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Biomedicines
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Multiple Sclerosis: Diagnosis and Treatment
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Multiple Sclerosis: Diagnosis and Treatment

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (31 January 2019) | Viewed by 86943

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Prof. Dr. Víctor M. Rivera

E-Mail Website
Guest Editor
Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA
Interests: demyelinating disorders; multiple sclerosis; epidemiology and genetic aspects; therapeutic trials
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Multiple Sclerosis (MS), an inflammatory demyelinating disease of the CNS, has acquired a world-wide recognition with its increasing global prevalence, including populations previously considered not to be commonly affected. Genetics and environmental factors play a determining role in its pathogenesis. Notable progress has been accomplished in diagnostic criteria (which evolve continuously) and therapeutic advances. In fact, in less than three decades, more therapies with diverse mechanisms of action (MOA) for relapsing and progressive MS have been developed for MS than for any other neurological disorder. Magnetic Resonance Imaging (MRI), the golden tool for diagnosis, is essential for monitoring the evolution of the disease and the response to therapy.

Despite this progress, substantial challenges have arisen, including the need for differential diagnosis with respect to other major inflammatory/demyelinating disorders relatively recent identification (totally different in mechanism and management), such as Neuromyelitis Optica (NMO) and Anti-MOG syndromes, and the role of environment and epigenetic factors in the mechanism of MS.

We cordially invite authors and investigators within this complex field of universal interest, to submit original research or review articles pertaining this special issue. Studies and opinions on risk factors related to the development of disease, molecular aspects of its pathogenesis, diagnostic intricacies despite current criteria, and the status of disease modifying therapies effect in relapsing and progressive forms of MS, and what is foreseen in the horizon.

Prof. Víctor M. Rivera
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Multiple Sclerosis
  • Pathogenesis
  • Progressive MS
  • MRI
  • Monoclonal Antibodies
  • Demyelinating Disorders
  • Cognitive Dysfunction
  • Intestinal Microbiota

Published Papers (10 papers)

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Research

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15 pages, 999 KiB  
Article
Genetic Association and Altered Gene Expression of CYBB in Multiple Sclerosis Patients
by Giulia Cardamone, Elvezia Maria Paraboschi, Giulia Soldà, Stefano Duga, Janna Saarela and Rosanna Asselta
Biomedicines 2018, 6(4), 117; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines6040117 - 18 Dec 2018
Cited by 9 | Viewed by 4660
Abstract
Multiple sclerosis (MS) is a chronic neurological disorder characterized by inflammation, demyelination, and axonal damage. Increased levels of reactive oxygen species (ROS), produced by macrophages and leading to oxidative stress, have been implicated as mediators of demyelination and axonal injury in both MS [...] Read more.
Multiple sclerosis (MS) is a chronic neurological disorder characterized by inflammation, demyelination, and axonal damage. Increased levels of reactive oxygen species (ROS), produced by macrophages and leading to oxidative stress, have been implicated as mediators of demyelination and axonal injury in both MS and experimental autoimmune encephalomyelitis, the murine model of the disease. On the other hand, reduced ROS levels can increase susceptibility to autoimmunity. In this work, we screened for association with MS 11 single nucleotide polymorphisms (SNPs) and two microsatellite markers in the five genes (NCF1, NCF2, NCF4, CYBA, and CYBB) of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) system, the enzymatic pathway producing ROS in the brain and neural tissues, in 347 Finnish patients with MS and 714 unaffected family members. This analysis showed suggestive association signals for NCF1 and CYBB (lowest p = 0.038 and p = 0.013, respectively). Functional relevance for disease predisposition was further supported for the CYBB gene, by microarray analysis in CD4+/− mononuclear cells of 21 individuals from five Finnish multiplex MS families, as well as by real-time RT-PCRs performed on RNA extracted from peripheral blood mononuclear cells of an Italian replication cohort of 21 MS cases and 21 controls. Our results showed a sex-specific differential expression of CYBB, suggesting that this gene, and more in general the NOX2 system, deserve to be further investigated for their possible role in MS. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment)
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Review

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23 pages, 538 KiB  
Review
Diagnosis and Management of Progressive Multiple Sclerosis
by Gabrielle Macaron and Daniel Ontaneda
Biomedicines 2019, 7(3), 56; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines7030056 - 29 Jul 2019
Cited by 47 | Viewed by 9153
Abstract
Multiple sclerosis is a chronic autoimmune disease of the central nervous system that results in varying degrees of disability. Progressive multiple sclerosis, characterized by a steady increase in neurological disability independently of relapses, can occur from onset (primary progressive) or after a relapsing–remitting [...] Read more.
Multiple sclerosis is a chronic autoimmune disease of the central nervous system that results in varying degrees of disability. Progressive multiple sclerosis, characterized by a steady increase in neurological disability independently of relapses, can occur from onset (primary progressive) or after a relapsing–remitting course (secondary progressive). As opposed to active inflammation seen in the relapsing–remitting phases of the disease, the gradual worsening of disability in progressive multiple sclerosis results from complex immune mechanisms and neurodegeneration. A few anti-inflammatory disease-modifying therapies with a modest but significant effect on measures of disease progression have been approved for the treatment of progressive multiple sclerosis. The treatment effect of anti-inflammatory agents is particularly observed in the subgroup of patients with younger age and evidence of disease activity. For this reason, a significant effort is underway to develop molecules with the potential to induce myelin repair or halt the degenerative process. Appropriate trial methodology and the development of clinically meaningful disability outcome measures along with imaging and biological biomarkers of progression have a significant impact on the ability to measure the efficacy of potential medications that may reverse disease progression. In this issue, we will review current evidence on the physiopathology, diagnosis, measurement of disability, and treatment of progressive multiple sclerosis. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment)
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24 pages, 1945 KiB  
Review
Neuromyelitis Optica Spectrum Disorder and Anti-MOG Syndromes
by Marco A. Lana-Peixoto and Natália Talim
Biomedicines 2019, 7(2), 42; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines7020042 - 12 Jun 2019
Cited by 88 | Viewed by 13099
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) and anti-myelin oligodendrocyte glycoprotein (anti-MOG) syndromes are immune-mediated inflammatory conditions of the central nervous system that frequently involve the optic nerves and the spinal cord. Because of their similar clinical manifestations and habitual relapsing course they are frequently [...] Read more.
Neuromyelitis optica spectrum disorder (NMOSD) and anti-myelin oligodendrocyte glycoprotein (anti-MOG) syndromes are immune-mediated inflammatory conditions of the central nervous system that frequently involve the optic nerves and the spinal cord. Because of their similar clinical manifestations and habitual relapsing course they are frequently confounded with multiple sclerosis (MS). Early and accurate diagnosis of these distinct conditions is relevant as they have different treatments. Some agents used for MS treatment may be deleterious to NMOSD. NMOSD is frequently associated with antibodies which target aquaporin-4 (AQP4), the most abundant water channel in the CNS, located in the astrocytic processes at the blood-brain barrier (BBB). On the other hand, anti-MOG syndromes result from damage to myelin oligodendrocyte glycoprotein (MOG), expressed on surfaces of oligodendrocytes and myelin sheaths. Acute transverse myelitis with longitudinally extensive lesion on spinal MRI is the most frequent inaugural manifestation of NMOSD, usually followed by optic neuritis. Other core clinical characteristics include area postrema syndrome, brainstem, diencephalic and cerebral symptoms that may be associated with typical MRI abnormalities. Acute disseminated encephalomyelitis and bilateral or recurrent optic neuritis are the most frequent anti-MOG syndromes in children and adults, respectively. Attacks are usually treated with steroids, and relapses prevention with immunosuppressive drugs. Promising emerging therapies for NMOSD include monoclonal antibodies and tolerization. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment)
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15 pages, 519 KiB  
Review
Women’s Health: Contemporary Management of MS in Pregnancy and Post-Partum
by Kelly Tisovic and Lilyana Amezcua
Biomedicines 2019, 7(2), 32; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines7020032 - 19 Apr 2019
Cited by 14 | Viewed by 4929
Abstract
Multiple sclerosis (MS) primarily affects women in childbearing age and is associated with an increased risk of adverse post-partum outcomes. Relapses and now fetal exposure to disease modifying treatments in the early phase of pregnancy and thereafter are of concern. Safe and effective [...] Read more.
Multiple sclerosis (MS) primarily affects women in childbearing age and is associated with an increased risk of adverse post-partum outcomes. Relapses and now fetal exposure to disease modifying treatments in the early phase of pregnancy and thereafter are of concern. Safe and effective contraception is required for women who wish to delay or avoid pregnancy while on disease-modifying treatments. Counseling and planning is essential to assess the risk of both fetal and maternal complications, particularly now in the era of highly efficient and riskier therapies. The purpose of this review is to provide a practical framework using the available data surrounding pregnancy in MS with the goal of optimizing outcomes during this phase in MS. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment)
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13 pages, 361 KiB  
Review
Stem Cell-Based Therapies for Multiple Sclerosis: Current Perspectives
by Fernando X. Cuascut and George J. Hutton
Biomedicines 2019, 7(2), 26; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines7020026 - 30 Mar 2019
Cited by 40 | Viewed by 8717
Abstract
Multiple sclerosis (MS) is an inflammatory and neurodegenerative autoimmune disease of the central nervous system (CNS). Disease-modifying therapies (DMT) targeting inflammation have been shown to reduce disease activity in patients with relapsing–remitting MS (RRMS). The current therapeutic challenge is to find an effective [...] Read more.
Multiple sclerosis (MS) is an inflammatory and neurodegenerative autoimmune disease of the central nervous system (CNS). Disease-modifying therapies (DMT) targeting inflammation have been shown to reduce disease activity in patients with relapsing–remitting MS (RRMS). The current therapeutic challenge is to find an effective treatment to halt disease progression and reverse established neural damage. Stem cell-based therapies have emerged to address this dilemma. Several types of stem cells have been considered for clinical use, such as autologous hematopoietic (aHSC), mesenchymal (MSC), neuronal (NSC), human embryonic (hESC), and induced pluripotent (iPSC) stem cells. There is convincing evidence that immunoablation followed by hematopoietic therapy (aHSCT) has a high efficacy for suppressing inflammatory MS activity and improving neurological disability in patients with RRMS. In addition, MSC therapy may be a safe and tolerable treatment, but its clinical value is still under evaluation. Various studies have shown early promising results with other cellular therapies for CNS repair and decreasing inflammation. In this review, we discuss the current knowledge and limitations of different stem cell-based therapies for the treatment of patients with MS. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment)
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19 pages, 7760 KiB  
Review
Assessment and Impact of Cognitive Impairment in Multiple Sclerosis: An Overview
by Miguel Ángel Macías Islas and Ethel Ciampi
Biomedicines 2019, 7(1), 22; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines7010022 - 19 Mar 2019
Cited by 80 | Viewed by 9165
Abstract
Cognitive impairment affects 40–60% of patients with multiple sclerosis. It may be present early in the course of the disease and has an impact on a patient’s employability, social interactions, and quality of life. In the last three decades, an increasing interest in [...] Read more.
Cognitive impairment affects 40–60% of patients with multiple sclerosis. It may be present early in the course of the disease and has an impact on a patient’s employability, social interactions, and quality of life. In the last three decades, an increasing interest in diagnosis and management of cognitive impairment has arisen. Neuropsychological assessment and neuroimaging studies focusing on cognitive impairment are now being incorporated as primary outcomes in clinical trials. However, there are still key uncertainties concerning the underlying mechanisms of damage, neural basis, sensitivity and validity of neuropsychological tests, and efficacy of pharmacological and non-pharmacological interventions. The present article aimed to present an overview of the assessment, neural correlates, and impact of cognitive impairment in multiple sclerosis. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment)
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13 pages, 833 KiB  
Review
Monoclonal Antibodies in Multiple Sclerosis: Present and Future
by Natalia V. Voge and Enrique Alvarez
Biomedicines 2019, 7(1), 20; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines7010020 - 14 Mar 2019
Cited by 39 | Viewed by 12273
Abstract
The global incidence of multiple sclerosis (MS) appears to be increasing. Although it may not be associated with a high mortality rate, this disease has a high morbidity rate which affects the quality of life of patients and reduces their ability to do [...] Read more.
The global incidence of multiple sclerosis (MS) appears to be increasing. Although it may not be associated with a high mortality rate, this disease has a high morbidity rate which affects the quality of life of patients and reduces their ability to do their activities of daily living. Thankfully, the development of novel disease modifying therapies continues to increase. Monoclonal antibodies (MABs) have become a mainstay of MS treatment and they are likely to continue to be developed for the treatment of this disease. Specifically, MABs have proven to be some of the most efficacious treatments at reducing relapses and the inflammation in MS patients, including the first treatment for primary progressive MS and are being explored as reparative/remyelinating agents as well. These relatively new treatments will be reviewed here to help evaluate their efficacy, adverse events, immunogenicity, and benefit-risk ratios in the treatment of the diverse spectrum of MS. The focus will be on MABs that are currently approved or may be approved in the near future. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment)
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19 pages, 2161 KiB  
Review
Daclizumab: Mechanisms of Action, Therapeutic Efficacy, Adverse Events and Its Uncovering the Potential Role of Innate Immune System Recruitment as a Treatment Strategy for Relapsing Multiple Sclerosis
by Stanley L. Cohan, Elisabeth B. Lucassen, Meghan C. Romba and Stefanie N. Linch
Biomedicines 2019, 7(1), 18; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines7010018 - 11 Mar 2019
Cited by 35 | Viewed by 7858
Abstract
Daclizumab (DAC) is a humanized, monoclonal antibody that blocks CD25, a critical element of the high-affinity interleukin-2 receptor (IL-2R). DAC HYP blockade of CD25 inhibits effector T cell activation, regulatory T cell expansion and survival, and activation-induced T-cell apoptosis. Because CD25 blockade reduces [...] Read more.
Daclizumab (DAC) is a humanized, monoclonal antibody that blocks CD25, a critical element of the high-affinity interleukin-2 receptor (IL-2R). DAC HYP blockade of CD25 inhibits effector T cell activation, regulatory T cell expansion and survival, and activation-induced T-cell apoptosis. Because CD25 blockade reduces IL-2 consumption by effector T cells, it increases IL-2 bioavailability allowing for greater interaction with the intermediate-affinity IL-2R, and therefore drives the expansion of CD56bright natural killer (NK) cells. Furthermore, there appears to be a direct correlation between CD56bright NK cell expansion and DAC HYP efficacy in reducing relapses and MRI evidence of disease activity in patients with RMS in phase II and phase III double-blind, placebo- and active comparator-controlled trials. Therapeutic efficacy was maintained during open-label extension studies. However, treatment was associated with an increased risk of rare adverse events, including cutaneous inflammation, autoimmune hepatitis, central nervous system Drug Reaction with Eosinophilia Systemic Symptoms (DRESS) syndrome, and autoimmune Glial Fibrillary Acidic Protein (GFAP) alpha immunoglobulin-associated encephalitis. As a result, DAC HYP was removed from clinical use in 2018. The lingering importance of DAC is that its use led to a deeper understanding of the underappreciated role of innate immunity in the potential treatment of autoimmune disease. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment)
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23 pages, 993 KiB  
Review
Mechanisms of Neurodegeneration and Axonal Dysfunction in Progressive Multiple Sclerosis
by Jorge Correale, Mariano Marrodan and María Célica Ysrraelit
Biomedicines 2019, 7(1), 14; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines7010014 - 20 Feb 2019
Cited by 76 | Viewed by 10960
Abstract
Multiple Sclerosis (MS) is a major cause of neurological disability, which increases predominantly during disease progression as a result of cortical and grey matter structures involvement. The gradual accumulation of disability characteristic of the disease seems to also result from a different set [...] Read more.
Multiple Sclerosis (MS) is a major cause of neurological disability, which increases predominantly during disease progression as a result of cortical and grey matter structures involvement. The gradual accumulation of disability characteristic of the disease seems to also result from a different set of mechanisms, including in particular immune reactions confined to the Central Nervous System such as: (a) B-cell dysregulation, (b) CD8+ T cells causing demyelination or axonal/neuronal damage, and (c) microglial cell activation associated with neuritic transection found in cortical demyelinating lesions. Other potential drivers of neurodegeneration are generation of oxygen and nitrogen reactive species, and mitochondrial damage, inducing impaired energy production, and intra-axonal accumulation of Ca2+, which in turn activates a variety of catabolic enzymes ultimately leading to progressive proteolytic degradation of cytoskeleton proteins. Loss of axon energy provided by oligodendrocytes determines further axonal degeneration and neuronal loss. Clearly, these different mechanisms are not mutually exclusive and could act in combination. Given the multifactorial pathophysiology of progressive MS, many potential therapeutic targets could be investigated in the future. This remains however, an objective that has yet to be undertaken. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment)
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8 pages, 246 KiB  
Commentary
Multiple Sclerosis: A Global Concern with Multiple Challenges in an Era of Advanced Therapeutic Complex Molecules and Biological Medicines
by Victor M. Rivera
Biomedicines 2018, 6(4), 112; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines6040112 - 30 Nov 2018
Cited by 15 | Viewed by 4703
Abstract
Multiple sclerosis (MS) has become a common neurological disorder involving populations previously considered to be infrequently affected. Genetic dissemination from high- to low-risk groups is a determining influence interacting with environmental and epigenetic factors, mostly unidentified. Disease modifying therapies (DMT) are effective in [...] Read more.
Multiple sclerosis (MS) has become a common neurological disorder involving populations previously considered to be infrequently affected. Genetic dissemination from high- to low-risk groups is a determining influence interacting with environmental and epigenetic factors, mostly unidentified. Disease modifying therapies (DMT) are effective in treating relapsing MS in variable degrees; one agent is approved for primary progressive disease, and several are in development. In the era of high-efficacy medications, complex molecules, and monoclonal antibodies (MAB), including anti-VLA4 (natalizumab), anti-CD52 (alemtuzumab), and anti-CD20 (ocrelizumab), obtaining NEDA (no evidence of disease activity) becomes an elusive accomplishment in areas of the world where access to MS therapies and care are generally limited. Countries’ income and access to public MS care appear to be a shared socioeconomic challenge. This disparity is also notable in the utilization of diagnostic tools to adhere to the proposed elements of the McDonald Criteria. The impact of follow-on medications (“generics”); injectable non-biological complex drugs (NBCD), oral sphingosine-1-phosphate receptor modulators, and biosimilars (interferon 1-a and 1-b), utilized in many areas of the world, is disconcerting considering these products generally lack data documenting their efficacy and safety. Potential strategies addressing these concerns are discussed from an international point of view. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment)
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