Natalizumab extended interval dosing: what about wearing-off effect?

BACKGROUND: Up to two thirds of patients with multiple sclerosis (MS) under natalizumab report a resurgence of symptoms at the end of the natalizumab cycle (wearing-off (WO) effect). At the outbreak of COVID-19, in line with the international recommendations for MS management, our centre switched all clinically stable patients on natalizumab therapy for more than one year from standard interval dosing (SID) to extended interval dosing (EID) with every six weeks infusions. This study aimed to evaluate the impact of EID in WO in MS patients under natalizumab. METHODS: An observational retrospective study in patients with MS under natalizumab on EID was conducted. A questionnaire regarding current (on EID) and past (on SID) experience of WO effect was applied. RESULTS: Seventy-six patients were included. No significant differences were found in the annual relapse rate after the switch to EID (p = 0.083). However, there was a significant increase in the proportion of patients complaining of WO from 38.2% to 56.6% (p = 0.001). Moreover, patients with WO on SID, referred a significant increase in severity (p = 0.019) and duration of WO symptoms (p = 0.029), due to an anticipation of the symptoms relative to the day of natalizumab infusion (p = 0.019), when switching to EID. Symptoms improved with treatment maintenance in 23.3% of patients; instead, a reduction in interval dosing was needed in 54.8% with symptom improvement. CONCLUSION: WO affects a significant proportion of MS patients under natalizumab. Its prevalence, severity, and duration increase on EID, therefore despite clinical effectiveness maintenance of this posology should be individualized.

Prevalence, Incidence, and Mortality of Multiple Sclerosis in Coimbra, Portugal.

Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system in young adults, representing the leading cause of nontraumatic disability in this population. The rising prevalence of MS worldwide makes it critical to recognize the absolute number of patients with MS, demanding the execution of a sustainable healthcare policy. In Portugal, only six studies evaluating MS rates were published, disclosing a prevalence of 64 cases per 100,000 persons and an incidence of 3.1 cases per 100,000 persons/year, but the mortality rates have not been reported. Thus, this observational, cross-sectional study aimed to assess MS prevalence, incidence, and mortality in the city of Coimbra, a region in the center of Portugal. Patients who fulfilled McDonald's Diagnosis Criteria (2017) for MS were recruited. Inclusion criteria were defined according to prevalence, incidence, and mortality studies. The baseline demographic and clinical characterization of the prevalence study population was performed. The MS prevalence rate in Coimbra was 143.45 cases per 100,000 inhabitants. Between 2018 and 2021, the cumulative incidence was 8.52 new cases per 100,000 persons/year. The mortality rate between 2018 and 2021 was 2.84 deaths per 100,000 inhabitants. MS prevalence and incidence in Coimbra are higher than reported in previous similar studies and comparable to Europe's mean prevalence and incidence.

Determining the Impacts of COVID-19 on Urban Deliveries in the Metropolitan Region of Belo Horizonte Using Spatial Analysis.

The COVID-19 pandemic has changed lifestyles, with consequent impacts on urban freight movements. This paper analyzes the impacts of COVID-19 on urban deliveries in the Belo Horizonte Metropolitan Region, Brazil. The Lee index and the Local Indicator of Spatial Association were calculated using data on urban deliveries (retail and home deliveries) and COVID-19 cases. The results confirmed the negative impacts on retail deliveries and the positive impacts on home deliveries. The spatial analysis demonstrated that the most interconnected cities presented more similar patterns. At the beginning of the pandemic, consumers were considerably concerned about the virus spread, and the changes in consumption behavior were slow. The findings suggest the importance of alternative strategies to traditional retail. In addition, the local infrastructure should adapt to the increased demand for home deliveries during pandemics.

Toxic profile of marinobufagin from poisonous Amazon toads and antitumoral effects on human colorectal carcinomas.

ETHNOPHARMACOLOGICAL RELEVANCE: South Americans natives have extensively used the toad "kururu" to reduce/treat skin infections, cutaneous lesions and sores. They release secretions rich in bufadienolides, polyhydroxy steroids with well-documented cardiotonic and antiproliferative actions, but in vivo antitumoral evaluations in mammals are rare, and toxicological safety has been left in second place. AIMS OF THE STUDY: This investigation used in silico, in vitro and in vivo tools to evaluate acute and subacute toxic effects of marinobufagin and the anticancer action in tumor-bearing mice models. MATERIALS AND METHODS: Initially, in silico toxic predictions were performed, followed by in vitro assays using human and murine normal and tumor lines. Next, acute and subacute studies on mice investigated the behavior, hematological and intestinal transit profile and antitumoral activity of marinobufagin in sarcoma 180- and HCT-116 colorectal carcinoma-transplanted mice for 7 and 15 days, respectively. Ex vivo and in vivo cytogenetic assays in Sarcoma 180 and bone marrow cells and histopathological examinations were also executed. RESULTS: In silico studies revealed ecotoxicological effects on crustaceans (Daphnia sp.), fishes (Pimephales promelas and Oryzias latipes), and algae. A 24-h marinobufagin-induced acute toxicity included signals of central activity, mainly (vocal frenzy, absence of body tonus, increased ventilation, ataxia, and equilibrium loss), and convulsions and death at 10 mg/kg. The bufadienolide presented effective in vitro cytotoxic action on human lines of colorectal carcinomas in a similar way to ouabain and tumor reduction in marinobufagin-treated SCID-bearing HCT-116 heterotopic xenografts. Animals under subacute nonlethal doses exhibited a decrease in creatinine clearance with normal levels of blood urea, probably as a result of a marinobufagin-induced renal perfusion fall. Nevertheless, only minor morphological side effects were identified in kidneys, livers, hearts and lungs. CONCLUSIONS: Marinobufagin has in vitro and in vivo anticancer action on colorectal carcinoma and mild and reversible alterations in key metabolic organs without direct chemotherapy-induced gastrointestinal effects at subacute exposure, but it causes acute ataxia, equilibrium loss, convulsions and death at higher acute exposure.

Consensus for the Early Identification of Secondary Progressive Multiple Sclerosis in Portugal: a Delphi Panel.

INTRODUCTION: Multiple sclerosis is a disease with a heterogeneous evolution. The early identification of secondary progressive multiple sclerosis is a clinical challenge, which would benefit from the definition of biomarkers and diagnostic tools applicable in the transition phase from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis. We aimed to reach a Portuguese national consensus on the monitoring of patients with multiple sclerosis and on the more relevant clinical variables for the early identification of its progression. MATERIAL AND METHODS: A Delphi panel which included eleven Portuguese Neurologists participated in two rounds of questions between July and August of 2021. In the first round, 39 questions which belonged to the functional, cognitive, imaging, biomarkers and additional evaluations were included. Questions for which no consensus was obtained in the first round (less than 80% of agreement), were appraised by the panel during the second round. RESULTS: The response rate was 100% in both rounds and consensus was reached for a total of 33 questions (84.6%). Consensus was reached for monitoring time, evaluation scales and clinical variables such as the degree of brain atrophy and mobility reduction, changes suggestive of secondary progressive multiple sclerosis. Additionally, digital devices were considered tools with potential to identify disease progression. Most questions for which no consensus was obtained referred to the cognitive assessment and the remaining referred to both functional and imaging domains. CONCLUSION: Consensus was obtained for the determination of the monitorization interval and for most of the clinical variables. Most questions that did not reach consensus were related with the confirmation of progression taking into account only one test/domain, reinforcing the multifactorial nature of multiple sclerosis.

Task-based functional MRI challenges in clinical neuroscience: Choice of the best head motion correction approach in multiple sclerosis.

Introduction: Functional MRI (fMRI) is commonly used for understanding brain organization and connectivity abnormalities in neurological conditions, and in particular in multiple sclerosis (MS). However, head motion degrades fMRI data quality and influences all image-derived metrics. Persistent controversies regarding the best correction strategy motivates a systematic comparison, including methods such as scrubbing and volume interpolation, to find optimal correction models, particularly in studies with clinical populations prone to characterize by high motion. Moreover, strategies for correction of motion effects gain more relevance in task-based designs, which are less explored compared to resting-state, have usually lower sample sizes, and may have a crucial role in describing the functioning of the brain and highlighting specific connectivity changes. Methods: We acquired fMRI data from 17 early MS patients and 14 matched healthy controls (HC) during performance of a visual task, characterized motion in both groups, and quantitatively compared the most used and easy to implement methods for correction of motion effects. We compared task-activation metrics obtained from: (i) models containing 6 or 24 motion parameters (MPs) as nuisance regressors; (ii) models containing nuisance regressors for 6 or 24 MPs and motion outliers (scrubbing) detected with Framewise Displacement or Derivative or root mean square VARiance over voxelS; and (iii) models with 6 or 24 MPs and motion outliers corrected through volume interpolation. To our knowledge, volume interpolation has not been systematically compared with scrubbing, nor investigated in task fMRI clinical studies in MS. Results: No differences in motion were found between groups, suggesting that recently diagnosed MS patients may not present problematic motion. In general, models with 6 MPs perform better than models with 24 MPs, suggesting the 6 MPs as the best trade-off between correction of motion effects and preservation of valuable information. Parsimonious models with 6 MPs and volume interpolation were the best combination for correcting motion in both groups, surpassing the scrubbing methods. A joint analysis regardless of the group further highlighted the value of volume interpolation. Discussion: Volume interpolation of motion outliers is an easy to implement technique, which may be an alternative to other methods and may improve the accuracy of fMRI analyses, crucially in clinical studies in MS and other neurological populations.

Late onset neuromyelitis optica spectrum disorders (LONMOSD) from a nationwide Portuguese study: Anti-AQP4 positive, anti-MOG positive and seronegative subgroups.

INTRODUCTION: Several neuroimmunological disorders have distinct phenotypes according to the age of onset, as in multiple sclerosis or myasthenia gravis. It is also described that late onset NMOSD (LONMOSD) has a different phenotype. OBJECTIVE: To describe the clinical/demographic characteristics of the LONMOSD and distinguish them from those with early onset (EONMOSD). METHODS: From a nationwide Portuguese NMOSD study we analyzed the clinical/demographic characteristics of the LONMOSD. RESULTS: From the 180 Portuguese patients 45 had disease onset after 50 years old, 80% were female. 23 had anti-AQP4 antibodies (51.1%), 13 anti-MOG antibodies (28.9%) and 9 were double seronegative (20.0%). The most common presenting phenotypes in LONMOSD were transverse myelitis (53.3%) and optic neuritis (26.7%), without difference from EONMOSD (p = 0.074). The mean EDSS for LONMOSD was 6.0 (SD=2.8), after a mean follow-up time of 4.58 (SD=4.47) years, which was significantly greater than the mean EDSS of EONMOSD (3.25, SD=1.80)(p = 0.022). Anti-AQP4 antibodies positive LONMOSD patients had increased disability compared to anti-MOG antibodies positive LONMOSD (p = 0.022). The survival analysis showed a reduced time to use a cane for LONMOSD, irrespective of serostatus (p<0.001). CONCLUSIONS: LONMOSD has increased disability and faster progression, despite no differences in the presenting clinical phenotype were seen in our cohort.

Posttranslational modifications of proteins are key features in the identification of CSF biomarkers of multiple sclerosis.

BACKGROUND: Multiple sclerosis is an inflammatory and degenerative disease of the central nervous system (CNS) characterized by demyelination and concomitant axonal loss. The lack of a single specific test, and the similarity to other inflammatory diseases of the central nervous system, makes it difficult to have a clear diagnosis of multiple sclerosis. Therefore, laboratory tests that allows a clear and definite diagnosis, as well as to predict the different clinical courses of the disease are of utmost importance. Herein, we compared the cerebrospinal fluid (CSF) proteome of patients with multiple sclerosis (in the relapse-remitting phase of the disease) and other diseases of the CNS (inflammatory and non-inflammatory) aiming at identifying reliable biomarkers of multiple sclerosis. METHODS: CSF samples from the discovery group were resolved by 2D-gel electrophoresis followed by identification of the protein spots by mass spectrometry. The results were analyzed using univariate (Student's t test) and multivariate (Hierarchical Cluster Analysis, Principal Component Analysis, Linear Discriminant Analysis) statistical and numerical techniques, to identify a set of protein spots that were differentially expressed in CSF samples from patients with multiple sclerosis when compared with other two groups. Validation of the results was performed in samples from a different set of patients using quantitative (e.g., ELISA) and semi-quantitative (e.g., Western Blot) experimental approaches. RESULTS: Analysis of the 2D-gels showed 13 protein spots that were differentially expressed in the three groups of patients: Alpha-1-antichymotrypsin, Prostaglandin-H2-isomerase, Retinol binding protein 4, Transthyretin (TTR), Apolipoprotein E, Gelsolin, Angiotensinogen, Agrin, Serum albumin, Myosin-15, Apolipoprotein B-100 and EF-hand calcium-binding domain-containing protein. ELISA experiments allowed validating part of the results obtained in the proteomics analysis and showed that some of the alterations in the CSF proteome are also mirrored in serum samples from multiple sclerosis patients. CSF of multiple sclerosis patients was characterized by TTR oligomerization, thus highlighting the importance of analyzing posttranslational modifications of the proteome in the identification of novel biomarkers of the disease. CONCLUSIONS: The model built based on the results obtained upon analysis of the 2D-gels and in the validation phase attained an accuracy of about 80% in distinguishing multiple sclerosis patients and the other two groups.

Optimizing EEG Source Reconstruction with Concurrent fMRI-Derived Spatial Priors.

Reconstructing EEG sources involves a complex pipeline, with the inverse problem being the most challenging. Multiple inversion algorithms are being continuously developed, aiming to tackle the non-uniqueness of this problem, which has been shown to be partially circumvented by including prior information in the inverse models. Despite a few efforts, there are still current and persistent controversies regarding the inversion algorithm of choice and the optimal set of spatial priors to be included in the inversion models. The use of simultaneous EEG-fMRI data is one approach to tackle this problem. The spatial resolution of fMRI makes fMRI derived spatial priors very convenient for EEG reconstruction, however, only task activation maps and resting-state networks (RSNs) have been explored so far, overlooking the recent, but already accepted, notion that brain networks exhibit dynamic functional connectivity fluctuations. The lack of a systematic comparison between different source reconstruction algorithms, considering potentially more brain-informative priors such as fMRI, motivates the search for better reconstruction models. Using simultaneous EEG-fMRI data, here we compared four different inversion algorithms (minimum norm, MN; low resolution electromagnetic tomography, LORETA; empirical Bayes beamformer, EBB; and multiple sparse priors, MSP) under a Bayesian framework (as implemented in SPM), each with three different sets of priors consisting of: (1) those specific to the algorithm; (2) those specific to the algorithm plus fMRI task activation maps and RSNs; and (3) those specific to the algorithm plus fMRI task activation maps and RSNs and network modules of task-related dFC states estimated from the dFC fluctuations. The quality of the reconstructed EEG sources was quantified in terms of model-based metrics, namely the expectation of the posterior probability P(model|data) and variance explained of the inversion models, and the overlap/proportion of brain regions known to be involved in the visual perception tasks that the participants were submitted to, and RSN templates, with/within EEG source components. Model-based metrics suggested that model parsimony is preferred, with the combination MSP and priors specific to this algorithm exhibiting the best performance. However, optimal overlap/proportion values were found using EBB and priors specific to this algorithm and fMRI task activation maps and RSNs or MSP and considering all the priors (algorithm priors, fMRI task activation maps and RSNs and dFC state modules), respectively, indicating that fMRI spatial priors, including dFC state modules, might contain useful information to recover EEG source components reflecting neuronal activity of interest. Our main results show that providing fMRI spatial derived priors that reflect the dynamics of the brain might be useful to map neuronal activity more accurately from EEG-fMRI. Furthermore, this work paves the way towards a more informative selection of the optimal EEG source reconstruction approach, which may be critical in future studies.

Smouldering multiple sclerosis: the 'real MS'.

Using a philosophical approach or deductive reasoning, we challenge the dominant clinico-radiological worldview that defines multiple sclerosis (MS) as a focal inflammatory disease of the central nervous system (CNS). We provide a range of evidence to argue that the 'real MS' is in fact driven primarily by a smouldering pathological disease process. In natural history studies and clinical trials, relapses and focal activity revealed by magnetic resonance imaging (MRI) in MS patients on placebo or on disease-modifying therapies (DMTs) were found to be poor predictors of long-term disease evolution and were dissociated from disability outcomes. In addition, the progressive accumulation of disability in MS can occur independently of relapse activity from early in the disease course. This scenario is underpinned by a more diffuse smouldering pathological process that may affect the entire CNS. Many putative pathological drivers of smouldering MS can be potentially modified by specific therapeutic strategies, an approach that may have major implications for the management of MS patients. We hypothesise that therapeutically targeting a state of 'no evident inflammatory disease activity' (NEIDA) cannot sufficiently prevent disability accumulation in MS, meaning that treatment should also focus on other brain and spinal cord pathological processes contributing to the slow loss of neurological function. This should also be complemented with a holistic approach to the management of other systemic disease processes that have been shown to worsen MS outcomes.

Spatial analysis of AIDS in the state of Maranhão: an ecological study 2011-2018 / Análisis espacial del sida en el estado de Maranhão: un estudio ecológico 2011-2018 / Análise espacial da aids no estado do Maranhão: um estudo ecológico 2011-2018

ABSTRACT Objective: Analyze the spatio-temporal distribution of AIDS cases in Maranhão. Methods: Ecological study of AIDS cases in the Notifiable Diseases Information System, 2011-2018. Gross and adjusted incidences were calculated using the Baysean method; then, the Moran Global and Local Indices to observe the existence of spatial autocorrelation of the cases and for the delimitation of high and low risk clusters. Results: 6,349 cases were reported, which were distributed heterogeneously. There was an advance of cases to new areas and persistence in old areas, such as in the capital São Luís and its surroundings. The dissemination did not occur at random, with positive spatial autocorrelation, with evidence of the formation of clusters in the municipalities of São Luís, São José de Ribamar and Paço do Lumiar. Conclusion: High-risk areas have been identified and should be considered a priority for investment in health, management, and organization of health services.

RESUMEN Objetivo: Analizar la distribución espacio-temporal de los casos de SIDA en Maranhão. Métodos: Estudio ecológico de casos de SIDA en el Sistema de Información de Enfermedades de Notificación, 2011-2018. Las incidencias brutas y ajustadas se calcularon utilizando el método de Baysean; luego, los Índices de Moran Global y Local para observar la existencia de autocorrelación espacial de los casos y para la delimitación de aglomerados de Alto y Bajo Riesgo. Resultados: se notificaron 6.349 casos, los cuales se distribuyeron de forma heterogénea. Hubo un avance de casos a nuevas áreas y persistencia en áreas antiguas, como en la capital São Luís y sus alrededores. La diseminación no ocurrió al azar, con autocorrelación espacial positiva, con evidencia de la formación de aglomerados en los municipios de São Luís, São José de Ribamar y Paço do Lumiar. Conclusión: Se han identificado áreas de alto riesgo y deben considerarse una prioridad para la inversión en salud, gestión y organización de los servicios de salud.

RESUMO Objetivo: Analisar a distribuição espaço-temporal dos casos de aids no Maranhão. Métodos: Estudo ecológico dos casos de aids no Sistema de Informação de Agravos de Notificação, 2011-2018. Calcularam-se as incidências bruta e ajustada pelo método bayseano; em seguida, os Índices de Moran Global e Local para observar a existência de autocorrelação espacial dos casos e para delimitação de aglomerados de Alto e Baixo Risco. Resultados: Foram notificados 6.349 casos, que se distribuíram de forma heterogênea. Houve o avanço de casos para novas áreas e persistência nas áreas antigas, como na capital São Luís e seu entorno. A disseminação não ocorreu de forma aleatória, existindo autocorrelação espacial positiva, com evidência da formação de aglomerados nos municípios de São Luís, São José de Ribamar e Paço do Lumiar. Conclusão: Foram identificadas áreas de alto risco, devendo ser consideradas prioridade para o investimento em saúde, gestão e organização dos serviços de saúde.

Variáveis sociodemográficas e sexuais associadas ao conhecimento sobre transmissão do vírus da imunodeficiência humana / Sociodemographic and sexual variables associated with knowledge about human immunodeficiency virus transmission

RESUMO Objetivo analisar a associação entre variáveis sociodemográficas e sexuais de mulheres em contexto de vulnerabilidade e seu conhecimento sobre as formas de transmissão do HIV. Métodos estudo transversal, analítico e exploratório ocorrido em Unidade de Atenção Primária à Saúde, com 221 mulheres. A coleta ocorreu com instrumentos contendo dados sociodemográficos, gineco-obstétricos, sexuais e mensuração do conhecimento acerca do HIV. Resultados o conhecimento sobre as formas de transmissão do HIV foi associado a faixa etária e escolaridade das entrevistadas. Conclusão a elevada prevalência de conhecimento inadequado quanto ao HIV foi explicada pela faixa etária mais jovem das mulheres, enquanto a redução deste desfecho foi verificada naquelas com maior escolaridade. Contribuições para a prática: os dados apresentados podem subsidiar novas abordagens e práticas assistenciais no campo da saúde sexual e reprodutiva a partir da análise proposta, objetivando a sensibilização quanto à realização de testagens, tratamento oportuno e quebra da cadeia de transmissão.

ABSTRACT Objective to analyze the association between sociodemographic and sexual variables of women in a context of vulnerability and their knowledge about the ways of HIV transmission. Methods cross-sectional, analytical, and exploratory study conducted in a Primary Health Care Unit, with 221 women. The collection occurred with instruments containing sociodemographic, gynecological, and obstetric, sexual data and measurement of knowledge about HIV. Results knowledge about the ways of HIV transmission was associated with age and education of the interviewees. Conclusion the high prevalence of inadequate knowledge about HIV was explained by the younger age group of women, while the reduction of this outcome was seen in those with higher education. Contributions to practice: the data presented can subsidize new approaches and care practices in the field of sexual and reproductive health from the proposed analysis, aiming to raise awareness about testing, timely treatment and breaking the chain of transmission.

Neuromyelitis optica spectrum disorders: A nationwide Portuguese clinical epidemiological study.

INTRODUCTION: Neuromyelitis optica spectrum disorder (NMOSD) is a rare disorder in which astrocyte damage and/or demyelination often cause severe neurological deficits. OBJECTIVE: To identify Portuguese patients with NMOSD and assess their epidemiological/clinical characteristics. METHODS: This was a nationwide multicenter study. Twenty-four Portuguese adult and 3 neuropediatric centers following NMOSD patients were included. RESULTS: A total of 180 patients met the 2015 Wingerchuk NMOSD criteria, 77 were AQP4-antibody positive (Abs+), 67 MOG-Abs+, and 36 seronegative. Point prevalence on December 31, 2018 was 1.71/100,000 for NMOSD, 0.71/100,000 for AQP4-Abs+, 0.65/100,000 for MOG-Abs+, and 0.35/100,000 for seronegative NMOSD. A total of 44 new NMOSD cases were identified during the two-year study period (11 AQP4-Abs+, 27 MOG-Abs+, and 6 seronegative). The annual incidence rate in that period was 0.21/100,000 person-years for NMOSD, 0.05/100,000 for AQP4-Abs+, 0.13/100,000 for MOG-Abs+, and 0.03/100,000 for seronegative NMOSD. AQP4-Abs+ predominated in females and was associated with autoimmune disorders. Frequently presented with myelitis. Area postrema syndrome was exclusive of this subtype, and associated with higher morbidity/mortality than other forms of NMOSD. MOG-Ab+ more often presented with optic neuritis, required less immunosuppression, and had better outcome. CONCLUSION: Epidemiological/clinical NMOSD profiles in the Portuguese population are similar to other European countries.

Spatial analysis of AIDS in the state of Maranhão: an ecological study 2011-2018.

OBJECTIVE: Analyze the spatio-temporal distribution of AIDS cases in Maranhão. METHODS: Ecological study of AIDS cases in the Notifiable Diseases Information System, 2011-2018. Gross and adjusted incidences were calculated using the Baysean method; then, the Moran Global and Local Indices to observe the existence of spatial autocorrelation of the cases and for the delimitation of high and low risk clusters. RESULTS: 6,349 cases were reported, which were distributed heterogeneously. There was an advance of cases to new areas and persistence in old areas, such as in the capital São Luís and its surroundings. The dissemination did not occur at random, with positive spatial autocorrelation, with evidence of the formation of clusters in the municipalities of São Luís, São José de Ribamar and Paço do Lumiar. CONCLUSION: High-risk areas have been identified and should be considered a priority for investment in health, management, and organization of health services.

Defining the prodromal phase of multiple sclerosis based on healthcare access in a Portuguese population - ProdMS study.

BACKGROUND: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system. Prodromal symptoms and higher healthcare use have been suggested in patients who later develop MS. OBJECTIVES: Assess the healthcare utilization pattern of relapsing-remitting MS (RRMS) patients in the five years prior to MS diagnosis. METHODS: Retrospective, multicentric study. Demographic and clinical data, drug prescriptions and diagnostic tests were collected from electronic health records five-years previous to MS diagnosis and compared with national data. RESULTS: Included 168 patients, 112 (66.7%) female, median age 34±11 years. The mean number of healthcare use per patient per year was 3.14±2,69, most of them in primary healthcare (47%). Most frequent symptoms were musculoskeletal (22%), gastrointestinal (17%), sensitive (14%) and sensory organs (14%). Median number of diagnostic tests per patient was 6 (IQR 7), and drug prescriptions per patient was 6 (IQR 9). Most frequently prescribed drugs were analgesic/anti-inflammatories, antibiotics and anxiolytics and there was a high request rate of MRIs. CONCLUSION: RRMS patients had a high frequency of healthcare utilization when compared to national data. This supports the current evidence showing a prodromal phase in MS.

Outcomes on Social and Classic Cognition in adults with Pediatric-onset Multiple Sclerosis.

BACKGROUND: Cognitive impairment affecting classic and social domains has been consistently reported in patients with Multiple Sclerosis (MS). However, little is known about the cognitive outcomes, particularly on social cognition, in adults with pediatric-onset multiple sclerosis (POMS). OBJECTIVES: To compare the performance in classic and social cognitive domains between adults with POMS and adult-onset MS (AOMS). METHODS: A group of 30 patients with POMS (age onset <18 years) was compared with age-matched (AOAMS, n=30) and disease duration-matched (AODMS, n= 30) patients who developed MS after the age of 18 years. Cognitive performance was assessed using the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) and Theory of Mind (ToM) tests. RESULTS: Cognitive impairment was more prevalent in POMS patients (40% vs. 16.7%, p=0.045), independently of age or disease duration, affecting more severely information-processing speed and visual memory domains. No statistically significant differences were found in ToM performance between patients with POMS and AOMS. When analyzing ToM performance according to age of disease onset (≤15 years; 15-20 years; ≥20 years), patients with disease onset ≤15 years old had significantly lower scores on ToM tests when compared to the other groups. CONCLUSION: Patients with POMS were more prone to develop impairment on classic cognitive domains than on ToM ability, when compared with AOMS patients. The interference of POMS with critical neurodevelopmental periods, specific for each cognitive domain, may explain different outcomes at adulthood on social and classic cognition.

Multiple Sclerosis Patient Management During the COVID-19 Pandemic: Practical Recommendations From the Portuguese Multiple Sclerosis Study Group (GEEM).

The spread of the COVID-19 pandemic has imposed significant challenges on healthcare provision, requiring changes in the conventional patient management, particularly in chronic diseases like multiple sclerosis (MS). To increase patient safety and reduce the risk of infection, while ensuring an appropriate and regular follow-up, tele-medicine gained prominence as a valid alternative to face-to-face appointments. However, the urgency of the implementation and the lack of experience in most MS centers led to "ad hoc" and extremely diverse approaches, which now merit to be standardized and refined. Indeed, while tele-consultation cannot fully replace face-to-face visits, it certainly can, and will, be incorporated as part of the routine care of MS patients in the near future. Bearing this in mind, the Portuguese Multiple Sclerosis Study Group (GEEM) has developed a set of recommendations for the usage of tele-medicine in the management of MS patients, both during the pandemic and in the future. The consensus was obtained through a two-step modified Delphi methodology, resulting in 15 recommendations, which are detailed in the manuscript.

TyPed study: Natalizumab for the treatment of pediatric-onset multiple sclerosis in Portugal.

BACKGROUND: A significant proportion of pediatric-onset multiple sclerosis (POMS) patients do not respond to first-line disease-modifying therapies. Clinical trials showed that natalizumab is effective and safe in adults, but there are limited clinical trial data for children. Natalizumab is currently prescribed off-label for POMS. We aimed to characterize the effectiveness, safety and tolerability of natalizumab in all POMS cases treated in Portugal (from 2007 to 2018). METHODS: Data from clinical records were retrospectively collected for all POMS cases treated with natalizumab in Portugal. RESULTS: Twenty-one patients were included, 14 (67%) of which were female. The median age at POMS diagnosis was 13 years old. The median duration of treatment with natalizumab was 2 years and 3 months. Median Expanded Disability Status Scale score decreased from 1.5 to 1.0 after 24 months. The Annualized Relapse Rate decreased from 1.31 events/patient/year before treatment with natalizumab to 0 after 12 months of treatment and to 0.04 after 24 months. No gadolinium-enhancing lesions or new or enlarged T2 hyperintense lesions were observed in 8/8 patients (100%) after 12 months, and 4/5 (80%) after 24 months. There was one possible serious adverse event, which did not require dose adjustment. Five patients discontinued treatment due to positive anti-JCV (JC virus) antibody JC serostatus. CONCLUSION: Natalizumab may be an effective and safe disease-modifying therapy for POMS. Our results are in line with data published for the adult population, as well as with similar observational studies in pediatric populations in other regions.

RISCOP-Cognitive profile in a Portuguese cohort of radiological isolated syndrome patients: A case-control study.

INTRODUCTION: Radiologically isolated syndrome (RIS) refers to the incidental discovery of white matter lesions suggestive of MS, on brain MRI, in asymptomatic patients. Recent studies suggest similar features of cognitive impairment between RIS and MS patients. Also, lower levels of health-related quality of life (QOL) and fatigue are reported in such patients. AIMS: characterize and compare the cognitive profile of a multicentric Portuguese cohort of RIS patients with a control group. METHODS: multicentric comparative study of a cohort of adult patients with RIS, and age and gender-matched controls followed in the headache outpatient clinic with prior MRI not fulfilling criteria for RIS diagnosis. We conducted interviews with participants, collected clinical data and applied the BICAMS battery and self-reported questionnaires (HADS, MFIS, MSQOL-54). RESULTS: we evaluated 31 patients with RIS (median age 46 years, IQR [(Dusankova et al., 2012-52], 72% women) and 19 control individuals (median age 32 years, IQR [(O'Jile et al., 2005-48], 71% women). Prevalence of cognitive impairment did not differ between groups (16% of the RIS and 10% of the controls, p=0.579). We found no differences between groups on the BICAMS tests, although the results of the California Verbal Learning Test (CVLT-II) score presented a trend to significance, with a lower value on the RIS group (53.9 vs. 59.3, p=0.066). There were no significant differences regarding fatigue, QOL, anxiety/depression scores. CONCLUSION: this is the first study on a Portuguese cohort of RIS patients assessing cognitive profile with BICAMS. A non-neglectable part of our cohort presented cognitive impairment. Our findings add to previous studies in suggesting that a more pronounced impairment of verbal memory and learning, evaluated by CVLT-II, may be present in RIS patients compared to controls. BICAMS should be assessed on future studies with larger cohorts.

Protective effects of cognitive and brain reserve in multiple sclerosis: Differential roles on social cognition and 'classic cognition'.

BACKGROUND: According to cognitive reserve (CR) and brain reserve (BR) theories, lifetime intellectual enrichment and maximal brain volume protect against cognitive decline. OBJECTIVE: To examine the effects of CR and BR on social cognition in multiple sclerosis (MS), and compare it with 'classic cognition'. METHODS: We included 60 MS patients and 60 healthy controls matched on age, sex, and education. Education was used has a proxy of CR and intracranial volume (ICV) as a proxy of BR. Participants underwent Theory of Mind (ToM) testing (Eyes Test, Videos Test), comprehensive neuropsychological assessment and 3Tesla brain MRI. Cortical and subcortical grey matter (GM) volumes were calculated. RESULTS: We found positive effects of education and ICV on general cognitive status and ToM performance, respectively. Higher education moderated the impact of subcortical GM atrophy on 'classic' cognitive status (R2=0.219, p=<0.001). Conversely, greater ICV attenuated the impact of cortical GM atrophy on Eyes Test (R2=0.158, p=0.002) and Videos Test (R2=0.198, p=0.001). Stratification for disease duration showed that the protective effect of education/ICV occurred in early stages of disease (<10 years). CONCLUSION: CR and BR have differential protective roles in MS, with BR having a positive effect on social cognition and CR on 'classic' cognitive domains.