Defining a standard set of health outcomes for patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Standardizing health outcomes is challenging in clinical management, but it also holds the potential for creating a healthcare system that is both more effective and efficient. The aim of the present study is to define a standardized set of health outcomes for managing Relapsing-Remitting Multiple Sclerosis (RRMS). METHODS: The project was led and coordinated by a multidisciplinary scientific committee (SC), which included a literature review, a patient-focused group, three nominal group meetings, and two SC meetings. RESULTS: 36 outcome variables were included in the standard set: 24 clinical (including weight, smoking habit, comorbidities, disability, mobility, diagnosis of secondary progressive multiple sclerosis, relapsed-related variables, radiological variables, cognitive status and disease-related symptoms), nine treatment-related (pharmacological and non-pharmacological information), and 3 related to the impact of RRMS on the patient's life (quality of life, pregnancy desire, work-related difficulties). In addition, experts also agreed to collect 10 case-mix variables that may affect but cannot be controlled as part of the management of the condition: 4 sociodemographic (age, sex, race, and employment status) and 6 clinical (height, date of diagnosis and first episode, serological status, early symptoms, and number of relapses pre-diagnosis). CONCLUSION: The information provided through the present standard set of outcome variables can improve the management of RRMS and promote patient-centred quality care.

Family Planning in Fertile-Age Patients With Multiple Sclerosis (MS) (ConPlanEM Study): Delphi Consensus Statements.

Family planning is essential for establishing Multiple Sclerosis (MS) prognosis, treatment decision, and disease monitoring. We aimed to generate an expert consensus addressing recommendations for family planning in MS patients of childbearing age. Initially, a committee comprising seven neurologists, experts in the MS field, identified the topics to be addressed. Then, the committee elaborated on different evidence-based preliminary statements. Next, using the Delphi methodology, a panel of neurologists manifested their level of agreement on the different statements using a Likert-type scale. Consensus was reached when ⩾70% of respondents expressed an agreement or disagreement using a five-point scale. Consensus was achieved on 47 out of 63 recommendations after three rounds of evaluations. The panel considered it essential to address family planning in all patients of childbearing age. There was also consensus that treatment should not be delayed due to the patient's desire for pregnancy. Additionally, in highly active patients, planning the pregnancy in the medium to long term using depletory drugs such as cladribine or alemtuzumab might represent a useful strategy. However, risks of adverse effects on the fetus due to drug-associated secondary autoimmunity should be addressed when alemtuzumab is considered. Moreover, the maintenance of natalizumab during pregnancy in very active patients reached expert consensus. Also, the panel supported the use of certain disease-modifying treatment (DMT) during lactation in selected cases. Our results identified specific areas of pregnancy planning in MS patients, where different treatment strategies might be considered to facilitate a safe and successful pregnancy while maintaining clinical and radiological stability.

Therapeutic effect of α7 nicotinic receptor activation after ischemic stroke in rats.

Nicotinic acetylcholine α7 receptors (α7 nAChRs) have a well-known modulator effect in neuroinflammation. Yet, the therapeutical effect of α7 nAChRs activation after stroke has been scarcely evaluated to date. The role of α7 nAChRs activation with PHA 568487 on inflammation after brain ischemia was assessed with positron emission tomography (PET) using [18F]DPA-714 and [18F]BR-351 radiotracers after transient middle cerebral artery occlusion (MCAO) in rats. The assessment of brain oedema, blood brain barrier (BBB) disruption and neurofunctional progression after treatment was evaluated with T2 weighted and dynamic contrast-enhanced magnetic resonance imaging (T2 W and DCE-MRI) and neurological evaluation. The activation of α7 nAChRs resulted in a decrease of ischemic lesion, midline displacement and cell neurodegeneration from days 3 to 7 after ischemia. Besides, the treatment with PHA 568487 improved the neurofunctional outcome. Treated ischemic rats showed a significant [18F]DPA-714-PET uptake reduction at day 7 together with a decrease of activated microglia/infiltrated macrophages. Likewise, the activation of α7 receptors displayed an increase of [18F]BR-351-PET signal in ischemic cortical regions, which resulted from the overactivation of MMP-2. Finally, the treatment with PHA 568487 showed a protective effect on BBB disruption and blood brain vessel integrity after cerebral ischemia.

Assessing care-related regret among nurses specialized in multiple sclerosis: A psychometric analysis of a new assessment battery.

Experiences of regret associated with caring for patients with multiple sclerosis (MS) can affect medical decisions. A non-interventional study was conducted to assess the dimensionality and item characteristics of a battery including the Regret Intensity Scale (RIS-10) and 15 items evaluating common situations experienced by nurses in MS care. A total of 97 nurses were included. The RIS-10 showed good internal reliability and a unidimensional structure according to Mokken analysis. All-item homogeneity coefficients exceeded 0.30, whereas scalability for the overall RIS-10 was 0.66, indicating a strong scale. This battery showed adequate psychometric properties to evaluate regret among MS nurses.

Consensus on early detection of disease progression in patients with multiple sclerosis.

Background: Early identification of the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS) can be challenging for clinicians, as diagnostic criteria for SPMS are primarily based on physical disability and a holistic interpretation. Objective: To establish a consensus on patient monitoring to identify promptly disease progression and the most useful clinical and paraclinical variables for early identification of disease progression in MS. Methods: A RAND/UCLA Appropriateness Method was used to establish the level of agreement among a panel of 15 medical experts in MS. Eighty-three items were circulated to the experts for confidential rating of the grade of agreement and recommendation. Consensus was defined when ≥66% agreement or disagreement was achieved. Results: Consensus was reached in 72 out of 83 items (86.7%). The items addressed frequency of follow-up visits, definition of progression, identification of clinical, cognitive, and radiological assessments as variables of suspected or confirmed SPMS diagnosis, the need for more accurate assessment tools, and the use of promising molecular and imaging biomarkers to predict disease progression and/or diagnose SPMS. Conclusion: Consensus achieved on these topics could guide neurologists to identify earlier disease progression and to plan targeted clinical and therapeutic interventions during the earliest stages of SPMS.

Sick leave and occupational burnout among nurses caring for patients with multiple sclerosis.

BACKGROUND: Sick leave is a common problem among healthcare professionals. Nurses play a critical role in the multidisciplinary management of multiple sclerosis (MS). However, limited information is available on the phenomenon of sick leave among MS nurses. OBJECTIVE: The aim of this study was to assess the presence of sick leave among nurses caring for patients with MS and to identify associated factors. METHODS: We conducted a multicenter, non-interventional, cross-sectional, web-based study. Nurses involved in MS care from across Spain answered a survey composed of demographic characteristics, professional background, questions about their standard practice, and a behavioral battery including the Maslach Burnout Inventory - Human Services Survey (MBI-HSS). A multivariable logistic regression analysis was conducted to determine the association between nurses' characteristics and sick leave. RESULTS: Ninety-six nurses were included in the study. Mean age (SD) was 44.6 (9.8) years, and 91.7% were female. Participants had a median of 6 (IQR 3.0, 11.0) years of expertise in MS managing a median of 15 (5.0, 35.0) patients per week. Sixteen participants (16.7%) had been on sick leave in the last 6 months, with a median absence of 14.5 days (7.0, 30.0). Sixteen nurses (16.7%) reported severe burnout. Participants on sick leave had higher levels of emotional exhaustion (mean MBI-HSS scores of 22.3 and 16.0, p=0.01) and inadequate interactions with their colleagues (mean Practice Environment Scale - Nursing Work Index scores of 11.8 and 13.1, p=0.01) than their counterparts. Burnout was associated with higher risk of sick leave in the multivariable analysis (OR=1.06 [95% CI 1.00, 1.13], p=0.04) after adjustment for confounders. CONCLUSIONS: Occupational burnout is associated with increased risk of sick leave among nurses managing patients with MS. Identifying burnout may be critical for implementing specific intervention strategies to maintain an adequate functioning of MS care units.

Disease modifying therapy switching in relapsing multiple sclerosis: A Delphi consensus of the demyelinating expert group of the Spanish society of neurology.

BACKGROUND: The increase in available disease modifying therapies (DMTs) for multiple sclerosis has led to greater emphasis on improving treatment sequencing paradigms. This article summarises the opinions from a panel of 25 experts on treatment switching approaches in relapsing multiple sclerosis (RMS). METHODS: A modified Delphi consensus process was carried out to develop clinically relevant statements for aiding treatment decisions in patients with RMS between the 16th January and the 9th October 2019. A sub-group of two experts (core group) carried out an extensive review of the literature and formulated 106 statements for the expert panel to evaluate. RESULTS: From a total number of 106 statements that were submitted to the expert panel for critical evaluation, consensus (at least 80% of the panelists agreed) was reached on 99 of them. These statements cover treatment objectives, reasons for DMT switching, suboptimal response criteria, strategies for treatment change and washout periods. CONCLUSION: The agreed statements provide up-to-date guidance on DMT sequencing for optimal patient management.

Neuropsychological Profile of Hereditary Ataxias: Study of 38 Patients.

Hereditary ataxias are a heterogeneous group of disorders characterized by degeneration of the cerebellum and its connections. It is known that patients with ataxia can manifest a broad spectrum of motor symptoms; however, current research has emphasized the relevance of cognitive disturbances. The aim of this study is to analyze the presence of cognitive impairment in a heterogeneous cohort of patients with hereditary ataxia (HA). A group of 38 patients with HA of different etiologies and a matched group of 38 healthy controls were recruited and evaluated through a comprehensive battery of neuropsychological tests. The findings show a worse performance in ataxic patients on planning, visuospatial skills, naming, and Theory of Mind tasks, regardless their physical and psychological symptomatology. The influence of clinical status as well as functional ability-related variables on their performance were analyzed, showing that the level of disability and motor disturbances have a significant effect on verbal memory, verbal fluency, and working memory. These findings suggest that patients with HA can manifest cognitive and neuropsychiatric symptoms as part of their clinical features, which demands its inclusion for the diagnosis and management of the disease.

Behavioral aspects of nurse practitioners associated with optimal multiple sclerosis care in Spain.

BACKGROUND: Nurse practitioners (NPs) play a critical role in the multidisciplinary management of patients with multiple sclerosis (MS). Neurologists´ behavioral characteristics have been associated with suboptimal clinical decisions. However, limited information is available on their impact among NPs involved in MS care. The aim of this study was to assess nurses´ therapeutic choices to understand behavioral factors influencing their decision making process. METHODS: A non-interventional, cross-sectional, web-based study was conducted. NPs actively involved in the care of patients with MS were invited to participate in the study by the Spanish Society of Neurology Nursing. Participants answered questions regarding their standard practice and therapeutic management of seven simulated relapsing-remitting MS (RRMS) case scenarios. A behavioral battery was used to measure participants´ life satisfaction, mood, positive social behaviors, feeling of helpfulness, attitudes toward adoption of evidence-based innovations, occupational burnout, and healthcare-related regret. The outcome of interest was therapeutic inertia (TI), defined as the lack of treatment escalation when there is clinical and radiological evidence of disease activity. A score to quantify TI was created based on the number of simulated scenarios where treatment intensification was warranted. RESULTS: Overall, 331 NPs were invited to participate, 130 initiated the study, and 96 (29%) completed the study. The mean age (SD) was 44.6 (9.8) years and 91.7% were female. Seventy-three participants (76.0%) felt their opinions had a significant influence on neurologists´ therapeutic decisions. Sixteen NPs (16.5%) showed severe emotional exhaustion related to work and 13 (13.5%) had depressive symptoms. The mean (SD) TI score was 0.97 (1.1). Fifty-six of NPs showed TI in at least one case scenario. Higher years of nursing experience (p = 0.014), feeling of helpfulness (p = 0.014), positive attitudes toward innovations (p = 0.046), and a higher intensity of care-related regret (p = 0.021) were associated with a lower risk of TI (adjusted R2 = 0.28). Burnout was associated with higher risk of TI (p = 0.001). CONCLUSIONS: Although NPs cannot prescribe MS treatments in Spain, their behavioral characteristics may influence the management of patients with RRMS. Continuing education and specific strategies for reducing occupational burnout may lead to better management skills and improve MS care.

Regret and Therapeutic Decisions in Multiple Sclerosis Care: Literature Review and Research Protocol.

Background: Decisions based on erroneous assessments may result in unrealistic patient and family expectations, suboptimal advice, incorrect treatment, or costly medical 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. Spanish National Register (SL42129-20/598-E).

Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55-IL6ST Gene Region in Immature Dendritic Cells.

Intronic single-nucleotide polymorphisms (SNPs) in the ANKRD55 gene are associated with the risk for multiple sclerosis (MS) and rheumatoid arthritis by genome-wide association studies (GWAS). The risk alleles have been linked to higher expression levels of ANKRD55 and the neighboring IL6ST (gp130) gene in CD4+ T lymphocytes of healthy controls. The biological function of ANKRD55, its role in the immune system, and cellular sources of expression other than lymphocytes remain uncharacterized. Here, we show that monocytes gain capacity to express ANKRD55 during differentiation in immature monocyte-derived dendritic cells (moDCs) in the presence of interleukin (IL)-4/granulocyte-macrophage colony-stimulating factor (GM-CSF). ANKRD55 expression levels are further enhanced by retinoic acid agonist AM580 but downregulated following maturation with interferon (IFN)-γ and lipopolysaccharide (LPS). ANKRD55 was detected in the nucleus of moDC in nuclear speckles. We also analyzed the adjacent IL6ST, IL31RA, and SLC38A9 genes. Of note, in healthy controls, MS risk SNP genotype influenced ANKRD55 and IL6ST expression in immature moDC in opposite directions to that in CD4+ T cells. This effect was stronger for a partially correlated SNP, rs13186299, that is located, similar to the main MS risk SNPs, in an ANKRD55 intron. Upon analysis in MS patients, the main GWAS MS risk SNP rs7731626 was associated with ANKRD55 expression levels in CD4+ T cells. MoDC-specific ANKRD55 and IL6ST mRNA levels showed significant differences according to the clinical form of the disease, but, in contrast to healthy controls, were not influenced by genotype. We also measured serum sgp130 levels, which were found to be higher in homozygotes of the protective allele of rs7731626. Our study characterizes ANKRD55 expression in moDC and indicates monocyte-to-dendritic cell (Mo-DC) differentiation as a process potentially influenced by MS risk SNPs.

Gene Expression Analysis of Astrocyte and Microglia Endocannabinoid Signaling during Autoimmune Demyelination.

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.

An Overground Robotic Gait Training Program for People With Multiple Sclerosis: A Protocol for a Randomized Clinical Trial.

Maintaining the ability to walk is one of the significant challenges in people with multiple sclerosis (MS) for keeping a good quality of life as the disease and the aging process progresses. Overground robotic (OR) wearable exoskeletons are promising tools for gait rehabilitation, but currently there is no evidence of their clinical effects on patients with MS. The present study aims to determine the effects of an OR intervention in people with MS and moderate to severe walking disabilities and ascertain if benefits are maintained over a follow-up period of 3 months. This randomized controlled trial will include 36 participants with MS. Inclusion criteria are: older than 18 years, definitive diagnosis of MS, 4.5-7 points on the EDSS (Expanded Disability Status Scale), and needing one or two canes or crutches for walking outdoors. Subjects in the control group will receive conventional physiotherapy sessions at ADEMBI (Asociación de Esclerosis Múltiple de Bizkaia) provided to control spasticity, maintain articular range and exercise balance. Subjects in the intervention group will receive the same physiotherapy but also participate in a progressive OR gait training program assisted by the EksoTM exoskeleton. The program consists of twice a week individually supervised sessions in two setting modalities: PreGait and ProStepPlus. The training parameters (duration, speed, cadence, length of steps) will be set during the first session and the progression and intensity of the intervention will be adapted to the tolerance of each participant. The primary outcome of this study is gait speed. Secondary outcomes will include physical and cognitive performance tests, clinical, fatigue and quality of life assessments, and changes in the plasma levels of inflammatory cytokines. The present trial is the first analyzing the effectiveness of an OR intervention for gait training in patients with MS. It will help clarify the applicability of robotic technologies to clinical practice, extending the functionality and quality of life of people with MS to face a successful aging process. (ACTRN12619000014156; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376548).

XII Reunión Post-ECTRIMS: revisión de las novedades presentadas en el Congreso ECTRIMS 2019 (II) / 12th Post-ECTRIMS Meeting: review of the novelties from the 2019 ECTRIMS Congress (II)

INTRODUCCIÓN: Como cada año, tras la celebración del Congreso del ECTRIMS, reconocidos neurólogos españoles expertos en esclerosis múltiple expusieron en la Reunión Post-ECTRIMS las principales novedades en investigación en este ámbito. OBJETIVO: Sintetizar el contenido presentado en la XII edición de la Reunión Post-ECTRIMS, que tuvo lugar en septiembre de 2019 en Sevilla y que se presenta en dos partes. DESARROLLO: En esta segunda parte, se exponen las evidencias más recientes sobre el uso de tratamientos modificadores de la enfermedad durante el embarazo. Se detallan los resultados de ensayos clínicos en fase 3 en los que se ha evaluado la eficacia y la seguridad de dos potenciales tratamientos modificadores de la enfermedad para la esclerosis múltiple remitente recurrente: ponesimod y ofatumumab. Para las formas progresivas, se revisan los tratamientos modificadores de la enfermedad disponibles y en investigación. En el ámbito de las terapias con células madre, se incluyen los resultados del único ensayo clínico hasta la fecha que compara a pacientes con esclerosis múltiple remitente recurrente tratados con trasplante autólogo de células madre hematopoyéticas y a los tratados con tratamientos modificadores de la enfermedad. No hay grandes novedades sobre tratamientos sintomáticos, aunque la Academia Europea de Neurología ha publicado una guía sobre cuidados paliativos. Se revisan las distintas fuentes de información que recogen datos de farmacovigilancia en el entorno poscomercialización. CONCLUSIONES: Los pacientes diagnosticados en los últimos años tienden a tener una menor gravedad de la esclerosis múltiple, probablemente debido al diagnóstico desde sus estadios más leves y al continuo aumento de tratamientos disponibles

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:l 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

XII Reunión Post-ECTRIMS: revisión de las novedades presentadas en el Congreso ECTRIMS 2019 (I) / 12th Post-ECTRIMS Meeting: review of the novelties from the 2019 ECTRIMS Congress (I)

INTRODUCCIÓN: Como cada año, tras la celebración del Congreso ECTRIMS, reconocidos neurólogos españoles expertos en esclerosis múltiple expusieron en la Reunión Post-ECTRIMS las principales novedades en investigación en este ámbito. OBJETIVO: Sintetizar el contenido presentado en la XII edición de la Reunión Post-ECTRIMS, que tuvo lugar en septiembre de 2019 en Sevilla y que se presenta en dos partes. DESARROLLO: Esta primera parte aborda los últimos estudios sobre el déficit de vitamina D y las discrepancias existentes acerca de su tratamiento. Los avances en epigenética realizados permiten presentar esta aproximación como un posible biomarcador de la esclerosis múltiple. Se explica el creciente protagonismo de las técnicas de imagen para detectar la atrofia y otros fenómenos que acontecen durante la enfermedad, como los cambios en la concentración de hierro o los procesos de remielinización, que nos permiten ganar comprensión sobre los mecanismos de la patología cortical, y sobre la dimensionalidad de la neurodegeneración durante su evolución. Se discuten los hallazgos relacionados con los mecanismos inmunológicos y los avances realizados en las potenciales terapias específicas del antígeno. Se presentan los últimos estudios sobre la evaluación del deterioro cognitivo y su rehabilitación, que cobran cada vez más importancia por la alta prevalencia de estas alteraciones y por la ausencia de su evaluación sistemática en la práctica clínica. Por último, se exponen las necesidades sociosanitarias no cubiertas de los pacientes de esclerosis múltiple en nuestro país, poniendo el acento en los déficits actuales del sistema de protección social

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

¿Va a cambiar la neurología tras la pandemia de Covid-19 en los próximos cinco años?. Estudio de enfoque mediante informadores clave / Will neurological care change over the next 5 years due to the COVID-19 pandemic?

INTRODUCCIÓN: La pandemia de Covid-19 va a conllevar cambios en la asistencia neurológica, que no se pueden prever fácilmente a largo plazo. MATERIAL Y MÉTODOS: A través de un modelo de informadores clave, se busca el consenso siendo los encuestados, jefes de servicio de Neurología con conocimiento amplio de la situación al haber actuado durante la pandemia, de cómo va a ser la especialidad en un plazo de cinco años. RESULTADOS: Aunque se obtiene un grado de acuerdo bajo entre encuestados, si se describen acuerdos por consenso a nivel mayor (85%) y menor (70%). Los principales acuerdos se refieren al incremento de precauciones, al uso de la telemedicina, al mantenimiento de las consultas telefónicas, a la reducción de asistencia a las consultas evitando que hayan salas de espera con un número alto de personas, al desarrollo de técnicas docentes no presenciales y a la adaptación en el desarrollo de ensayos clínicos en relación a la visita de los monitores. Sin embargo, no se acuerda que haya cambios en la indicación de exploraciones complementarias, ni en la propia exploración neurológica. CONCLUSIÓN: El método de informadores clave ha permitido conocer que cambios se pueden prever tras la pandemia

INTRODUCTION: The COVID-19 pandemic will give rise to long-term changes in neurological care, which are not easily predictable. MATERIAL AND METHODS: A key informant survey was used to enquire about the changes expected in the specialty over the next 5 years. The survey was completed by heads of neurology departments with broad knowledge of the situation, having been active during the pandemic. RESULTS: Despite a low level of consensus between participants, there was strong (85%) and moderate consensus (70%) about certain subjects, mainly the increase in precautions to be taken, the use of telemedicine and teleconsultations, the reduction of care provided in in-person consultations to avoid the presence of large numbers of people in waiting rooms, the development of remote training solutions, and the changes in monitoring visits during clinical trials. There was consensus that there would be no changes to the indication of complementary testing or neurological examination. CONCLUSION: The key informant survey identified the foreseeable changes in neurological care after the pandemic

The Rare IL22RA2 Signal Peptide Coding Variant rs28385692 Decreases Secretion of IL-22BP Isoform-1, -2 and -3 and Is Associated with Risk for Multiple Sclerosis.

The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly (p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset (p = 3.17 × 10-4). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50%-60% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS.

Positive oligoclonal bands and CSF pleocytosis in narcolepsy type 1: A case report supporting the immune-mediated hypothesis.

Narcolepsy-type 1 is a neurological sleep-disorder caused by a selective loss of hypothalamic orexin/hypocretin-producing neurons whose underlying mechanism is considered to be immune-mediated. We report the case of a 16 year-old girl with excessive daytime sleepiness, hypnagogic/hypnopompic hallucinations and cataplexy, fulfilling narcolepsy-type 1 diagnostic criteria. She was HLA-DQB1*06:02/DQA1*01:02 positive. CSF analysis demonstrated positive IgG oligoclonal bands, pleocytosis and hypocretin-1 below detection limit. Other autoimmune processes were excluded, including autoimmune encephalitis. After treatment with intravenous immunoglobulins sleep-related hallucinations transiently improved for a month. This case's CSF inflammatory findings support the role of neuroinflammation in narcolepsy-type 1 development in genetically predisposed patients.

Recomendaciones de uso de cladribina comprimidos en la esclerosis múltiple recurrente / Recommendations for the use of cladribine tablets in recurring multiple sclerosis

Introducción. La cladribina es un profármaco, análogo sintético de la desoxiadenosina, aprobado como terapia de reconstitución inmune selectiva en la esclerosis múltiple (EM) recurrente muy activa del adulto. Objetivos. Revisar el desarrollo del fármaco, su mecanismo de acción y los datos de eficacia y seguridad obtenidos hasta la fecha, y establecer recomendaciones de manejo por expertos españoles en la práctica clínica. Desarrollo. El tratamiento de la EM se ha simplificado con cladribina comprimidos, y se necesitan dos cursos cortos de administración durante dos años consecutivos (máximo 20 días) para mantener una eficacia de hasta cuatro años tras la primera dosis. Los resultados de los ensayos clínicos han demostrado la seguridad, la tolerabilidad y la eficacia a largo plazo de la cladribina comprimidos en pacientes con EM recurrente. Así, los pacientes tratados con cladribina presentaron una reducción significativa de la tasa de brotes, del riesgo de progresión de la discapacidad y del desarrollo de nuevas lesiones en la resonancia magnética en comparación con los tratados con placebo. En cuanto a la seguridad, los pacientes tratados presentaron una mayor frecuencia de linfopenia, en relación con su mecanismo de acción, y de infecciones por el virus del herpes zóster. Los resultados a largo plazo con ocho años de seguimiento han mostrado que los pacientes tratados no tienen mayor riesgo de desarrollar efectos graves, como neoplasias malignas o infecciones oportunistas. Conclusiones. La cladribina es la primera terapia oral de corta administración que ha demostrado ser eficaz y segura en pacientes con EM recurrente muy activa, y con un efecto sostenido en el tiempo. Las recomendaciones de expertos españoles sobre su manejo suponen un complemento fundamental a las consideraciones descritas por las agencias reguladoras

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

Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways (PLAU, MASP1, C2), inflammasome assembly (NLRP12), Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), nuclear receptor complexes (NCOA3), and cation channels and exchangers (KCNG4, SLC24A6, SLC8B1). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients.