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What is already known about the topic?•Autologous hematopoietic stem cell transplantation (AHSCT) is a highly effective therapy for relapsing remitting MS (RRMS).•Few studies have investigated costs of AHSCT in this patient population.What does the paper add to existing knowledge?•The first micro-costing study estimating healthcare utilization and costs associated with AHSCT in Norwegian RRMS patients.•Patient-level data extracted from medical journals of 30 RRMS patients receiving AHSCT treatment in the period from January 2015 to January 2018.What insights does the paper provide for informing healthcare-related decision making?•Average total healthcare cost of AHSCT for RRMS patients estimated to EUR 66 304 (95 % CI: EUR 63 598 – EUR 69 010) in a one year perspective.•This study presents relevant methods for estimating healthcare costs associated with AHSCT, which may be of value for an upcoming cost-effectiveness evaluations.•Long-term healthcare cost savings may be achieved using AHSCT in selected patients with aggressive RRMS. This is due to the high costs of most used disease modifying treatments which varies from 20 000 to 30 000 EUR per year.

Exercise training (ET) should be a mainstay of comprehensive care in multiple sclerosis (MS), yet there is reluctance regarding its implementation among healthcare providers. This reluctance has its roots in the lack of evidence from randomized controlled trials (RCTs) that provide a neurobiological mechanism for beneficial outcomes. We argue that ET training is efficacious for improving mobility and cognitive dysfunction as hallmark consequences of MS, and propose an experimental medicine framework for guiding research focusing on CNS mechanisms-of-action for ET benefits. The framework establishes three hierarchical pathways as preconditions for applying a mediation framework in a fourth pathway for fully testing mechanistic research questions using a RCT. This paper describes the conceptual basis of the pathways, and then reviews the existing evidence within the pathways of the framework for ET effects on the CNS, mobility, and cognition in MS. Lastly, this paper discusses future directions and challenges for testing the pathways of the framework for advancing the evidence regarding CNS mechanisms of ET benefits in this population. Our objective is guiding the field toward evidence that facilitates the prescription and promotion of ET as a neurorestorative approach within MS clinical practice.

•The study is considered a pilot study due to the small number of cases examined in a single facility. This clarification has been added to the end of the INTRODUCTION section.•A control column has been added to the table to clarify the integrity of the data.•The findings of Carotenuto 2022 indicate that the ALPS index is abnormal within the first 4 years of the start of MS disease conversion and then does not seem to change over time. This is similar to the findings of the current paper, but it should be better highlighted and discussed. The risk of conversion is front-loaded into the glymphatic system from very early on in the disease and may only declare itself after some time, which raises a conundrum. It is normally thought that the disease duration is one of the factors which will lead to conversion from RRMS to progressive disease.

When the Greek letter beta(β) is accidentally confused for the German letter Eszett(ß), and replaced by it, this can lead to some unfortunate consequences in science, academic publishing, and thus the accuracy of the academic record. In this letter, I document the existence – due to this substitution – of a false positive of amyloid-beta(Aβ), namely amyloid-Eszett(Aß), which does not exist. In total, 242 false positives were identified in PubMed. Of these, 21 were published in 2022, and these were examined in more detail. Although fundamental findings of papers related to Alzheimer's disease are likely not affected by this error, these papers do carry an error nonetheless.

Regulatory T cells (Treg cells), defined as CD4+CD25+FoxP3+T cells by expression of CD4, high-affinity IL-2 receptor and the transcription factor, forkhead box P3 (FoxP3). They play a pivotal role in protecting individuals from autoimmunity and a growing body of evidence suggests their role in the prevention of multiple sclerosis development. However, there are discrepancies about the type of defect in the Treg cells of multiple sclerosis patients and especially whether the Treg number alteration could be contributed to multiple sclerosis pathogenesis. Indeed, whether low number of Treg cells can be a risk factor contributing to multiple sclerosis pathogenesis is the matter of debate and there is not any comprehensive agreement on it. Thus, the objective of this systematic review and meta-analysis was to precisely quantify the nature and magnitude of the association between Treg cell number and the risk ratio/odds ratio (OR) of multiple sclerosis in the case-control studies. Hence, medical databases of Embase, PubMed/Medline, PubMed, PubMed Central and SCOPUS were searched for empirical papers using “Regulatory T cell frequency”, “Treg frequency” in combination with “multiple sclerosis”. In the case-control studies, papers were reviewed for inclusion/exclusion criteria and 8 publications were included. Under random-effect model meta-analysis the data showed that the frequency of Treg cells was not a risk factor in multiple sclerosis using current laboratory methods.

•Sexual dysfunction (SD) is a common and distressing symptom for people with multiple sclerosis (MS). Populations included in studies of SD may not fully reflect the diversity of people living with MS.•We evaluated 204 studies including 77,902 participants. Of these, 98 included both male and female participants; 78 included females only, and 27 males only. No studies reported including non-binary patients or gender identities other than male or female.•The overwhelming majority of studies (167/204) did not report sexual orientation. Only 10 studies reported the inclusion of participants who were homosexual and/or bisexual in addition to heterosexual participants.•Whilst studies originated from a range of countries, there were no studies from Central Asia, Eastern Asia, South-Eastern Asia and all subregions of Africa. The geographic spread of papers may have impacted on our findings, as culture, stigma and legal concerns may have limited representation and disclosure.

•The pain, which is a major symptom and triggers disability in multiple sclerosis (MS) patients, can be significantly relieved by electrical stimulation therapy.•MS patients were able to maximize the effect of electrical stimulation therapy (2 weeks-4 weeks) on pain symptoms from the medium-term EST treatment. However, little benefit was seen in MS-related symptoms such as depression, fatigue, low back pain-related dysfunction and decreased quality of life, the reasons for which are analyzed and discussed in this paper.•The amount of effect of different electrical stimulation therapies for the treatment of MS varied widely, where transcranial direct current stimulation was recommended because of the best pain-relieving effect.•More research is needed on the effects of electrical stimulation therapy on cognition, pain-related disability and quality of life for MS.

Cognitive dysfunction affects 40–65% of multiple sclerosis (MS) patients. To date, conventional paper and pencil neuropsychological testing has been the method of choice for detecting deficits. However, the expense and lack of access to these tests make it difficult for many patients to obtain an assessment. With the introduction of computerized cognitive testing, certain barriers to assessment can be reduced. This paper critically reviews the currently available computerized batteries, including the Automated Neuropsychology Assessment Matrix (ANAM), the Mindstreams Computerized Cognitive Battery (MCCB), the Amsterdam Neuropsychological Tasks (ANT), the Cognitive Stability Index (CSI), and the Cognitive Drug Research (CDR) battery. Recent developments in this field show promise, although further research is required before this approach can be more widely implemented.

Animal models of neurodegenerative and inflammatory diseases, have greatly contributed to our understanding of human disorders such as multiple sclerosis (MS). These models play a key role in drug development and have led to novel therapeutic approaches to treat human diseases. Nevertheless, some studies showing efficacy of therapies in animal models have not translated well to the clinic. In part, this disparity can be explained by differences in the biology of animals and humans. Another contributing factor is the quality of execution and reporting of studies, which is the responsibility of the authors. However, the acceptance of these papers depends on the quality of refereeing and editorial proficiency. When reporting animal studies, it is recommended that manuscripts conform to the principals of the Animals in Research: Reporting In Vivo Experiments (ARRIVE) guidelines (). This provides a list of 20 guidelines that should be employed in order to make papers consistent as well as transparent. However, conformation to the ARRIVE guidelines requires significantly more information than current publications often report.

•Neuromyelitis optica has new diagnostic criteria since 2015.•The new criteria considers it neuromyelitis optica spectrum disorders (NMOSD).•Clinical data on NMOSD is important for better diagnoses and management.•Brazil adds to the present literature with this paper.

People with multiple sclerosis (MS) commonly experience cognitive impairment associated with the disease, but there is currently no agreed-upon operational definition for identifying the presence of that impairment, in either research or clinic contexts. The International MS Cognition Society (IMSCOGS) established a task force to begin to examine this issue and this paper represents the results of an initial pilot investigation. The aim of this paper was to compare two criterion sets to determine how to identify cognitive impairment among people with MS: the general Diagnostic and Statistical Manual (DSM-5) Criteria for neurocognitive disorders and criteria derived from existing MS research (scores in two domains fall 1.5 standard deviations below normative controls).

•We evaluated a novel point-of-care, filter paper-based test for serum antibodies to AQP4 (AQP4-Ab) in neuromyelitis optica spectrum disorder (NMOSD).•25 cases (adults with AQP4-Ab seropositive NMOSD) and 15 controls used lancets to place blood drops on filter paper cards and mailed their samples for lab processing.•The point-of-care test yielded a sensitivity of 80% and a specificity of 93%.•Point-of-care testing may be a pragmatic option to diagnose AQP4-Ab seropositive NMOSD in low-resource settings.

Rehabilitation is the mainstay of management for people with disabilities of neurological origin to maximize function and reduce disability. Access to in-patient rehabilitation is usually reserved for people after crises or those who are discharged from acute care such as in stroke or trauma. Access to people with Multiple Sclerosis (MS) differs across countries and unknown for Canada. With the progression of MS, quality of life (QOL) becomes more closely coupled with independence and hence timely access to rehabilitation is important. The objectives of this paper are (i) to characterize the disability profiles of people with MS admitted to in-patient rehabilitation in Canada; and (ii) to estimate the extent to which disability profiles differ from admission to discharge.

•This paper reviewed research on vascular function and dysfunction in MS.•The research indicated diminished vascular function in MS compared with controls.•Vascular dysfunction in MS was associated with worse walking and cognition.•Physical activity was associated with better vascular function in MS.•We present an agenda that guides research on vascular function in MS.

•The paper presents a comparative study of first-line disease-modifying treatments (DMT) for multiple sclerosis (MS) in a real-world setting, which is valuable as no head-to-head studies are currently available.•The primary outcome of the study is the median time to discontinuation of any DMT, and the results show that there is no significant difference in persistence between teriflunomide, dimethyl fumarate, and injectable drugs. While there is no significant difference in persistence between DMT, there is a trend towards favoring oral DMT over injectable drugs.•The most frequent reason for discontinuation differs within groups, with lack of efficacy being the primary reason for teriflunomide, and adverse effects being the primary reason for dimethyl fumarate and injectable drugs.•A trend towards early treatment and lower EDSS scores was observed after 2018, particularly in the teriflunomide group, suggesting a shift towards more aggressive and proactive MS management.

•This paper indicates that familial HLH may present with pure neurological involvement.•A high index of suspicion should be practiced with patients who present with non-specific recurrent neurological symptoms associated with abnormal non-specific neuroradiological findings.•Genetic testing should be included in the investigations of such cases.

•Mendelian randomization studies have become increasingly common due to the maturation of genome-wide association studies and its potential to ascertain causal relationships.•Mendelian randomization attempts to ascertain a causal relationship between some risk factor of interest and some outcome or disease of interest.•In this paper we provide a readable introduction to the rationale behind Mendelian randomization and its limitations.•We discuss and interpret several examples of Mendelian randomization analyses which pertain to neurological diseases.

•We believe our paper is ground-breaking in terms of presenting a possible link between cortisol fluctuation and yawning.•Many people with MS become regularly fatigued and yawn, and it is known that cortisol may help lower brain temperature.•We present a study of MS participants and healthy controls and show that the link between yawning and cortisol elevation is more pronounced in MS.

Natalizumab (NTZ, Tysabri®; Biogen-Idec, Cambridge, MA, USA) is a humanized anti-α4 integrin monoclonal antibody, largely used in the treatment of Relapsing-Remitting Multiple Sclerosis (RRMS). Although the drug has shown great efficacy in clinical trials (AFFIRM and SENTINEL) and in post-marketing observational studies (TYGRIS), by reducing clinical signs as disability status progression, brain lesions and annual relapse rate, there are numerous papers concerning the associated risk of progressive multifocal leukoencephalopathy (PML). PML is a brain infection caused by John Cunningham virus (JCV) and its incidence is related to intrinsic and extrinsic risk factors, such as long-term natalizumab therapy (more than 24 infusion doses), previous pharmacological immunosuppressive treatment and JVC antibody-positive status. The identification of risk factors provides an instrument to improve treatment decisions and to obtain an accurate benefit-risk evaluation. In order to evaluate the most appropriate natalizumab-MS therapy and to obtain minor incidence of PML, an accurate description of risk factors and a biological markers identification are needed. This article review aims to list some biomarkers that have been proposed to evaluate the safety of natalizumab therapy.

Paraneoplastic syndromes are remote effects of cancer caused by an autoimmune response triggered by tumor cells. Paraneoplastic Neuromyelitis Optica Spectrum Disorders (NMOSD) has been previously described, but the underlying mechanism for these rare cases is not well characterized. This paper presents a newly described case series of paraneoplastic NMOSD, including 2 new histological types of cancer and histological validation.

Survival in MS has increased during the era of disease modifying therapies, but life expectancy in MS patients is still reduced by several years. Increased risk for common comorbidities related to brain health, such as risk for circulatory diseases have been reported in MS and could affect survival. In this paper, we studied age- and gender adjusted risks for circulatory diseases and related disorders, and their impact on overall MS survival in population of Southwest Finland.

Aggressive, highly active, or rapidly evolving severe relapsing-remitting multiple sclerosis (RRMS) is characterized by frequent relapses and active disease on magnetic resonance imaging, ultimately leading to a high risk for rapid disability accumulation. The treatment approach for high-risk patients is evolving into a model of individualized therapy in which early initiation of high-efficacy disease-modifying therapy (DMT), which I refer to as “early and strong” therapy, is viewed as a rational strategy to prevent the irreversible damage that occurs at disease onset and early in the disease course. This approach uses an individualized benefit-risk assessment to match the level of DMT efficacy with the patient's risk of disease progression and balances it against the risk of drug-related adverse events. It also includes consideration of the patient's risk tolerance and desire for a high-efficacy treatment. This paper discusses the rationale for early treatment, and summarizes the available clinical data on high-efficacy and moderately-high efficacy DMTs in patients with high-risk RRMS.

Multiple sclerosis is a chronic disease considered the major cause of neurological disability in young adults worldwide. While depression is considered a determinant factor of impaired quality of life and poorer prognosis among patients with multiple sclerosis, it is very often dismissed and undertreated by physicians. Depression has been related to treatment with some immunomodulatory drugs, such as IFNβ. Data from patients who committed suicide during the pivotal study of interferon used as a disease modifying treatment in multiple sclerosis support this association. Moreover, there is plenty of evidence of neuropsychiatric toxicity caused by the use of IFNα as a treatment for other medical conditions. Although this link still remains relatively unknown, the presence of warnings regarding the possible relationship between depression and IFNβ led to restriction in medical indications in these patients. The purpose of this paper is to try to understand the reasons for an increased prevalence in depression in multiple sclerosis and to examine the impact that IFNβ treatment has on their mood.

•Remote administration of the SDMT is interchangeable with traditional paper-based administration in persons with MS.•Findings support the use of current normative data rather than separate telehealth-derived norms.•The authors discuss the critical distinction between “highly correlated” and “interchangeable.”

•This paper examines the psychosocial effect of the pandemic on people living with Multiple Sclerosis.•An important proportion of people living with Multiple Sclerosis stopped their economic activities or studies and became unemployed.•We found predictors for psychological and physical impact and Quality of life that are related to neuropsychiatric symptoms during the COVID-19 pandemic.

•We present a comprehensive review focusing on the radiological abnormalities in progressive multifocal leukoencephalopathy (PML), a rare CNS demyelinating disease primarily affecting immunocompromised individuals. Our objective is to aid clinicians and radiologists in early diagnosis and differentiation from other conditions by providing a practical overview of both typical and atypical imaging patterns. By emphasizing the importance of timely recognition, we aim to contribute to improved clinical outcomes through prompt immune-system restoration. We believe this paper will provide valuable insights for readers.

Despite convergent evidence that upwards of 50% of patients with MS transition from a relapsing to progressive phase within 20 years of disease onset, and the recent acknowledgement of the commonality of progression independent of relapses, there remains no consensus regarding the nature and timing of a discussion about the possibility of a secondary progressive phase with relapsing-remitting MS patients. Some neurologists prefer to conduct this at the inaugural visit to provide more information about disease behaviour and potential planning that might entail, while others may defer any discussion about this phase, as there is no clear consensus for it and it can be a sensitive topic, with concern that too early a discussion could worsen anxiety and discourage or delay decisions regarding disease modifying treatments. Furthermore, it is unknown at onset which patients will transition to a progressive phenotype. This review and opinion paper will outline some of the opportunities and challenges associated with such a disclosure, and attempt to provide a balanced, patient-centred approach to address this delicate topic.

•The number of papers published in the last 20 years on MS has increased over time.•A total of 101 unique topics have been identified through use of NLP algorithm BERT.•Between 2000 and 2005 interferons and EAE were the most commonly discussed topics.•Between 2005 and 2015 genetics, environmental factors, and emerging treatments became more prevalent.•Recently, the focus of attention switched to progressive MS and MS-related.

•The body of research on exercise and physical activity among persons with multiple sclerosis(MS) has expanded rapidly in quantity, but not necessarily quality, over the past 20+ years.•There is heterogeneity in the outcomes of exercise and physical activity, and a recognition of substantial challenges for improving the effectiveness of those behaviors in MS.•This paper provides a resource that can inform researchers, particularly new investigators or established investigators transitioning into MS, on conducting high-quality randomized controlled trials on exercise and physical activity in MS.

Natalizumab is a monoclonal antibody that significantly reduces the occurrence of relapses in relapse-remitting multiple sclerosis (RRMS) patients. Early papers on the clinical use of natalizumab in RRMS patients reported erythroblastemia as occasional and transient.

•This systematic review examines papers published on stress in multiple sclerosis.•It is the first review on the impact of stress on multiple sclerosis onset/relapse.•It novelly considers the timing of stressors on multiple sclerosis onset/relapse.•There is conflicting evidence that stress impacts multiple sclerosis onset.•Evidence supports a link between stress at any age and multiple sclerosis relapse.

This paper addresses the ethical acceptability of a proposed placebo controlled trial of a new intervention as a possible relapse prevention treatment for Neuromyelitis Optica (NMO). In the analysis of this controversial ethical issue, the author points out significant factors that are often overlooked or ignored, such as the life-long implications for study participants and others living with the disease, and also addresses commonly noted issues, such as vulnerability, benefits, harms, and justice that always require attention in research review.

Experimental allergic encephalomyelitis (EAE) is the commonest, readily induced, organspecific, autoimmune disorder of laboratory animals of its kind. It is an artificial disorder brought about by the immunisation of susceptible animals with brain antigens in complete Freund׳s adjuvant (CFA). Variations can be induced by altering the nature of the antigen and the conditions involving immunisation. Whilst it is often described as a demyelinating disease, in strict terms it is not, since the primary pathologic process is not demyelination but rather an encephalomyelitis that is immunologically induced. Rather, the prototype demyelinating disease is multiple sclerosis and its variants. In this paper, the central question we ask is whether the data gleaned from the EAE model contributes to our understanding of the pathological events in MS. Towards answering this, we describe the historical development of EAE and its hyperacute form, and discuss the findings studied extensively in the non-human primate which show that ordinary EAE is an exact model for ADEM in the human, and that the hyperacute form of EAE is represented by AHLE in the human. Additionally, we shall comment on the latest research on new variants of EAE, and explain our opinion regarding the use of EAE models in research aiming to understand the pathogenesis of multiple sclerosis.