The first global landscape analysis of multiple sclerosis research funding.

INTRODUCTION: Multiple sclerosis (MS) is an immune-mediated central nervous system disorder and a growing global health challenge affecting nearly 3 million people worldwide. Incidence and prevalence continue to increase with no known cause or cure. Globally governments and non-profit organizations fund research toward better understanding of and treatments for multiple sclerosis. METHODS: This study identified MS research projects funded between 2021 and 2023 by government and non-profit organization sources. Projects were described by type of scientific approach, Pathways to Cure research category (i.e. Stop, Restore, End), and other key characteristics. RESULTS: Over 2,300 MS research projects were identified through 16 non-profit MS organizations and 18 government databases. The overall global portfolio of these projects is valued at nearly one and a half billion Euros. The majority of projects were classified in the Stop category (60%). Research collaboration occurs in many forms among the research community; around 272 projects were reported to be co-funded. CONCLUSION: Global MS research collaboration will accelerate progress toward increased knowledge, effective treatments, improved health outcomes, and ultimately cures for MS. This landscape analysis highlights the current distribution of MS research investment between topics and begins to suggest where the MS community should focus to increase potential impact for current and future endeavors.

The global patient-reported outcomes for multiple sclerosis initiative: bridging the gap between clinical research and care - updates at the 2023 plenary event.

Significant advancements have been achieved in delineating the progress of the Global PROMS (PROMS) Initiative. The PROMS Initiative, a collaborative endeavor by the European Charcot Foundation and the Multiple Sclerosis International Federation, strives to amplify the influence of patient input on MS care and establish a cohesive perspective on Patient-Reported Outcomes (PROs) for diverse stakeholders. This initiative has established an expansive, participatory governance framework launching four dedicated working groups that have made substantive contributions to research, clinical management, eHealth, and healthcare system reform. The initiative prioritizes the global integration of patient (For the purposes of the Global PROMS Initiative, the term "patient" refers to the people with the disease (aka People with Multiple Sclerosis - pwMS): any individual with lived experience of the disease. People affected by the disease/Multiple Sclerosis: any individual or group that is affected by the disease: E.g., family members, caregivers will be also engaged as the other stakeholders in the initiative). insights into the management of MS care. It merges subjective PROs with objective clinical metrics, thereby addressing the complex variability of disease presentation and progression. Following the completion of its second phase, the initiative aims to help increasing the uptake of eHealth tools and passive PROs within research and clinical settings, affirming its unwavering dedication to the progressive refinement of MS care. Looking forward, the initiative is poised to continue enhancing global surveys, rethinking to the relevant statistical approaches in clinical trials, and cultivating a unified stance among 'industry', regulatory bodies and health policy making regarding the application of PROs in MS healthcare strategies.

National plans and awareness campaigns as priorities for achieving global brain health.

Neurological conditions are the leading cause of death and disability combined. This public health crisis has become a global priority with the introduction of WHO's Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders 2022-2031 (IGAP). 18 months after this plan was adopted, global neurology stakeholders, including representatives of the OneNeurology Partnership (a consortium uniting global neurology organisations), take stock and advocate for urgent acceleration of IGAP implementation. Drawing on lessons from relevant global health contexts, this Health Policy identifies two priority IGAP targets to expedite national delivery of the entire 10-year plan: namely, to update national policies and plans, and to create awareness campaigns and advocacy programmes for neurological conditions and brain health. To ensure rapid attainment of the identified priority targets, six strategic drivers are proposed: universal community awareness, integrated neurology approaches, intersectoral governance, regionally coordinated IGAP domestication, lived experience-informed policy making, and neurological mainstreaming (advocating to embed brain health into broader policy agendas). Contextualised with globally emerging IGAP-directed efforts and key considerations for intersectoral policy design, this novel framework provides actionable recommendations for policy makers and IGAP implementation partners. Timely, synergistic pursuit of the six drivers might aid WHO member states in cultivating public awareness and policy structures required for successful intersectoral roll-out of IGAP by 2031, paving the way towards brain health for all.

Introducing a core dataset for real-world data in multiple sclerosis registries and cohorts: Recommendations from a global task force.

BACKGROUND: As of September 2022, there was no globally recommended set of core data elements for use in multiple sclerosis (MS) healthcare and research. As a result, data harmonisation across observational data sources and scientific collaboration is limited. OBJECTIVES: To define and agree upon a core dataset for real-world data (RWD) in MS from observational registries and cohorts. METHODS: A three-phase process approach was conducted combining a landscaping exercise with dedicated discussions within a global multi-stakeholder task force consisting of 20 experts in the field of MS and its RWD to define the Core Dataset. RESULTS: A core dataset for MS consisting of 44 variables in eight categories was translated into a data dictionary that has been published and disseminated for emerging and existing registries and cohorts to use. Categories include variables on demographics and comorbidities (patient-specific data), disease history, disease status, relapses, magnetic resonance imaging (MRI) and treatment data (disease-specific data). CONCLUSION: The MS Data Alliance Core Dataset guides emerging registries in their dataset definitions and speeds up and supports harmonisation across registries and initiatives. The straight-forward, time-efficient process using a dedicated global multi-stakeholder task force has proven to be effective to define a concise core dataset.

Barriers to accessing multiple sclerosis disease-modifying therapies in the Middle East and North Africa region: A regional survey-based study.

BACKGROUND: Multiple sclerosis (MS) management varies markedly between different countries of the Middle East and North Africa (MENA) region based on the availability and accessibility of disease-modifying therapies (DMTs). OBJECTIVE: To evaluate the accessibility to DMTs in each MENA country, identify barriers to treatment and make recommendations for improved access to DMTs across the region. METHODS: This is a descriptive, survey-based study whereby we extracted data collected, between October 2019 and April 2020, for countries in the MENA region by the Multiple Sclerosis International Federation (MSIF) through their Atlas of MS survey. RESULTS: 16 out of 19 countries in the MENA region were included in this study. Sudan and Syria did not have any originator DMTs approved. Interferons were the most widely low-efficacy originator approved DMTs. Three countries did not have any high efficacy DMTs approved. Moreover, follow-on DMTs were approved in half (50%) of the countries. Cost of treatment was the most important barrier, reported in nearly half (47%) of the MENA countries. CONCLUSION: Although most MENA countries have access to DMTs, more than half of countries report problems with treatment continuation, highlighting the need for a targeted regional strategy to address the variations in access to MS treatments.

Global Barriers to the Diagnosis of Multiple Sclerosis: Data From the Multiple Sclerosis International Federation Atlas of MS, Third Edition.

BACKGROUND AND OBJECTIVES: Recent data suggest increasing global prevalence of multiple sclerosis (MS). Early diagnosis of MS reduces the burden of disability-adjusted life years and associated health care costs. Yet diagnostic delays persist in MS care and even within national health care systems with robust resources, comprehensive registries, and MS subspecialist referral networks. The global prevalence and characteristics of barriers to expedited MS diagnosis, particularly in resource-restricted regions, have not been extensively studied. Recent revisions to MS diagnostic criteria demonstrate potential to facilitate earlier diagnosis, but global implementation remains largely unknown. METHODS: The Multiple Sclerosis International Federation third edition of the Atlas of MS was a survey that assessed the current global state of diagnosis including adoption of MS diagnostic criteria; barriers to diagnosis with respect to the patient, health care provider, and health system; and existence of national guidelines or national standards for speed of MS diagnosis. RESULTS: Coordinators from 107 countries (representing approximately 82% of the world population), participated. Eighty-three percent reported at least 1 "major barrier" to early MS diagnosis. The most frequently reported barriers included the following: "lack of awareness of MS symptoms among general public" (68%), "lack of awareness of MS symptoms among health care professionals" (59%), and "lack of availability of health care professionals with knowledge to diagnose MS" (44%). One-third reported lack of "specialist medical equipment or diagnostic tests." Thirty-four percent reported the use of only 2017 McDonald criteria (McD-C) for diagnosis, and 79% reported 2017 McD-C as the "most commonly used criteria." Sixty-six percent reported at least 1 barrier to the adoption of 2017 McD-C, including "neurologists lack awareness or training" by 45%. There was no significant association between national guidelines pertaining to MS diagnosis or practice standards addressing the speed of diagnosis and presence of barriers to early MS diagnosis and implementation of 2017 McD-C. DISCUSSION: This study finds pervasive consistent global barriers to early diagnosis of MS. While these barriers reflected a lack of resources in many countries, data also suggest that interventions designed to develop and implement accessible education and training can provide cost-effective opportunities to improve access to early MS diagnosis.

Global synergistic actions to improve brain health for human development.

The global burden of neurological disorders is substantial and increasing, especially in low-resource settings. The current increased global interest in brain health and its impact on population wellbeing and economic growth, highlighted in the World Health Organization's new Intersectoral Global Action Plan on Epilepsy and other Neurological Disorders 2022-2031, presents an opportunity to rethink the delivery of neurological services. In this Perspective, we highlight the global burden of neurological disorders and propose pragmatic solutions to enhance neurological health, with an emphasis on building global synergies and fostering a 'neurological revolution' across four key pillars - surveillance, prevention, acute care and rehabilitation - termed the neurological quadrangle. Innovative strategies for achieving this transformation include the recognition and promotion of holistic, spiritual and planetary health. These strategies can be deployed through co-design and co-implementation to create equitable and inclusive access to services for the promotion, protection and recovery of neurological health in all human populations across the life course.

Updated Results of the COVID-19 in MS Global Data Sharing Initiative: Anti-CD20 and Other Risk Factors Associated With COVID-19 Severity.

BACKGROUND AND OBJECTIVES: Certain demographic and clinical characteristics, including the use of some disease-modifying therapies (DMTs), are associated with severe acute respiratory syndrome coronavirus 2 infection severity in people with multiple sclerosis (MS). Comprehensive exploration of these relationships in large international samples is needed. METHODS: Clinician-reported demographic/clinical data from 27 countries were aggregated into a data set of 5,648 patients with suspected/confirmed coronavirus disease 2019 (COVID-19). COVID-19 severity outcomes (hospitalization, admission to intensive care unit [ICU], requiring artificial ventilation, and death) were assessed using multilevel mixed-effects ordered probit and logistic regression, adjusted for age, sex, disability, and MS phenotype. DMTs were individually compared with glatiramer acetate, and anti-CD20 DMTs with pooled other DMTs and with natalizumab. RESULTS: Of 5,648 patients, 922 (16.6%) with suspected and 4,646 (83.4%) with confirmed COVID-19 were included. Male sex, older age, progressive MS, and higher disability were associated with more severe COVID-19. Compared with glatiramer acetate, ocrelizumab and rituximab were associated with higher probabilities of hospitalization (4% [95% CI 1-7] and 7% [95% CI 4-11]), ICU/artificial ventilation (2% [95% CI 0-4] and 4% [95% CI 2-6]), and death (1% [95% CI 0-2] and 2% [95% CI 1-4]) (predicted marginal effects). Untreated patients had 5% (95% CI 2-8), 3% (95% CI 1-5), and 1% (95% CI 0-3) higher probabilities of the 3 respective levels of COVID-19 severity than glatiramer acetate. Compared with pooled other DMTs and with natalizumab, the associations of ocrelizumab and rituximab with COVID-19 severity were also more pronounced. All associations persisted/enhanced on restriction to confirmed COVID-19. DISCUSSION: Analyzing the largest international real-world data set of people with MS with suspected/confirmed COVID-19 confirms that the use of anti-CD20 medication (both ocrelizumab and rituximab), as well as male sex, older age, progressive MS, and higher disability are associated with more severe course of COVID-19.

Severity of COVID19 infection among patients with multiple sclerosis treated with interferon-ß.

BACKGROUND: Interferon-ß, a disease-modifying therapy (DMT) for MS, may be associated with less severe COVID-19 in people with MS. RESULTS: Among 5,568 patients (83.4% confirmed COVID-19), interferon-treated patients had lower risk of severe COVID-19 compared to untreated, but not to glatiramer-acetate, dimethyl-fumarate, or pooled other DMTs. CONCLUSIONS: In comparison to other DMTs, we did not find evidence of protective effects of interferon-ß on the severity of COVID-19, though compared to the untreated, the course of COVID19 was milder among those on interferon-ß. This study does not support the use of interferon-ß as a treatment to reduce COVID-19 severity in MS.

From the prodromal stage of multiple sclerosis to disease prevention.

A prodrome is an early set of signs or symptoms that indicate the onset of a disease before more typical symptoms develop. Prodromal stages are well recognized in some neurological and immune-mediated diseases such as Parkinson disease, schizophrenia, type 1 diabetes mellitus and rheumatoid arthritis. Emerging evidence indicates that a prodromal stage exists in multiple sclerosis (MS), raising the possibility of intervention at this stage to delay or prevent the development of classical MS. However, much remains unclear about the prodromal stage of MS and considerable research is needed to fully characterize the prodrome and develop standardized criteria to reliably identify individuals with prodromal MS who are at high risk of progressing to a diagnosis of MS. In this Roadmap, we draw on work in other diseases to propose a disease framework for MS that incorporates the prodromal stage, and set out key steps and considerations needed in future research to fully characterize the MS prodrome, identify early disease markers and develop standardized criteria that will enable reliable identification of individuals with prodromal MS, thereby facilitating trials of interventions to slow or stop progression beyond the prodrome.

The agenda of the global patient reported outcomes for multiple sclerosis (PROMS) initiative: Progresses and open questions.

On 12 September 2019, the global Patient Reported Outcome for Multiple Sclerosis (PROMS) Initiative was launched at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The multi-stakeholder PROMS Initiative is jointly led by the European Charcot Foundation (ECF) and the Multiple Sclerosis International Federation (MSIF), with the Italian Multiple Sclerosis Society (AISM) acting as the lead agency for and on behalf of the global MSIF movement. The initiative has the ambitious mission to (i) maximize the impact of science with and of patient input on the life of people affected by MS, and (ii) to represent a unified view on Patient-Reported Outcomes for MS to people affected by MS, healthcare providers, regulatory agencies and Health Technologies Assessments agencies. Equipped with an innovative participatory governance of an international and interdisciplinary network of different stakeholders, PROMS has the potential to guide future breakthroughs in MS patient-focused research and care. In this paper we present the progresses of the global PROMS Initiative and discuss the open questions that we aim to address.

Charting a global research strategy for progressive MS-An international progressive MS Alliance proposal.

BACKGROUND: Progressive forms of multiple sclerosis (MS) affect more than 1 million individuals globally. Recent approvals of ocrelizumab for primary progressive MS and siponimod for active secondary progressive MS have opened the therapeutic door, though results from early trials of neuroprotective agents have been mixed. The recent introduction of the term 'active' secondary progressive MS into the therapeutic lexicon has introduced potential confusion to disease description and thereby clinical management. OBJECTIVE: This paper reviews recent progress, highlights continued knowledge and proposes, on behalf of the International Progressive MS Alliance, a global research strategy for progressive MS. METHODS: Literature searches of PubMed between 2015 and May, 2021 were conducted using the search terms "progressive multiple sclerosis", "primary progressive multiple sclerosis", "secondary progressive MS". Proposed strategies were developed through a series of in-person and virtual meetings of the International Progressive MS Alliance Scientific Steering Committee. RESULTS: Sustaining and accelerating progress will require greater understanding of underlying mechanisms, identification of potential therapeutic targets, biomarker discovery and validation, and conduct of clinical trials with improved trial design. Encouraging developments in symptomatic and rehabilitative interventions are starting to address ongoing challenges experienced by people with progressive MS. CONCLUSION: We need to manage these challenges and realise the opportunities in the context of a global research strategy, which will improve quality of life for people with progressive MS.

Ethical use of off-label disease-modifying therapies for multiple sclerosis.

BACKGROUND: Off-label disease-modifying therapies (DMTs) for multiple sclerosis (MS) are used in at least 89 countries. There is a need for structured and transparent evidence-based guidelines to support clinical decision-making, pharmaceutical policies and reimbursement decisions for off-label DMTs. OBJECTIVES/RESULTS: The authors put forward general principles for the ethical use of off-label DMTs for treating MS and a process to assess existing evidence and develop recommendations for their use. CONCLUSION: The principles and process are endorsed by the World Federation of Neurology (WFN), American Academy of Neurology (AAN), European Academy of Neurology (EAN), Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Middle-East North Africa Committee for Treatment and Research in Multiple Sclerosis (MENACTRIMS) and Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (PACTRIMS), and we have regularly consulted with the Brain Health Unit, Mental Health and Substance Use Department at the World Health Organization (WHO).

Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition.

BACKGROUND: High-quality epidemiologic data worldwide are needed to improve our understanding of disease risk, support health policy to meet the diverse needs of people with multiple sclerosis (MS) and support advocacy efforts. OBJECTIVES: The Atlas of MS is an open-source global compendium of data regarding the epidemiology of MS and the availability of resources for people with MS reported at country, regional and global levels. METHODS: Country representatives reported epidemiologic data and their sources via survey between September 2019 and March 2020, covering prevalence and incidence in males, females and children, and age and MS type at diagnosis. Regional analyses and comparisons with 2013 data were conducted. RESULTS: A total of 2.8 million people are estimated to live with MS worldwide (35.9 per 100,000 population). MS prevalence has increased in every world region since 2013 but gaps in prevalence estimates persist. The pooled incidence rate across 75 reporting countries is 2.1 per 100,000 persons/year, and the mean age of diagnosis is 32 years. Females are twice as likely to live with MS as males. CONCLUSIONS: The global prevalence of MS has risen since 2013, but good surveillance data is not universal. Action is needed by multiple stakeholders to close knowledge gaps.

What do rooks (Corvus frugilegus) understand about physical contact?

Rooks (Corvus frugilegus) do not use tools, but rapidly solve tests of physical cognition. The authors tested whether rooks understand the concept of physical contact using a task comprising a clear horizontal tube containing a stick with a disk attached to it and a piece of food. The rooks chose which side to pull the stick from to make the food accessible. Two configurations were used, with either the food or disk central along the tube. All 8 rooks solved the food-central configuration, but failed the disk-central configuration. Although they did not demonstrate an understanding of contact, further tests established that they could learn to solve these tasks provided there were salient stick cues. This result may arise because sticks are ecologically important for rooks.

What do bonobos (Pan paniscus) understand about physical contact?

The present study aimed to test what bonobos (Pan paniscus) understand about contact. The task consisted of a clear horizontal tube containing a piece of food and a stick with a disk attached. The bonobos chose which side to push or pull the stick for the disk to contact the food and make it accessible. There were 9 variations in tube design, which differed in the positions of the stick, disk, and food. All 5 bonobos passed at least 1 configuration. A recent study (A. E. Helme, N. S. Clayton, & N. J. Emery, 2006) found that rooks could learn only tube configurations that provided an asymmetrical stick cue, whereas bonobos did not demonstrate an understanding of contact but showed more individual variation, attending to the positions of the food, disk, and stick.