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Annals of Neurology Jul 2024Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of the... (Review)
Review
Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of the disease and underlies the progression of disability, which proceeds relentlessly and independently of clinical and radiological relapses (PIRA). The complex system of pathological events driving "chronic" worsening is likely linked with the early accumulation of compartmentalized inflammation within the central nervous system as well as insufficient repair phenomena and mitochondrial failure. These mechanisms are partially lesion-independent and differ from those causing clinical relapses and the formation of new focal demyelinating lesions; they lead to neuroaxonal dysfunction and death, myelin loss, glia alterations, and finally, a neuronal network dysfunction outweighing central nervous system (CNS) compensatory mechanisms. This review aims to provide an overview of the state of the art of neuropathological, immunological, and imaging knowledge about the mechanisms underlying the smoldering disease activity, focusing on possible early biomarkers and their translation into clinical practice. ANN NEUROL 2024;96:1-20.
Topics: Humans; Disease Progression; Biomarkers; Multiple Sclerosis; Recurrence
PubMed: 38568026
DOI: 10.1002/ana.26913 -
Revue Medicale Suisse Jan 2024
Topics: Humans; Multiple Sclerosis
PubMed: 38268369
DOI: 10.53738/REVMED.2024.20.858.163 -
Frontiers in Immunology 2023Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms... (Review)
Review
Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms of the disease where cells in the central nervous system play a critical role. To our knowledge, alemtuzumab, fumarates (dimethyl, diroximel, and monomethyl), glatiramer acetates, interferons, mitoxantrone, natalizumab, ocrelizumab, ofatumumab, and teriflunomide are either limited to the periphery or insufficiently studied to confirm direct central nervous system effects in participants with multiple sclerosis. In contrast, cladribine and sphingosine 1-phosphate receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are central nervous system-penetrant and could have beneficial direct central nervous system properties.
Topics: Humans; Multiple Sclerosis; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Cladribine; Central Nervous System Diseases
PubMed: 38162670
DOI: 10.3389/fimmu.2023.1290666 -
PloS One 2024Multiple Sclerosis (MS) is an immune-related disease and the relationship between MS and cancer has raised attention. Previous studies of the relationship between MS and...
Multiple Sclerosis (MS) is an immune-related disease and the relationship between MS and cancer has raised attention. Previous studies of the relationship between MS and cancer have reached conflicting conclusions. In this study, the two-sample MR method is used to investigate whether MS has a causal correlation with cancers and offer scientific evidence for cancer prevention. Single nucleotide polymorphisms (SNPs) related to MS were obtained from the genome-wide association study (GWAS) based on International Multiple Sclerosis Genetics Consortium (IMSGC) and SNPs related to 15 types of cancers were obtained from the GWASs based on UK Biobank. Inverse variance weighted (IVW) method was mainly used to assess causal effects. Sensitivity analyses were conducted with Cochran's Q-test, MR Egger intercept, leave-one-out test, and MR Steiger method. IVW analysis showed that MS was only associated with a marginal increased risk of cervical cancer (OR 1.0004, 95% CI 1.0002-1.0007, p = 0.0003). Sensitivity analyses showed that the results of MR analysis were robust and found no heterogeneity, no pleiotropy, and no reverse causation. In conclusion, this study finds no causal relationship between MS and 15 types of cancers except cervical cancer.
Topics: Female; Humans; Uterine Cervical Neoplasms; Genome-Wide Association Study; Mendelian Randomization Analysis; Multiple Sclerosis; Nonoxynol
PubMed: 38502664
DOI: 10.1371/journal.pone.0298271 -
EBioMedicine Jun 2024
Topics: Humans; Multiple Sclerosis; Neurofilament Proteins; Biomarkers
PubMed: 38880550
DOI: 10.1016/j.ebiom.2024.105214 -
Identification and management of subclinical disease activity in early multiple sclerosis: a review.Journal of Neurology Apr 2024Early treatment initiation in multiple sclerosis (MS) is crucial in preventing irreversible neurological damage and disability progression. The current assessment of... (Review)
Review
IMPORTANCE
Early treatment initiation in multiple sclerosis (MS) is crucial in preventing irreversible neurological damage and disability progression. The current assessment of disease activity relies on relapse rates and magnetic resonance imaging (MRI) lesion activity, but inclusion of other early, often "hidden," indicators of disease activity may describe a more comprehensive picture of MS.
OBSERVATIONS
Early indicators of MS disease activity other than relapses and MRI activity, such as cognitive impairment, brain atrophy, and fatigue, are not typically captured by routine disease monitoring. Furthermore, silent progression (neurological decline not clearly captured by standard methods) may occur undetected by relapse and MRI lesion activity monitoring. Consequently, patients considered to have no disease activity actually may have worsening disease, suggesting a need to revise MS management strategies with respect to timely initiation and escalation of disease-modifying therapy (DMT). Traditionally, first-line MS treatment starts with low- or moderate-efficacy therapies, before escalating to high-efficacy therapies (HETs) after evidence of breakthrough disease activity. However, multiple observational studies have shown that early initiation of HETs can prevent or reduce disability progression. Ongoing randomized clinical trials are comparing escalation and early HET approaches.
CONCLUSIONS AND RELEVANCE
There is an urgent need to reassess how MS disease activity and worsening are measured. A greater awareness of "hidden" indicators, potentially combined with biomarkers to reveal silent disease activity and neurodegeneration underlying MS, would provide a more complete picture of MS and allow for timely therapeutic intervention with HET or switching DMTs to address suboptimal treatment responses.
Topics: Humans; Multiple Sclerosis; Cognition; Cognitive Dysfunction; Magnetic Resonance Imaging; Recurrence; Multiple Sclerosis, Relapsing-Remitting
PubMed: 37864717
DOI: 10.1007/s00415-023-12021-5 -
Neurologic Clinics Feb 2024Chronologic aging is associated with multiple pathologic and immunologic changes that impact the clinical course of multiple sclerosis (MS). Clinical phenotypes evolve... (Review)
Review
Chronologic aging is associated with multiple pathologic and immunologic changes that impact the clinical course of multiple sclerosis (MS). Clinical phenotypes evolve across the lifespan, from a highly inflammatory course in the very young to a predominantly neurodegenerative phenotype in older patients. Thus, unique clinical considerations arise for the diagnosis and management of the two age extremes of pediatric and geriatric MS populations. This review covers epidemiology, diagnosis, and treatment strategies for these populations with nuanced discussions on therapeutic approaches to effectively care for patients living with MS at critical transition points during their lifespan.
Topics: Humans; Child; Aged; Multiple Sclerosis; Aging
PubMed: 37980118
DOI: 10.1016/j.ncl.2023.07.003 -
Multiple Sclerosis and Related Disorders Nov 2023Cognitive impairment in multiple sclerosis (MS) affects approximately 40-70% of patients and can have varying degrees of severity. Even mild cognitive impairment can... (Review)
Review
Cognitive impairment in multiple sclerosis (MS) affects approximately 40-70% of patients and can have varying degrees of severity. Even mild cognitive impairment can impact on quality of life and productivity. Despite this, patients are not routinely screened or monitored for cognitive impairment in Australia due to a range of issues, with time and space being the main limiting factors. This Australian multidisciplinary perspective provides recommendations on cognition management in Australia. It gives a broad overview of cognition in MS, advice on the screening and monitoring tools available to clinicians, and strategies that can be implemented in clinics to help monitor for cognitive impairment in patients with MS. We suggest a routine baseline assessment and multidomain cognitive battery in regular intervals; a change should trigger a thorough investigation of the cause.
Topics: Humans; Multiple Sclerosis; Quality of Life; Neuropsychological Tests; Australia; Cognitive Dysfunction; Cognition
PubMed: 37683558
DOI: 10.1016/j.msard.2023.104952 -
Neurological Sciences : Official... Nov 2023Over the years, disease registers have been increasingly considered a source of reliable and valuable population studies. However, the validity and reliability of data...
INTRODUCTION
Over the years, disease registers have been increasingly considered a source of reliable and valuable population studies. However, the validity and reliability of data from registers may be limited by missing data, selection bias or data quality not adequately evaluated or checked. This study reports the analysis of the consistency and completeness of the data in the Italian Multiple Sclerosis and Related Disorders Register.
METHODS
The Register collects, through a standardized Web-based Application, unique patients. Data are exported bimonthly and evaluated to assess the updating and completeness, and to check the quality and consistency. Eight clinical indicators are evaluated.
RESULTS
The Register counts 77,628 patients registered by 126 centres. The number of centres has increased over time, as their capacity to collect patients. The percentages of updated patients (with at least one visit in the last 24 months) have increased from 33% (enrolment period 2000-2015) to 60% (enrolment period 2016-2022). In the cohort of patients registered after 2016, there were ≥ 75% updated patients in 30% of the small centres (33), in 9% of the medium centres (11), and in all the large centres (2). Clinical indicators show significant improvement for the active patients, expanded disability status scale every 6 months or once every 12 months, visits every 6 months, first visit within 1 year and MRI every 12 months.
CONCLUSIONS
Data from disease registers provide guidance for evidence-based health policies and research, so methods and strategies ensuring their quality and reliability are crucial and have several potential applications.
Topics: Humans; Multiple Sclerosis; Reproducibility of Results; Italy
PubMed: 37311951
DOI: 10.1007/s10072-023-06876-9 -
Computers in Biology and Medicine Jun 2024In light of extensive work that has created a wide range of techniques for predicting the course of multiple sclerosis (MS) disease, this paper attempts to provide an... (Review)
Review
In light of extensive work that has created a wide range of techniques for predicting the course of multiple sclerosis (MS) disease, this paper attempts to provide an overview of these approaches and put forth an alternative way to predict the disease progression. For this purpose, the existing methods for estimating and predicting the course of the disease have been categorized into clinical, radiological, biological, and computational or artificial intelligence-based markers. Weighing the weaknesses and strengths of these prognostic groups is a profound method that is yet in need and works directly at the level of diseased connectivity. Therefore, we propose using the computational models in combination with established connectomes as a predictive tool for MS disease trajectories. The fundamental conduction-based Hodgkin-Huxley model emerged as promising from examining these studies. The advantage of the Hodgkin-Huxley model is that certain properties of connectomes, such as neuronal connection weights, spatial distances, and adjustments of signal transmission rates, can be taken into account. It is precisely these properties that are particularly altered in MS and that have strong implications for processing, transmission, and interactions of neuronal signaling patterns. The Hodgkin-Huxley (HH) equations as a point-neuron model are used for signal propagation inside a small network. The objective is to change the conduction parameter of the neuron model, replicate the changes in myelin properties in MS and observe the dynamics of the signal propagation across the network. The model is initially validated for different lengths, conduction values, and connection weights through three nodal connections. Later, these individual factors are incorporated into a small network and simulated to mimic the condition of MS. The signal propagation pattern is observed after inducing changes in conduction parameters at certain nodes in the network and compared against a control model pattern obtained before the changes are applied to the network. The signal propagation pattern varies as expected by adapting to the input conditions. Similarly, when the model is applied to a connectome, the pattern changes could give an insight into disease progression. This approach has opened up a new path to explore the progression of the disease in MS. The work is in its preliminary state, but with a future vision to apply this method in a connectome, providing a better clinical tool.
Topics: Humans; Multiple Sclerosis; Models, Neurological; Computer Simulation; Disease Progression; Connectome
PubMed: 38657465
DOI: 10.1016/j.compbiomed.2024.108416