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Multiple Sclerosis Journal

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• Description
• Aims and Scope
• Editorial Board
• Abstracting / Indexing
• Submission Guidelines

Multiple Sclerosis Journal is a peer-reviewed international journal that focuses on all aspects of multiple sclerosis, neuromyelitis optica and other related autoimmune diseases of the central nervous system.

The journal for your research in the following areas:

• Biologic basis: pathology, myelin biology, pathophysiology of the blood/brain barrier, axo-glial pathobiology, remyelination, virology and microbiome, immunology, proteomics, experimental models

• Epidemology and genetics: genetics epigenetics, epidemiology

• Clinical and Neuroimaging: clinical neurology, biomarkers, neuroimaging, Clinical Trials and clinical outcome measures,

• Therapeutics and rehabilitation: therapeutics, rehabilitation, psychology, neuroplasticity, neuroprotection, and systematic management

Outstanding information presented in a topical based format.

• Biologic basis: pathology, myelin biology, pathophysiology of the blood/brain barrier, axo-glial pathobiology, remyelination, virology and microbiome, immunology, proteomics, experimental models

• Academic Search Premier
• BIOSIS database
• Biological Abstracts Family of Products
• Chemical Abstracts Service (CAS)
• Clarivate Analytics: BIOSIS Previews
• Clarivate Analytics: Biological Abstracts
• Current Contents / Clinical Medicine
• Current Contents / Life Sciences
• Current Contents/ Life Sciences
• EMBASE/Excerpta Medica
• Elsevier BIOBASE/Current Awareness in Biological Sciences
• ISI Discovery Agent
• Index Medicus
• Index Medicus (Ceased 2004)
• Neuroscience Citation Index
• Neurosciences Abstracts
• Physiotherapy Evidence Database (PEDRO)
• Reference Update
• Science Citation Index
• Science Citation Index Expanded
• UK Health Centre Index
• e-Psyche (Ceased)

Manuscript Submission Guidelines: Multiple Sclerosis Journal

This Journal is a member of the  Committee on Publication Ethics .

This Journal recommends that authors follow the Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals  formulated by the International Committee of Medical Journal Editors (ICMJE).

Please read the guidelines below then visit the Journal’s submission site http://mc.manuscriptcentral.com/multiple-sclerosis to upload your manuscript. Please note that manuscripts not conforming to these guidelines may be returned .

Only manuscripts of sufficient quality that meet the aims and scope of Multiple Sclerosis Journal will be reviewed.

There are no fees payable to submit or publish in this Journal. Open Access options are available - see section 3.3 below.

As part of the submission process you will be required to warrant that you are submitting your original work, that you have the rights in the work, and that you have obtained and can supply all necessary permissions for the reproduction of any copyright works not owned by you, that you are submitting the work for first publication in the Journal and that it is not being considered for publication elsewhere and has not already been published elsewhere. Please see our guidelines on prior publication and note that Multiple Sclerosis Journal  may accept submissions of papers that have been posted on pre-print servers; please alert the Editorial Office when submitting (contact details are at the end of these guidelines) and include the DOI for the preprint in the designated field in the manuscript submission system. Authors should not post an updated version of their paper on the preprint server while it is being peer reviewed for possible publication in the journal. If the article is accepted for publication, the author may re-use their work according to the journal's author archiving policy.

• What do we publish? 1.1 Aims & Scope 1.2 Article types 1.3 Writing your paper
• Editorial policies 2.1 Peer review policy 2.2 Authorship 2.3 Acknowledgements 2.4 Funding 2.5 Declaration of conflicting interests 2.6 Research ethics and patient consent 2.7 Clinical trials 2.8 Reporting guidelines 2.9 Research Data
• Publishing policies 3.1 Publication ethics 3.2 Contributor's publishing agreement 3.3 Open access and author archiving
• Preparing your manuscript 4.1 Formatting 4.2 Artwork, figures and other graphics 4.3 Supplemental material 4.4 Reference style 4.5 English language editing services
• Submitting your manuscript 5.1 ORCID 5.2 Information required for completing your submission 5.3 Permissions
• On acceptance and publication 6.1 Sage Production 6.2 Online First publication 6.3 Access to your published article 6.4 Promoting your article
• Further information

1. What do we publish?

1.1 Aims & Scope

Before submitting your manuscript to Multiple Sclerosis Journal , please ensure you have read the Aims & Scope .

1.2 Article Types

Please read the following carefully and ensure that your submission meets the requirements to avoid automatic return or delay in the consideration of your paper.

IMPORTANT: The journal no longer solicits Systematic Reviews.

MSJ is now requiring authors to provide the essential requirements of MRI imaging as supplementary data in order to help replication of studies. If submitting a manuscript using MRI data please use this msj_mri_journal.doc  to supply the necessary data in a suitable format.

Original research papers Original research papers should be no more than 3,000 words and contain the following sections: Title page, Abstract, Introduction, Materials (or patients or animals) and Methods, Results, Discussion, Acknowledgements, References, Tables, Figure legends, Figures (see ‘Sections of the manuscript’ for further details).

Case Reports, Short Reports The Editors will consider for rapid publication Case Reports and Short Reports that illustrate important points. These must not exceed 1000 words in length, must have a title page, a short summary of no more than 100 words, up to 10 references, one figure and one table.

Letters to the Editor Brief letters raising pertinent issues relating to recently published papers in Multiple Sclerosis Journal or stand-alone letters on topics of interest are welcome. They will be reviewed and may be sent to the first author of the article being discussed for a possible response. They should be in letter format without an abstract. Stand-alone letters on topics of interest will be reviewed and should be in letter format without an abstract.

Personal Viewpoints Viewpoints which bring new ideas and stimulate discussion and debate are welcomed by the Editors, in particular those that will be of general interest, and which question or comment on new and significant MS-related studies. These will be reviewed and should be no more than 1,500 words, up to 10 references, one figure and one table (if necessary). 

Topical Reviews Topical Reviews focus on specific subjects of current interest where there have been recent and significant advances, ranging from basic neuroscience to clinical and more ‘applied’ areas. They are short, factual, focussed updates, comprising: Title page, an Abstract of 100-150 words, 5 or so Keywords, 2,500 words of text (excluding references), a limited number of relevant and recent references (up to 35 or so), and a figure if appropriate. See examples from the journal for more information. Topical Reviews are generally by invitation.

Controversies in Multiple Sclerosis Controversies focus on current issues, with contrasting contributions from leading experts, and cover topics of debate from basic neuroscience to clinical and more ‘applied’ areas. They necessarily represent an opinion, but are founded on factual evidence. Each Controversy comprises: i) a proposal for a particular view; ii) a presentation of a contrasting view; and iii) an overview/summary. The two opposing views comprise no more than 1,000 words each, supported by no more than 10 key references. The summary piece is based on the opposing statements, and is about 500 words in length. See examples from the journal for more information. We welcome ideas for topics and potential authors, if you have an appropriate idea for a topic and authors to write a Proposal or Rebuttal, please contact the Controversies editors via the editorial office to discuss further:  [email protected] .

Editorials Editorials may be solicited by the Editors to address particular topics relating to one or more papers in a given issue.

Insights into Insights into… is a series of short pieces that provide clear, concise and straightforward information into areas that many of us find challenging. They must be no more than 500 words a piece and provided in a collection of related pieces on the same topic (4-6). They should have a title page, a short summary of no more than 100 words (optional), up to 10 references, one figure and one table.

Future Perspectives  Future Perspectives can provide a forum to help capture the work of groups established to improve or update areas of fundamental importance to MS such as clinical and imaging outcomes. Articles will be reviewed and ideally should be no more than 1,500 words, up to 10 references, one figure and one table (if required).

Book and Meeting Reviews These reviews are solicited by the Editors. 

Note :  While Editorials, Reviews (including book and meeting reviews), and Topical Reviews will usually be solicited by the Editors, suggestions for topics or brief outlines of proposals are very welcome and can be sent to the nearest regional Editor.

Data previously published in un-reviewed format The Editors will also consider for publication manuscripts containing data already in press elsewhere or published previously in un-reviewed format, such as abstracts or camera-ready papers for proceedings of scientific meetings. The new manuscript should differ from the one previously published and should not contain any identical tables or figures. It will be the responsibility of the senior author to bring to the Editor’s attention details of previous publications and if necessary, attach relevant documents for the use of referees. The existence of such related paper(s) (published or in press) should be mentioned as a footnote to the manuscript or documented with appropriate references. The Editorial decision will take account of the originality of the work submitted for publication and the extent to which readers of  Multiple Sclerosis Journal  may be expected to have access to the book or journal in which the associated papers have appeared.

Related papers Related papers either published or in press may be sent with the manuscript for the attention of the Editor.

Short reports on null or negative results  The journal considers the results of rigorous, well-designed studies that demonstrate “no effect” or that fail to replicate previous work (“negative data”) as important to the advancement of science.  MSJ  welcomes short reports on null or negative results as long as the papers are based on strong hypothesis testing. 

Table 1: Overview of the requirements for manuscript submissions for MSJ :

*Excludes references, tables and legends **For reference style please see section 4.4

1.3 Writing your paper

The Sage Author Gateway has some general advice and on  how to get published , plus links to further resources. Sage Author Services also offers authors a variety of ways to improve and enhance their article including English language editing, plagiarism detection, and video abstract and infographic preparation.

1.3.1 Make your article discoverable

When writing up your paper, think about how you can make it discoverable. The title, keywords and abstract are key to ensuring readers find your article through search engines such as Google. For information and guidance on how best to title your article, write your abstract and select your keywords, have a look at this page on the Gateway:  How to Help Readers Find Your Article Online .

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2. Editorial policies

2.1 Peer review policy

Sage does not permit the use of author-suggested (recommended) reviewers at any stage of the submission process, be that through the web-based submission system or other communication. Reviewers should be experts in their fields and should be able to provide an objective assessment of the manuscript. Our policy is that reviewers should not be assigned to a paper if:

•  The reviewer is based at the same institution as any of the co-authors

•  The reviewer is based at the funding body of the paper

•  The author has recommended the reviewer

•  The reviewer has provided a personal (e.g. Gmail/Yahoo/Hotmail) email account and an institutional email account cannot be found after performing a basic Google search (name, department and institution). 

2.2 Authorship

Papers should only be submitted for consideration once consent is given by all contributing authors. Those submitting papers should carefully check that all those whose work contributed to the paper are acknowledged as contributing authors.

The list of authors should include all those who can legitimately claim authorship. This is all those who:

• Made a substantial contribution to the concept or design of the work; or acquisition, analysis or interpretation of data,
• Drafted the article or revised it critically for important intellectual content,
• Approved the version to be published,
• Each author should have participated sufficiently in the work to take public responsibility for appropriate portions of the content.

Authors should meet the conditions of all of the points above. When a large, multicentre group has conducted the work, the group should identify the individuals who accept direct responsibility for the manuscript. These individuals should fully meet the criteria for authorship.

Acquisition of funding, collection of data, or general supervision of the research group alone does not constitute authorship, although all contributors who do not meet the criteria for authorship should be listed in the Acknowledgments section. Please refer to the International Committee of Medical Journal Editors (ICMJE) authorship guidelines  for more information on authorship.

Please note that AI chatbots, for example ChatGPT, should not be listed as authors. For more information see the policy on Use of ChatGPT and generative AI tools .

2.3 Acknowledgements

All contributors who do not meet the criteria for authorship should be listed in an Acknowledgements section. Examples of those who might be acknowledged include a person who provided purely technical help, or a department chair who provided only general support.

2.3.1 Third party submissions

Where an individual who is not listed as an author submits a manuscript on behalf of the author(s), a statement must be included in the Acknowledgements section of the manuscript and in the accompanying cover letter. The statements must:

• Disclose this type of editorial assistance – including the individual’s name, company and level of input
• Identify any entities that paid for this assistance
• Confirm that the listed authors have authorized the submission of their manuscript via third party and approved any statements or declarations, e.g. conflicting interests, funding, etc.

Where appropriate, Sage reserves the right to deny consideration to manuscripts submitted by a third party rather than by the authors themselves .

2.3.2 Writing assistance

Individuals who provided writing assistance, e.g. from a specialist communications company, do not qualify as authors and so should be included in the Acknowledgements section. Authors must disclose any writing assistance – including the individual’s name, company and level of input – and identify the entity that paid for this assistance”).

It is not necessary to disclose use of language polishing services.

Any acknowledgements should appear first at the end of your article prior to your Declaration of Conflicting Interests (if applicable), any notes and your References.

2.4 Funding

Multiple Sclerosis Journal requires all authors to acknowledge their funding in a consistent fashion under a separate heading. Please visit the Funding Acknowledgements  page on the Sage Journal Author Gateway to confirm the format of the acknowledgment text in the event of funding, or state that: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. 

2.5 Declaration of conflicting interests

It is the policy of Multiple Sclerosis Journal to require a declaration of conflicting interests from all authors enabling a statement to be carried within the paginated pages of all published articles.

Please ensure that a ‘Declaration of Conflicting Interests’ statement is included at the end of your manuscript, after any acknowledgements and prior to the references. If no conflict exists, please state that ‘The Author(s) declare(s) that there is no conflict of interest’. For guidance on conflict of interest statements, please see the ICMJE recommendations  here .

2.6 Research ethics and patient consent

Medical research involving human subjects must be conducted according to the  World Medical Association Declaration of Helsinki .

Submitted manuscripts should conform to the ICMJE Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals , and all papers reporting animal and/or human studies must state in the methods section that the relevant Ethics Committee or Institutional Review Board provided (or waived) approval. Please ensure that you have provided the full name and institution of the review committee, in addition to the approval number.

For research articles, authors are also required to state in the methods section whether participants provided informed consent and whether the consent was written or verbal.

Information on informed consent to report individual cases or case series should be included in the manuscript text. A statement is required regarding whether written informed consent for patient information and images to be published was provided by the patient(s) or a legally authorized representative. Please do not submit the patient’s actual written informed consent with your article, as this in itself breaches the patient’s confidentiality. The Journal requests that you confirm to us, in writing, that you have obtained written informed consent but the written consent itself should be held by the authors/investigators themselves, for example in a patient’s hospital record. The confirmatory letter may be uploaded with your submission as a separate file.

Please also refer to the  ICMJE Recommendations for the Protection of Research Participants .

All research involving animals submitted for publication must be approved by an ethics committee with oversight of the facility in which the studies were conducted. The Journal has adopted the ARRIVE guidelines.

2.7 Clinical trials

Multiple Sclerosis Journal conforms to the ICMJE requirement  that clinical trials are registered in a WHO-approved public trials registry at or before the time of first patient enrolment as a condition of consideration for publication. The trial registry name and URL, and registration number must be included at the end of the abstract.

2.8 Reporting guidelines

The relevant EQUATOR Network  reporting guidelines should be followed depending on the type of study. For example, all randomized controlled trials submitted for publication should include a completed CONSORT   flow chart as a cited figure and the completed CONSORT checklist should be uploaded with your submission as a supplementary file. Systematic reviews and meta-analyses should include the completed PRISMA   flow chart as a cited figure and the completed PRISMA checklist should be uploaded with your submission as a supplementary file. The EQUATOR wizard  can help you identify the appropriate guideline.

Other resources can be found at  NLM’s Research Reporting Guidelines and Initiatives .

2.9 Research Data

The journal is committed to facilitating openness, transparency and reproducibility of research, and has the following research data sharing policy. For more information, including FAQs please visit the Sage Research Data policy pages .

Subject to appropriate ethical and legal considerations, authors are encouraged to:

• share your research data in a relevant public data repository
• include a data availability statement linking to your data. If it is not possible to share your data, we encourage you to consider using the statement to explain why it cannot be shared.
• cite this data in your research

Multiple Sclerosis Journal requests all authors submitting any primary data used in their research articles alongside their article submissions to be published in the online version of the journal, or provide detailed information in their articles on how the data can be obtained. This information should include links to third-party data repositories or detailed contact information for third-party data sources. Data available only on an author-maintained website will need to be loaded onto either the journal’s platform or a third-party platform to ensure continuing accessibility. Examples of data types include but are not limited to statistical data files, replication code, text files, audio files, images, videos, appendices, and additional charts and graphs necessary to understand the original research. The editor may consider limited embargoes on proprietary data. The editor can also grant exceptions for data that cannot legally or ethically be released. All data submitted should comply with Institutional or Ethical Review Board requirements and applicable government regulations.thors should also follow data citation principles. For more information please visit the Sage Author Gateway , which includes information about Sage’s partnership with the data repository Figshare.

3. Publishing Policies

3.1 Publication ethics

Sage is committed to upholding the integrity of the academic record. We encourage authors to refer to the Committee on Publication Ethics’ International Standards for Authors  and view the Publication Ethics page on the  Sage Author Gateway .

3.1.1 Plagiarism

Multiple Sclerosis Journal and Sage take issues of copyright infringement, plagiarism or other breaches of best practice in publication very seriously. We seek to protect the rights of our authors and we always investigate claims of plagiarism or misuse of published articles. Equally, we seek to protect the reputation of the journal against malpractice. Submitted articles may be checked with duplication-checking software. Where an article, for example, is found to have plagiarised other work or included third-party copyright material without permission or with insufficient acknowledgement, or where the authorship of the article is contested, we reserve the right to take action including, but not limited to: publishing an erratum or corrigendum (correction); retracting the article; taking up the matter with the head of department or dean of the author's institution and/or relevant academic bodies or societies; or taking appropriate legal action.

3.1.2 Prior publication

If material has been previously published it is not generally acceptable for publication in a Sage journal. However, there are certain circumstances where previously published material can be considered for publication. Please refer to the guidance on the Sage Author Gateway  or if in doubt, contact the Editor at the address given below.

3.2 Contributor's publishing agreement

Before publication, Sage requires the author as the rights holder to sign a Journal Contributor’s Publishing Agreement. Sage’s Journal Contributor’s Publishing Agreement is an exclusive licence agreement which means that the author retains copyright in the work but grants Sage the sole and exclusive right and licence to publish for the full legal term of copyright. Exceptions may exist where an assignment of copyright is required or preferred by a proprietor other than Sage. In this case copyright in the work will be assigned from the author to the society. For more information please visit the  Sage Author Gateway .

3.3 Open access and author archiving

Multiple Sclerosis Journal offers optional open access publishing via the Sage Choice programme and Open Access agreements, where authors can publish open access either discounted or free of charge depending on the agreement with Sage. Find out if your institution is participating by visiting Open Access Agreements at Sage . For more information on Open Access publishing options at Sage please visit Sage Open Access . For information on funding body compliance, and depositing your article in repositories, please visit Sage’s Author Archiving and Re-Use Guidelines and Publishing Policies .

4. Preparing your manuscript for submission

4.1 Formatting

The preferred format for your manuscript is Word. LaTeX files are also accepted. Word and (La)Tex templates are available on the Manuscript Submission Guidelines  page of our Author Gateway.

Manuscript Preparation: Submitting a new manuscript through the online system:

When making a submission, the following  separate, unpaginated  documents should be uploaded. Please do not submit one combined document. The separate files will be combined into a pdf in the online system.

• Title page (title, names of authors, affiliations, keywords, corresponding author)
• Main document (includes structured abstract, main text, acknowledgements, references)
• Tables (each as a  separate  Word document)
• Figure legends (Word document)
• Figures (as  separate  tiff, jpg or eps files)
• Any supplementary files

Submitting a Revision: After review the editors may invite submission of a revised manuscript. When submitting a revision, delete the original files (as these are saved with your original submission), and upload your revised manuscript only, following the usual submission guidelines. Changes to the manuscript must be marked using highlighting or track changes, and the authors’ response to the reviewers’ comments should be placed in appropriate box during the submission process. The text should be double-spaced throughout and with a minimum of 3cm for left and right hand margins and 5cm at head and foot. Text should be standard 10 or 12 point. Word counts as outlined in Table 1 re initial submissions, should still be adhered to.

Title page The title should be concise with no abbreviations. Please provide the surname, initials, department, institution, city and country of each author, and the name, email address, full mailing address, telephone number and fax number of the corresponding author to whom proofs should be sent. List six to eight keywords (chosen from Index Medicus, Medical Subject Headings if possible).

Abstract The second page of the manuscript must contain only the abstract, which should be of no more then 200 words and must be clearly written and comprehensive to readers before they have to read the paper. The abstract should be structured according to the following sub headings: Background, Objective, Methods, Results and Conclusion. Abbreviations should be avoided and reference citations are not permitted.  Any manuscripts submitted without a structured abstract will be returned to the author immediately without peer review, thus delaying the evaluation process of the manuscript. 

Introduction The introduction should assume that the reader is knowledgeable in the field and be as brief as possible.  

Materials and Methods Methods that have been published in detail elsewhere should not be described in detail. Avoid unnecessary detailed descriptions of widely used techniques. SI Units should be used throughout the text. Reports of experiments involving patients and healthy volunteers must describe the steps taken to obtain consent and to maintain confidentiality. Experiments involving animals must conform to accepted ethical standards.  

Tables Tables should be submitted in Word, typed on separate pages. Tables should be numbered consecutively with Arabic numerals, and cited as such in the manuscript. The preferred placing of tables in the main text should be indicated. Tables should include a brief descriptive title and be self-explanatory. Footnotes to tables indicated by lower-case superscript letters are acceptable, but they should not include extensive experimental details.

4.1.1 Units, Symbols and abbreviation

For detailed advice please refer to the guidelines in Baron, DN (1988). Units, symbols and abbreviations, 4th edn. (Obtainable from The Royal Society of Medicine, 1 Wimpole Street, London W1M 8AE, UK).

Note that the SI system of units is preferred. Due to the multidisciplinary nature of the readership and to avoid confusion, the number of abbreviations in the text should be kept to a minimum. Standard abbreviations acceptable without definition are limited to the following:

- CNS (central nervous system); CSF (cerebrospinal fluid); DNA (deoxyribonucleic acid); HLA (human leukocyte antigen; MRI (magnetic resonance imaging); CT (computerized tomography); MS (multiple sclerosis); RNA (ribonucleic acid).

Nonstandard definitions must be defined in full at their first usage in the abstract and again at their first use in the text.

4.2 Artwork, figures and other graphics

For guidance on the preparation of illustrations, pictures and graphs in electronic format, please visit Sage’s Manuscript Submission Guidelines .   

Authors should provide artwork and graphics in the best image quality possible. Figures supplied in colour will appear in colour online regardless of whether or not these illustrations are reproduced in colour in the printed version. For specifically requested colour reproduction in print, you will receive information regarding the costs from Sage after receipt of your accepted article. Please be aware that the ability to interpret the figure in black and white is important if colour printing is not chosen. 

4.3 Supplemental material

Multiple Sclerosis Journal is able to host additional materials online (e.g. datasets, podcasts, videos, images etc) alongside the full-text of the article. For more information please refer to our  guidelines on submitting supplemental files .

At submission authors are able to provide video abstracts or supplementary material in the format of a video. For further information regarding video abstracts please see the Sage Video Abstract guidelines . 

The video needs submitted along with the submitted manuscript with final decisions made by the Editor in Chief. All videos must be accompanied by written permission of any individuals featuring in all media forms for print and online publication.  Please note that an audio-visual release from must be completed for each individual contributor to the video. This form should be signed and submitted as 'audio-visual release form'. The form is located here .

Video properties:

• At least 640x480 resolution and at least 20 fps.
• The video compression should be of high quality. The Journal expects compression technology to evolve and so does not wish to be prescriptive over compression types. Today H.264 codec in an MP4 or AVI contained is a good choice. MPEG-1 and MPEG-2 are portable but have lower quality and larger files than the more modern codecs. We expect videos to be able to play on Windows 8 and back, Linux and Mac so proprietry formats, such as WMV and FLV, are discouraged.
• Note the Editors reserve the right to request authors to change the compression codec before publication.
• Videos should be below the 50MB mark and any video over this amount should provide a short preview to be hosted alongside the full file. Exceptions may be made at the discretion of the Editors.
• Format needs to follow the guidelines found here:  https://uk.sagepub.com/en-gb/eur/supplementary-files-on-sage-journals-sj-guidelines-for-authors

4.4 Reference style

Multiple Sclerosis Journal adheres to the Sage Vancouver reference style. View the Sage Vancouver  guidelines to ensure your manuscript conforms to this reference style.

If you use EndNote   to manage references, you can download the  Sage Vancouver EndNote output file .

4.5 English language editing services

Authors seeking assistance with English language editing, translation, or figure and manuscript formatting to fit the journal’s specifications should consider using Sage Language Services. Visit Sage Language Services  on our Journal Author Gateway for further information.

5. Submitting your manuscript

Multiple Sclerosis Journal is hosted on Sage Track, a web based online submission and peer review system powered by ScholarOne™ Manuscripts. Visit http://mc.manuscriptcentral.com/multiple-sclerosis to login and submit your article online.

IMPORTANT: Please check whether you already have an account in the system before trying to create a new one. If you have reviewed or authored for the journal in the past year it is likely that you will have had an account created.  For further guidance on submitting your manuscript online please visit ScholarOne Online Help .

As part of our commitment to ensuring an ethical, transparent and fair peer review process Sage is a supporting member of ORCID , the Open Researcher and Contributor ID. ORCID provides a persistent digital identifier that distinguishes researchers from every other researcher and, through integration in key research workflows such as manuscript and grant submission, supports automated linkages between researchers and their professional activities ensuring that their work is recognised.

The collection of ORCID iDs from corresponding authors is now part of the submission process of this journal. If you already have an ORCID iD you will be asked to associate that to your submission during the online submission process. We also strongly encourage all co-authors to link their ORCID ID to their accounts in our online peer review platforms. It takes seconds to do: click the link when prompted, sign into your ORCID account and our systems are automatically updated. Your ORCID iD will become part of your accepted publication’s metadata, making your work attributable to you and only you. Your ORCID iD is published with your article so that fellow researchers reading your work can link to your ORCID profile and from there link to your other publications.

If you do not already have an ORCID iD please follow this link  to create one or visit our ORCID homepage to learn more.

5.2 Information required for completing your submission

You will be asked to provide contact details and academic affiliations for all co-authors via the submission system and identify who is to be the corresponding author. These details must match what appears on your manuscript. The affiliation listed in the manuscript should be the institution where the research was conducted. If an author has moved to a new institution since completing the research, the new affiliation can be included in a manuscript note at the end of the paper. At this stage please ensure you have included all the required statements and declarations and uploaded any additional supplementary files (including reporting guidelines where relevant).

5.2.1 Social Media – Twitter @MSJ_Research

MSJ uses Twitter (@MSJ_Research) to engage with debate on Social Media. Authors and readers are encouraged to join the ongoing discussion around the twitter account on issues related to the Journal. MSJ authors are offered the option of providing their Twitter handle to be published alongside their name and email address within their article. Providing a Twitter handle for publication is entirely optional, if you are not comfortable with MSJ promoting your article along with your personal Twitter handle then please do not supply it.

By providing your personal Twitter handle you agree to let MSJ and Sage Publications to use it in any posts related to your Journal article. To include your Twitter handle within your article please provide this within the ScholarOne submission form when prompted and on the separate title page in the format outline below (please refrain from adding it to the manuscript itself to facilitate anonymous peer review).

As an example of how to supply this information please see the example below:

Joe Bloggs, Department of Neuroscience, University Hospital, Town, Zip code, USA Email:  [email protected] Twitter: @drjoebloggs

5.3 Permissions

Please also ensure that you have obtained any necessary permission from copyright holders for reproducing any illustrations, tables, figures or lengthy quotations previously published elsewhere. For further information including guidance on fair dealing for criticism and review, please see the Copyright and Permissions page on the  Sage Author Gateway .

6. On acceptance and publication

6.1 Sage Production

Your Sage Production Editor will keep you informed as to your article’s progress throughout the production process. Proofs will be made available to the corresponding author via our editing portal Sage Edit or by email, and corrections should be made directly or notified to us promptly. Authors are reminded to check their proofs carefully to confirm that all author information, including names, affiliations, sequence and contact details are correct, and that Funding and Conflict of Interest statements, if any, are accurate.

6.2 Online First publication

Online First allows final articles (completed and approved articles awaiting assignment to a future issue) to be published online prior to their inclusion in a journal issue, which significantly reduces the lead time between submission and publication. Visit the Sage Journals help page  for more details, including how to cite Online First articles.

6.3 Access to your published article

Sage provides authors with online access to their final article.

6.4 Promoting your article

Publication is not the end of the process! You can help disseminate your paper and ensure it is as widely read and cited as possible. The Sage Author Gateway has numerous resources to help you promote your work. Visit the Promote Your Article  page on the Gateway for tips and advice. 

7. Further information

Any correspondence, queries or additional requests for information on the manuscript submission process should be sent to the Multiple Sclerosis Journal editorial office as follows: [email protected]

Business   correspondence should be addressed to:

Multiple Sclerosis Journal   Sage Publications Ltd., 1 Oliver’s Yard, 55 City Road, London EC1Y 1SP, UK. Email:  [email protected]   Tel: +44-(0)20-7324-8500 Fax: +44-(0)20-7324-8600

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Multiple sclerosis - a review

Affiliations.

• 1 Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, London, UK.
• 2 Royal London Hospital, London, UK.
• 3 Blizard Institute, London, UK.
• PMID: 30300457
• DOI: 10.1111/ene.13819

Multiple sclerosis (MS) is the commonest non-traumatic disabling disease to affect young adults. The incidence of MS is increasing worldwide, together with the socioeconomic impact of the disease. The underlying cause of MS and mechanisms behind this increase remain opaque, although complex gene-environment interactions almost certainly play a significant role. The epidemiology of MS indicates that low serum levels of vitamin D, smoking, childhood obesity and infection with the Epstein-Barr virus are likely to play a role in disease development. Changes in diagnostic methods and criteria mean that people with MS can be diagnosed increasingly early in their disease trajectory. Alongside this, treatments for MS have increased exponentially in number, efficacy and risk. There is now the possibility of a diagnosis of 'pre-symptomatic MS' being made; as a result potentially preventive strategies could be studied. In this comprehensive review, MS epidemiology, potential aetiological factors and pathology are discussed, before moving on to clinical aspects of MS diagnosis and management.

Keywords: clinically isolated syndrome; diagnosis; disease-modifying therapy; epidemiology; multiple sclerosis.

© 2018 EAN.

Publication types

• Research Support, Non-U.S. Gov't
• Multiple Sclerosis / classification
• Multiple Sclerosis / epidemiology
• Multiple Sclerosis / genetics
• Multiple Sclerosis / therapy*

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• Published: 08 November 2018
• Multiple sclerosis
• Massimo Filippi 1 , 2 ,
• Amit Bar-Or 3 ,
• Fredrik Piehl 4 , 5 , 6 ,
• Paolo Preziosa 1 , 2 ,
• Alessandra Solari 7 ,
• Sandra Vukusic 8 &
• Maria A. Rocca 1 , 2  

Nature Reviews Disease Primers volume  4 , Article number:  43 ( 2018 ) Cite this article

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• Demyelinating diseases
• Immunological disorders

An Author Correction to this article was published on 22 November 2018

This article has been updated

Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system in young adults. This disorder is a heterogeneous, multifactorial, immune-mediated disease that is influenced by both genetic and environmental factors. In most patients, reversible episodes of neurological dysfunction lasting several days or weeks characterize the initial stages of the disease (that is, clinically isolated syndrome and relapsing–remitting MS). Over time, irreversible clinical and cognitive deficits develop. A minority of patients have a progressive disease course from the onset. The pathological hallmark of MS is the formation of demyelinating lesions in the brain and spinal cord, which can be associated with neuro-axonal damage. Focal lesions are thought to be caused by the infiltration of immune cells, including T cells, B cells and myeloid cells, into the central nervous system parenchyma, with associated injury. MS is associated with a substantial burden on society owing to the high cost of the available treatments and poorer employment prospects and job retention for patients and their caregivers.

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Progressive multiple sclerosis: from pathophysiology to therapeutic strategies

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Change history, 22 november 2018.

In the originally published version of this article, in Table 4, Ocrelizumab was incorrectly referred to as an anti-CD25 antibody. This has been corrected in the HTML and PDF versions of the article to an anti-CD20 antibody.

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Massimo Filippi, Paolo Preziosa & Maria A. Rocca

Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy

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Fredrik Piehl

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Introduction (M.F.); Epidemiology (S.V.); Mechanisms/pathophysiology (P.P. and A.B.-O.); Diagnosis, screening and prevention (P.P. and M.A.R.); Management (F.P.); Quality of life (A.S.); Outlook (all authors); Overview of Primer (M.F.).

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MINI REVIEW article

A quantitative synthesis of eight decades of global multiple sclerosis research using bibliometrics.

• 1 Department of Neurology, Ibn Sina Hospital, Kuwait City, Kuwait
• 2 School of Computing, University of Eastern Finland, Joensuu, Finland

Bibliometric studies on the field of multiple sclerosis (MS) research are scarce. The aim of this study is to offer an overarching view of the body of knowledge about MS research over eight decades–from 1945 to 2021–by means of a bibliometric analysis. We performed a quantitative analysis of a massive dataset based on Web of Science. The analysis included frequencies, temporal trends, collaboration networks, clusters of research themes, and an in-depth qualitative analysis. A total of 48,356 articles, with 1,766,086 citations were retrieved. Global MS research showed a steady increase with an annual growth rate of 6.4%, with more than half of the scientific production published in the last decade. Published articles came from 98 different countries by 123,569 authors in 3,267 journals, with the United States ranking first in a number of publications (12,770) and citations (610,334). A co-occurrence network analysis formed four main themes of research, covering the pathophysiological mechanisms, neuropsychological symptoms, diagnostic modalities, and treatment of MS. A noticeable increase in research on cognition, depression, and fatigue was observed, highlighting the increased attention to the quality of life of patients with MS. This bibliometric analysis provided a comprehensive overview of the status of global MS research over the past eight decades. These results could provide a better understanding of this field and help identify new directions for future research.

Introduction

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS) characterized by inflammation, demyelination, followed by neurodegeneration. MS typically presents in young adults in the third or fourth decade of life, with females two times as likely to be affected ( 1 ). MS is one of the leading causes of neurological disability in young adults, resulting in remarkable socioeconomic impacts and the need for lifetime support and management ( 2 ). A total of 2.8 million people are estimated to have MS worldwide ( 3 ). The prevalence of MS in the population has shown a 30% increase in 2020, compared to 2013, in every world region. The 2020 global prevalence of MS is 35.9 per 100,000 people, while the pooled incidence rate is 2.1 per 100,000 persons/year ( 3 ).

Since the first modern clinical description of a case of MS in the medical literature by Ollivierd' Angers in 1824 ( 4 ), there has been a considerable growth in scientific publications in the field of MS research ( 5 ). In the last few decades, technological advances in genetics, molecular medicine, pathology, and imaging had encouraged researchers all over the world to publish a vast amount of papers, aiming at a better understanding of the etiology, pathogenesis, clinical features, diagnosis, and treatment of MS ( 6 ).

The number of articles and their citations are considered a strong indicator of the importance of this disease. However, there has been little examination of the precise publication patterns and characteristics in MS, and bibliometric studies are rare. Aleixandre-Benavent and his colleagues ( 7 ) presented the only global bibliometric analysis of MS research from 2003 to 2012 to the best of our knowledge, while Espiritu and colleagues ( 8 ) examined the scientific impact of MS and Neuromyelitis Optica spectrum disorder research in Southeast Asia. The most recent analysis has been an Altimetric study based on the top 100 discussed papers over social media ( 9 ).

Bibliometrics is an interdisciplinary science that uses mathematical and statistical methods to analyze and quantitatively evaluate the contribution and productivity of a research field, including different countries, institutions, journals, or authors. Bibliometric studies have been used to provide a clear presentation of publication characteristics, hotspots, and research trends in a specific field to help guide policy decision-making ( 10 ). In doing so, bibliometrics allow an overarching view of a field of knowledge, the creators (authors and countries), the dissemination outlets (e.g., journals), the themes of knowledge, and their evolution ( 11 ). There is, of course, a tradeoff between inclusivity of thousands of articles (e.g., in bibliometrics) and in-depth fine-grained evaluation (e.g., in systematic reviews). Both types of scientific synthesis serve a function that is rather complementary.

In this work, we conducted a bibliometric analysis of the published literature related to MS research included in the Web of Science databases (WoS), over the past eight decades worldwide, which has not been performed so far, to our knowledge. This bibliometric analysis provides insight into the core body of knowledge about MS, the creators, the way it was disseminated, and the trends in MS research to have a better understanding of the current research, impact, gaps, and possible future scientific research.

The data were retrieved from the Web of Science (WoS) database on April 29, 2021 using the query “multiple sclerosis” OR “disseminated sclerosis.” WoS offers a robust database with curated sources that are subject to rigorous quality control and therefore, ensures that all journals are of good scientific integrity ( 12 ). Only original English articles that were peer-reviewed were retrieved with them with all their meta-data available in WoS. Since the data were retrieved from a single database, there were no duplicates. The data were retrieved and cleaned, so misspelled author names, names with several spellings, and special characters were fixed and combined. Keywords were cleaned with Google Openrefine, which has several natural language processing and clustering algorithms for the detection of keywords with similar spellings, e.g., (“ autoimmune disease ,” “ autoimmune diseases ,” “ auto-immune disease ,” and “ auto-immune diseases ”), all of such keywords were detected and combined. Manual combination was also performed to combine identical keywords that were not similar in spelling, e.g., (“MS,” “ multiple sclerosis ”) but had an identical meaning. This step was necessary to avoid the fragmentation of keywords, i.e., the same keyword written in different forms and therefore, could cloud the accuracy of the different counts and trends. The original keywords were retained and tabulated in the results section. Two other types of keywords were mined from the titles and abstracts to extract the most frequently recurring keywords in articles abstracts or titles.

The cleaned dataset was analyzed using Bibliometrix package ( 13 ). Bibliometrix offers a comprehensive platform for the analysis of bibliometrics data, which includes the extraction, tabulation, and calculation of the frequencies of articles, authors, keywords, countries, and citations (according to WoS). Since a manuscript has no formal country, the country was extracted according to the corresponding author of each country. For the country collaboration network, authors who are collaborating on the same article are considered connected. The network was partitioned (divided into connected clusters) using the Louvain modularity for community detection ( 14 ) and plotted using the Fruchterman Reingold layout algorithm ( 15 ). A similar network was constructed for the keywords by considering the keywords that co-occurred in the same manuscript as connected; the network was partitioned and plotted in the same way as the country network. For clarity, the topmost connected nodes were displayed using a threshold of degree centrality of 850, which left 57 nodes in the network.

The dataset statistics and frequencies were plotted using the functions provided by the Bibliometrix package. For keyword trends, two trends were created: (1) a simple frequency plot with the number of articles on the Y-axis and the year on the X-axis (2) a proportional plot where the fraction of the total articles published at each given year was plotted against the Y-axis.

General Analysis

The dataset for this study spanned over eight decades during the period of 1945–2021 ( Table 1 ). The dataset included 48,356 original research articles; the majority of which were journal articles, 46,611 (96.4%), who received a total of 1,766,086 citations. This long journey started with only seven articles in 1945 and expanded exponentially to reach 3,101 articles in 2020. Just around half of the articles ( n = 24,424; 50.5%) were published during the last decade, which indicates that our dataset is more representative of recent research. Each of the included manuscripts was cited on average 36.5 with a yearly citation rate of 2.8, an indication of the relatively high potential for MS articles to be cited. Only 5.3% of the documents in our dataset were not cited, given that our dataset contained articles from 2020 and 2021 that were too soon to be cited; this is a very low percentage. A total of 123,569 authors contributed to the articles in our dataset, with only a small number of articles authored by a single author, 1,747 (3.7%), indicating that collaboration on articles was the rule. In the same vein, the average number of authors in the manuscript was 2.6. The average yearly growth rate of articles was 6.4 over the entire duration, 5.1 over the last decade, and 6.5 over the last two decades, indicating a steady and relatively stable rate of increase of MS research.

Table 1 . Main information about the bibliometric dataset.

Country Analysis

The published articles on MS during this period came from 98 different countries. A world map of country productivity and a list of the top 25 countries are illustrated in Figure 1 . The country with the greatest number of published articles was the USA ( n = 12,770), followed by Italy ( n = 4,310), the United Kingdom ( n = 3,503), Germany ( n = 3,369), and Canada (2,404). Other countries that exceeded 1,000 manuscripts were France ( n = 1,502), the Netherlands ( n = 1,463), Spain ( n = 1,437), China ( n = 1,410), Japan ( n = 1,203), Sweden ( n = 1,154), Iran ( n = 1,140), and Australia ( n = 1,115). The country with the highest number of citations was also the USA ( n = 610,334). Other countries that exceeded 100,000 citations were the United Kingdom ( n = 184,932), Italy ( n = 128,079), Germany ( n = 116,697), and Canada ( n = 103,437).

Figure 1. (A) A world map with the distribution of country productivity, (B) a cumulative evolution of the number of MS papers by the top 25 countries.

With regards to scientific collaboration, the USA was the leading country with a total of 10,272 single country publications (SCP), and 2,498 multiple country publications (MCP), with an MCP ratio of 0.195, which shows that the majority of the publications from the USA were single country publications. As shown in Figure 2 , the network of collaboration shows a pink cluster representing developed countries who share languages, e.g., the USA, Canada, Australia, and New Zealand and their collaborators from Asia, e.g., China, Korea, Japan, India, and Singapore, and the Middle East and North Africa (MENA) region, e.g., Egypt, Kuwait, Iran, and Saudi Arabia. Another green cluster of countries is made of northern European countries, Sweden, Denmark, Finland, and their collaborators. A blue cluster is seen showing countries who have German as their official language, in addition to France. We also see an orange cluster made of other European countries, e.g., the UK, Italy, and the Netherlands. Over the last decade, several MS societies around the globe have been collaborating in data collection to accelerate research insights into innovative care and treatment for people with MS through better use of real-world data ( 16 , 17 ).

Figure 2 . Network of international collaborations in MS-related articles (countries that frequently collaborate have a similar color; circle size indicates papers per country, and line thickness indicates the number of co-authored articles).

Our findings could also be explained—at least partially—by epidemiological data of MS as well as country development, i.e., well-developed countries that suffered from considerable MS prevalence have shown a strong appearance in our data. The Atlas of MS ( www.atlasofms.org ), which is an open-source global compendium of data on the epidemiology of MS compiled by the Multiple Sclerosis International Federation (MSIF), collected epidemiologic data from 115 countries representing 87% of the world's population in 2020 ( 3 ). It has shown significant increase in MS cases, both as a proportion of their populations (MS prevalence) and in terms of growing cases (MS incidence) across North America and several European countries (the United Kingdom, Germany, Denmark). Although Europe had the highest reported incidence at 6.8, followed by the Americas at 4.8, Canada showed the highest prevalence as a country, at 168 people per 100,000, and the highest incidence, at 5.63 per 100,000 ( 18 ), while the US almost doubled its prevalence (913,925 cases) from 2013 to 2019 ( 19 ). Moreover, increasing prevalence was also reported across the MENA region, in addition to the Russian Federation, and Australia. South East Asia and Africa had the lowest reported incidence rates of 0.4 ( 3 ), which can explain the underrepresentation of these countries in our data.

Most Cited Papers

The analysis of the most seminal articles gives an idea about the directions of the research on MS and how the community of MS researchers responded to or were influenced by certain strands of research. A total of 48 articles in literature received 1,000 citations or more. Table 2 presents the top 20 most cited articles, where all of them exceeded 1,500 citations. Among them, six articles evaluated the pathophysiological underpinnings of MS, five articles investigated MS treatments, five articles described MS diagnostic criteria or its revisions, two articles proposed severity scales, one article evaluated antibody markers to differentiate neuromyelitis optica from MS, and a single article on the role of vitamin D in immune disorders.

Table 2 . The list of the top 20 most cited papers within our dataset.

The article that received the most citations was the seminal work of Kurtzke et al. on rating neurologic impairment in patients with MS using an expanded disability status scale (EDSS) by 10,052 citations ( 20 ). John Francis Kurtzke (1926–2015) was a renowned neuro-epidemiologist and Professor of Neurology at Georgetown University, who authored more than 200 peer-reviewed articles. However, he is best known for developing the Disability Status Scale (DSS) in 1954 and EDSS in 1983. Since then, EDSS has become the most commonly used clinical scoring system to evaluate the overall functional disability of patients with MS, with a score ranging from 0 (normal) to 10 (death due to MS) in half-point increments. It has the merits of objectively displaying the differences in an MS clinical picture over time, which can be said for only a small number of scales ( 21 ).

The rest of the top five most cited articles discussed the diagnostic criteria of MS. The work of Poser et al., which proposed a new diagnostic criterion of MS in 1983, was second with 6,770 citations ( 22 ). Charles Poser and a group of American, Canadian, and British MS experts met in April 1982 for the purpose of developing new diagnostic criteria for MS, using the increasing availability of evoked potentials and neuroimaging in the late 1970's. The criteria were published in 1983 and consisted of two major groups, definite and probable, each with two subgroups: clinical and laboratory supported ( 22 ). The third article was the work of Polman et al. on revising McDonald diagnostic criteria of MS in 2011 with 5,428 citations ( 23 ), followed by the original famous diagnostic criteria proposed by McDonald et al. and published in 2001 in fourth place, with 4,985 citations ( 24 ). William Ian McDonald (1933–2006) was a professor of neurology at the Institute of Neurology of the University of London, England, who was the world's leading authority on MS in the second half of the twentieth century. The McDonald criteria were named after him as he directed an international panel in association with the National Multiple Sclerosis Society (NMSS). Two major changes were introduced: magnetic resonance imaging (MRI) criteria were incorporated into the scheme, and long-needed guidelines for the diagnosis of primary progressive MS were defined. The criteria underwent three revisions in 2005, 2010, and 2017, with the 2005 revision by Polman et al. coming in fifth place with 3,732 citations ( 25 ). It is worth mentioning that Chris Polman, a professor of neurology at VU University Medical Center, Amsterdam, Netherlands, and his colleagues published three articles of the top 10 articles; two on revising McDonald diagnostic criteria of MS in 2005 and 2011, and a randomized, controlled clinical trial of the use of natalizumab in MS ( 26 ). In a 2014 study, two papers published by Polman et al. received the most citations in MS research ( 7 ). A scale assessing fatigue severity in patients with MS by Krupp et al. came in sixth place with 3,218 citations.

Among the top 20 most cited articles, six articles evaluated the pathophysiological mechanisms in MS. The work of Trapp et al. ( 27 ) on axonal transection as the pathologic correlate of the irreversible neurologic impairment in MS came in 7th place with 3,032 citations. This was followed by the work of Lucchinetti et al. on the different patterns of demyelination in MS plaques (2,157) ( 28 ), Liddelow et al. on the neurotoxic role of reactive astrocytes in CNS (1,761) ( 29 ), Maurano et al. on the involvement of regulatory DNA variations in diseases (1,708) ( 30 ), Sawcer et al. on genetic risk in cell-mediated immune mechanisms in MS (1,707) ( 31 ), and Chen et al. on suppression of autoimmune encephalomyelitis by regulatory T cell clones, induced by oral tolerance (1,621) ( 32 ). These important studies had been a cornerstone in the current knowledge regarding fundamental pathophysiological processes behind the disease, which led to better disease diagnosis, classifications, and management. Another five articles investigated MS therapeutics, two articles on interferon β-1a ( 33 , 34 ), one article for each of interferon β-1b ( 35 ), natalizumab ( 26 ), and fingolimod ( 36 ). These were randomized double-blind placebo-controlled trials that had been the result of a collaborative work of several international research groups, which eventually led to the U.S. Food and Drug Administration (FDA) approval of these therapeutics.

Author Analysis

The list of the top 10 most influential authors in MS research is shown in Table 3 , representing those with the highest numbers of total citations, in addition to h-index, g-index, and total number of publications. Interestingly, all of the top 10 came from European countries, with half of them coming from the UK and Italy. Six of them authored articles that were cited 30,000 times or more. Massimo Filippi holds the top position of the list in both the number of total citations (39,896), as well as the number of publications (522). Filippi M is a professor of neurology at Università Vita-Salute San Raffaele, Milan, Italy. His most cited work was titled “Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria” with 5,428 citations ( 23 ). In May 2010 in Dublin, Ireland, the International Panel on the Diagnosis of MS revised the 2005 version of the McDonald criteria, simplifying the criteria, and allowing for a more rapid diagnosis, with equivalent or improved specificity and/or sensitivity. The panel adopted new MRI criteria for dissemination in time (simultaneous asymptomatic gadolinium-enhancing and non-enhancing lesions on baseline MRI scans), and dissemination in space (i.e., at least one T2-lesion in two or more of the following CNS regions: periventricular, juxta-cortical, infratentorial, and spinal cord). Moreover, this revision improved the criteria's applicability to other populations (pediatric, Asian and Latin Americans).

Table 3 . Top 10 authors with the highest number of total citations, also showing h-index, g-index, number of publications, and country.

The second author is Miller DH (38,080) with his paper titled “A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis,” receiving the highest number of citations with 2,094 citations ( 26 ). The data from this 2-year study (the AFFIRM study), in addition to data from (the SENTINEL study) demonstrated clear and dramatic reduction in MS clinical relapse activity, disability progression, and new MRI lesions, ultimately leading to the FDA approval of natalizumab for relapsing forms of MS. Comi G came third (36,256 citations), with a total of 1,707 citations for his most cited paper titled “Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis” ( 31 ). This collaborative genome-wide association study (GWAS) involved 9,772 cases of a European descent, collected by 23 research groups from 15 different countries. The paper confirmed the major role of genes related to T-cell-mediated inflammation in the pathogenesis of MS through replicating almost all of the previously suggested susceptibility loci and identifying at least further 29 novel loci.

The following three authors in the list were Kappos L in the fourth place (35,641), followed by Thompson AJ in fifth (32,417), and Polman CH in the sixth place (30,563). Their article on revising the McDonald diagnostic criteria for MS in 2010, which was the same article by the first author, was their most cited work ( 23 ). Of the top 10 authors, four had <30,000 citations; Hartung HP came in the 7th place (28,908); Barkhof F in the 8th place (28,515); Montalban X in the 9th place (26,556); and Olsson T (15,209) in the 10th place. The work on genetic risk and the role of cell-mediated immune mechanisms in MS was the most cited for both Hartung HP and Olsson T, the same as Comi G ( 31 ). Furthermore, the 2010 revisions to the McDonald criteria were the most cited work for Montalban X ( 23 ).

The highest cited paper for Barkhof F was “Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis” by 1,470 citations ( 37 ). This important phase III study was a 1-year, double-blind, double-dummy trial conducted on 1,292 patients by TRANSFORMS Study Group (ClinicalTrials.gov number, NCT00340834). It showed superior efficacy of oral fingolimod over intramuscular IFN-β1a as regards to relapse rates and MRI outcomes in patients with MS. This study, along with another 2-year, double-blind Phase III study (known as FREEDoMS), led to the FDA approval of fingolimod in 2010, as the first oral disease-modifying therapy. Finally, as regards to h -Index, Barkhof F was found to have the highest score (97), followed by Comi G (92), Filippi M (90), and Hartung HP (89). Despite its shortcomings, h -Index is an important tool in evaluating the output of an individual researcher, as well as providing an indication of the quality and consistency of the researcher's work by measuring the number of articles published and the number of citations received over time.

Journal Analysis

The papers were published in 3,267 journals, of which 8 journals published more than 1,000 articles, as shown in Table 4 . Unsurprisingly, the journal with the highest number of articles was Multiple Sclerosis Journal ( MSJ ) with 3,335 articles. MSJ (formerly Multiple Sclerosis ) was first established in 1995, and as of 2020, it ranked 28 out of 208 journals in the category “clinical neurology,” The impact factor (IF) of MSJ has tripled since it was first included in the Journal Citation Reports (JCR), from 2.154 in 1999 to 6.312 in 2020. The journal is in the first quartile of their subject category (Q1), with an h-index of 131.

Table 4 . The top journals in the field of MS research.

This was followed by Journal of Neuroimmunology ( n = 2,003), a Q2 journal interested in publishing articles that involve immunologic methodology or fundamental immunology, with an IF of 3.478 in 2020. Neurology , the official journal of the American Academy of Neurology, came in third place with 1,531 citations. The journal is one of the most widely read and highly cited journals in the field of neurology, with an IF of 9.901 in 2020. This was followed by two Q2 journals : Journal of the Neurological Sciences , the official journal of the World Federation of Neurology, in the fourth place ( n = 1,409), and Multiple Sclerosis and Related Disorders ( n = 1,229), with an IF of 3.181 and 4.339, respectively.

Regarding the total number of citations, six journals exceeded 50,000 citations, with the greatest number for Multiple Sclerosis Journal ( n = 103,608), followed by Neurology ( n = 99,242). Annals of Neurology came in third place with 82,166 citations. This journal has a broad interest in the mechanisms and treatment of neurological diseases, with an IF of 10.422. It ranks 9th out of 208 journals in the category “clinical neurology.” This was followed by Brain ( n = 73,186), Journal of Neuroimmunology ( n = 63,074), and Journal of Immunology ( n = 50,997). However, the journal with the highest number of citations per article among the top 50 articles was The Lancet (166.76), despite publishing only 148 articles with a total citation of 24,681. This high-impact general medical journal ranks second among 169 general and internal medicine journals globally (2020), with an IF of 79.321. This metric illustrates the importance of MS research and its impact on the scientific community. Annals of Neurology came in the second place (139.11), followed by Brain (134.573), and Proceedings of the National Academy of Sciences of the United States of America (97.09). Brain is a high-impact peer-reviewed neurology journal, founded in 1878 and published by Oxford University Press. It has an IF of 13.501 and ranks six out of 208 journals in the category “clinical neurology,” while Proceedings of the National Academy of Sciences of the United States of America is the official journal of the US National Academy of Sciences, which was published in 1914, with an IF of 11.205.

Research Topics

MS literature has a broad spectrum of research fields, and most of the authors include their research topic in the document keywords. In this section, author keywords were analyzed to find the main trends in the different topics. The analysis of keywords can give valuable information about the themes of research. The evolution of keywords can inform us about the trends of past and future research, while analysis of the groups of keywords (clusters) can help us infer the main strands of MS research. Therefore, our analysis has included frequencies, trends, and keywords network with clusters.

Keywords Frequency

Our dataset analysis shows that the most frequent keywords were multiple sclerosis (25,191), experimental autoimmune encephalomyelitis (EAE) (3,374), MRI (3,292), inflammatory (1,577), and demyelinating disease (1,507). The most common titles included patients with multiple sclerosis (2,253), EAE (2,158), relapsing remitting multiple sclerosis (1,178), central nervous system (784), progressive multiple sclerosis (701), and MRI (505). The rest of the top 20 keywords, titles, and abstracts are shown in Table 5 .

Table 5 . The top 20 most frequent keywords, keywords extracted from titles and abstracts.

Keyword Co-occurrence Network Clusters

A keyword knowledge co-occurrence network was created, as visualized in Figure 3 . The network shows a tightly knit group of clusters, representing the hotspots and main trends of research topics in MS over the previous eight decades based on the top authors' keywords. The larger the node is, the more significant the keyword will be, and the thicker the line is, the stronger the link would be.

Figure 3 . A co-occurrence network analysis map showing associations between keywords in the dataset, with the keyword “multiple sclerosis” removed. The size of the circle indicates the keyword count in the sample, line thickness indicates co-occurrence frequency, and colors indicate a cluster of keywords.

The main research hotspots are summarized in the following themes.

Pathophysiology of MS

Further left on this map were the clusters representing the main pathophysiological mechanisms implicated in the development of MS (orange, light-green, dark-green) and included the following main keywords: “EAE,” “inflammatory,” “demyelinating disease,” “autoimmune disease,” “T-cells,” “lymphocytes,” “cytokines,” “chemokines,” “interleukins,” “blood-brain barrier,” “microglia,” “oligodendrocytes,” “astrocytes,” “macrophages,” “neurodegenerative disease,” and “oxidative.”

The largest node was the experimental autoimmune encephalomyelitis (EAE), which is the most commonly used experimental animal model for MS. It represents an interaction between a variety of immunopathological and neuropathological mechanisms that led to an approximation of the key pathological features of MS: inflammation, demyelination, axonal loss, and gliosis ( 42 ). This model is produced by administering a myelin basic protein peptide (MBP) fragment that induces an autoimmune response directed to the myelin sheath surrounding motor neurons ( 43 ). EAE was first described more than 85 years ago ( 44 ) and has been extensively used in MS research as a good model for understanding MS pathophysiological mechanisms. Furthermore, the use of EAE has expanded beyond the laboratory study of MS into the development of MS therapeutics as well.

The role of T-cells, cytokines, chemokines, and interleukins was evident in MS research, as illustrated by their node size and dense connections. T-cells play a key role in CNS inflammation through the regulation of a complex interplay between pro- and anti-inflammatory cytokines and interleukins, leading to the disruption of a blood-brain barrier and CNS demyelination ( 45 ). Several interleukins have been implicated in MS development, including IL-1β, IL-6, IL-17 TNFα (Tumor Necrosis Factor-α), and IFN-γ (Interferon-γ) ( 46 ). Although current evidence suggests that “B-cells” play a comparably important role to T-cells in CNS demyelination through differentiating plasma cells, producing autoreactive antibodies, and regulation of pro- and anti-inflammatory cytokines ( 47 ), this keyword was absent from the map. This could be related to the use of other keywords (e.g., lymphocytes, antibody) that could refer to B-cells, along with the relative recency of these emerging theories to be among the top keywords. Moreover, the role of activated macrophages and microglia in driving ongoing neurodegeneration was illustrated in the map, in addition to the role of oxidative injury as a major mechanism of both demyelination and neurodegeneration ( 48 ).

Interestingly, other neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease, were among the hotspots in the map. This could be explained through the pathophysiological mechanisms of neurodegeneration that affect these disorders. Chronic inflammation with microglia activation is also believed to play a major role in the formation of AD ( 49 ). In addition, studies have shown that MS could affect deep gray matter structures, leading to axonal loss in dopaminergic pathways, which could be responsible for the Parkinsonian features in such cases ( 50 ).

Neuropsychological Symptoms, Disability, Quality of Life, and Rehabilitation

To the far right of the map, a cluster representing neuropsychological symptoms of MS is present (red), containing the following keywords: “depression,” “cognition,” “fatigue,” and “psychology.” They were also quite closely related to “disability,” “quality of life,” and “function.” This highlights the importance of non-motor symptoms and the increasing attention in MS research to their impact on disability and quality of life (QoL). Moreover, the trends in Figure 4 show that these topics are increasing in both frequency and trends, although their total fraction is still thin, ranging from the low of 0.5–2.5% of all MS articles.

Figure 4. (A) The trend of the proportion of articles containing the top 20 most used keywords at each given year; (B) the trend of their frequency at each given year.

The literature on cognition in MS has grown exponentially over the last 25 years, since Rao et al. ( 51 ) brought renewed attention to cognitive dysfunction as a core symptom of MS. Cognitive rehabilitation research is a nascent field, aiming at restoring cognitive function, or teaching compensatory strategies to attenuate the deleterious effect of refractory cognitive deficits on QoL ( 52 ). Fatigue, as one of the most common and troubling symptoms of MS, was found to be equally important as well. Evidence in literature showed a strong correlation between fatigue and physical functioning, disability, and QoL scores in patients with MS ( 53 ).

MS-related depression is another important clinical entity, with an estimated lifetime prevalence of more than 50%, and an annual prevalence of 20% ( 54 ). It took more than 100 years for researchers to turn their attention to the substantially negative impact of depression on QoL. The past two decades showed a growing trend of MS-related depression research; however, future studies still require a rigorous definition of a valid clinical phenotype of depression based on quantitative assessment, and constructing validity through brain imaging, immunological, and psychosocial research ( 55 ).

The keyword “rehabilitation” appeared among the top 20 in the analyzed studies; such findings are significantly different from the earlier bibliometrics which reported a negligible frequency of “rehabilitation” in their study ( 56 ). This could be partially attributed to the use of other keywords (e.g., functional assessment, disability) in earlier studies, besides the increasing attention to the value of rehabilitation in recent years.

Diagnosis of Multiple Sclerosis

The largest node of this cluster (purple) represents MRI, which can be seen densely connected to other clusters concerned with the pathophysiology and treatment of MS. It is also connected to other important diagnostic modalities, including “CSF,” “biomarkers,” and “antibody” (light blue). MRI was first introduced in the late 1970's, while the first MRI for a patient with MS was performed in 1981. Since then, this new technology has become an important paraclinical tool for diagnosing MS, monitoring therapeutic response, and in MS research ( 57 ). The main principle of MS diagnosis is based on showing dissemination of white matter lesions in space and time, and MRI was found to be the most sensitive method for revealing such dissemination, allowing for early diagnosis of CIS and MS and to rule out other differential diagnoses ( 58 ). Advanced MRI techniques, such as magnetization transfer imaging, spectroscopy, and functional MRI, have also been used in detecting tissue changes in MS, expanding our understanding of the pathogenesis of the disease ( 59 ).

In recent years, the use of the term “biomarkers” has shown a vast expansion in MS scientific literature, aiming at improving disease diagnosis, predicting disease progression, and improving clinical outcomes. Biomarkers currently in clinical use include oligoclonal bands (OCBs), MRI, JC viral titers, neurofilaments and GFAP in blood, and cerebrospinal fluid (CSF) ( 60 ).

Treatment of MS

At the top of the map (purple), there are four main disease-modifying therapies (DMTs): interferons, glatiramer acetate, natalizumab, and fingolimod. Although the pharmacological armamentarium for MS is currently expanding significantly, these drugs had been proved to be effective and well-researched throughout the past decades. In the 1980's, clinical trials were conducted to develop new MS treatments, and in the early 1990's, interferons and GA were approved as the first long-term treatments to affect the course of MS. IFNs impact the immune system in several ways, such as regulation of interleukins, and decreasing T helper (Th)-1 and Th17 production, which leads to an overall anti-inflammatory effect ( 61 ). Meanwhile, the mechanism of action of GA is not completely understood; however, most investigations have attributed its immunomodulatory effect to its capability to alter T-cell differentiation through promoting the development of Th2-polarized GA-reactive CD4 (+) T-cells ( 62 ).

In 2004, natalizumab was FDA approved as the first monoclonal antibody treatment for MS. It inhibits the migration of leukocytes into the brain, which results in reduced inflammation through blocking leukocyte α4 integrins binding to their endothelial receptors. In addition, fingolimod, a sphingosine-1 phosphate (S1P) receptor modulator, was the first oral DMT to be approved for MS. Both drugs had shown high-efficacy in clinical trials, compared to IFNs, with a relatively acceptable safety profile ( 63 ). However, more research is still needed to develop therapies for halting neurodegeneration, promoting remyelination, and promoting neuronal repair.

Keyword Trends

Keyword trends explain the increase and decline of popularity in particular research areas. Figure 4 illustrates the absolute frequency (number) of the top 20 most used keywords and their relative frequency (share) throughout the years. Certain research topics have shown increase in frequency and in proportional trends (i.e., the ratio of the yearly articles), such as cognition, depression, disability, and fatigue. The growth of these research themes in recent years has indicated the increased awareness of MS researchers to the importance of the non-motor symptoms of MS and their impact on QoL. However, their increase constituted only 2.5% of the percentage of research, and more studies are still needed to optimize the overall outcome of patients with MS. Other research topics have declined over time such as interferons. The focus of research seems to have shifted away from interferons by the end of 2000's, coinciding with the development and approval of newer drugs with higher efficacy, although they are still used as active comparators in clinical trials ( 64 ). It is worth mentioning that a down trending keyword share is not synonymous with decreasing research, as the keyword may have become so prevalent that it is no longer necessary to use it as a keyword (e.g., autoimmune disease, demyelinating disease, and MRI).

Our bibliometric study on MS research spanned around eight decades, from 1945 to 2020, with a total of 48,356 articles. We offer a comprehensive and quantitative overview on the distribution of MS research by country, author, and journal during the assigned period of time. Moreover, we highlight the main themes and trends of research and how they evolved over time through reviewing the important keywords, keyword clusters, and seminal articles.

The number of published articles on MS has increased by 79.3% over the past 20-year period, with more than half of the scientific production published in the last decade. Although such a rate of growth is below the rate of all medical disciplines, which was around 96%, it is still higher than other specialties such as cardiovascular medicine, which had a growth rate of 64% during the same period ( 65 ). This notable growth may be a result of the increasing awareness of the burden of MS, the recent technological advances in diagnostic modalities, along with the significant increase in the number of registered clinical trials in recent years ( 66 ). Furthermore, we noticed increasing trends of research addressing the QoL of patients with MS, such as cognitive dysfunction, fatigue, and depression. Such themes of research have been barely visible within the earlier decades' studies, despite their huge impact on the disease outcome. Interestingly, only 5.3% of the documents in our dataset were not cited. This was found to be much lower than the reported percentage in 2012, which was 14.88% ( 7 ), reflecting the high impact and relevance of MS research in recent years.

Analysis by country affiliation of the primary author showed that the USA and European countries are still leading the research and the scientific collaborations on MS. The order of the top five countries remained the same when compared to what Aleixandre-Benavent et al. ( 7 ) reported in their bibliometric analysis in 2014, with the USA on top, followed by Italy, the UK, Germany, and Canada. The USA has produced a number of publications that are almost equal to the number of articles produced by the other four countries combined, with the majority being single-country publications. The number of articles published by Asian countries was found to be growing rapidly. China, for example, ranked 9th in MS scientific production, compared to the 25th place in 2012 ( 7 ). Besides population size, the socioeconomic status as illustrated by the gross domestic product (GDP) is one of the main factors related to research productivity. Countries with rapidly growing economies are expected to have more investment in research and subsequently contribute more to the growth of MS research ( 67 , 68 ).

The number of articles published by countries from the MENA region has increased in recent years, which can be explained by the increase in disease prevalence in various MENA countries, as well as the recent advances in MS registries, allowing for nation-wide studies ( 69 ). It should be noted that some authors who are not native English speakers tend to publish their research in regional journals of their own language. This may explain why some big countries such as Russia do not appear among the top 25 producers of MS research, with most of their scientific production published in Russian language journals. Thus, their actual contribution to MS literature might be underrepresented in our analyses, especially as non-English articles are infrequently cited in international literature ( 70 ). As is common to most scientific fields, the knowledge we have at hand about MS remains heavily skewed toward the Western and industrialized countries ( 71 ). Therefore, we cannot claim in any credible way that we know the full breadth of MS as a disease in terms of pathology, symptomatology, or neuropsychological burden. A collaborative research that brings different countries together may help bridge the chasm in human knowledge.

The top 10 journals identified in the present study differed slightly from those reported in the bibliometric study between 2003 and 2012 ( 7 ), as MSARD (5th) and Acta Neurologica Scandinavica (8th) joined the list, while Annals of Neurology (11th) and European Journal of Neurology (14th) left. They contributed to 29.2% of the total number of publications. Although nine out of those 10 were neurological journals, MS research had been published in non-neurological subject areas as well, including but not limited to, general and internal medicine, psychiatry, biochemistry, and biology journals. MS requires a coordinated multidisciplinary collaboration of different medical specialties, which can be seen reflected on scientific publications. Multiple Sclerosis Journal still has the largest share of published articles with a contribution of 6.9% of all MS research, in addition to receiving the most citations.

The most cited original article was the famous work of Kurtzke et al. on assessing physical disability in patients with MS using EDSS ( 20 ), which has been used unchanged for more than 30 years, signifying its importance in clinical practice and in MS literature. Interestingly, this article was not among the top 20 in the earlier 2012 analysis ( 7 ), which could imply a recent trend in research that focuses on disability in the past decade, as a part of improving QoL and the general wellbeing of patients with MS, in addition to its well-known advantages as a standardization measure in clinical trials ( 72 ). However, EDSS has some documented weaknesses, including its heavy dependence on mobility, limited inter-and intra-rater reliability, insensitivity to changes in performing activities of daily living, and the lack of cognitive function assessment ( 73 ). As a result, several supplemental scales have been proposed to ameliorate these limitations in the last decade ( 74 , 75 ).

According to the results of the co-occurrence network analysis, four highly connected clusters were observed. The main cluster, judged by its node size and connections, was the pathophysiological mechanisms of MS. Researchers have been extensively using the EAE model for more than 85 years, not only for better understanding of MS, but also for development of new therapeutic options ( 76 ). These studies have led to the generally accepted hypothesis that MS is mediated by pathogenic CD4+ T-cells, which secrete several proinflammatory interleukins against myelin antigens, followed by a broader neurodegenerative process ( 77 ). The next highly connected cluster was concerned mostly with the neuropsychological dysfunction in patients with MS. Despite its previous identification by Charcot ( 78 ), it has been overlooked for a long time. Our data over the past two decades showed that neuropsychological symptoms have been increasingly investigated, of which cognition, depression, and fatigue were among the most important ( 79 ). Furthermore, rehabilitation appeared among the top keywords in the analyzed data, which had been a neglected area of MS research as well ( 56 ). This increased awareness among researchers demonstrates the huge impact of non-motor problems on health-related QoL in patients with MS.

The other two connected clusters were concerned with the diagnosis and treatment of MS. It was not surprising to observe a large cluster formed around the keyword “MRI.” It has revolutionized the diagnosis of MS since the beginning of the 1980's and has been a cornerstone in MS diagnostic criteria. It has been widely used as an invaluable tool in understanding and monitoring disease activity in clinical trials and clinical practice ( 57 ). The recent interest in biomarkers was also observable in MS research, although this has not yet been translated in clinical settings.

The last cluster focused on the most important therapeutics based on their weight in literature. Our data showed that four DMTs (interferons, glatiramer acetate, natalizumab, and fingolimod) were the most studied MS drugs. Interferons and glatiramer acetate were the first approved drugs for MS; however, they have shown decline in the research trend in recent years. The era of high-efficacy drugs started with the approval of natalizumab (2004) and fingolimod (2010), and they have been a part of clinical practice and research since then ( 63 ).

However, our study demonstrated that some research gaps still exist in MS literature. First, most research came from Western countries, and although increasing recently, contribution from developing countries is still insufficient. Efforts should be made to support MS research in such countries for better understanding of the disease. Second, MS in special populations (the pediatric-age group, women during pregnancy, and the postpartum period) and MS in racial and ethnic minorities, who have distinct disease characteristics but historically low participation in clinical trials of DMTs, are still underrepresented. Furthermore, several new therapeutic options had less weight in MS research, despite being widely used in clinical practice, probably due to their relative recency. We hope that MS researchers can benefit from this analysis to fill these gaps in future studies.

A recent study that analyzed the top 100 articles that were discussed over social media has found the most discussed topics are related to the new treatment modalities and their side effects, while articles discussing pathology and symptomatology accounted for a fraction of the results. The authors recognized the particularity of social media in bringing topics of public concern into attention compared to traditional scientific venues, i.e., journals and conferences, which highlight academic community interests and opinions ( 9 ).

There are some limitations to the current study that should be addressed. First, this bibliometric analysis retrieved publications solely from the WoS database to include journals with impact factors. There are several other sources that were not included, e.g., research in other languages and emerging journals that are not indexed. In making this choice, we prioritized quality of the database, consistency of the meta-data, and credibility of the sources. Including other databases with no rigorous selection processes, e.g., Google Scholar, would risk the integrity of our results. Including data from rigorous databases would mix the citation counts from different sources, resulting in imbalanced metrics ( 80 ). Therefore, our results should be viewed and interpreted as representative of data published in venues with impact factors, and not necessarily representative of the full breadth of MS research ( 11 ). We reiterate the concerns and guidelines of interpreting bibliometrics data issued by the Leiden Manifesto, and therefore, we recommend our readers to interpret the results in the view of these guidelines ( 81 ). Bibliometric studies had a potential length time-effect bias, where the older articles receive more citations, and the long-standing authors are more likely to have published more; therefore, caution should be exercised when interpreting the results. Lastly, a bibliometric study is only as good as the meta-data; these are far from perfect and have known documented short-comings; while they do not affect the general conclusions, they are worth pointing out. Nonetheless, we have taken extra measures to clean the data to avoid these problems by cleaning the authors' names, keywords, etc.

In conclusion, the output of MS research has increased dramatically over the past 20 years, and analyzing these changes can provide important insights into the contribution of each country as well as international collaborations all over the world. Leaders of production of MS research were from the US and Western Europe; however, the number of articles published by Asian and MENA countries is on the rise. Multiple Sclerosis Journal had the highest number of articles and citations in MS research. The most cited article was by Kurtzke et al. on rating neurologic impairment in patients with MS using EDSS. Four main themes of research could be identified, focusing on understanding the pathophysiology of the disease, improving its diagnosis, and studying the efficacy and safety of the current and future treatments. Moreover, we see a rise of research themes addressing health-related QoL in recent years, with depression, cognition, and fatigue being the most studied. We hope that this bibliometric analysis can provide useful information for determining research and publication strategies in future investigations of MS.

Author Contributions

III contributed to the concept, design, data collection, and draft of the manuscript. MS contributed to the concept, design, data analysis, interpretation, revision of the manuscript, and provided supervision. All authors provided critical feedback on drafts and approved the final manuscript.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: multiple sclerosis, bibliometrics, articles, citations, impact factor, scientific collaboration, publication trends, country productivity

Citation: Ismail II and Saqr M (2022) A Quantitative Synthesis of Eight Decades of Global Multiple Sclerosis Research Using Bibliometrics. Front. Neurol. 13:845539. doi: 10.3389/fneur.2022.845539

Received: 29 December 2021; Accepted: 24 January 2022; Published: 24 February 2022.

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Copyright © 2022 Ismail and Saqr. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Mohammed Saqr, mohammed.saqr@uef.fi

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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1.1 Introduction

1.2 epidemiology and genetics of multiple sclerosis, 1.2.1 susceptibility genes for ms in the mhc, 1.2.2 susceptibility genes for ms outside of the mhc, 1.2.3 protective genes in ms, 1.3 environmental factors in multiple sclerosis, 1.3.1 infections and multiple sclerosis risk, 1.3.2 lifestyle and multiple sclerosis, 1.3.3 the 25-hydroxy-vitamin d and multiple sclerosis risk, 1.4 clinical manifestations of multiple sclerosis, 1.4.1 phenotypes of multiple sclerosis, 1.4.2 clinical manifestations of multiple sclerosis in initial stages, 1.4.3 clinical symptoms of ms in the established phase, 1.5 unmet needs, chapter 1: multiple sclerosis: epidemiology, genetics, symptoms, and unmet needs.

• Published: 18 Jun 2019
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I. Moreno-Torres, J. Sabín-Muñoz, and A. García-Merino, in Emerging Drugs and Targets for Multiple Sclerosis, ed. A. Martinez, The Royal Society of Chemistry, 2019, pp. 1-32.

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Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system. MS is more prevalent in women and is estimated to affect some 2.3 million people across the world. There is unequivocal genetic susceptibility in MS. The most consistent genetic determinant identified is the major histocompatibility complex (MHC). The haplotypes more strongly related to susceptibility and protection for MS are HLA-DR2 and HLA-DR11, respectively. Some genes outside the MHC, such as IL2RA , IL7R and TNFRSF1A , have also been related to MS. There is a latitudinal gradient of MS prevalence, probably due to environmental factors on the genetic susceptibility. The most important MS risk factors are seropositivity against Epstein–Barr virus, infectious mononucleosis, and smoking. Other factors such as vitamin D or parasitic infections require further investigation. The clinical manifestations of relapsing forms of MS in initial stages are related to demyelination of the susceptible structures such as the optic nerves or spinal cord. In established MS, the clinical symptoms are related to the multisystemic affectation and neurodegeneration such as cognitive impairment or sphincter disorders. An unmet need exists for highly effective medications with low risk for deep immunosuppression and for the symptomatic relief of MS.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system (CNS) 1   and is thought to be autoimmune in nature. It is characterized by the appearance of areas of demyelination in the white and gray substances of the CNS, 2   infiltration of inflammatory cells in the parenchyma, glial reaction, and axonal damage. 3,4   All these processes occur from the early stages of the disease with the consequent accumulation of disability.

Although the underlying cause of MS still remains unknown, there is increasing evidence that immune dysregulation may play a role in genetically susceptible individuals. Some risk factors related to immune dysregulation have been identified, such as infections (Epstein–Barr virus, varicella/zoster, and HHV-6), environmental factors (latitude, vitamin D), and epigenetic factors (post-genomic rearrangements or somatic mutations). The sum of one or more risk factors on a genetic susceptibility leads to the loss of homeostasis between the inflammatory response and self-tolerance, tilting the balance towards autoimmunity directed against the CNS. 3  

Between 1831 and 1842, Robert Carswell and Jean Cruveilhier presented their collections of autopsy material of MS patients in London and Paris, respectively. They described in vivo the brain lesions on plates for the first time. Cruveilhier was the first to relate these lesions to clinical findings and called it the medullar disease with paraplegia. Despite some preliminary clinical descriptions, made by Friedrich Theodor von Frerichs (1849), his pupil Valentiner (1856), Carl Rokitansky (1857) and Eduard Rindfleisch (1863), it was not until 1865 when Jean-Martin Charcot made the first detailed description of the disease. 5   This description included plaque-like lesions disseminated in time and space with a predominant myelin involvement, mainly in the optic nerve, the periventricular region, and spinal cord, which were correlated with clinical manifestations alternating periods of exacerbation and remission. He explained the most characteristic clinical signs of the disease: oculomotor disorders, ataxia and dysarthria. In this way, MS was recognized for the first time as an entity distinct from other diseases.

The term “sclérose en plaques disseminées” was coined by Edmé Félix Alfred Vulpian in 1866. 6   Later, his friend and collaborator Charcot reduced the term to “sclérose en plaques,” and the term “multiple sclerosis” was introduced in the medical literature by Edward Seguin in 1878, 5   but it was not until McAlpine, Compston, and Lumsden's classic publication in 1955 that the term gained international usage.

In Diseases of the Nervous System , a book published in 1933, the author Russell Brain reported data on the incidence and course of MS, together with precise explanations on the underlying pathophysiology, some of which continue to be valid today. Since then, a series of clinical criteria have been used and updated periodically to make the diagnosis of the disease. 7   Magnetic resonance imaging (MRI) techniques and cerebrospinal fluid (CSF) analysis have been incorporated into the diagnostic algorithms. This has allowed an improvement in the criteria sensitivity and specificity, resulting in the current McDonald criteria 2017. 4  

Age at onset of MS can vary from childhood to adult life, and the average is between 20 and 40 years. MS is the first cause of non-traumatic disability in young patients, which has a great impact on the quality of life, a high health cost, and important social repercussions. 8   MS is estimated to affect some 700 000 people in Europe and 2.3 million across the world. Longitudinal studies have revealed an increase in MS prevalence in recent years, but this does not necessarily carry an increased risk of MS. The increase in prevalence is related to a higher life expectancy in MS patients (as in the general population) over the last decades as a result of the improvement in healthcare, better disability rehabilitation, and access to health resources. The continuous review of McDonald's criteria has allowed earlier diagnosis, which also increases the incidence of MS. An increase in Europe and North America of 0.064 per 100 000 each year has been reported. 9   MS patients have a 7-year shorter life expectancy and two to three times higher mortality compared with the general population. 10  

MS is universally found to be more prevalent in women than men, and the MS prevalence ratio of women to men has increased markedly during the last 60 years. 9,11   According to a Canadian study published in 2006, the sex ratio increased from 2 : 1 in 1936–1940 to 3.2 : 1 in 1976–1980. 12   Similar data supporting this increase have been published by other groups in Germany, France, and Norway. 9,11,13   An analysis carried out in Europe and the United States indicated that the sex ratio not only changes over time but has also been shown to be negatively correlated with latitude. 9  

There is unequivocal evidence to support genetic susceptibility as an important factor involved in the occurrence of MS. In the general population, the MS risk is about 0.1–0.25% 13   and increases up 2–5% in individuals with an affected family member in proportion to the number of shared genes. The published study with the largest number of patients in this regard involved 15 000 Canadian patients with MS and their families. 14   It has been demonstrated that first-degree relatives (parents, children, and siblings) of an affected individual have a risk of approximately 2–5%, which can increase up to 30% if both parents are affected or up to 27% in monozygotic twins. The concordance between dizygotic twins is 3.5%, and up to 14% of asymptomatic monozygotic twins have MRI lesions compatible with demyelination. Second-degree relatives (aunts and uncles) have a risk of about 1–2%, and third-degree relatives (cousins) have a risk of less than 1%. The risk of MS decreases with age, and after 43 years it does not exceed 0.5%. A variation in MS risk has also been observed according to geographic area, being 2.4% in high prevalence areas and 0.1% in low prevalence areas. 14  

It has been suggested that the origin of the disease is the result of genetic mutations in the Scandinavian population during the first millennium, which were spread through the offspring by the Vikings during invasions and migrations to the rest of the known world. 15   This hypothesis can explain the highest prevalence rates for MS in the Scandinavian peninsula and the countries settled by their descendants, such as Canada, Australia, New Zealand, and the United States 16   as well as the greater prevalence among the mestizo population compared with the native population in the Americas.

There is a clear relationship between latitude and prevalence of MS 17   since a latitudinal gradient has been demonstrated, with the prevalence of MS increasing as one moves farther from the equator. The most extensive survey on MS worldwide was published as the Atlas of MS 2013 and was conducted by The MS International Federation. 18   Data on prevalence were available from more than 50 countries through official and unofficial sources. According to this report, the prevalence of MS varies between the different regions from above 100–200 cases per 100 000 population in high latitudes to below 5 cases per 100 000 in the regions near the tropics ( Figure 1.1 ). Subsequent publications have been reporting new data of prevalence in different countries. The highest prevalence of MS is found in the Canadian population, with 291 per 100 000 population, followed by San Marino (250), Sweden (189), Hungary (176), Cyprus (175), United Kingdom (164), Czech Republic (160), Norway (160), Denmark (154), and Germany (149). The lowest prevalence has been reported in sub-Saharan Africa (2.1), Eastern Asia (2.2), and the equator region (3). 18–24   The reason for this latitude gradient is not yet fully understood but is probably related to genetic factors, hygiene of populations, and environmental factors such as the contribution of vitamin D, which will be discussed in detail later. However, this gradient is changing as more studies of geographical areas where prevalence was considered low are been published. In Latin America, for example, an increase in prevalence has been observed due to factors related to improvement in diagnosis, accessibility to MRI and to different healthcare resources. 19  

World prevalence of multiple sclerosis. The map was designed using the online program Mapchart available at https://mapchart.net/detworld.html using the prevalence data obtained from the Atlas of MS 2013 (Multiple Sclerosis International Federation) 18   plus more recent publications in different countries. 20–24  

As a result, great interest has been generated in searching MS-related genes to explain the latitude gradient. The strongest and most consistent genetic determinant identified in MS is the major histocompatibility complex (MHC), which is located on chromosome 6p-21-23 and includes the Human Leukocyte Antigen (HLA) genes. The MHC type I region includes the genes HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, and HLA-G and the type II region includes the genes HLA-DM, HLA-DO, HLA- DP, HLA-DQ, and HLA-DR. These molecules participate in the antigenic presentation to CD4+ (MHC type II) and CD8+ (MHC type I) lymphocytes. The genetic variability of this region is the highest in humans, with a large number of polymorphisms that allow them to serve as antigens of differentiation between different individuals.

The first studies that demonstrated an increased frequency of some types of HLA (HLA-B7, HLA-A3, and HLA-A9) in multiple sclerosis were published in 1972. 25   Subsequent publications continued to document an increase in the expression of some alleles of the HLA-DRB1, HLA-DRA, HLA-DQA1, HLA-DQB1, HLA-DMB, and TCRB genes as well as an increased frequency of combinations of alleles (haplotypes) in patients with MS compared to healthy controls in different populations. 26–28   The alleles most frequently found in MS are HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01, HLA-DQA1*01:02, and HLA-DQB1*03:02 , 29   and the haplotype most strongly related to MS is DRB*1501-DQA1*0102-DQB1*0602, defined serologically as DR15 and abbreviated as HLA-DR2 or HLA-DRB1. The presence of HLA-DR2 significantly increases the risk of MS, especially in populations where this haplotype is more frequent, as in Caucasians of northern European descent 30   and to a lesser extent in southern regions of Europe and in the Brazilian population from Rio de Janeiro to Sao Paolo. 31   There has also been reported a greater concordance of these associations between monozygotic twins compared with dizygotic twins. 32   On the other hand, the allele HLA-DRB1*15:03 has been related to susceptibility to MS in the African-American population 33   and in the mulatto population of Brazil but not in the black population. 34   An association between the HLA-DRB1*17 allele and the susceptibility to MS in the Swedish and Canadian populations has also been found. 35,36  

The risk of MS among the Latin American community is generally low to medium, but the frequencies are increasing. The mestizos are the most representative ethnic population in Latin America and are the product of centuries of interracial mixing between Native Americans (or Amerindians), European whites, and African blacks. Epidemiological studies show an extremely low prevalence of MS among non-mixed Amerindians. 33   This has been attributed to Mongolian ancestral protective genetics and possibly to environmental factors. The mestizos and the biracial community of Latin America with African ancestry have more susceptibility to MS, apparently due to the historical introduction of the European HLA-DR2 haplotype. Latin populations with a predominant European background (Argentina or Puerto Rico) seem to have a higher frequency of this haplotype. 19  

The populations of Sardinia and Sicily have a prevalence of MS and other autoimmune diseases similar to those of the northern European countries despite their geographical location and the low frequency of the HLA-DR2 haplotype. In these populations, as well as in populations of the Canary Islands and Turkey, there is a stronger association with other haplotypes such as DR4 and DR3. 37,38     Figure 1.2 summarizes the relationship between HLA-DR1 allele frequency, MS prevalence, and latitude with data obtained from the Atlas of MS 2013  18   and more recent publications in the different countries. 20–24,31,39–67  

Multiple sclerosis prevalence, latitude, and HLA-DR1 allele frequency. Prevalence data were obtained from the Atlas of MS 2013 (Multiple Sclerosis International Federation) 18   plus more recent publications in different countries. 20–24   HLA-DR1 allele frequencies were obtained from different publications in each country. 31,39–67  

In 2007, the first genome-wide association study (GWAS) using DNA microarray technology was completed. In that study, carried out by the international MS genetics consortium (IMSGC), the common single nucleotide polymorphisms (SPN) were identified and tested for disease association in 931 family trios (consisting of a person with MS and both parents) and 2431 healthy controls from the UK and USA. For replication purposes, another 609 trios (2322 case subjects) and 789 control subjects were genotyped from another source. The final analysis involved 12 360 subjects. Forty-nine single nucleotide polymorphisms (SNPs) were found associated with MS, most in the HLA genes. However, new genes outside the MHC related to MS were also described, such as IL2RA (CD25 chr 10p15), IL7R (CD127 chr 5p13), EVI5 ( ectopic viral integration site 5 chr 1p22), and KIAA0350 (CLEC16A chr 16p13). 68   Alleles of IL2RA and IL7RA genes have been associated with regulatory T cells, which are dysfunctional in MS. IL-2 is a cytokine related to the development of several autoimmune diseases, since it participates as an inductor of the differentiation 69   and proliferation 70   of autoreactive T cells. The IL-2-related proliferation process of T lymphocytes is carried out through the interaction of the cytokine with the α subunit of the interleukin-2 receptor (IL-2RA or CD25) on the surface of monocytes and lymphocytes. CD25 has also been described as a surface marker of regulatory T lymphocytes. 71   CD127 interacts with the cytokine IL-7, an essential process for the proliferation of B and T cells.

Subsequently, several GWAS were published in different countries and populations (The Netherlands, Switzerland, Australia, Germany, Spain, and Sardinia), confirming the previous findings and describing new associations between SNPs of genes outside the MHC and MS, such as TNFRSF1A (chr 12p13), IRF8 (chr 16q24), CD6 (chr 11q12 ), GPC5 (chr 13q31), and IL2A (chr 4 26q27) . 72–79   The TNFRSF1A gene codes for the tumor necrosis factor receptor alpha (TNF-α), which exerts a regulatory effect on inflammation, having anti-apoptotic properties, by stimulating NFKB. The IRF8 and CD6 molecules are involved in the myeloid and lymphoid differentiation, respectively, and the GPC5 in a heparan sulfate proteoglycan. Two meta-analyses of all GWAS were published in 2011 and 2012, assembling data of 5545 and 2619 patients, respectively. These analyses confirmed the previous associations and added new genes ( EOMES, MLADA, THADA ). 80,81  

A new generation of GWAS was implemented in 2011 with the possibility of analyzing 10–15 times more patients and allowing the discovery of a greater number of genes. 81–84   In 2011 and 2013, the IMSGC published two studies carried out with 9972 and 14 498 patients, respectively, in the US, Europe, and Australia. From these two studies the list of genes related to MS was expanded by more than 100. 82,85   The last GWAS meta-analysis was published in 2017 with data from 47 341 MS patients and 68 248 healthy controls and from which MS association data were obtained for 200 SNPs outside the MHC, 1 variant on the X chromosome, and 32 associations with variants of the MHC. 86     Figure 1.3 shows a summary of the main genes discovered in order of appearance.

Multiple sclerosis gene discovery. A list of the main genes related to MS in order of temporary discovery as the GWAS advance from the first reported association between HLA and MS to the second generation of GWAS.

On the island of Malta, the prevalence of MS is remarkably low compared with that of neighboring Sicily. Initially, it was thought that a low frequency of the HLA-DR2 haplotype was related to the low susceptibility of the Maltese population, but in a study published in 2008 it was demonstrated that the HLA-DRB1*15 allele is also significantly present in MS patients on Malta. The apparent inhibition of MS risk in the Maltese has been related to the presence of an apparently strong protective factor, the HLA-DR11 haplotype. 64   The HLA-B*44:02 is frequently expressed in people of Northern European ancestry, but carriers have a 46% reduction in the risk of developing MS. Other haplotypes described as protective factors are HLA-A*02:01, HLA-B*38:01, and HLA-B*55:01 . 29   Ancestral communities such as the Sami in Laponia, 87   the Uzbeks in Central Asia (Uzbekistan and Afghanistan), the Kirguis in Kirguistan, the Siberians, and African black natives have a low prevalence of MS, and Bedouin ethnicity appears to be protective. 88,89   The frequency of the DR2 haplotype is significantly reduced among Sami people compared with non-Sami Norwegian controls, contributing to the low prevalence of MS in the Sami. 89  

According to an Australian study, the CD58 gene (chr 1p13), whose product binds to CD2 to facilitate the entry of immune cells into the CNS, and the DBC1 gene have been found to be up-regulated during remission. 90   The CD58 gene has also been linked to the inhibition of endothelial adhesion and the decrease in the penetration of inflammatory cells in the CNS.

Data obtained from migratory dynamic studies 32,91   have confirmed that individuals under 15 years who emigrate from high-risk to low-risk zones are significantly less likely to develop MS than those who migrate at an older age, suggesting that the environmental component plays a very important role in the risk of MS. More than 40 environmental factors have been tested in relation to the risk of MS in numerous studies, 92   including infections, vaccines, toxic agents, weather agents and serum markers.

A systematic review of meta-analyses published in 2015 assessed the statistical weight of each of the environmental risk factors according to the number of patients and the methodology they used and found that the only three factors that meet the requirements to be unequivocally considered MS risk factors are: seropositivity in antibodies against EBV type IgG, infectious mononucleosis, and smoking. The other factors require further investigation to differentiate simple association with genuine pathogenesis. 92  

There is a large body of evidence implicating Epstein–Barr virus (EBV) infection in the pathogenesis of MS, although its exact role is incompletely understood. Approximately 95% of the world's population is thought to have been infected by EBV at some point in their lives. Why only some of those people develop MS is an unresolved question. On the other hand, a meta-analysis of multiple studies with different EBV test methodologies confirmed 100% of MS patients as seropositive when two different methods were used. 93   The hygiene hypothesis suggests that contact with the virus at a young age reduces the risk of MS. This contact is almost 90% at 4 years in tropical countries and almost null in individuals from developed countries before adolescence. 94   It is not clear whether the infection is directly related to the pathophysiology of the MS or is only a reflection of the gradient in hygiene and health inequalities among children. An individual who suffers a primary infection from EBV that results in infectious mononucleosis has a 2–3 times higher risk of MS than one who presents an asymptomatic contagion. 95  

Likewise, there are statistically significant data from large studies that link serum antibody titers against the nuclear protein 1 of EBV (EBNA1) with the risk of MS. 96–98   Although the data about the EBV infection related to a higher risk of conversion from the first demyelinating episode (clinically isolated syndrome, CIS) to MS are contradictory, 99,100   in established MS, the serum level of IgG antibodies to EBNA1 correlates with the number of gadolinium-enhanced lesions in MRI and with the total number of T2 MRI brain lesions. 101,102   In addition to elevated levels of EBNA1 antibodies in the serum, patients with MS also have elevated levels of IgG antibodies to EBNA1 in the CSF, suggesting a high EBV-specific intrathecal immune response related to MS, in particular at the onset of the disease. 103,104  

EBV-specific CD4 + and CD8 + lymphocytes are enriched in the serum and CSF of patients with MS compared with healthy controls. 105–107   However, the presence of EBV in MS lesions in the CNS has been controversial 108–111   and this is probably due to the lack of unification in pathological techniques. Recently, a study was published with the largest number of CNS samples (101 patients and more than 1000 tissue samples), in which the presence of the virus was documented in 90% of B cells, microglia, and astrocytes of patients with MS and only in a small proportion of healthy controls. 112   EBV infection also interacts with other risk factors in MS: women with DRB1*15 and higher anti-EBNA-1 levels had a nine-fold increased risk of MS compared to those with lower EBNA-1 levels and DRB1*15 presence. 113  

The human cytomegalovirus (CMV) belongs to the herpes virus family and has been widely studied as a possible etiological agent in MS. It is present in 60–100% of the world population as a latent infection. In post-mortem studies of demyelinating lesions of patients with MS, the presence of CMV-specific CD8 + cells has been documented. 114   Additionally, anti-CMV IgG titers in CSF are higher in patients with MS than in healthy controls. 115   However, unlike EBV, CMV appears to have a protective role in MS, and two meta-analyses concluded that the seropositivity for CMV confers a decrease in the risk of developing MS. 116,117   It has also been described that high titers of anti-CMV antibodies in MS patients correlate negatively with relapses and T2 lesion load in MRI 118   and that the expansion of a CMV-induced NK cell type carries a lower risk of progression in MS. 119  

Parasitic infections seem to be another environmental factor, with a theoretically protective role against MS. Infection by some species of helminths and other parasites such as Trypanosoma cruzi and Paracoccidioides have been related to a decrease in the appearance of relapses and radiological activity, as well as to an increase in the differentiation of IL-10-producing regulatory lymphocytes (CD4 + CD25 + FoXP3 + IL-10 + ). 120   However, there is not enough evidence to infer that parasitism, despite its attractive role in the hygiene hypothesis, can have an essential impact on the epidemiology of MS. 19  

Multiple studies have shown the relationship between smoking and the increased risk of MS. 121–125   The increased risk is estimated at 40%, with a dose-response effect from 20% for moderate smokers to 60% for heavy smokers. 94   Obesity at early ages of life and increased salt intake have also been risk factors related to MS in several studies. 126–128  

Several investigations have suggested that low exposure to ultraviolet light and the consequent decrease in vitamin D skin synthesis, measured as 25-hydroxy-vitamin D [25 (OH) D], is an important environmental risk factor implicated in the onset of demyelination at an early age, 129   and it has even been proposed that the month of birth, the maternal exposure to ultraviolet light and 25(OH)D levels during pregnancy have an effect on MS risk. 130  

It has been reported that a decreased risk of MS in individuals with high levels of 25(OH)D compared to those who have low levels and different cut-off points have been proposed to establish an increased risk of MS. 92,131,132   The concentration of vitamin D fluctuates with the seasons and the implication of this variation in MS risk has not yet been established. According to these findings, sun exposure has also been positively correlated with a low risk of MS, 133,134   and the prevalence of MS is inversely proportional to the solar radiation of a determined population 135   being a risk factor 20 times more important than latitude according to a Scandinavian study. 136   However, it is a fact that solar radiation depends mainly on latitude, and this could partially explain the geographical gradient of MS incidence in relation to vitamin D. In MS patients, low levels of vitamin D have been correlated with an increased risk of relapses and long-term disability. 137  

A prospective longitudinal study showed that women who take a dietary supplement of vitamin D with a content greater than 400 IU/d have a 40% lower risk of developing MS 138   as well as those individuals who regularly consumed cod liver oil, an important source of vitamin D, during childhood. 139,140   However, a recent meta-analysis of similar studies found no evidence of the therapeutic benefit of vitamin D as an add-on treatment in MS. 141  

MS is a disease in which there is an accumulation of demyelinating lesions and axonal loss in the CNS that generates progressive neurological disability. It is clinically heterogeneous, which leads to the definition of different forms of presentation.

1.4.1.1 Relapsing Forms of MS at Onset

The relapsing–remitting form of MS (RRMS) is the most frequent (90% of patients) and is characterized by episodes of a focal neurological deficit (relapses) of greater or lesser magnitude that alternate with periods of neurological remission or stability. Patients may accumulate secondary disability, depending on the number, severity, and level of recovery after each relapse.

Following this course, within 20–25 years, 60–70% of RRMS patients transform into secondary progressive multiple sclerosis (SPMS), which is characterized by progressive neurological decline (mediated by the cumulative damage of the relapses and the underlying degenerative component of the disease). Age markedly influences the phenotype before progression. RRMS patients who are younger at onset are more likely to display a predominantly inflammatory course, although the number of relapses does not affect the age at onset of progression. 142   In general, SPMS is diagnosed retrospectively, since there are no clinical and imaging criteria for establishing the transition from RRMS.

Clinically isolated syndrome (CIS) is a recently added category, although the term has been used for years. It refers to the first typical focal event of the disease, accompanied, in many cases, by the evidence of a possible demyelinating disease (positive MRI with typical abnormalities of the CSF) but has yet to fulfill criteria of dissemination in time. Clinical trials in MS have shown that CIS coupled with brain MRI lesions carry a high risk for a second relapse and therefore for MS conversion. 1   For that reason, the current clinical criteria allow some patients with CIS and radiological evidence of dissemination to be diagnosed with MS. 143  

1.4.1.2 Progressive Form of MS at Onset

There is a clinical form in which the accumulation of neurological disability occurs from the onset of the disease without the presence of clinically evident relapses. It has been called primary progressive multiple sclerosis (PPMS) and represents between 10 and 15% of patients with MS. It frequently manifests as a slowly progressive asymmetric spastic paraparesis or symptoms of cerebellar dysfunction. According to the North American Research Committee on Multiple Sclerosis (NARCOMS) survey, the age at onset and diagnosis of PPMS is greater than that of relapsing forms: 36 and 44 years old, respectively. 144   Although their course is progressive, PPMS patients are not free from acute exacerbations or worsening consistent with relapses. The natural history of disability progression in PPMS seems identical to SPMS when compared from the beginning of the progressive phase. These data indicate that progressive forms, regardless of their start, have a similar progress. 145   Age and bilateral motor symptoms at onset are the most important predictors of disability accumulation in PPMS throughout its course. 146  

1.4.1.3 Active and Progressive Disease

MS phenotypes can be categorized as active or progressive. According to the description by Lublin et al. in 2014, clinical activity is defined as the occurrence of new relapses frame and imaging activity is defined as the occurrence of contrast-enhancing T1 hyperintense lesions or new or unequivocally enlarging T2 hyperintense lesions in a determined time. 147  

In addition to the concept of activity, it is important to define progression since it would mark the beginning of the secondary progressive form in an RRMS patient or a suboptimal response to treatment in a patient with an established progressive form. Clinical progression is defined as a progressive increase of neurological dysfunction/disability, objectively documented, without unequivocal recovery. 147   The appearance of clinical progression does not necessarily imply a continuous course: stationary periods of greater or lesser duration throughout the disease are possible. The term “confirmed progression” describes an increase in neurological dysfunction confirmed throughout a defined time interval (3, 6, or 12 months). The most common definition of progression used in clinical trials is the worsening of more than one point on Kurtzke's scale of neurological disability (EDSS) confirmed for more than 6 months.

The diagnosis of MS must include the clinical form and the presence or absence of activity or progression. It is recommended that the assessments for disease activity and progression be conducted at least annually by clinical and MRI examinations. 147   This periodic evaluation is necessary, especially because of the availability of highly effective therapies that can be used when the response is suboptimal.

1.4.1.4 Other Presentation Forms

The increasing availability of MRI in medicine has led to an increase in incidental abnormal findings suggestive of multiple sclerosis. The detection of demyelinating lesions in individuals with no neurological symptoms and whose presence is not explained by other pathologies (vascular, toxic, neuro-infections, etc. ) has been called isolated radiological syndrome (RIS). Approximately one-third of these patients will develop MS within a 5-year follow-up period. 148  

The study with the largest number of individuals with RIS revealed that the main risk factors associated with conversion to MS are younger age (<37 years), male gender, high lesion load in MRI, family history of MS, positive CSF (intrathecal synthesis of IgG), and the presence of at least one asymptomatic spinal cord lesion. 149   Therefore, RIS is considered as a possible pre-symptomatic form of MS, and it might be expected that treatment with disease modifying therapy (DMT) at this stage might protect some individuals against the development of MS. However, there is no consensus on the possible therapy for RIS. 143  

In most cases, relapses are confined to only one functional system; less frequently they can be multifocal. The symptoms of a relapse depend on the location of damage in the CNS and the structures most frequently affected are the optic nerves, spinal cord, brainstem, and cerebellum. According to data published in the Atlas of MS 2013, the most common symptoms at onset are sensitive (40%), motor (39%), visual (30%), and cerebellar (24%), and the least common are pain (15%) and cognitive complaints (10%). 18   Multifocal syndromes due to simultaneous involvement of two or more regions of the CNS occur in up to 25% of patients. There is a tendency to recurrence in the same anatomical location.

Certain circumstances such as anesthesia, fever, surgical interventions, stress, infections or other intercurrent diseases can temporarily worsen a pre-existing neurological deficit, causing what is known as a pseudo-exacerbation or pseudo-relapse. The most frequent types of clinical relapses and their characteristics are as follows.

1.4.2.1 Optic Neuritis

Optic neuritis (ON) is one of the most frequent symptoms of presentation in MS, in approximately 20% of cases, and affects about half of MS patients at some point in the course of their disease. 150   ON is characterized by a subacute decrease of visual acuity (VA), evolving over hours to days. This is typically unilateral, although less frequently both eyes can be affected simultaneously.

Patients may complain of blurred vision or loss as well as a blind or blurry spot within the visual field and a scotoma can be evident on formal visual field testing. Visual field defects include diffuse visual loss (48%), altitudinal defects (15%), central or cecocentral scotomata (8.3%), arcuate or double arcuate (4.5%) and hemianopic defects (4.2%). 151   In 90% of cases ON is associated with eye pain, which can precede the loss of vision. On visual examination, low-contrast vision and color desaturation (dyschromatopsia) are affected. The dyschromatopsia is especially for red color and may not be proportional to the level of visual impairment.

In two-thirds of cases, the optic disc is normal on funduscopic examination and in the other third of patients papilledema can be found. If the ON is unilateral, a relative afferent pupillary defect may be evident in the affected eye (Marcus Gunn sign). Recovery is progressive, at least 90% of the visual acuity after 6 months, and depends largely on the severity of visual loss. The low-contrast test and some complementary tests, such as visual evoked potentials (VEP), continue to be pathological despite full recovery of visual acuity.

1.4.2.2 Acute Myelitis

Acute myelitis is the presenting symptom in about 40% of MS patients and usually presents sub-acutely. The spinal lesions related to MS are usually small and peripheral, located especially in the lateral or posterior region of the spinal cord, are asymmetrical and have a longitudinal extension less than two vertebral segments. The myelitis that occurs in MS is typically partial with the involvement of one or more, but not all, functional spinal tracts such as motor, sensory, and bowel or bladder tracts. 152  

The symptoms evolve over hours to days and are usually bilateral. Patients usually complain of a sensory abnormality with a horizontal level or a band-like constriction sensation around the abdomen or chest. There is a predominance of the sensory symptoms over the motors and of the deep sensitivity over the superficial one. Cervical location of myelitis can cause a Lhermitte phenomenon, which consists of an uncomfortable electric shock-like sensation extending down the cervical spine and radiating to the limbs, triggered by cervical flexion. It is common to find patchy areas of sensory alteration in the trunk, as well as the abolition of cutaneous-abdominal reflexes in dorsal myelitis. In the acute phase, sphincteric dysfunction is usually milder than in established MS.

1.4.2.3 Relapses with Symptoms of Brain Stem and Cerebellar Involvement

The clinical syndromes produced by brainstem involvement are the first manifestation of MS in 10–20% of cases and include diplopia, oculomotor palsy, nystagmus, vertigo, facial hypoesthesia, neuropathic facial pain, facial weakness, myokymia, dysarthria, dysphagia, tongue weakness, postural and gait instability. Less frequent brainstem symptoms include hearing loss and severe bulbar signs.

Diplopia and oculomotor palsy are caused by the involvement of the intra-axial portion of the nerves or the cranial nerve (CN) nuclei responsible for ocular motility in the brainstem (III, IV, and VI CN) and the VI CN is the most frequently affected.

Internuclear ophthalmoplegia (INO) is a common disorder in MS and consists of a limitation for the abduction of the eye ipsilateral to the lesion with nystagmus in the contralateral eye and convergent movements not altered. The lesion of INO is located in the medial longitudinal fascicle and may be unilateral or bilateral. It may be asymptomatic, but occasionally it may generate a sensation of movement (oscillopsia) or, more rarely, diplopia.

One-and-a-half syndrome is also a common abnormality in MS, characterized by conjugate horizontal gaze palsy in one direction plus an INO, with the abduction of the eye contralateral to the lesion as only conserved movement.

1.4.2.4 Initial Symptoms in PPMS

In PPMS, symptoms at onset are predominantly motor, typically a slowly progressive spastic paraparesis (80% of patients), cerebellar dysfunction (60%), sensory symptoms, or sphincteric involvement. The diagnosis can be difficult and may go unrecognized by patients or physicians for some time, with multiple visits to different specialists such as orthopedic surgeons, rheumatologists, etc. Additionally, the differential diagnosis of spastic paraparesis includes a wide range of hereditary, degenerative, inflammatory, and toxic-metabolic disorders. Cognitive progressive syndromes, long motor pathway affectation, or visual symptoms are infrequent as initial manifestation of PPMS. The delay in diagnosis of PPMS leads to an accumulation of disability, and early-detection strategies are needed.

The disability accumulation after relapses and the disease progression generate different symptoms and signs in MS patients that differ according to the affected domains. The systems mainly affected are visual, pyramidal, sensory, and cerebellar, as well as the brainstem and the control of sphincter functions. Some manifestations of the established phase of MS are not a direct consequence of the pathological process of MS but are due to secondary changes such as the pain in immobile joints due to muscle spasticity.

NARCOMS 153   is a self-reported registry for MS, with over 37 500 patients who complete semi-annual surveys collecting information on perceived impairment in 11 domains commonly affected in MS: hand function, vision, fatigue, cognition, bowel/bladder function, sensory, spasticity, pain, depression, tremor/coordination, and mobility. In 2013, data from the NARCOMS registry were presented as a function of disease duration (up 30 years).

According to these data, most patients exhibited some degree of impairment in nearly all domains after disease onset. Certain symptoms such as sensory and fatigue were particularly prevalent from early in the disease within the first year after diagnosis: 85% and 81%, respectively. More than 50% of patients complained of some degree of cognitive impairment at onset. Motor symptoms such as mobility, hand function, and spasticity were progressively more common with longer disease duration. Other symptoms such as vision, cognition, pain, and depression had no significative cumulative change. The worsening impairment was more evident throughout the first decade for 11 domains and few changes between 15 and 30 years of follow-up were observed. In Figure 1.4 , a summary of the prevalence of MS symptoms according NARCOMS is presented.

Prevalence of neurologic symptoms in multiple sclerosis patients. Data on prevalence of symptoms in 11 domains were obtained from the NARCOMS survey. General data are presented, as well as data of severe symptoms at disease onset, at 15 and 30 years.

A recent study with 611 RRMS and 244 progressive MS (PMS) patients evaluated the frequency of MS symptoms. Among participants with RRMS the most frequent symptoms were paresthesia (77.1%), fatigue (74.1%), weakness (54.8%), problems with balance (51.6%), and memory problems (48.4). In PMS group gait problems (90.6%), balance problems (84.0%), fatigue (83.2%), paresthesia (80.3%), and spasticity (79.5%) were the most common. Epilepsy and dysarthria were the least common symptoms in both groups. In this study, the impact of MS symptoms on the quality of life (QoL) was also quantified. In RRMS patients, the biggest QoL losses are caused by balance problems, spasticity, and depression, while in PMS patients, the QoL is most affected by spasticity, paralysis, weakness, and pain. 154  

1.4.3.1 Visual Disturbances and Eye Movements

As previously described, in the neurological examination of MS patients, sequelae of past ON can be found, such as decreased uni- or bilateral visual acuity, alteration in contrast perception, or pallor in the temporal region of the papilla. It is also common to find alterations in the conjugation of the horizontal gaze and palsy of oculomotor muscles of which the patient is not conscious as a sequel to brainstem relapses, and less frequently an evident diplopia.

1.4.3.2 Pyramidal Pathway Disorders

Weakness is a constant symptom in advanced MS and affects up to 89% of MS patients at some point in the disease. 155   Paraparesis and lower monoparesis are more frequent patterns of weakness than hemiparesis. The weakness severity can vary from a slight difficulty in walking to a complete inability to walk, making necessary the use of support devices or a wheelchair. In some patients, weakness is evident only during physical activity.

Weakness in MS is mainly due to lesions of the corticospinal tract and is usually accompanied by other signs of upper motor neuron syndrome, such as exaggerated myotatic reflexes (hyperreflexia), spasticity, or the presence of extensor plantar reflex (Babinski sign). It is common to observe repetitive and rhythmic muscle contractions called clonus. Occasionally, myotatic reflexes are found to be diminished or absent if lesions in the dorsal root entry area are present. Atrophy is infrequent, seen in very advanced stages and in relation to prolonged immobilization.

As the disease progresses, weakness is usually accompanied by spasticity, defined as muscle stiffness and spasms that occur in up to 90% of patients at some point. 156   Clinically, it is characterized by increased pyramidal tone, slowing down the muscle contraction-relaxation sequence and decreasing the range of voluntary movements. In the initial phases, spasticity may be an aid to gait by providing involuntary support of body weight in standing, but in the long term, it usually causes painful spasms and ultimately ankylosis in limb flexion, limitation of ambulation, and hygienic difficulties. Spasticity predominates in the lower extremities and is a determinant factor of disability.

1.4.3.3 Sensory Pathway Disorders

Sensory symptoms are commonly experienced by MS patients (more than 90% of them) and reflect the involvement of the spinothalamic tracts, the dorsal-medial lemniscus column system or the dorsal root entrance region. They are often described as numbness, tingling, stinging, or tightness in the trunk (such as an abdominal band) or the extremities.

Neurological examination shows frequent alterations of deep sensation (vibration and positional hypoesthesia) with a predominant involvement of the lower limbs. The presence of a sensory level is more frequently unilateral than bilateral and is sometimes accompanied by allodynia. A posterior spinal cord injury in the region of entry of the posterior root at the cervical level and affecting the posterior cords can generate an infrequent but typical syndrome of MS, the useless hand syndrome, which consists of difficulty in the tactile recognition of objects, and sparing superficial sensation and motor function.

Pain is a frequent symptom in MS of multifactorial origin. In some cases, it is caused by an injury in the area of entry of the fifth cranial nerve (trigeminal neuralgia), the dorsal root entrance area (root pain), or directly by a spinal cord injury (painful dysesthesiae). Pain in MS usually has neuropathic features such as burning, electrical, or sharp sensations. The radicular pain may be unilateral or bilateral and there may be also a sensation of intense unilateral cervical itching. However, in most patients, pain is not a direct effect of the pathological process but is due to abnormal postures or to prolonged immobilization.

1.4.3.4 Cerebellar Disorders

The cerebellum is a commonly affected structure in MS and cerebellar dysfunction contributes significantly to clinical disability. It usually manifests as: limb ataxia with dysmetria, decomposition of movement, final tremor, and hypotonia predominantly in the upper limbs; truncal ataxia with postural instability for sitting and standing; and gait ataxia with increased support base that is usually aggravated by proprioceptive sensory deficit. Severely affected patients may be unable to stand or move their arms in the presence of a violent intentional tremor. Dysarthria and scanty speech are also frequent symptoms, and patients with advanced disease can show an incomprehensible speech. 157  

Involvement of the brainstem-cerebellum networks that are implicated in neural integration of gaze can lead to acquired pendular nystagmus, a disorder characterized by involuntary oscillating movements of the eyes and by the detection of pendular movements of the optic disc at fundoscopic examination. On the other hand, the disruption of the cerebellar-pontine networks leads to uncoordinated limb movements (limb ataxia) with or without tremor, nystagmus, postural (truncal ataxia) and gait (gait ataxia) instability, dysarthria, or scanty speech. Vertigo is usually accompanied by alteration in vestibular function or, less frequently, by hearing loss. Alterations of saccadic movements such as fixation instability (macro-saccadic oscillations), saccadic dysmetria, and abnormal pursuit movements also suggest cerebellar alteration. 157  

1.4.3.5 Cognitive Impairment, Fatigue, and Neuropsychiatric Disorders

The impairment of cognition correlates with the severity of hemispheric lesions and the degree of cortical and corpus callosum atrophy. 158   It is more common in advanced stages of the disease, although it can occur at any time. Studies show that 45–65% of patients with MS have cognitive dysfunction of a subcortical profile. 159,160   The most frequently altered neuropsychological functions are sustained attention, speed of information processing, abstract reasoning, executive functions, and long-term verbal and visual memory. The memory impairment is secondary to decreased attention and information retrieval rather than to problems in storage or encoding capacity. The involvement of cortical functions such as aphasia or negligence is exceptional. MS can lead to frank dementia, but this is rare and usually occurs in the context of extensive disease. 161  

Exceptionally, cognitive dysfunction is the first manifestation of MS, and these patients develop a progressive cognitive deterioration from the beginning of disease.

Fatigue is a very disabling symptom reported by 80–90% of patients with MS and is defined as the subjective sensation of lack of energy (physical or mental), disproportionate to physical activity or as resting asthenia that worsens with the passing of the hours of the day. Fatigue is associated with a negative impact in the quality of life by approximately 30% of patients. The pathophysiological mechanisms involved are unknown and there is a poor correlation between fatigue and the degree of disability. 162  

Patients with MS have an increased risk of psychiatric disorders. Depression occurs in up to 60% of patients and correlates with cognitive impairment. 163   It is considered that there is a relationship between genetic susceptibility to develop MS and hereditary susceptibility to suffer depression. The risk of suicide is also increased, especially when certain predisposing circumstances are associated such as social isolation, poor psychosocial support, alcoholism, or a family history of depression and suicide, among others. 163   Bipolar disorder and psychotic symptoms are less frequent and occur in the advanced stages of the disease.

1.4.3.6 Sphincter Disorders and Sexual Dysfunction

Impairment of bowel and bladder control occurs in more than 75% of patients in advanced stages of the disease and correlates, in most cases, with the degree of motor involvement in the lower extremities. The most frequent alterations (>70%) are increased micturition frequency, urinary urgency, and incontinence secondary to hyperactivity of the detrusor muscle, which is present in about two-thirds of MS patients who undergo formal urodynamic testing. 164   The hyperactivity of the muscle is caused by a loss of inhibition of the detrusor reflex, which involves the contraction of the detrusor in coordination with the urethral sphincter relaxation.

It is also common to observe a delay or difficulty in emptying the bladder, urinary retention, increased post-voiding residue or overflow incontinence as a result of inappropriate detrusor muscle contraction or a detrusor-sphincter dyssynergia (20–25% of the patients). Detrusor overactivity and detrusor-sphincter dyssynergia often coexist in the same patient. The alteration of bowel function referred as constipation is also frequent and may be aggravated by the anticholinergic drugs used in the treatment of urinary disorders. Fecal incontinence and retention are infrequent. 164  

Erectile dysfunction is a common symptom present in up to 75% of men 165   with MS and correlated with high degrees of paraparesis and sphincter disorders. In women, a decrease in libido and anorgasmia are also frequent. Depression, motor symptoms, severe spasticity, and perineal sensory disturbances can aggravate sexual problems. 162  

1.4.3.7 Other Symptoms in MS

Gait disturbance is one of the main causes of disability and diminished quality of life in patients with MS. The cause is multifactorial, including paresis, spasticity, and proprioceptive alteration of the lower limbs, truncal ataxia and gait, and visual disorders. The most frequent patterns are spastic and cerebellar gait.

Dysphagia is present in up to 30% of patients with MS and is accompanied by other signs of brainstem dysfunction such as dysarthria or diplopia. In advanced stages, it can generate problems of nutrition or pulmonary infections requiring a multidisciplinary treatment.

Epilepsy affects up to 4% of MS patients and is thought to be due to cortical or juxta-cortical lesions. The most frequent seizures are focal, with or without secondary generalization.

Paroxysmal phenomena are episodes of sudden onset and very short duration consisting of repetitive neurological symptoms such as tonic or dystonic spasms, hemifacial spasm, facial myokymias, dysarthria or paroxysmal diplopia, Lhermitte phenomenon, sudden muscular atony, or kinesigenic choreoathetosis. The associated pathophysiological mechanisms are not known.

Uhthoff phenomenon is defined as the worsening of any focal symptom during processes in which body temperature rises, such as physical exercise or fever, secondary to a blockage of conduction in the optic nerve induced by heat when exceeding the safety threshold. This mechanism is not unique to the optic nerve, and patients with MS often complain of worsening of various neurological symptoms when there are increases in body temperature due to exercise, fever, or hot environments.

MS has been termed the disease of “the thousand faces” since it can affect any region of the CNS and produce a large number of symptoms and signs. However, there are symptoms that, due to their low frequency of presentation in MS, make it necessary to consider alternative diagnoses. Table 1.1 presents a summary of the typical and atypical symptoms of the disease.

Typical symptoms of MS-RR and symptoms suggestive of an alternative diagnosis

Despite the available armamentarium of DMTs for MS, current agents are effective in reducing relapses and radiological activity but have a limited impact on the accumulation of disability and have not been shown to be effective in progressive forms of the disease. The existing agents are directed to reduce inflammation but lack efficacy for repairing the existing damage, restoring function, or inducing remyelination.

One difficulty in conducting studies in progressive forms of MS is the lack of a primary outcome of progression that can be reliably measured early in the disease. Monitoring disability progression over time is a need, which can require longer and more costly trials. Disability progression has been defined as an increase in the EDSS score of 0.5–1.0 point after 3 or 6 months. The EDSS often has problems of reliability and validity because interrater variation has been reported to be greater than a 1-point increase in about 40% of times. Therefore, the EDSS may be inaccurate at determining disease progression in RRMS patients after a short time period and new outcomes of disability progression are needed.

Loss of brain volume is greater in patients with MS than in healthy individuals and is independent of the clinical phenotypes of the disease. 166   Brain atrophy has generated great expectation as a measure of neurodegeneration, and its reduction is proposed as a therapeutic objective. Additionally, new techniques and MRI sequence advances such as magnetization transfer (MTR), diffusion tensor images (DTI), and magnetic resonance spectroscopy (MRS) may serve to quantify demyelination and remyelination processes. However, both brain atrophy measures and new MRI techniques are not available in clinical practice yet.

A substantial percentage of patients show a suboptimal and unpredictable response and continue to accumulate disability. There are no accurate markers of response to treatments that can be applied in daily clinical practice. Furthermore, the best measure of response to treatment in MS is still to be determined.

The absence of relapses is a good indicator of stability, but it does not consider the appearance of inflammation in areas of the CNS that do not manifest clinically. MRI has become very important in the follow-up of inflammatory activity, since new lesions are 5–10 times more frequent than relapses and, nowadays, radiological activity is considered a virtual surrogate marker of activity. 167   However, the best response data are obtained through a combination of clinical and radiological measures. Different response measurement schemes with combined variables have been proposed such as Río criteria, 168   modified Río criteria, 169   Canadian model, 170   German model, 171   NEDA3, 172,173   and NEDA4 status, 174   but there is no general agreement on the best way to measure the response or what is the expected time to determine suboptimal response to each treatment.

A high efficacy is achieved with high levels of immunosuppression, increasing the risk of toxicity problems, of long-term adverse events as well as of potential effects on protective autoimmunity. An unmet need exists for new medications, with more specific treatment targets, that provide efficacy while avoiding risk for the adverse events associated with deep immunosuppression.

As previously described, a large number of symptoms may be experienced by MS patients and only a few medications are available to treat them. Effective symptom control without adverse effects is still a challenge.

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Signs of multiple sclerosis show up in blood years before symptoms

Scientists clear a potential path toward earlier treatment for a disease that affects nearly 1,000,000 people in the united states.

In a discovery that could hasten treatment for patients with multiple sclerosis (MS), UC San Francisco scientists have discovered a harbinger in the blood of some people who later went on to develop the disease.

In about 1 in 10 cases of MS, the body begins producing a distinctive set of antibodies against its own proteins years before symptoms emerge. These autoantibodies appear to bind to both human cells and common pathogens, possibly explaining the immune attacks on the brain and spinal cord that are the hallmark of MS.

The findings were published in Nature Medicine on April 19.

MS can lead to a devastating loss of motor control, although new treatments can slow the progress of the disease and, for example, preserve a patient's ability to walk. The scientists hope the autoantibodies they have discovered will one day be detected with a simple blood test, giving patients a head start on receiving treatment.

"Over the last few decades, there's been a move in the field to treat MS earlier and more aggressively with newer, more potent therapies," said UCSF neurologist Michael Wilson, MD, a senior author of the paper. "A diagnostic result like this makes such early intervention more likely, giving patients hope for a better life."

Linking infections with autoimmune disease

Autoimmune diseases like MS are believed to result, in part, from rare immune reactions to common infections.

In 2014, Wilson joined forces with Joe DeRisi, PhD, president of the Chan Zuckerberg Biohub SF and a senior author of the paper, to develop better tools for unmasking the culprits behind autoimmune disease. They took a technique in which viruses are engineered to display bits of proteins like flags on their surface, called phage display immunoprecipitation sequencing (PhIP-Seq), and further optimized it to screen human blood for autoantibodies.

PhIP-Seq detects autoantibodies against more than 10,000 human proteins, enough to investigate nearly any autoimmune disease. In 2019, they successfully used it to discover a rare autoimmune disease that seemed to arise from testicular cancer.

MS affects more than 900,000 people in the US. Its early symptoms, like dizziness, spasms, and fatigue, can resemble other conditions, and diagnosis requires careful analysis of brain MRI scans.

The phage display system, the scientists reasoned, could reveal the autoantibodies behind the immune attacks of MS and create new opportunities to understand and treat the disease.

The project was spearheaded by first co-authors Colin Zamecnik, PhD, a postdoctoral researcher in DeRisi's and Wilson's labs; and Gavin Sowa, MD, MS, former UCSF medical student and now internal medicine resident at Northwestern University.

They partnered with Mitch Wallin, MD, MPH, from the University of Maryland and a senior author of the paper, to search for autoantibodies in the blood of people with MS. These samples were obtained from the U.S. Department of Defense Serum Repository, which stores blood taken from armed service members when they apply to join the military.

The group analyzed blood from 250 MS patients collected after their diagnosis, plus samples taken five or more years earlier when they joined the military. The researchers also looked at comparable blood samples from 250 healthy veterans.

Between the large number of subjects and the before-and-after timing of the samples, it was "a phenomenal cohort of individuals to look at to see how this kind of autoimmunity develops over the course of clinical onset of this disease," said Zamecnik.

A consistent signature of MS

Using a mere one-thousandth of a milliliter of blood from each time point, the scientists thought they would see a jump in autoantibodies as the first symptoms of MS appeared.

Instead, they found that 10% of the MS patients had a striking abundance of autoantibodies years before their diagnosis.

The dozen or so autoantibodies all stuck to a chemical pattern that resembled one found in common viruses, including Epstein-Barr Virus (EBV), which infects more than 85% of all people, yet has been flagged in previous studies as a contributing cause for MS.

Years before diagnosis, this subset of MS patients had other signs of an immune war in the brain. Ahmed Abdelhak, MD, co-author of the paper and a postdoctoral researcher in the UCSF laboratory of Ari Green, MD, found that patients with these autoantibodies had elevated levels of neurofilament light (Nfl), a protein that gets released as neurons break down.

Perhaps, the researchers speculated, the immune system was mistaking friendly human proteins for some viral foe, leading to a lifetime of MS.

"When we analyze healthy people using our technology, everybody looks unique, with their own fingerprint of immunological experience, like a snowflake," DeRisi said. "It's when the immunological signature of a person looks like someone else, and they stop looking like snowflakes that we begin to suspect something is wrong, and that's what we found in these MS patients."

A test to speed patients toward the right therapies

To confirm their findings, the team analyzed blood samples from patients in the UCSF ORIGINS study. These patients all had neurological symptoms and many, but not all, went on to be diagnosed with MS.

Once again, 10% of the patients in the ORIGINS study who were diagnosed with MS had the same autoantibody pattern. The pattern was 100% predictive of an MS diagnosis. Across both the Department of Defense group and the ORIGINS group, every patient with this autoantibody pattern had MS.

"Diagnosis is not always straightforward for MS, because we haven't had disease specific biomarkers," Wilson said. "We're excited to have anything that can give more diagnostic certainty earlier on, to have a concrete discussion about whether to start treatment for each patient."

Many questions remain about MS, ranging from what's instigating the immune response in some MS patients to how the disease develops in the other 90% of patients. But the researchers believe they now have a definitive sign that MS is brewing.

"Imagine if we could diagnose MS before some patients reach the clinic," said Stephen Hauser, MD, director of the UCSF Weill Institute for Neurosciences and a senior author of the paper. "It enhances our chances of moving from suppression to cure."

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Materials provided by University of California - San Francisco . Original written by Levi Gadye. Note: Content may be edited for style and length.

Journal Reference :

• Colin R. Zamecnik, Gavin M. Sowa, Ahmed Abdelhak, Ravi Dandekar, Rebecca D. Bair, Kristen J. Wade, Christopher M. Bartley, Kerry Kizer, Danillo G. Augusto, Asritha Tubati, Refujia Gomez, Camille Fouassier, Chloe Gerungan, Colette M. Caspar, Jessica Alexander, Anne E. Wapniarski, Rita P. Loudermilk, Erica L. Eggers, Kelsey C. Zorn, Kirtana Ananth, Nora Jabassini, Sabrina A. Mann, Nicholas R. Ragan, Adam Santaniello, Roland G. Henry, Sergio E. Baranzini, Scott S. Zamvil, Joseph J. Sabatino, Riley M. Bove, Chu-Yueh Guo, Jeffrey M. Gelfand, Richard Cuneo, H.-Christian von Büdingen, Jorge R. Oksenberg, Bruce A. C. Cree, Jill A. Hollenbach, Ari J. Green, Stephen L. Hauser, Mitchell T. Wallin, Joseph L. DeRisi, Michael R. Wilson. An autoantibody signature predictive for multiple sclerosis . Nature Medicine , 2024; DOI: 10.1038/s41591-024-02938-3

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Track Record of Progress

• Recruited and provided training to more than 1,000 new MS researchers to the field
• Provided early career support and funding to many thought leaders in MS research
• Set standards in diagnosis, symptom management, pediatric MS, integrative therapies, rehabilitation and wellness research, clinical trial strategies and stem cell research
• Targeted highly promising areas of research, such as race and gender differences — to expedite progress and set the stage for clinical trials
• Helped launch the MS field of nerve and myelin repair, which resulted in trials of repair strategies to restore function for people living with MS
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• Paved the way for the development of disease-modifying therapies for MS and launched a unique commercial research funding program to support the creation of new treatment strategies

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• We fostered the creation of the International Progressive MS Alliance , an unprecedented global collaboration of MS organizations, researchers, health professionals, the pharmaceutical industry, companies, trusts, foundations, donors and people affected by progressive MS — working together to address the unmet needs of people with progressive MS.
• We led the MS Outcome Assessments Consortium , working toward creating robust clinical outcome measures to improve and speed MS clinical trials of new therapies.
• Our funding supported the International MS Genetics Consortium in completing the largest MS genetics study to date .
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Multiple sclerosis.

Dawood Tafti ; Moavia Ehsan ; Kathryn L. Xixis .

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Last Update: September 7, 2022 .

• Continuing Education Activity

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by chronic inflammation, demyelination, gliosis, and neuronal loss. The course may be relapsing-remitting or progressive in nature. Lesions in the CNS occur at different times and in different CNS locations. Because of this, multiple sclerosis lesions are sometimes said to be "disseminated in time and space." The clinical course of the disease is quite variable, ranging from stable chronic disease to a rapidly evolving and debilitating illness. This activity reviews the pathophysiology, presentation, and diagnosis of MS and highlights the role of the interprofessional team in its management.

• Explain the pathophysiology of multiple sclerosis.
• Describe the typical presentations of multiple sclerosis.
• Summarize the workup of a patient suspected of having multiple sclerosis.
• Review the need for enhanced coordination of care among interprofessional teams to improve outcomes for patients affected by multiple sclerosis.
• Introduction

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by inflammation, demyelination, gliosis, and neuronal loss. [1] Pathologically, perivascular lymphocytic infiltrates, and macrophages produce degradation of myelin sheaths that surround neurons. Neurological symptoms vary and can include vision impairment, numbness and tingling, focal weakness, bladder and bowel incontinence, and cognitive dysfunction. Symptoms vary depending on lesion location. Clinical symptoms characterized by acute relapses typically first develop in young adults. A gradually progressive course then ensues with permanent disability in 10 to 15 years. [2]

MS groups into seven categories based on disease course:

1) Relapsing-remitting (RR): 70 to 80% of MS patients demonstrate an initial onset characterized by a relapsing-remitting (RR) course, demonstrating the following neurologic presentation:

• New or recurrent neurological symptoms consistent with MS
• Symptoms last 24 to 48 hours
• They develop over days to weeks

2) Primary progressive (PP): 15 to 20% of patients present with a gradual deterioration from the onset, with an absence of relapses.

3) Secondary progressive (SP): this is characterized by a more gradual neurologic deterioration after an initial RR course. Superimposed relapses can be a feature of this clinical course, as well, although this is not a mandatory feature.

4) Progressive-relapsing (PR) MS: in 5% of patients, a gradual deterioration with superimposed relapses occurs.

The following three categories are sometimes included in the spectrum of MS:

5) Clinically isolated syndrome (CIS): often classified as a single episode of inflammatory CNS demyelination.

6) Fulminant: characterized by severe MS with multiple relapses and rapid progression towards disability.

7) Benign: a clinical course characterized by an overall mild disability. Relapses are rare.

When discussing MS, clinicians most often describe the RR course, considering its high prevalence amongst affected patients. Relapses often recover either partially or completely over weeks and months, frequently without treatment. Over time, residual symptoms from relapses without complete recovery accumulate and contribute to general disability. The diagnosis of RR MS is made with at least two CNS inflammatory events. Although different diagnostic criteria have been used for MS, the general principle of diagnosing the RR course has involved establishing episodes separated in "time and space." [3]  This means that episodes must be separated in time and affect different locations of the CNS. Making the diagnosis of MS expeditiously allows for the early and effective institution of disease-modifying therapy. [1] Treatment aims at decreasing relapses and MRI activity. Long-term therapy aims at reducing the risk of permanent disability.

The exact etiology of MS is unknown. Factors involved in pathogenesis broadly group into three categories:

• Immune factors
• Environmental factors
• Genetic associations

Dysimmunity with an autoimmune attack on the central nervous system is the leading hypothesized etiology of MS. Although there are various proposed hypothetical mechanisms, the postulated “out-side-in” mechanism involves CD4+ proinflammatory T cells. [4]  Researchers hypothesize that an unknown antigen triggers and activates both Th1 and Th17, leading to CNS endothelium attachment, the crossing of the blood-brain barrier, and subsequent immune attack through cross-reactivity. The “inside-out” hypothesis suggests an intrinsic CNS abnormality that triggers and results in inflammatory-mediated tissue damage. [4]

Environmental factors, including latitudinal gradients in different countries, have been well-studied phenomena. [5] Vitamin D deficiency has been considered a possible etiology for the noted predisposition of the population in higher latitudes being affected. [6] Different infections, including Epstein Barr virus (EBV), may also play a role. [7]  There are likely complex interactions between various environmental factors with patient genetics, and understanding these pathways is an area of ongoing research.

There is a high risk of MS in patients with biological relatives with MS. Heritability is estimated to be between 35 and 75%. [8] Monozygotic twins have a concordance rate of 20 to 30%, while dizygotic twins have a concordance rate of 5%. [9] There is a 2% concordance in parents and children, and this is still 10 to 20 fold higher risk than in the general population. [10]  The human leukocyte antigen (HLA) DRB1*1501 has a strong correlation with multiple sclerosis and is one of the most studied alleles relative to MS linkage. [11]   To date, there is no defined Mendelian form of genetic occurrence, and implications point to numerous genes. [12]

• Epidemiology

Approximately 400,000 individuals in the United States and 2.5 million individuals worldwide have multiple sclerosis. [13] The disease is three-fold more common in females than in males. [13] While the age of onset is usually between 20 to 40 years, the disease can present at any age. Almost 10% of the cases present before the age of 18. [14] An overall prevalence of 1 in 1000 is cited for populations of European ancestry. [15]  Less is understood about the prevalence in non-European populations, and most data suggests lower prevalence in those of East Asian and African descent. [16]  Recent studies have noted a high prevalence in African-American populations, similar to that of European ancestry. [16]

MS demonstrates a prevalence based on latitude gradient with increased prevalence in northern latitudes of Europe and North America. Observations noting variable genetic susceptibility factors amongst different human subpopulations apart from latitude have also been documented, suggesting poorly understood genetic factors interacting with environmental ones. Various studies have noted that populations that migrate to areas of greater MS prevalence during childhood also adopt a higher risk of acquiring MS. [17] Other studies have called this observation into question. [18]  Neither genetic or exogenous risk factors can independently explain the epidemiological observations of MS.

• Pathophysiology

The pathophysiology of MS is limited to the primary CNS. Two fundamental processes constitute general pathological process seen in MS patients:

• Focal inflammation resulting in macroscopic plaques and injury to the blood-brain barrier (BBB)
• Neurodegeneration with microscopic injury involving different components of the CNS including axons, neurons, and synapse

Together, these two primary processes result in macroscopic and microscopic injury. Lesions referred to as plaques occur in waves throughout the disease course and result from focal inflammation. MS plaques predominantly center around small veins and venules and show sharp margins. Myelin loss, edema, and axonal injury are the chief components of plaque pathology. BBB disruption during active plaque inflammation corresponds to enhancement seen on MRI. Over time, the inflammatory process subsides, resulting in an astrocytic scar. 

Microscopically MS lesions show mononuclear infiltrate with perivenular cuffing and surrounding white matter infiltration. Monocytes and macrophages, which represent innate immunity, stimulate T-cell migration across the BBB. The overall net result is an injury to the BBB and the entry of systemic immune cells. Activation of microglia, the main antigen-presenting cells of the primary CNS, often precedes cell entry. CNS injury results in the initiation of cytotoxic activities of microglia with the release of nitrous oxide and other superoxide radicals. Recently, there has been a greater understanding of the critical role of B cells and antibody production in the pathogenesis of MS. [19] B cell follicles in the meninges of MS patients have been noted, with an association with early-onset MS. [20]

• Histopathology

Histologically, MS plaques are characterized primarily by inflammation and myelin breakdown. Other features include neurodegeneration and oligodendrocyte injury. Multiple histologic stains are employed with adjunct immunohistochemistry aiding in diagnosis:

• Hematoxylin and eosin staining
• Myelin stains (i.e., Luxol fast blue)
• Monocyte and macrophage markers(i.e., CD68)
• Axonal and astrocyte stains

Active plaques are characterized in varying degrees by the following features:

• Extensive macrophage infiltration
• Myelin debris frequently contained within macrophages
• The presence of major myelin protein (in late active plaques)
• Perivascular inflammatory infiltrates
• Presence of lymphocytes (particularly CD8-positive cytotoxic T cells)
• Plump shaped and mitotic astrocytes
• Variable degrees of oligodendrocytes injury
• Activated microglia (particularly the peri-plaque white matter zone)

Chronic plaques characteristically demonstrate circumscribed demyelinated lesions. They occur more frequently and are characterized by the following features:

• Hypocellularity and demyelination
• Macrophages laden with myelin
• Perivascular inflammation, relatively decreased compared to active plaques
• Resolving edema
• In remyelinated plaques, there are thinly myelinated axons and axons with newly formed myelin sheaths
• The appearance of oligodendrocyte precursor cells(classically in remyelinated plaques)
• History and Physical

MS presents with a broad range of symptoms reflective of the multifocal lesions of the CNS. The severity and wide range of symptoms are reflective of lesion burden, location, and degree of tissue injury. Symptoms are often not reflective of MRI evidence of active plaques given repair mechanisms and neural plasticity involved in tissue injury.

Typical clinical manifestations noted on history include:

• Vision symptom: includes vision loss(either monocular or homonymous), double vision, symptoms relating to optic neuritis.
• Vestibular symptoms: vertigo, gait imbalance
• Bulbar dysfunction: dysarthria, dysphagia
• Motor: weakness, tremor, spasticity, fatigue
• Sensory: loss of sensation, paresthesias, dysesthesias
• Urinary and bowel symptoms: incontinence, retention, urgency, constipation, diarrhea, reflux
• Cognitive symptoms: memory impairment, impairment of executive functions, trouble concentrating
• Psychiatric symptoms: depression, anxiety

The RR course of MS is observed in a majority of patients and is characterized by exacerbation and relapses of neurological symptoms, with stability between episodes. The following features generally characterize the RR course of MS:

• New or recurrent neurological symptoms
• Symptoms developing over days and weeks
• Symptoms lasting 24 to 48 hours

Symptoms from relapses frequently resolve, however over time, residual symptoms relating to episodes of exacerbation accrue. This accrual of symptoms, generally after 10 to 15 years, results in long term disability over time. Neurologic manifestations are heterogeneous in severity and degree of recovery. The secondary-progressive (SP) course is often noted in patients with RR after 10 to 15 years of onset and is characterized by a more gradual worsening of symptoms with continued progression with or without superimposed relapses. A small proportion of patients demonstrate gradual worsening of disability from onset of disease, described as the primary progressive (PP) course of MS. Myelopathy, cognitive symptoms, and visual symptoms are most frequently the clinical manifestations in this clinical course.

The physical exam mirrors evaluation of the patient's history of present illness and includes:

• Evaluation for optic neuritis, classically manifesting as subacute monocular central vision loss; pain on eye movement is also classically noted.
• Difficulty with adducting in lateral gaze suggesting internuclear ophthalmoplegia (INO)
• Hearing loss
• Facial pain

Neuromuscular/neurologic:

• Partial transverse myelitis which is typically unilateral or bilateral and characterized by sensory disturbances
• Brainstem symptoms classically involving diplopia, dysphagia, dysarthria, and ataxia
• L'hermittes sign; often described as a shock-like sensation that occurs with neck flexion
• Hyperreflexia
• Muscle spasms

Genitourinary:

• Urinary incontinence/retension(residual bladder volume evaluation) 
• Erectile dysfunction (nocturnal penile tumescence stamp test if indicated)

No single pathognomonic test exists for the diagnosis of MS. Diagnosis is made by weighing the history and physical, MRI, evoked potentials, and CSF/blood studies and excluded other causes of the patient's symptoms. Clinically a diagnosis can be made with evidence of two or more relapses: this is possible through objective clinical evidence of two or more lesions or objective clinical evidence of one lesion with reliable historical evidence of a prior relapse. Dissemination in space (DIS) and dissemination in time(DIT) are two hallmarks of the accurate diagnosis of MS. DIS is assessed using information from the history and physical and understanding in determining the location of CNS involvement. MRI and evoked potentials have vital roles in also establishing DIS. DIT is established by charting the disease course with a thorough history and documenting the presence of multiple exacerbations. The 2010 McDonald criteria determined that DIT can be demonstrated by new lesions on a follow-up MRI when compared to a baseline scan. [21] DIS is established by noting at least one T2 lesion in two of the four following CNS sites: spinal cord, infratentorial, juxtacortical, and periventricular regions. Revisions in the 2017 McDonald criteria increased sensitivity of diagnosis by introducing oligoclonal bands in the CSF analysis as a marker for establishing DIT. Symptomatic lesions were also included as a parameter for establishing DIT and DIS, and cortical lesions to demonstrate DIS. [22]

Evoked potentials are useful to demonstrate slowed conduction indicative of subclinical involvement. Of note, these findings are often asymmetric. MRI, CSF, and blood studies are essential in ruling out other etiologies. All patients should obtain an MRI when possible. Specific blood studies to include CBC, TSH, vitamin B12, sedimentation rate, and ANA should also be obtained in all patients.

The chief characteristics of MS lesions on MRI can be summarized as the following:

• Lesions are T2 hyperintense, T1 isointense/hypointense.
• Lesions are classically oval or can be patchy.
• A high predilection for periventricular white matter
• Lesions are perpendicular to the ependymal surface(Dawson's fingers)
• Gadolinium enhancement with active lesions noted as classically diffuse or rim enhancement.
• Thinning of the corpus callosum and parenchymal atrophy
• Cord lesions classically involve the cervical or thoracic cord

The classic abnormal CSF findings in MS are as follows:

• Elevated protein and elevated myelin basic protein
• Leukocytes(occasionally seen, and typically mononuclear cells)
• Increased total IgG, increased free kappa light chains, oligoclonal bands
• Treatment / Management

Disease-modifying therapies are the mainstay of treatment of relapsing-remitting MS. Glatiramer acetate, dimethyl fumarate, fingolimod, interferon-beta preparations, natalizumab, and mitoxantrone are some of the primary disease-modifying therapies available. Early treatment should commence upon establishing a diagnosis of MS. Short term goal includes a reduction in MRI lesion activity. Long term goals include prevention of secondary progressive MS. The primary issues after initiating therapy include patient compliance and monitoring for drug toxicity.

• Glatiramer acetate is a mixture of synthetic polypeptides, possibly functioning as a ligand for the major histocompatibility complex (MHC) molecules. Binding limits activation and induces regulatory cells. Possible neuroprotective and repair mechanisms are also possibilities. [23] Administration is subcutaneous. Glatiramer acetate is well tolerated; however, it is not useful for the treatment of progressive forms of MS.
• Interferon-beta preparations have various mechanisms of possible action. Interferon-beta modulates T, and B-cell function possibly alters cytokine expression, plays a role in blood-brain barrier recovery, and potentially decreases matrix metalloproteinase expression. Administration is either subcutaneous or intramuscular, depending on the preparation. Side effects include flu-like symptoms and possible brief worsening of the patient's existing neurologic symptoms.
• Natalizumab is an intravenously administered humanized monoclonal antibody that blocks leukocyte adhesion with vascular endothelial cells. This drug inhibits leukocyte migration into the central nervous system. Natalizumab is usually well tolerated. Mild headaches and flushing often occur during intravenous administration.
• Mitoxantrone is an intravenously administered chemotherapeutic agent that interferes with DNA repair and RNA synthesis. A possible effect on cellular and humoral immunity may represent the mechanism of therapy for MS. [24] Different adverse effects have been documented, including amenorrhea and alopecia.
• Fingolimod is an orally administered drug with immunomodulatory effects, possibly relating to inhibition of T cell migration. Possible side effects include lymphopenia, bradycardia, and hepatotoxicity.

Patients with secondary progressive MS, progressive-relapsing MS, and primary progressive MS appear to represent primarily neurodegenerative processes. Disease-modifying therapies are, therefore, less effective, and treatment with these therapies has ranged from possible benefit to little effect on disease progression. Young patients with a short duration of progression seem to derive the most benefit.

The following principles highlight the treatment of acute relapses:

• Treatment of a possible underlying process which could have triggered a relapse (such as an infection or metabolic derangement)
• Symptomatic treatment based on specific neurologic symptoms
• A short course of corticosteroids to assist in recovery
• Rehabilitation with involvement of physical and occupational therapy
• Differential Diagnosis

The differential diagnosis of MS is extensive and broad and can categorize into seven categories:

• Other demyelinating or inflammatory CNS syndromes: Examples include optic neuritis, Marburg disease, acute disseminated encephalomyelitis, Devic neuromyelitis optica, and partial transverse myelitis.
• General inflammatory and autoimmune syndromes. Examples include systemic lupus erythematosus, Wegener granulomatosis, sarcoidosis, and Sjogren syndrome.
• Infectious etiologies such as Lyme disease, syphilis, HIV, and herpes viruses
• Vascular etiologies such as migraine headaches, small vessel ischemia, vascular malformations and emboli
• Metabolic causes that include vitamin deficiencies and thyroid disease
• Uncommon genetic etiologies that include mitochondrial cytopathy, Fabry disease, Alexander disease, hereditary spastic paraplegia
• Neoplastic causes that include primary CNS malignancies or metastasis

The prognosis and severity of the disease vary between patients. [25]  The condition is often mild early on in the disease and worsens as time progresses. 

Factors that suggest a worse prognosis include:

• Male gender
• Progressive course
• Primarily pyramidal or cerebellar symptoms
• More frequent relapses
• Minimal recovery between relapses
• Multifocal onset
• High early relapse rate
• Large lesion load and brain atrophy on MRI

Factors that suggest a favorable diagnosis include:

• Female gender
• Relapsing course
• Mild relapses
• Good recovery between exacerbations
• Primarily sensory symptoms
• Long interval between first and second relapses
• Low lesion load on MRI
• Presentation of optic neuritis
• Full recovery from exacerbations
• Complications

The long term disability of MS reflects an accumulation of symptoms from each successive incomplete recovery from relapse.

• Impaired mobility occurs in a majority of patients with long term MS. Reduction in mobility is multifactorial and possibly relates to defective motor control and vestibular symptoms.
• Brain stem lesions involving the oculomotor pathways can cause chronic diplopia. This condition is potentially addressable by prisms and surgery.
• Chronic vertigo is a possible source of morbidity and may respond to meclizine, ondansetron, or diazepam.
• Chronic dysphagia from bulbar dysfunction can be a source of chronic aspiration.
• Cerebellar tremor is a possibly significant source of disability. Wrist weights have a possible role in the management of tremors; however, potential superimposed weakness can preclude the use of wrist weights.
• Urinary tract infections from bladder dysfunction is a known longer-term complication and often requires urology consultation.
• Constipation is the most frequent gastrointestinal complication, and management includes patient education and treatment with increased fiber intake and bulk-forming agents.
• Erectile dysfunction, when present, is often treated with oral phosphodiesterase-5 inhibitors
• Cognitive impairment, mood disorders, and generalized fatigue are known long term sources of morbidity and are managed in various ways, often with the help of subspecialty care.
• Consultations

MS is a complex neurologic disorder that results in both neurologic and non-neurologic symptoms, disability, and complaints. A multidisciplinary team approach includes the involvement of the following specialties:

• Neurology and neuro-ophthalmology
• Psychiatry/ cognitive psychology
• Pain management
• Nursing/physician assistants
• Speech therapy
• Occupational therapy
• Social work
• Physical medicine and rehabilitation
• Urology (in the setting of genitourinary complications)
• Gastroenterology (in the setting of gastrointestinal complications)
• Deterrence and Patient Education

A diagnosis of MS can be difficult for a patient, and the physician plays a supportive role in counseling the patient about the diagnosis. Predicting disease course is difficult, and a provider should educate the patient on the wide range of possibilities in disease progression.

Clinicians should emphasize that patients often do well and explain the role of effective medications on disease treatment. Patients should receive counsel on reliable sources online on learning about their diagnosis. Reliable sources include the MS International Federation and the National MS Society. Educating the patient on the nature of relapses and long term complications is essential. Patients should know to contact their provider if they experience new neurologic symptoms that last greater than 24 hours, as this may require the administration of corticosteroids. Emphasizing smoking cessation, Vitamin D supplementation, a balanced diet, and other lifestyle medications is also important. A patient should also be counseled on the importance of compliance with disease-modifying therapy, considering the side-effect profile of these medications. 

• Enhancing Healthcare Team Outcomes

Multiple sclerosis is a complex disease process. In addition to sensory and visual changes, weakness, coordination problems, or spasticity can present. Other complaints relating to overall health include bladder and bowel dysfunction, depression, cognitive impairment, fatigue, sexual dysfunction, sleep disturbances, and vertigo. Because of reduced life expectancy and multisystem involvement, the disorder is best managed by an interprofessional team that includes a neurologist, pain specialist, physical and/or occupational therapist, nurse specialist, ophthalmologist, mental health nurse, gastroenterologist, and a urologist. [Level 5]

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optic neuritis in multiple sclerosis Image courtesy S Bhimji MD

Multiple sclerosis Contributed by Sunil Munakomi, MD.

Multiple sclerosis: saggital FLAIR sequence demonstrates a hyperintense lesion perpendicular to the right lateral ventricle(These are classically called "Dawson's fingers"). Contributed by Dawood Tafti, MD.

Multiple sclerosis: axial FLAIR sequence demonstrates advanced lesion burden along the callososeptal interface. Contributed by Dawood Tafti, MD.

Multiple sclerosis: linear hyperintense lesions on a saggital AXIAL sequence. These lesions are arranged perpendicular to the left lateral ventricle("Dawson's fingers"). Contributed by Dawood Tafti, MD.

Disclosure: Dawood Tafti declares no relevant financial relationships with ineligible companies.

Disclosure: Moavia Ehsan declares no relevant financial relationships with ineligible companies.

Disclosure: Kathryn Xixis declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Tafti D, Ehsan M, Xixis KL. Multiple Sclerosis. [Updated 2022 Sep 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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