-0308-6) contains supplementary material, which is available to authorized users.

Background: The presence of oligoclonal IgM bands (OCMB) in cerebrospinal fluid (CSF) is an unfavourable prognostic marker in multiple sclerosis. There is no commercial test to investigate OCMB status. However, a sensitive and specific isoelectrofocusing (IEF) and western blot method was described. We aimed to study the inter-centre reproducibility of this technique, a necessary condition for a reliable test to be incorporated into clinical practice. Methods: The presence of OCMB was analysed by IEF and western blot with prior reduction of pentameric IgM. We assayed the reproducibility of this test in a blinded multicentre study performed in 13 university hospitals. Paired-CSF and serum samples from 52 neurological patients were assayed at every centre. Results: Global analysis rendered a concordance of 89.8% with a kappa value of 0.71. Conclusion: These data indicate that OCMB detection by means of IEF and western blot with IgM reduction shows a good interlaboratory reproducibility and thus can be used in daily clinical setting. 2014 Elsevier B.V. All rights reserved.

Background: Single nucleotide polymorphisms (SNPs) near SOCS1 are associated with multiple sclerosis (MS), but the most important SNPs in the area and mechanisms by which they influence the disease are unknown. Methods: A haplotype-tagging association study was performed covering 60.5kbp around SOCS1, and the index SNP was validated in a total of 2292 individuals. mRNA expression of SOCS1 and nearby genes was measured in MS patients with different disease courses and healthy controls. SOCS1 protein expression was studied by flow cytometry in a separate cohort of patients and controls. Differentiation and maturation of monocyte-derived dendritic cells (moDCs) were also studied. Results: One SNP, rs423674, reached genome-wide significance. No genotype-specific mRNA expression differences were seen, but, by flow cytometry, significant interactions were observed between genotypes for rs423674 and disease activity (relapse or remission) in B cells and regulatory T cells. Furthermore, homozygotes for the risk allele (GG) showed higher levels of CD1a and CD86 than carriers of the protective allele (GT) in immature moDCs and a greater increase of HLA-DR+ cell percentage than GT heterozygotes upon maturation. Conclusions: rs423674, or its genetic proxies, may influence MS risk by modulating SOCS1 expression in a cell-specific manner and by influencing dendritic cell function.

Background: Mortality studies of multiple sclerosis (MS) patients are scarce. Objective: To assess mortality of MS patients included in a large MS cohort from the county of Bizkaia in Spain. Methods: Patients were collected from a dynamic population-based cohort of patients with MS from the county of Bizkaia (named the ‘Bizkaia cohort') in the Basque Country (Spain). Data from official registries were used for estimating mortality indicators. Results: During a 24-year period (1987-2011), a total of 1,283 patients were included in the Bizkaia cohort. Eighty-nine patients (6.9%) had died before December 31, 2011. The standardized mortality ratio was 2.78 for the whole group (3.26 for men and 2.73 for women), with a decreased life expectancy of 6.53 years. The mean survival from the onset of MS in deceased patients was 22.4 years. Death was related directly or indirectly to MS in 57 patients and unrelated in 27, while the cause of death was unknown in the remaining 5. Respiratory infection and sepsis were the most frequent MS-related causes of death. Differences in survival according to gender or disease course were not observed. Conclusion: Patients with MS included in the ‘Bizkaia cohort' had an almost threefold increase in the risk for death. Life expectancy is reduced by 6-10 years.

Objectives: To investigate the roles of 2 polymorphisms of the tumor necrosis factor (TNF) receptor superfamily member 1A ( TNFRSF1A ) gene, rs1800693 (a common variant) and rs4149584 (a coding polymorphism that results in an amino acid substitution—R92Q), as genetic modifiers of multiple sclerosis (MS), and to evaluate their potential functional implications in the disease. Methods: The effects of rs1800693 and rs4149584 on 2 measures of disease severity, age at disease onset and Multiple Sclerosis Severity Score, were analyzed in 2,032 patients with MS. In a subgroup of patients, serum levels of the soluble form of TNF-R1 (sTNF-R1) were measured by ELISA; mRNA expression levels of the full-length TNF-R1 and ∆6-TNF-R1 isoform were investigated in peripheral blood mononuclear cells (PBMC) by real-time PCR; cell surface expression of the TNF-R1 was determined in T cells by flow cytometry. Results: For rs4149584, R92Q carriers were younger at disease onset and progressed slower compared to noncarriers. However, no association with disease severity was observed for rs1800693. Serum levels of sTNF-R1 and mRNA expression levels of the full-length receptor were significantly increased in patients with MS carrying the R92Q mutation ( p = 0.003 and p = 0.011, respectively), but similarly distributed among rs1800693 genotypes; cell surface TNF-R1 expression in T cells did not differ between rs4149584 and rs1800693 genotypes. The truncated soluble ∆6-TNF-R1 isoform was identified in PBMC from patients carrying the risk allele for rs1800693. Conclusions: These findings suggest that both rs1800693 and rs4149584 TNFRSF1A polymorphisms have functional consequences in the TNF-R1.

Cantó, E. et al., [Background] Chitinase 3-like 1 (CHI3L1) is upregulated in a wide variety of inflammatory conditions. Recent studies have pointed to a role of CHI3L1 in multiple sclerosis (MS) pathogenesis., [Objective] The objective of this study was to investigate the role of plasma CHI3L1 in MS clinical course and disease activity and to evaluate the effect of interferon-beta (IFNβ) treatment on protein levels., [Methods] Plasma CHI3L1 levels were determined by ELISA in 57 healthy controls (HC), 220 untreated MS patients [66 primary progressive MS patients (PPMS), 30 secondary progressive MS patients (SPMS), and 124 relapsing-remitting MS patients (RRMS), 94 during clinical remission and 30 during relapse], and 32 MS patients receiving IFNβ treatment. A polymorphism of the CHI3L1 gene, rs4950928, was genotyped in 3274 MS patients and 3483 HC., [Results] Plasma CHI3L1 levels were significantly increased in patients with progressive forms of MS compared with RRMS patients and HC. CHI3L1 levels were similar between RRMS patients in relapse and remission. A trend towards decreased CHI3L1 levels was observed in IFNβ-treated patients. Allele C of rs4950928 was significantly associated with PPMS patients and with higher plasma CHI3L1 levels., [Conclusions] These findings point to a role of CHI3L1 in patients with progressive forms of MS, particularly in those with PPMS. © The Author(s) 2012., This work was supported by grants from the ‘Fondo de Investigación Sanitaria’ (FIS; grant numbers PI09/00788 and CP10/00526), Ministry of Science and Innovation, Spain. EC is supported by a contract from the FIS (contract number FI 09/00705), Ministry of Science and Innovation, Spain. The authors thank the ‘Red Española de Esclerosis Múltiple (REEM)’ sponsored by the ‘Fondo de Investigación Sanitaria’ (FIS), Ministry of Science and Innovation, Spain, and the ‘Ajuts per donar Suport als Grups de Recerca de Catalunya’ (SGR 2005-1081), sponsored by the ‘Agència de Gestió d’Ajuts Universitaris i de Recerca’ (AGAUR), Generalitat de Catalunya, Spain.

Background Glutamate excitotoxicity contributes to oligodendrocyte and tissue damage in multiple sclerosis (MS). Intriguingly, glutamate level in plasma and cerebrospinal fluid of MS patients is elevated, a feature which may be related to the pathophysiology of this disease. In addition to glutamate transporters, levels of extracellular glutamate are controlled by cystine/glutamate antiporter xc -, an exchanger that provides intracellular cystine for production of glutathione, the major cellular antioxidant. The objective of this study was to analyze the role of the system xc - in glutamate homeostasis alterations in MS pathology. Methods Primary cultures of human monocytes and the cell line U-937 were used to investigate the mechanism of glutamate release. Expression of cystine glutamate exchanger (xCT) was quantified by quantitative PCR, Western blot, flow cytometry and immunohistochemistry in monocytes in vitro, in animals with experimental autoimmune encephalomyelitis (EAE), the animal model of MS, and in samples of MS patients. Results and discussion We show here that human activated monocytes release glutamate through cystine/glutamate antiporter xc - and that the expression of the catalytic subunit xCT is upregulated as a consequence of monocyte activation. In addition, xCT expression is also increased in EAE and in the disease proper. In the later, high expression of xCT occurs both in the central nervous system (CNS) and in peripheral blood cells. In particular, cells from monocyte-macrophage-microglia lineage have higher xCT expression in MS and in EAE, indicating that immune activation upregulates xCT levels, which may result in higher glutamate release and contribution to excitotoxic damage to oligodendrocytes. Conclusions Together, these results reveal that increased expression of the cystine/glutamate antiporter system xc - in MS provides a link between inflammation and excitotoxicity in demyelinating diseases.

Different studies point to the implication of the endocannabinoid system in multiple sclerosis (MS) and animal models of MS. The purpose of this study was to evaluate a possible association of MS with polymorphic markers at the CNR1 gene, encoding the cannabinoid 1 (CB1) receptor. We have performed a genetic analysis of an AAT repeat microsatellite localized in the downstream region of the CNR1 gene, in two case—control groups of MS patients and healthy controls (HC) from Spain (Madrid and Bilbao). MS patients with primary progressive MS (PPMS) had more commonly long ((AAT) ≥13) alleles and genotypes with a significant difference for genotype 7/8 in Madrid (p = 0.043) and in the sum of both groups (p = 0.016); short alleles were less frequently found in PPMS with a significant difference for allele 5 in the analysis of both groups together (p = 0.039). In patients with relapsing MS, no consistent differences in allele and genotype distribution were found. Disease severity and progression was unrelated to AAT repeat variations. In conclusion, long (AAT) ≥13 CNR1 genotypes could behave as risk factors for PPMS.

Background A new formulation of subcutaneous (s.c.) interferon-β-1a has been developed (Rebif® New Formulation, RNF), produced without fetal bovine serum and without human serum albumin as an excipient, with the aim of improving injection tolerability, and reducing immunogenicity. Objectives This article reports 96-week analyses of a Phase IIIb, open-label study of the safety and immunogenicity of RNF compared with historical (EVIDENCE study) and recent (REGARD study) data on the original formulation. Methods Patients with relapsing multiple sclerosis (McDonald criteria) and an Expanded Disability Status Scale score < 6.0 received RNF, 44 μg s.c. three times weekly. Results The proportion of neutralizing antibody-positive (NAb+) patients (serum NAb status ≥20 neutralizing units/mL) at week 96 (last observation carried forward; primary endpoint) was 17.4% (exact 95% confidence interval [CI]: 13.0–22.5), compared with 21.4% (95% CI: 17.2–26.2) in the EVIDENCE study, and 27.3% (95% CI: 22.8–32.1) in the REGARD study. The proportion of patients NAb+ at any time during the 96 weeks was 18.9% (95% CI: 14.4–24.2), compared with 27.1% (95% CI: 22.4–32.2) and 33.7% (95% CI: 28.9–38.7), respectively. Most pre-specified categories of adverse events were reported by patients in the RNF study at a similar or lower proportion than in the EVIDENCE and REGARD studies. Injection-site reactions were experienced by fewer patients than in the EVIDENCE and REGARD studies. Conclusions RNF has improved overall immunogenicity and safety profiles compared with the original formulation.

Renowned national specialists in multiple sclerosis (MS) met, for the eighth year in a row, to give details of the latest novelties presented at the last ECTRIMS Congress 2015, which are included in this review. One of the highlights at this Congress was the new classification of the phenotypes of MS. Both the diagnostic criteria of the neuromyelitis optica spectrum and the problems involved in the differential diagnosis derived from the lack of definition of the radiological spectrum were reviewed. The microbiota comes to the fore as a possible factor determining the disease, together with extrinsic factors such as tobacco, salt ingestion or vitamin D deficiency. Advances made in immunomodulation are driving the progress being made in the treatment of MS. Ocrelizumab is the first treatment with positive results in the primarily progressive forms and tocilizumab, a drug product for rheumatoid arthritis, stands out as a potential candidate for the treatment of neuromyelitis optica. Certain antibiotics and vitamins could also play a role in the treatment of MS. In this edition of the Congress special attention was paid to personalised therapy. To date, 11 drugs have been approved for use in Europe. There is a need for therapeutic algorithms that help us to choose the best treatment for each patient. Likewise, we need to be able to identify, in the early stages of the disease, the risk of developing disability, so as to be able to design therapeutic strategies. To do so, molecular biomarkers and other predictive tools are required. The problems that still exist in software technology in magnetic resonance hinder its application in daily clinical practice.

Oligodendrocyte death and demyelination are hallmarks of multiple sclerosis (MS). Here we show that ATP signaling can trigger oligodendrocyte excitotoxicity via activation of calcium-permeable P2X7purinergic receptors expressed by these cells. Sustained activation of P2X7receptorsin vivocauses lesions that are reminiscent of the major features of MS plaques, i.e., demyelination, oligodendrocyte death, and axonal damage. In addition, treatment with P2X7antagonists of chronic experimental autoimmune encephalomyelitis (EAE), a model of MS, reduces demyelination and ameliorates the associated neurological symptoms. Together, these results indicate that ATP can kill oligodendrocytes via P2X7activation and that this cell death process contributes to EAE. Importantly, P2X7expression is elevated in normal-appearing axon tracts in MS patients, suggesting that signaling through this receptor in oligodendrocytes may be enhanced in this disease. Thus, P2X7receptor antagonists may be beneficial for the treatment of MS.

OBJECTIVES: We aimed to investigate the association between polymorphisms located in type I interferon (IFN)-induced genes, genes belonging to the toll-like receptor (TLR) pathway, and genes encoding neurotransmitter receptors and the response to IFN-β treatment in patients with multiple sclerosis (MS). METHODS: In a first or screening phase of the study, 384 polymorphisms were genotyped in 830 patients with MS classified into IFN-β responders (n = 416) and nonresponders (n = 414) according to clinical criteria. In a second or validation phase, the most significant polymorphisms associated with IFN-β response were genotyped in an independent validation cohort of 555 patients with MS (281 IFN-β responders and 274 nonresponders). RESULTS: Seven single nucleotide polymorphisms (SNPs) were selected from the screening phase for further validation: rs832032 (GABRR3; p = 0.0006), rs6597 (STUB1; p = 0.019), rs3747517 (IFIH1; p = 0.010), rs2277302 (PELI3; p = 0.017), rs10958713 (IKBKB; p = 0.003), rs2834202 (IFNAR1; p = 0.030), and rs4422395 (CXCL1; p = 0.017). None of these SNPs were significantly associated with IFN-β response when genotyped in an independent cohort of patients. Combined analysis of these SNPs in all patients with MS (N = 1,385) revealed 2 polymorphisms associated with IFN-β response: rs2277302 (PELI3; p = 0.008) and rs832032 (GABRR3; p = 0.006). CONCLUSIONS: These findings do not support an association between polymorphisms located in genes related to the type I IFN or TLR pathways or genes encoding neurotransmitter receptors and the clinical response to IFN-β. Nevertheless, additional genetic and functional studies of PELI3 and GABRR3 are warranted. SM is early stage researcher of the FP7 (2007-2013) Marie Curie Initial Training Network "UEPHA*MS" (2008-2012; Grant Agreement Number 212877). Spanish Ministry of Economy and Competitiveness, SAF/ 2012-34670, MS research, 2013-2015. Ministerio de Economía y Competitividad (MINECO) Convocatoria Proyectos de Investigación 2012 (Madrid, Spain); Funciones intracelulares de tipo-no-citoquina de las subunidades de la familia IL-12; SAF2012-32118. Dirección General de Investigación Científica y Técnica - DGICYT. Spanish Government (BFU2012-38236).

Multiple sclerosis is a chronic, demyelinating and inflammatory disease of the central nervous system that mainly affects young adults. It is characterised by processes involving inflammation, demyelination and axonal destruction, and as a result the pathogenic aspects and response to treatment of the disease vary widely. It is therefore difficult to establish a prognosis for these patients or to determine the effectiveness of the different drugs that are employed. Current clinical research into the development of new biomarkers has advanced a great deal in recent years, especially in the early stages of the disease. Yet, it is essential to further our knowledge about novel markers of the disease, and not only in the more advanced stages, so as to be able to stop disability from progressing and to establish new therapy regimens in these patients. This review presents an update on the information available about the biomarkers that are currently validated and used in multiple sclerosis, together with the possible candidates for utilisation in routine clinical practice.

Multiple sclerosis is the most frequent disabling neurological disease in young adults. Its development includes independent processes of inflammation, demyelination, neurodegeneration, gliosis and repair, which are responsible for the heterogeneity and individual variability in the expression of the disease, its prognosis and response to treatment. As part of personalised medicine, the progress made in the search for new biomarkers has identified promising candidates that may be useful for the early diagnosis of the disease, for detecting prognostic and developmental profiles of the disease, and for monitoring the response to treatment. Unfortunately, few of them have been validated adequately, which prevents them from being applied in clinical practice. In view of the latest findings, the experts recommend orienting research in another direction, not so much towards the discovery of new molecules or imaging techniques, but instead towards a clinical validation of these markers, with the aim of fostering translational research. This review offers an update on the information about the biomarkers in multiple sclerosis that have currently been validated and are thus potential candidates, as well as looking at their value in the diagnosis, prognosis, evaluation of the development of the disability caused by the disease and the response to therapy.

Hematocrits of 131 cerebral infarction cases were correlated with the outcome at 2 weeks. Bivariate analysis showed that cases with more intense admission deficit had lower admission hematocrit and that cases with poorer outcome had lower Day 2 and 4 hematocrits. However, multivariate analysis of several prognostic factors (including hematocrit, glycemia, blood pressure, age, and sex) showed that hematocrit was not independently related to outcome. Higher hematocrit thus is not indicative of less favorable short-term outcome.