Editing Multiple sclerosis

{{Short description|Disease that damages the myelin sheaths around nerves}}
{{More medical citations needed|date=July 2022|references that do not meet [[WP:MEDRS|Wikipedia's guidelines for medical content]], or are excessively dated, are contained in this article}}
{{Use dmy dates|date=March 2023}}
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{{Infobox medical condition (new)
| name          = Multiple sclerosis
| image         = MS Demyelinisation CD68 10xv2.jpg
| caption       = [[CD68]]-stained tissue shows several [[macrophages]] in the area of a demyelinated lesion caused by MS.
| field         = [[Neurology]]
| synonyms      = Multiple cerebral sclerosis, multiple cerebro-spinal sclerosis, disseminated sclerosis, encephalomyelitis disseminata
| symptoms      = Involving [[autonomic nervous system|autonomic]], visual, motor, and sensory systems, almost any central or [[Peripheral neuropathy|peripheral neurological symptom]].<ref name="pmid1897097722"/>
| onset         = Age 20–50<ref name=Milo2010 />
| duration      = Long term<ref name=NIH2015 />
| causes        = Unknown<ref name="Nak20122">{{cite journal | vauthors = Nakahara J, Maeda M, Aiso S, Suzuki N | title = Current concepts in multiple sclerosis: autoimmunity versus oligodendrogliopathy | journal = Clinical Reviews in Allergy & Immunology | volume = 42 | issue = 1 | pages = 26–34 | date = February 2012 | pmid = 22189514 | doi = 10.1007/s12016-011-8287-6 | s2cid = 21058811 }}</ref>
| risks         =
| diagnosis     = Based on symptoms and medical tests<ref name="Tsang20112"/>
| treatment     = {{Plain list|
* Disease-modifying therapies<ref name="Liu_2021">{{cite journal | vauthors = Liu Z, Liao Q, Wen H, Zhang Y | title = Disease modifying therapies in relapsing-remitting multiple sclerosis: A systematic review and network meta-analysis | journal = Autoimmunity Reviews | volume = 20 | issue = 6 | pages = 102826 | date = June 2021 | pmid = 33878488 | doi = 10.1016/j.autrev.2021.102826 | s2cid = 233325057 }}</ref>
* Physiotherapy<ref name="Alphonsus_20192">{{cite journal | vauthors = Alphonsus KB, Su Y, D'Arcy C | title = The effect of exercise, yoga and physiotherapy on the quality of life of people with multiple sclerosis: Systematic review and meta-analysis | journal = Complementary Therapies in Medicine | volume = 43 | pages = 188–195 | date = April 2019 | pmid = 30935529 | doi = 10.1016/j.ctim.2019.02.010 | s2cid = 86669723 }}</ref>
* Occupational therapy<ref name="Alphonsus_20192"/>
}}
}}

'''Multiple sclerosis''' ('''MS''') is an [[autoimmune disease]] resulting in damage to [[myelin]]{{snd}}the insulating covers of [[nerve cells]]{{snd}}in the brain and [[spinal cord]].<ref name=NIH2015>{{cite web|title=NINDS Multiple Sclerosis Information Page|url=http://www.ninds.nih.gov/disorders/multiple_sclerosis/multiple_sclerosis.htm|website=National Institute of Neurological Disorders and Stroke|access-date=6 March 2016|date=19 November 2015|url-status=dead|archive-url=https://web.archive.org/web/20160213025406/http://www.ninds.nih.gov/disorders/multiple_sclerosis/multiple_sclerosis.htm|archive-date=13 February 2016}}</ref> As a [[demyelinating disease]], MS disrupts the nervous system's ability to [[Action potential|transmit signals]], resulting in a range of [[signs and symptoms]], including physical, [[cognitive disability|mental]], and sometimes psychiatric problems.<ref name="pmid1897097722">{{cite journal | vauthors = Compston A, Coles A | title = Multiple sclerosis | journal = Lancet | volume = 372 | issue = 9648 | pages = 1502–1517 | date = October 2008 | pmid = 18970977 | doi = 10.1016/S0140-6736(08)61620-7 | s2cid = 195686659 | author1-link = Alastair Compston }}</ref><ref name="pmid119555563">{{cite journal | vauthors = Compston A, Coles A | title = Multiple sclerosis | journal = Lancet | volume = 359 | issue = 9313 | pages = 1221–1231 | date = April 2002 | pmid = 11955556 | doi = 10.1016/S0140-6736(02)08220-X | s2cid = 14207583 }}</ref><ref>{{cite book |vauthors=Murray ED, Buttner EA, Price BH |chapter=Depression and Psychosis in Neurological Practice |veditors=Daroff R, Fenichel G, Jankovic J, Mazziotta J|title=Bradley's neurology in clinical practice.|year=2012|publisher=Elsevier/Saunders|location=Philadelphia, PA|isbn=978-1-4377-0434-1|edition=6th }}</ref> Symptoms include [[double vision]], vision loss, eye pain, muscle weakness, and loss of [[Sensation (psychology)|sensation]] or coordination.<ref name=NIH2015 /><ref name="Piryonesi-2021">{{cite journal | vauthors = Piryonesi SM, Rostampour S, Piryonesi SA | title = Predicting falls and injuries in people with multiple sclerosis using machine learning algorithms | journal = Multiple Sclerosis and Related Disorders | volume = 49 | pages = 102740 | date = April 2021 | pmid = 33450500 | doi = 10.1016/j.msard.2021.102740 | s2cid = 231624230 }}</ref><ref>{{cite journal | vauthors = Mazumder R, Murchison C, Bourdette D, Cameron M | title = Falls in people with multiple sclerosis compared with falls in healthy controls | journal = PLOS ONE | volume = 9 | issue = 9 | pages = e107620 | date = 25 September 2014 | pmid = 25254633 | pmc = 4177842 | doi = 10.1371/journal.pone.0107620 | doi-access = free | bibcode = 2014PLoSO...9j7620M }}</ref> MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms).<ref>{{cite journal | vauthors = Baecher-Allan C, Kaskow BJ, Weiner HL | title = Multiple Sclerosis: Mechanisms and Immunotherapy | journal = Neuron | volume = 97 | issue = 4 | pages = 742–768 | date = February 2018 | pmid = 29470968 | doi = 10.1016/j.neuron.2018.01.021 | s2cid = 3499974 | doi-access = free }}</ref><ref name="pmid8780061">{{medical citation needed|date=July 2022}}{{cite journal | vauthors = Lublin FD, Reingold SC | title = Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis | journal = Neurology | volume = 46 | issue = 4 | pages = 907–911 | date = April 1996 | pmid = 8780061 | doi = 10.1212/WNL.46.4.907 | s2cid = 40213123 | author1-link = Fred D. Lublin }}</ref> In relapsing forms of MS, symptoms may disappear completely between attacks, although some permanent neurological problems often remain, especially as the disease advances.<ref name="pmid8780061" /> In progressive forms of MS, bodily function slowly deteriorates once symptoms manifest and will steadily worsen if left untreated.<ref>{{cite journal | vauthors = Loma I, Heyman R | title = Multiple sclerosis: pathogenesis and treatment | journal = Current Neuropharmacology | volume = 9 | issue = 3 | pages = 409–416 | date = September 2011 | pmid = 22379455 | pmc = 3151595 | doi = 10.2174/157015911796557911 }}</ref>

<!-- Cause, pathophysiology, and diagnosis -->
While its cause is unclear, the underlying mechanism is thought to be due to either [[Autoimmune disease|destruction by the immune system]] or inactivation of myelin-producing cells.<ref name="Nak20122"/> Proposed causes for this include immune dysregulation, [[genetics]], and environmental factors, such as [[viral infection]]s.<ref name="Ward 988–1005">{{cite journal |vauthors=Ward M, Goldman MD |date=August 2022 |title=Epidemiology and Pathophysiology of Multiple Sclerosis |journal=Continuum |volume=28 |issue=4 |pages=988–1005 |doi=10.1212/CON.0000000000001136 |pmid=35938654 |s2cid=251375096}}</ref><ref name="Aloisi20222">{{cite journal | vauthors = Aloisi F, Cross AH | title = MINI-review of Epstein-Barr virus involvement in multiple sclerosis etiology and pathogenesis | journal = Journal of Neuroimmunology | volume = 371 | issue =  | pages = 577935 | date = October 2022 | pmid = 35931008 | doi = 10.1016/j.jneuroim.2022.577935 | s2cid = 251152784 }}</ref><ref name="pmid119555563"/><ref name="Ascherio_2007">{{cite journal | vauthors = Ascherio A, Munger KL | title = Environmental risk factors for multiple sclerosis. Part I: the role of infection | journal = Annals of Neurology | volume = 61 | issue = 4 | pages = 288–299 | date = April 2007 | pmid = 17444504 | doi = 10.1002/ana.21117 | s2cid = 7682774 | doi-access = free }}</ref> The [[McDonald criteria]] are a frequently updated set of guidelines used to establish an MS diagnosis.<ref>{{Cite web |date=31 May 2023 |title=The McDonald criteria |url=https://www.mssociety.org.uk/about-ms/diagnosis/the-tests-for-ms/mcdonald-criteria |access-date=November 26, 2024 |website=MS Society UK |archive-date=2 December 2024 |archive-url=https://web.archive.org/web/20241202055738/https://www.mssociety.org.uk/about-ms/diagnosis/the-tests-for-ms/mcdonald-criteria |url-status=live }}</ref>

<!-- Treatment, prognosis -->
There is no cure for MS.<ref name="NIH20152">{{cite web |date=19 November 2015 |title=NINDS Multiple Sclerosis Information Page |url=http://www.ninds.nih.gov/disorders/multiple_sclerosis/multiple_sclerosis.htm |url-status=dead |archive-url=https://web.archive.org/web/20160213025406/http://www.ninds.nih.gov/disorders/multiple_sclerosis/multiple_sclerosis.htm |archive-date=13 February 2016 |access-date=6 March 2016 |website=National Institute of Neurological Disorders and Stroke}}</ref> Current treatments aim to mitigate inflammation and resulting symptoms from acute flares and prevent further attacks with disease-modifying medications.<ref name="pmid119555563"/><ref name="McGinley_2021">{{cite journal | vauthors = McGinley MP, Goldschmidt CH, Rae-Grant AD | title = Diagnosis and Treatment of Multiple Sclerosis: A Review | journal = JAMA | volume = 325 | issue = 8 | pages = 765–779 | date = February 2021 | pmid = 33620411 | doi = 10.1001/jama.2020.26858 | s2cid = 232019589 }}</ref> [[Physical therapy]]<ref name="Alphonsus_20192"/> and [[occupational therapy]],<ref>{{cite journal | vauthors = Quinn É, Hynes SM | title = Occupational therapy interventions for multiple sclerosis: A scoping review | journal = Scandinavian Journal of Occupational Therapy | volume = 28 | issue = 5 | pages = 399–414 | date = July 2021 | pmid = 32643486 | doi = 10.1080/11038128.2020.1786160 | hdl-access = free | s2cid = 220436640 | hdl = 10379/16066 }}</ref> along with patient-centered symptom management, can help with people's ability to function. The long-term outcome is difficult to predict; better outcomes are more often seen in women, those who develop the disease early in life, those with a relapsing course, and those who initially experienced few attacks.<ref name="pmid80178902">{{cite journal | vauthors = Weinshenker BG | title = Natural history of multiple sclerosis | journal = Annals of Neurology | volume = 36 | issue = Suppl | pages = S6-11 | year = 1994 | pmid = 8017890 | doi = 10.1002/ana.410360704 | s2cid = 7140070 }}</ref>

<!-- Epidemiology and history -->
MS is the most common [[immune disorder|immune-mediated disorder]] affecting the [[central nervous system]] (CNS).<ref name="pmid24746689">{{cite journal | vauthors = Berer K, Krishnamoorthy G | title = Microbial view of central nervous system autoimmunity | journal = FEBS Letters | volume = 588 | issue = 22 | pages = 4207–13 | date = November 2014 | pmid = 24746689 | doi = 10.1016/j.febslet.2014.04.007 | bibcode = 2014FEBSL.588.4207B | s2cid = 2772656 }}</ref> In 2020, about 2.8 million people were affected by MS globally, with rates varying widely in different regions and among different populations.<ref name="Lane2022">{{cite journal |vauthors=Lane J, Ng HS, Poyser C, Lucas RM, Tremlett H |title=Multiple sclerosis incidence: A systematic review of change over time by geographical region |journal=Mult Scler Relat Disord |volume=63 |issue= |pages=103932 |date=July 2022 |pmid=35667315 |doi=10.1016/j.msard.2022.103932 |s2cid=249188137 |doi-access=free }}</ref> The disease usually begins between the ages of 20 and 50 and is twice as common in women as in men.<ref name="Milo2010">{{cite journal | vauthors = Milo R, Kahana E | title = Multiple sclerosis: geoepidemiology, genetics and the environment | journal = Autoimmunity Reviews | volume = 9 | issue = 5 | pages = A387-94 | date = March 2010 | pmid = 19932200 | doi = 10.1016/j.autrev.2009.11.010 }}</ref> MS was first described in 1868 by French neurologist [[Jean-Martin Charcot]].<ref name="Charcot1" />

<!-- Etymology -->
The name "multiple [[Sclerosis (medicine)|sclerosis]]" is short for '''multiple cerebro-spinal sclerosis''', which refers to the numerous [[glial scar]]s (or sclerae – essentially plaques or lesions) that develop on the [[white matter]] of the brain and spinal cord.<ref name="Charcot1">{{cite journal | vauthors = Clanet M | title = Jean-Martin Charcot. 1825 to 1893 | journal = International MS Journal | volume = 15 | issue = 2 | pages = 59–61 | date = June 2008 | pmid = 18782501 }}<br />* {{cite journal |vauthors = Charcot J |year=1868 |title=Histologie de la sclerose en plaques |journal=Gazette des Hopitaux, Paris |volume=41 |pages=554–5 }}</ref>
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== Signs and symptoms ==
{{Main|Multiple sclerosis signs and symptoms}}
[[File:Symptoms of multiple sclerosis.svg|thumb|Main symptoms of multiple sclerosis]]

MS lesions can affect any part of the [[central nervous system]] so a person with MS can have almost any [[neurological]] signs or symptoms.<ref>{{Cite web |title=MS Symptoms and Signs of MS {{!}} MS Society |url=https://www.mssociety.org.uk/about-ms/signs-and-symptoms |access-date=2025-02-25 |website=www.mssociety.org.uk |language=en}}</ref>

[[Fatigue]] is one of the most common symptoms of MS.<ref>{{Cite web | url = https://mstrust.org.uk/a-z/fatigue | title = Fatigue | location = Letchworth Garden City, United Kingdom | publisher = Multiple Sclerosis Trust | access-date = 16 January 2024 | archive-date = 16 January 2024 | archive-url = https://web.archive.org/web/20240116234819/https://mstrust.org.uk/a-z/fatigue | url-status = live }}</ref><ref>{{cite journal | vauthors = Moore H, Nair KP, Baster K, Middleton R, Paling D, Sharrack B | title = Fatigue in multiple sclerosis: A UK MS-register based study | journal = Multiple Sclerosis and Related Disorders | volume = 64 | pages = 103954 | date = August 2022 | pmid = 35716477 | doi = 10.1016/j.msard.2022.103954 }}</ref> Roughly 65% of people with MS experience fatigue.  Of these, some 15–40% report fatigue as their most disabling symptom.<ref name="pmid37602098">{{cite journal | vauthors = Bakalidou D, Giannopapas V, Giannopoulos S | title = Thoughts on Fatigue in Multiple Sclerosis Patients | journal = Cureus | volume = 15 | issue = 7 | pages = e42146 | date = July 2023 | pmid = 37602098 | pmc = 10438195 | doi = 10.7759/cureus.42146 | doi-access = free }}</ref>

[[Autonomic nervous system|Autonomic]], visual, motor, and sensory problems are also among the most common symptoms.<ref name="pmid1897097722"/>

The specific symptoms depend on the locations of the lesions within the nervous system and may include [[Hypoesthesia|loss of sensitivity]] or [[Paresthesia|changes in sensation]] in the limbs, such as tingling, “pins and needles,” or numbness; limb motor weakness or pain, [[blurred vision]],<ref>{{cite web |title=MS Signs |url=http://www.webmd.com/multiple-sclerosis/ |url-status=live |archive-url=https://web.archive.org/web/20160930181511/http://www.webmd.com/multiple-sclerosis/ |archive-date=30 September 2016 |access-date=7 October 2016 |website=[[Webmd]]}}</ref> [[Clonus|pronounced reflexes]], [[muscle spasms]], difficulty walking, or with coordination or balance ([[ataxia]]); [[Dysarthria|problems with speech]]<ref>{{cite journal | vauthors = Plotas P, Nanousi V, Kantanis A, Tsiamaki E, Papadopoulos A, Tsapara A, Glyka A, Mani E, Roumelioti F, Strataki G, Fragkou G, Mavreli K, Ziouli N, Trimmis N | title = Speech deficits in multiple sclerosis: a narrative review of the existing literature | journal = European Journal of Medical Research | volume = 28 | issue = 1 | pages = 252 | date = July 2023 | pmid = 37488623 | pmc = 10364432 | doi = 10.1186/s40001-023-01230-3 | doi-access = free }}</ref> or [[Dysphagia|swallowing]], visual problems ([[optic neuritis]] manifesting as eye pain & vision loss,<ref name="Petzold_2022">{{cite journal | vauthors = Petzold A, Fraser CL, Abegg M, Alroughani R, Alshowaeir D, Alvarenga R, Andris C, Asgari N, Barnett Y, Battistella R, Behbehani R, Berger T, Bikbov MM, Biotti D, Biousse V, Boschi A, Brazdil M, Brezhnev A, Calabresi PA, Cordonnier M, Costello F, Cruz FM, Cunha LP, Daoudi S, Deschamps R, de Seze J, Diem R, Etemadifar M, Flores-Rivera J, Fonseca P, Frederiksen J, Frohman E, Frohman T, Tilikete CF, Fujihara K, Gálvez A, Gouider R, Gracia F, Grigoriadis N, Guajardo JM, Habek M, Hawlina M, Martínez-Lapiscina EH, Hooker J, Hor JY, Howlett W, Huang-Link Y, Idrissova Z, Illes Z, Jancic J, Jindahra P, Karussis D, Kerty E, Kim HJ, Lagrèze W, Leocani L, Levin N, Liskova P, Liu Y, Maiga Y, Marignier R, McGuigan C, Meira D, Merle H, Monteiro ML, Moodley A, Moura F, Muñoz S, Mustafa S, Nakashima I, Noval S, Oehninger C, Ogun O, Omoti A, Pandit L, Paul F, Rebolleda G, Reddel S, Rejdak K, Rejdak R, Rodriguez-Morales AJ, Rougier MB, Sa MJ, Sanchez-Dalmau B, Saylor D, Shatriah I, Siva A, Stiebel-Kalish H, Szatmary G, Ta L, Tenembaum S, Tran H, Trufanov Y, van Pesch V, Wang AG, Wattjes MP, Willoughby E, Zakaria M, Zvornicanin J, Balcer L, Plant GT | title = Diagnosis and classification of optic neuritis | journal = The Lancet. Neurology | volume = 21 | issue = 12 | pages = 1120–1134 | date = December 2022 | pmid = 36179757 | doi = 10.1016/s1474-4422(22)00200-9 | doi-access = free }}</ref> or [[nystagmus]] manifesting as [[Diplopia|double vision]]), fatigue, and bladder and [[neurogenic bowel dysfunction|bowel difficulties]] (such as urinary or fecal incontinence or retention), among others.<ref name="pmid1897097722"/> When MS is more advanced, walking difficulties lead to a higher risk of falling.<ref>{{cite book |vauthors=Cameron MH, Nilsagard Y |chapter=Balance, gait, and falls in multiple sclerosis | veditors = Day BL, Lord SR |title=Balance, Gait, and Falls  |year=2018 |isbn=978-0-444-63916-5 |series=Handbook of Clinical Neurology |volume=159 |pages=237–250 |doi=10.1016/b978-0-444-63916-5.00015-x |pmid=30482317}}</ref><ref name="McGinley_2021" /><ref>{{cite journal | vauthors = Ghasemi N, Razavi S, Nikzad E | title = Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy | journal = Cell Journal | volume = 19 | issue = 1 | pages = 1–10 | date = January 2017 | pmid = 28367411 | pmc = 5241505 | doi = 10.22074/cellj.2016.4867 | doi-broken-date = 11 November 2024 }}</ref>

Difficulties in thinking and emotional problems such as depression or [[labile affect|unstable mood]] are also common.<ref name="pmid1897097722"/><ref>{{cite journal | vauthors = Chen MH, Wylie GR, Sandroff BM, Dacosta-Aguayo R, DeLuca J, Genova HM | title = Neural mechanisms underlying state mental fatigue in multiple sclerosis: a pilot study | journal = Journal of Neurology | volume = 267 | issue = 8 | pages = 2372–2382 | date = August 2020 | pmid = 32350648 | doi = 10.1007/s00415-020-09853-w }}</ref> The primary deficit in cognitive function that people with MS experience is slowed information-processing speed, with memory also commonly affected, and [[Executive functions|executive function]] less commonly. Intelligence, language, and [[semantic memory]] are usually preserved, and the level of cognitive impairment varies considerably between people with MS.<ref>{{cite journal | vauthors = Oreja-Guevara C, Ayuso Blanco T, Brieva Ruiz L, Hernández Pérez MÁ, Meca-Lallana V, Ramió-Torrentà L | title = Cognitive Dysfunctions and Assessments in Multiple Sclerosis | journal = Frontiers in Neurology | volume = 10 | pages = 581 | date = 2019 | pmid = 31214113 | pmc = 6558141 | doi = 10.3389/fneur.2019.00581 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kalb R, Beier M, Benedict RH, Charvet L, Costello K, Feinstein A, Gingold J, Goverover Y, Halper J, Harris C, Kostich L, Krupp L, Lathi E, LaRocca N, Thrower B, DeLuca J | title = Recommendations for cognitive screening and management in multiple sclerosis care | journal = Multiple Sclerosis | volume = 24 | issue = 13 | pages = 1665–1680 | date = November 2018 | pmid = 30303036 | pmc = 6238181 | doi = 10.1177/1352458518803785 }}</ref><ref>{{cite journal | vauthors = Benedict RH, Amato MP, DeLuca J, Geurts JJ | title = Cognitive impairment in multiple sclerosis: clinical management, MRI, and therapeutic avenues | language = English | journal = The Lancet. Neurology | volume = 19 | issue = 10 | pages = 860–871 | date = October 2020 | pmid = 32949546 | doi = 10.1016/S1474-4422(20)30277-5 | pmc = 10011205 | s2cid = 221744328 }}</ref>

[[Uhthoff's phenomenon]], a reversible exacerbation of patient symptoms following a rise in body temperature, and [[Lhermitte's sign]], an electrical sensation that runs down the back when flexing the neck, are particularly characteristic of MS, although may not always be present.<ref name="pmid1897097722"/> Another presenting manifestation that is rare but highly suggestive of a demyelinating process such as MS is bilateral [[internuclear ophthalmoplegia]], where the patient experiences double vision when attempting to move their gaze to the right & left.<ref>{{cite journal | vauthors = Zainal Abidin N, Tuan Jaffar TN, Ahmad Tajudin LS | title = Wall-Eyed Bilateral Internuclear Ophthalmoplegia as an Early Presentation of Multiple Sclerosis | journal = Cureus | volume = 15 | issue = 3 | pages = e36835 | date = March 2023 | pmid = 37123672 | pmc = 10147486 | doi = 10.7759/cureus.36835 | doi-access = free }}</ref>

Some 60% or more of MS patients find their symptoms, particularly including fatigue,<ref name="Multiple Sclerosis Trust">{{Cite web | url = https://mstrust.org.uk/news/hot-and-bothered-heat-sensitivity-ms | title = Hot and bothered: how heat makes MS symptoms worse | location = Letchworth Garden City, United Kingdom | publisher = Multiple Sclerosis Trust | access-date = 17 January 2024 | archive-date = 17 January 2024 | archive-url = https://web.archive.org/web/20240117003924/https://mstrust.org.uk/news/hot-and-bothered-heat-sensitivity-ms | url-status = live }}</ref> are affected by changes in body temperature.<ref name="Christogianni-2018">{{cite journal | vauthors = Christogianni A, Bibb R, Davis SL, Jay O, Barnett M, Evangelou N, Filingeri D | title = Temperature sensitivity in multiple sclerosis: An overview of its impact on sensory and cognitive symptoms | journal = Temperature | volume = 5 | issue = 3 | pages = 208–223 | date = 17 January 2018 | pmid = 30377640 | pmc = 6205043 | doi = 10.1080/23328940.2018.1475831 }}</ref><ref name="Heat Sensitivity">{{Cite web|url=https://www.msaustralia.org.au/symptom/heat-sensitivity/|title=Heat Sensitivity|access-date=17 January 2024|archive-date=17 January 2024|archive-url=https://web.archive.org/web/20240117003926/https://www.msaustralia.org.au/symptom/heat-sensitivity/|url-status=live}}</ref><ref name="Multiple Sclerosis Trust-2">{{cite web | url = https://mstrust.org.uk/a-z/temperature-sensitivity | title = Temperature sensitivity | location = Letchworth Garden City, United Kingdom | publisher = Multiple Sclerosis Trust | access-date = 17 January 2024 | archive-date = 17 January 2024 | archive-url = https://web.archive.org/web/20240117003924/https://mstrust.org.uk/a-z/temperature-sensitivity | url-status = live }}</ref>

===Measures of disability===
The main measure of disability and severity is the [[expanded disability status scale]] (EDSS), with other measures such as the [[multiple sclerosis functional composite]] being increasingly used in research.<ref>{{cite journal | vauthors = Kurtzke JF | author-link=John F. Kurtzke | title = Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS) | journal = Neurology | volume = 33 | issue = 11 | pages = 1444–52 | date = November 1983 | pmid = 6685237 | doi = 10.1212/WNL.33.11.1444 | doi-access = free }}</ref><ref name="pmid10467378">{{cite journal | vauthors = Amato MP, Ponziani G | title = Quantification of impairment in MS: discussion of the scales in use | journal = Multiple Sclerosis | volume = 5 | issue = 4 | pages = 216–9 | date = August 1999 | pmid = 10467378 | doi = 10.1177/135245859900500404 | s2cid = 6763447 }}</ref><ref name="pmid12356200">{{cite journal | vauthors = Rudick RA, Cutter G, Reingold S | title = The multiple sclerosis functional composite: a new clinical outcome measure for multiple sderosis trials | journal = Multiple Sclerosis | volume = 8 | issue = 5 | pages = 359–65 | date = October 2002 | pmid = 12356200 | doi = 10.1191/1352458502ms845oa | s2cid = 31529508 }}</ref> EDSS is also correlated with falls in people with MS.<ref name="Piryonesi-2021" /> While it is a popular measure, EDSS has been criticized for some of its limitations, such as overreliance on walking.<ref>{{cite journal | vauthors = van Munster CE, Uitdehaag BM | title = Outcome Measures in Clinical Trials for Multiple Sclerosis | journal = CNS Drugs | volume = 31 | issue = 3 | pages = 217–236 | date = March 2017 | pmid = 28185158 | pmc = 5336539 | doi = 10.1007/s40263-017-0412-5 }}</ref><ref name="Piryonesi-2021" />

==Disease course==
=== Prodromal phase ===
MS may have a [[prodromal]] phase in the years leading up to its manifestation, characterized by psychiatric issues, cognitive impairment, and increased use of healthcare.<ref name="Makhani2021Prodrome">{{cite journal | vauthors = Makhani N, Tremlett H | title = The multiple sclerosis prodrome | journal = Nature Reviews. Neurology | volume = 17 | issue = 8 | pages = 515–521 | date = August 2021 | pmid = 34155379 | pmc = 8324569 | doi = 10.1038/s41582-021-00519-3 }}</ref><ref name="Marrie2019_Prodrome">{{cite journal | vauthors = Marrie RA | title = Mounting evidence for a multiple sclerosis prodrome | journal = Nature Reviews. Neurology | volume = 15 | issue = 12 | pages = 689–690 | date = December 2019 | pmid = 31654040 | doi = 10.1038/s41582-019-0283-0 | s2cid = 204887642 }}</ref>

===Onset===
85% of cases begin as a [[clinically isolated syndrome]] (CIS) over a number of days with 45% having motor or sensory problems, 20% having [[optic neuritis]],<ref name="Petzold_2022" /> and 10% having symptoms related to [[brainstem]] dysfunction, while the remaining 25% have more than one of the aforementioned difficulties.<ref name="Tsang20112">{{cite journal |vauthors=Tsang BK, Macdonell R |date=December 2011 |title=Multiple sclerosis- diagnosis, management and prognosis |journal=Australian Family Physician |volume=40 |issue=12 |pages=948–955 |pmid=22146321}}</ref> With optic neuritis as the most common presenting symptom, people with MS notice sub-acute loss of vision, often associated with pain worsening on eye movement, and reduced color vision. Early diagnosis of MS-associated optic neuritis helps timely initiation of targeted treatments. However, it is crucial to adhere to established diagnostic criteria when treating optic neuritis due to the broad range of alternative causes, such as [[neuromyelitis optica]] spectrum disorder (NMOSD), and other autoimmune or infectious conditions. The course of symptoms occurs in two main patterns initially: either as episodes of sudden worsening that last a few days to months (called [[relapse]]s, exacerbations, bouts, attacks, or flare-ups) followed by improvement (85% of cases) or as a gradual worsening over time without periods of recovery (10–15% of cases).<ref name=Milo2010 /> A combination of these two patterns may also occur<ref name="pmid8780061" /> or people may start in a relapsing and remitting course that then becomes progressive later on.<ref name=Milo2010 />

===Relapses===
Relapses are usually unpredictable, occurring without warning.<ref name="pmid1897097722"/> Exacerbations rarely occur more frequently than twice per year.<ref name="pmid1897097722"/> Some relapses, however, are preceded by common triggers and they occur more frequently during spring and summer.<ref name="pmid168043312">{{cite journal | vauthors = Tataru N, Vidal C, Decavel P, Berger E, Rumbach L | title = Limited impact of the summer heat wave in France (2003) on hospital admissions and relapses for multiple sclerosis | journal = Neuroepidemiology | volume = 27 | issue = 1 | pages = 28–32 | year = 2006 | pmid = 16804331 | doi = 10.1159/000094233 | s2cid = 20870484 }}</ref> Similarly, viral infections such as the [[common cold]], [[influenza]], or [[gastroenteritis]] increase their risk.<ref name="pmid1897097722"/> [[Stress (medicine)|Stress]] may also trigger an attack.<ref name="pmid17439878">{{cite journal | vauthors = Heesen C, Mohr DC, Huitinga I, Bergh FT, Gaab J, Otte C, Gold SM | title = Stress regulation in multiple sclerosis: current issues and concepts | journal = Multiple Sclerosis | volume = 13 | issue = 2 | pages = 143–148 | date = March 2007 | pmid = 17439878 | doi = 10.1177/1352458506070772 | s2cid = 8262595 }}</ref>

Many events do not affect rates of relapse requiring hospitalization including [[vaccination]],<ref>{{cite journal | vauthors = Confavreux C, Suissa S, Saddier P, Bourdès V, Vukusic S | title = Vaccinations and the risk of relapse in multiple sclerosis. Vaccines in Multiple Sclerosis Study Group | journal = The New England Journal of Medicine | volume = 344 | issue = 5 | pages = 319–326 | date = February 2001 | pmid = 11172162 | doi = 10.1056/NEJM200102013440501 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Grimaldi L, Papeix C, Hamon Y, Buchard A, Moride Y, Benichou J, Duchemin T, Abenhaim L | title = Vaccines and the Risk of Hospitalization for Multiple Sclerosis Flare-Ups | journal = JAMA Neurology | volume = 80 | issue = 10 | pages = 1098–1104 | date = October 2023 | pmid = 37669073 | pmc = 10481324 | doi = 10.1001/jamaneurol.2023.2968 }}</ref> [[breast feeding]],<ref name="pmid1897097722"/> physical trauma,<ref name="pmid112053612">{{cite journal | vauthors = Martinelli V | title = Trauma, stress and multiple sclerosis | journal = Neurological Sciences | volume = 21 | issue = 4 Suppl 2 | pages = S849–S852 | year = 2000 | pmid = 11205361 | doi = 10.1007/s100720070024 | s2cid = 2376078 }}</ref> and [[Uhthoff's phenomenon]].<ref name="pmid168043312"/>

===Pregnancy===
Many women with MS [[pre-existing disease in pregnancy|who become pregnant]] experience lower symptoms during pregnancy.<ref>{{cite journal | vauthors = Dobson R, Dassan P, Roberts M, Giovannoni G, Nelson-Piercy C, Brex PA | title = UK consensus on pregnancy in multiple sclerosis: 'Association of British Neurologists' guidelines | journal = Practical Neurology | volume = 19 | issue = 2 | pages = 106–114 | date = April 2019 | pmid = 30612100 | doi = 10.1136/practneurol-2018-002060 }}</ref><ref name="Varytė-2020">{{cite journal | vauthors = Varytė G, Zakarevičienė J, Ramašauskaitė D, Laužikienė D, Arlauskienė A | title = Pregnancy and Multiple Sclerosis: An Update on the Disease Modifying Treatment Strategy and a Review of Pregnancy's Impact on Disease Activity | journal = Medicina | volume = 56 | issue = 2 | page = 49 | date = January 2020 | pmid = 31973138 | pmc = 7074401 | doi = 10.3390/medicina56020049 | doi-access = free }}</ref><ref>{{cite web |title=Pregnancy, birth, breastfeeding and MS |url=https://www.mssociety.org.uk/about-ms/what-is-ms/women-and-ms/pregnancy-and-birth |website=Multiple Sclerosis Society |access-date=8 April 2024 |archive-date=8 April 2024 |archive-url=https://web.archive.org/web/20240408181959/https://www.mssociety.org.uk/about-ms/what-is-ms/women-and-ms/pregnancy-and-birth |url-status=live }}</ref> During the first months after delivery, the risk increases.<ref name="pmid1897097722"/> Overall, pregnancy does not seem to influence long-term disability.<ref name="pmid1897097722"/>

== Causes ==
MS is an autoimmune disease with a combination of genetic and environmental causes underlying it. Both T-cells and B-cells are involved, although T-cells are often considered to be the driving force of the disease. The causes of the disease are not fully understood. The [[Epstein–Barr virus|Epstein-Barr Virus]] (EBV) has been shown to be directly present in the brain of most cases of MS and the virus is transcriptionally active in infected cells.<ref>{{cite journal | vauthors = Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P, Andreoni L, Trivedi P, Salvetti M, Faggioni A, Aloisi F | title = Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain | journal = The Journal of Experimental Medicine | volume = 204 | issue = 12 | pages = 2899–2912 | date = November 2007 | pmid = 17984305 | pmc = 2118531 | doi = 10.1084/jem.20071030 }}</ref><ref name="Hassani-2018">{{cite journal | vauthors = Hassani A, Corboy JR, Al-Salam S, Khan G | title = Epstein-Barr virus is present in the brain of most cases of multiple sclerosis and may engage more than just B cells | journal = PLOS ONE | volume = 13 | issue = 2 | pages = e0192109 | date = 2018 | pmid = 29394264 | pmc = 5796799 | doi = 10.1371/journal.pone.0192109 | doi-access = free | bibcode = 2018PLoSO..1392109H }}</ref> EBV nuclear antigens are believed to be involved in the pathogenesis of multiple sclerosis, but not all people with MS have signs of EBV infection.<ref name="Ward 988–1005" /> Dozens of human [[peptide]]s have been identified in different cases of the disease, and while some have plausible links to infectious organisms or known environmental factors, others do not.<ref>{{cite journal | vauthors = Lutterotti A, Hayward-Koennecke H, Sospedra M, Martin R | title = Antigen-Specific Immune Tolerance in Multiple Sclerosis-Promising Approaches and How to Bring Them to Patients | journal = Frontiers in Immunology | volume = 12 | pages = 640935 | date = 2021 | pmid = 33828551 | pmc = 8019937 | doi = 10.3389/fimmu.2021.640935 | doi-access = free }}</ref>

=== Immune dysregulation ===
Failure of both central and peripheral nervous system clearance of autoreactive immune cells is implicated in MS development.<ref name="Ward 988–1005"/> The thymus is responsible for the immune system's central tolerance, where autoreactive T-cells are killed without being released into circulation. A similar mechanism kills autoreactive B-cells in the bone marrow. Some autoreactive T-cells & B-cells may escape these defense mechanisms, which is where peripheral immune tolerance defenses take action by preventing them from causing disease. However, these additional lines of defense can still fail.<ref name="Ward 988–1005"/><ref name="McGinley_2021"/> Further detail on immune dysregulation's contribution to MS risk is provided in the [[Multiple sclerosis#Pathophysiology|pathophysiology]] section of this article as well as the standalone article on the [[Pathophysiology of multiple sclerosis|pathophysiology of MS]].

=== Infectious agents ===

Early evidence suggested the association between several viruses with human demyelinating [[encephalomyelitis]], and the occurrence of demyelination in animals caused by some viral infections.<ref name="pmid15721830">{{cite journal | vauthors = Gilden DH | title = Infectious causes of multiple sclerosis | journal = The Lancet. Neurology | volume = 4 | issue = 3 | pages = 195–202 | date = March 2005 | pmid = 15721830 | doi = 10.1016/S1474-4422(05)01017-3 | pmc = 7129502 }}</ref> One such virus, [[Epstein–Barr virus|Epstein-Barr]] [[Herpesviridae#Human herpesvirus types|virus]] (EBV), can cause [[infectious mononucleosis]] and infects about 95% of adults, though only a small proportion of those infected later develop MS.<ref>{{cite journal | vauthors = Soldan SS, Lieberman PM | title = Epstein-Barr virus and multiple sclerosis | journal = Nature Reviews. Microbiology | volume = 21 | issue = 1 | pages = 51–64 | date = January 2023 | pmid = 35931816 | pmc = 9362539 | doi = 10.1038/s41579-022-00770-5 }}</ref><ref name="Aloisi20222" /><ref name="Bjornevik2022">{{cite journal | vauthors = Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, Elledge SJ, Niebuhr DW, Scher AI, Munger KL, Ascherio A | title = Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis | journal = Science | volume = 375 | issue = 6578 | pages = 296–301 | date = January 2022 | pmid = 35025605 | doi = 10.1126/science.abj8222 | s2cid = 245983763 | bibcode = 2022Sci...375..296B }} See lay summary: {{cite news |vauthors=Gallagher J |title=Is a virus we all have causing multiple sclerosis? |url=https://www.bbc.com/news/health-61042598 |work=BBC |date=13 April 2022 |archive-date=25 April 2022 |access-date=14 April 2022 |archive-url=https://web.archive.org/web/20220425142547/https://www.bbc.com/news/health-61042598 |url-status=live }}</ref><ref name="Hassani-2018" /> A study of more than 10 million US military members compared 801 people who developed MS to 1,566 matched controls who did not. The study found a 32-fold increased risk of MS development following EBV infection. It did not find an increased risk after infection with other viruses, including the similar [[cytomegalovirus]]. These findings strongly suggest that EBV plays a role in MS onset, although EBV alone may be insufficient to cause it.<ref name="Aloisi20222" /><ref name="Bjornevik2022" />

The [[Epstein–Barr virus nuclear antigen 1|nuclear antigen of EBV]], which is the most consistent marker of EBV infection across all strains,<ref>{{cite journal | vauthors = Münz C | title = Epstein-barr virus nuclear antigen 1: from immunologically invisible to a promising T cell target | journal = The Journal of Experimental Medicine | volume = 199 | issue = 10 | pages = 1301–1304 | date = May 2004 | pmid = 15148332 | pmc = 2211815 | doi = 10.1084/jem.20040730 }}</ref> has been identified as a direct source of autoreactivity in the human body. These antigens appear more likely to promote autoimmunity in vitamin D-deficient persons. The exact nature of this relationship is poorly understood.<ref>{{cite journal | vauthors = Miclea A, Bagnoud M, Chan A, Hoepner R | title = A Brief Review of the Effects of Vitamin D on Multiple Sclerosis | journal = Frontiers in Immunology | volume = 11 | pages = 781 | date = 2020-05-06 | pmid = 32435244 | pmc = 7218089 | doi = 10.3389/fimmu.2020.00781 | doi-access = free }}</ref><ref name="Ward 988–1005" />

=== Genetics ===
[[File:HLA.svg|thumb|HLA region of chromosome&nbsp;6: Changes in this area increase the probability of getting MS.]]

MS is not considered a [[hereditary disease]], but several [[genetics|genetic variations]] have been shown to increase its risk.<ref name="pmid14747002">{{cite journal | vauthors = Dyment DA, Ebers GC, Sadovnick AD | title = Genetics of multiple sclerosis | journal = The Lancet. Neurology | volume = 3 | issue = 2 | pages = 104–10 | date = February 2004 | pmid = 14747002 | doi = 10.1016/S1474-4422(03)00663-X | s2cid = 16707321 | citeseerx = 10.1.1.334.1312 }}</ref> Some of these genes appear to have higher expression levels in [[microglia|microglial cells]] than expected by chance.<ref name="SkeneGrant2016">{{cite journal | vauthors = Skene NG, Grant SG | title = Identification of Vulnerable Cell Types in Major Brain Disorders Using Single Cell Transcriptomes and Expression Weighted Cell Type Enrichment | journal = Frontiers in Neuroscience | volume = 10 | pages = 16 | year = 2016 | pmid = 26858593 | doi = 10.3389/fnins.2016.00016 | pmc = 4730103 | doi-access = free }}</ref> The probability of developing MS is higher in relatives of an affected person, with a greater risk among those more closely related.<ref name="pmid119555563"/> An [[identical twin]] of an affected individual has a 30% chance of developing MS, 5% for a nonidentical twin, 2.5% for a sibling, and an even lower chance for a half-sibling.<ref name="pmid1897097722"/><ref name="pmid119555563"/><ref>{{cite journal | vauthors = Hassan-Smith G, Douglas MR | title = Epidemiology and diagnosis of multiple sclerosis | journal = British Journal of Hospital Medicine | volume = 72 | issue = 10 | pages = M146-51 | date = October 2011 | pmid = 22041658 | doi = 10.12968/hmed.2011.72.Sup10.M146 }}</ref> MS is also more common in some ethnic groups than others.<ref name="pmid11603614">{{cite journal | vauthors = Rosati G | title = The prevalence of multiple sclerosis in the world: an update | journal = Neurological Sciences | volume = 22 | issue = 2 | pages = 117–39 | date = April 2001 | pmid = 11603614 | doi = 10.1007/s100720170011 | s2cid = 207051545 }}</ref>

Specific [[gene]]s linked with MS include differences in the [[human leukocyte antigen]] (HLA) system—a group of genes on [[chromosome 6 (human)|chromosome 6]] that serves as the [[major histocompatibility complex]] (MHC).<ref name="pmid1897097722"/> The contribution of HLA variants to MS susceptibility has been known since the 1980s,<ref name="pmid21247752">{{cite journal | vauthors = Baranzini SE | title = Revealing the genetic basis of multiple sclerosis: are we there yet? | journal = Current Opinion in Genetics & Development | volume = 21 | issue = 3 | pages = 317–24 | date = June 2011 | pmid = 21247752 | pmc = 3105160 | doi = 10.1016/j.gde.2010.12.006 }}</ref> and it has also been implicated in the development of other autoimmune diseases, such as [[diabetes type I|type 1 diabetes]] and [[systemic lupus erythematosus]].<ref name="pmid21247752" /> The most consistent finding is the association between higher risk MS development and the MHC [[allele]] ''[[HLA-DR15|DR15]]'', which is present in 30% of the U.S. and Northern European population.<ref name="Ward 988–1005"/><ref name="pmid1897097722"/> Other [[Locus (genetics)|loci]] exhibit a protective effect, such as ''[[HLA-C554]] ''and ''[[HLA-DRB1]]*11''.<ref name="pmid1897097722"/> HLA differences account for an estimated 20 to 60% of the [[genetic predisposition]].<ref name="pmid21247752" /> [[Genome-wide association study|Genome-wide association studies]] have revealed at least 200 MS-associated variants outside the HLA locus.<ref name="pmid31604244">{{cite journal| author=International Multiple Sclerosis Genetics Consortium| title=Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. | journal=Science | year= 2019 | volume= 365 | issue= 6460 | pmid=31604244 | doi=10.1126/science.aav7188 | pmc=7241648 }}</ref>

=== Geography ===
[[File:MS Risk.svg|thumb|Geographic risk distribution of MS]]

The prevalence of MS from a geographic standpoint resembles a gradient, with it being more common in people who live farther from the [[equator]] (e.g., those who live in northern regions of the world), although exceptions exist. The cause of this geographical pattern is not clear, although exposure to [[Ultraviolet|ultraviolet B]] (UVB) radiation and [[vitamin D]] levels may be a possible explanation.<ref name="Milo2010"/><ref name="Ward 988–1005"/> For example, those who live in northern regions of the world have less exposure to UVB radiation and lower levels of vitamin D, and a higher risk for developing MS.<ref name="Ward 988–1005"/> Inversely, those who live in areas of higher sun exposure and increased UVB radiation have a decreased risk of developing MS.<ref name="Ward 988–1005"/> As of 2019, the north–south gradient of incidence is still present and is increasing.<ref name="pmid31217172">{{cite journal | vauthors = Simpson S, Wang W, Otahal P, Blizzard L, van der Mei IA, Taylor BV | title = Latitude continues to be significantly associated with the prevalence of multiple sclerosis: an updated meta-analysis | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 90 | issue = 11 | pages = 1193–1200 | date = November 2019 | pmid = 31217172 | doi = 10.1136/jnnp-2018-320189 }}</ref>

On the other hand, MS is more common in regions with northern European populations,<ref name="pmid1897097722"/> so the geographic variation may simply reflect the distribution of these higher-risk populations.<ref name=Milo2010 />

A relationship between season of birth and MS lends support to this idea, with fewer people born in the Northern Hemisphere in winter than in spring.<ref name="pmid19897699">{{cite journal |vauthors= Kulie T, Groff A, Redmer J, Hounshell J, Schrager S |title= Vitamin D: an evidence-based review |journal= Journal of the American Board of Family Medicine |volume= 22 |issue= 6|pages= 698–706 |year= 2009 |pmid= 19897699 |doi= 10.3122/jabfm.2009.06.090037 |doi-access= free}}</ref>

Environmental factors during childhood may play a role, with several studies finding that people who move to a different region of the world before the age of 15 acquire the new region's risk of MS. If migration takes place after age 15, the person retains the risk of their childhood region.<ref name="pmid1897097722"/><ref name="pmid15556803" /> However, some evidence indicates that the effect of moving may apply to people older than 15.<ref name="pmid1897097722"/>

There are some exceptions to the above-mentioned geographic pattern. These include ethnic groups that are at low risk and that live far from the equator, such as the [[Sami people|Sami]], [[Indigenous peoples of the Americas|Amerindians]], Canadian [[Hutterite]]s, New Zealand [[Māori people|Māori]],<ref name="pmid121276522">{{cite journal |vauthors=Pugliatti M, Sotgiu S, Rosati G |date=July 2002 |title=The worldwide prevalence of multiple sclerosis |journal=Clinical Neurology and Neurosurgery |volume=104 |issue=3 |pages=182–91 |doi=10.1016/S0303-8467(02)00036-7 |pmid=12127652 |s2cid=862001}}</ref> and Canada's [[Inuit]],<ref name="Milo2010" /> as well as groups that have a relatively high risk and that live closer to the equator such as [[Sardinian people|Sardinians]],<ref name="Milo2010" /> inland [[Sicily|Sicilians]],<ref>{{cite journal |vauthors=Grimaldi LM, Salemi G, Grimaldi G, Rizzo A, Marziolo R, Lo Presti C, Maimone D, Savettieri G |date=November 2001 |title=High incidence and increasing prevalence of MS in Enna (Sicily), southern Italy |journal=Neurology |volume=57 |issue=10 |pages=1891–3 |doi=10.1212/wnl.57.10.1891 |pmid=11723283 |s2cid=34895995}}</ref> [[Palestinians]], and [[Parsi]].<ref name="pmid121276522" />

===Impact of temperature===
MS symptoms may increase if body temperature is dysregulated.<ref name="Heat and cold sensitivity in multiple sclerosis">{{Cite journal|url=https://www.msard-journal.com/article/S2211-0348(22)00583-1/fulltext|title=Heat and cold sensitivity in multiple sclerosis: A patient-centred perspective on triggers, symptoms, and thermal resilience practices - Multiple Sclerosis and Related Disorders|date=2022 |pmid=35963205 |access-date=15 March 2024|archive-date=15 March 2024|archive-url=https://web.archive.org/web/20240315165409/https://www.msard-journal.com/article/S2211-0348(22)00583-1/fulltext|url-status=live |journal=Multiple Sclerosis and Related Disorders |volume=67 |doi=10.1016/j.msard.2022.104075 | vauthors = Christogianni A, O'Garro J, Bibb R, Filtness A, Filingeri D }}</ref><ref name="Davis-2010">{{cite journal | vauthors = Davis SL, Wilson TE, White AT, Frohman EM | title = Thermoregulation in multiple sclerosis | journal = Journal of Applied Physiology | volume = 109 | issue = 5 | pages = 1531–1537 | date = November 2010 | pmid = 20671034 | pmc = 2980380 | doi = 10.1152/japplphysiol.00460.2010 }}</ref><ref name="Davis-2018">{{cite book | vauthors = Davis SL, Jay O, Wilson TE |chapter=Thermoregulatory dysfunction in multiple sclerosis | veditors = Romanovsky AA |title=Thermoregulation: From Basic Neuroscience to Clinical Neurology, Part II |series=Handbook of Clinical Neurology |date=2018 |volume=157 |pages=701–714 |isbn=978-0-444-64074-1 |pmid=30459034 |doi=10.1016/B978-0-444-64074-1.00042-2 }}</ref> Fatigue is particularly affected.<ref name="Multiple Sclerosis Trust"/><ref name="Christogianni-2018"/><ref name="Heat Sensitivity"/><ref name="Multiple Sclerosis Trust-2"/><ref name="Staff-2014">{{Cite web|url=https://multiplesclerosisnewstoday.com/multiple-sclerosis-news/2014/08/11/higher-body-temperature-in-rrms-patients-could-cause-increased-fatigue/|title=Higher Body Temperature in RRMS Patients Could Cause Increased Fatigue|first=BioNews|last=Staff|date=August 11, 2014|website=multiplesclerosisnewstoday.com|access-date=15 March 2024|archive-date=15 March 2024|archive-url=https://web.archive.org/web/20240315125742/https://multiplesclerosisnewstoday.com/multiple-sclerosis-news/2014/08/11/higher-body-temperature-in-rrms-patients-could-cause-increased-fatigue/|url-status=live}}</ref><ref name="Sumowski-2014">{{cite journal | vauthors = Sumowski JF, Leavitt VM | title = Body temperature is elevated and linked to fatigue in relapsing-remitting multiple sclerosis, even without heat exposure | journal = Archives of Physical Medicine and Rehabilitation | volume = 95 | issue = 7 | pages = 1298–1302 | date = July 2014 | pmid = 24561056 | pmc = 4071126 | doi = 10.1016/j.apmr.2014.02.004 }}</ref><ref>{{cite journal | vauthors = Leavitt VM, De Meo E, Riccitelli G, Rocca MA, Comi G, Filippi M, Sumowski JF | title = Elevated body temperature is linked to fatigue in an Italian sample of relapsing-remitting multiple sclerosis patients | journal = Journal of Neurology | volume = 262 | issue = 11 | pages = 2440–2442 | date = November 2015 | pmid = 26223805 | doi = 10.1007/s00415-015-7863-8 }}</ref><ref name="Christogianni-2022">{{cite journal | vauthors = Christogianni A, O'Garro J, Bibb R, Filtness A, Filingeri D | title = Heat and cold sensitivity in multiple sclerosis: A patient-centred perspective on triggers, symptoms, and thermal resilience practices | journal = Multiple Sclerosis and Related Disorders | volume = 67 | pages = 104075 | date = November 2022 | pmid = 35963205 | doi = 10.1016/j.msard.2022.104075 }}</ref>

=== Other ===
[[Tobacco smoking|Smoking]] may be an independent risk factor for MS.<ref name="pmid17492755" /> [[Stress (biological)|Stress]] may also be a risk factor, although the evidence to support this is weak.<ref name="pmid15556803" /> 

Environmental risk factor reviews have correlated lower sun exposure with higher MS rates though the effect does not completely align with earth's [[solar irradiance]] [[latitude]] gradient.  Regional perturbations exist indicating involvement of additional, more influential localized MS risk factors.<ref name="FPH-2023">{{cite journal |last1=Vitturi |first1=Bruno Kusznir |last2=Montecucco |first2=Alfredo |last3=Rahmani |first3=Alborz |last4=Dini |first4=Guglielmo |last5=Durando |first5=Paolo |title=Occupational risk factors for multiple sclerosis: a systematic review with meta-analysis |journal=Frontiers in Public Health |date=November 15, 2023 |volume=11 |issue=2023 |page=Introduction, Results |doi=10.3389/fpubh.2023.1285103 |doi-access=free|pmid=38054069 |pmc=10694508 }}</ref> See also: [[Multiple sclerosis#Geography]].

A 2023 meta-analysis screened data from 4,183,166 individuals identifying environmental and occupational risks associated with MS development. High environmental risks were found from oil well fumes, pesticides and [[Extremely low frequency|low-frequency magnetic fields]], e.g., [[electric power transmission]] towers and passageways. Cleaning agents, solvents and animal contact did not appear to elevate MS risks.<ref name="FPH-2023" /> The highest occupational risks were observed for hairdressers, having a 8.25-fold increased risk versus the general population (GP) ([[Odds ratio|OR]] = 8.25, 95% [[Confidence interval|CI]] 1.02–66.52); offshore workers with a 3.56-fold risk (OR = 3.56, 95% CI 2.74–4.61); and agricultural workers with a 1.44-fold risk, (OR = 1.44, 95% CI 1.13–1.83).<ref name="FPH-2023" /> Occupational risks for MS development, relative to GP, were not observed for shoe and leather workers, construction and tradesmen, healthcare aides, chemical industry workers, food industry staff, cleaning company technicians or military servicepersons.<ref name="FPH-2023" /> 

[[vaccine|Vaccinations]] were studied as causal factors; most studies, though, show no association.<ref name="pmid15556803" /><ref>{{cite journal | vauthors = Stowe J, Andrews N, Miller E | title = Do Vaccines Trigger Neurological Diseases? Epidemiological Evaluation of Vaccination and Neurological Diseases Using Examples of Multiple Sclerosis, Guillain-Barré Syndrome and Narcolepsy | journal = CNS Drugs | volume = 34 | issue = 1 | pages = 1–8 | date = January 2020 | pmid = 31576507 | pmc = 7224038 | doi = 10.1007/s40263-019-00670-y }}</ref> Several other possible risk factors, such as [[Diet (nutrition)|diet]] and [[hormone]] intake, have been evaluated, but evidence on their relation with the disease is "sparse and unpersuasive".<ref name="pmid17492755" /> [[Gout]] occurs less than would be expected and lower levels of [[uric acid]] have been found in people with MS. This has led to the theory that uric acid is protective, although its exact importance remains unknown.<ref name="pmid18219824">{{cite book | vauthors = Spitsin S, Koprowski H | chapter = Role of Uric Acid in Multiple Sclerosis | veditors = Rodriguez M | title = Advances in multiple Sclerosis and Experimental Demyelinating Diseases | series = Current Topics in Microbiology and Immunology | volume = 318 | pages = 325–342 | year = 2008 | pmid = 18219824 | doi = 10.1007/978-3-540-73677-6_13 | isbn = 978-3-540-73676-9 }}</ref> Obesity during adolescence and young adulthood is a risk factor for MS.<ref name="Nourbakhsh2019RisksPathogenesis">{{cite journal | vauthors = Nourbakhsh B, Mowry EM | title = Multiple Sclerosis Risk Factors and Pathogenesis | journal = Continuum | volume = 25 | issue = 3 | pages = 596–610 | date = June 2019 | pmid = 31162307 | doi = 10.1212/CON.0000000000000725 | s2cid = 174806511 }}</ref>

== Pathophysiology ==
{{Main|Pathophysiology of multiple sclerosis}}
[[File:Multiple Sclerosis.png|thumb|Multiple sclerosis]]
Multiple sclerosis is an autoimmune disease, primarily mediated by T-cells.<ref name="Ward 988–1005" /> The three main characteristics of MS are the formation of lesions in the [[central nervous system]] (also called plaques), inflammation, and the destruction of [[myelin sheath]]s of [[neuron]]s. These features interact in a complex and not yet fully understood manner to produce the breakdown of nerve tissue, and in turn, the signs and symptoms of the disease.<ref name="pmid1897097722"/> Damage is believed to be caused, at least in part, by attack on the nervous system by a person's own immune system.<ref name="pmid1897097722"/>

=== Immune dysregulation ===
As briefly detailed in the [[Multiple sclerosis#Immune dysregulation|causes section]] of this article, MS is currently thought to stem from a failure of the body's immune system to kill off autoreactive T-cells & B-cells.<ref name="Ward 988–1005"/> Currently, the T-cell subpopulations that are thought to drive the development of MS are autoreactive CD8+ T-cells, CD4+ helper T-cells, and T<sub>H</sub>17 cells. These autoreactive T-cells produce substances called [[cytokine]]s that induce an inflammatory immune response in the CNS, leading to the development of the disease.<ref name="Ward 988–1005"/> More recently, however, the role of autoreactive B-cells has been elucidated. Evidence of their contribution to the development of MS is implicated through the presence of [[oligoclonal bands|oligoclonal IgG bands]] (antibodies produced by B-cells) in the [[cerebrospinal fluid|CSF]] of patients with MS.<ref name="Ward 988–1005"/><ref name="McGinley_2021"/> The presence of these oligoclonal bands has been used as supportive evidence in clinching a diagnosis of MS.<ref name="Thompson-2018">{{cite journal | vauthors = Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, Correale J, Fazekas F, Filippi M, Freedman MS, Fujihara K, Galetta SL, Hartung HP, Kappos L, Lublin FD, Marrie RA, Miller AE, Miller DH, Montalban X, Mowry EM, Sorensen PS, Tintoré M, Traboulsee AL, Trojano M, Uitdehaag BM, Vukusic S, Waubant E, Weinshenker BG, Reingold SC, Cohen JA | title = Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria | journal = The Lancet. Neurology | volume = 17 | issue = 2 | pages = 162–173 | date = February 2018 | pmid = 29275977 | doi = 10.1016/s1474-4422(17)30470-2 | url = https://discovery.ucl.ac.uk/id/eprint/10041020/ | archive-date = 28 May 2023 | access-date = 20 January 2024 | archive-url = https://web.archive.org/web/20230528035839/https://discovery.ucl.ac.uk/id/eprint/10041020/ | url-status = live }}</ref> As similarly described before, B-cells can also produce cytokines that induce an inflammatory immune response via activation of autoreactive T-cells.<ref name="Ward 988–1005"/><ref>{{cite journal | vauthors = Hassani A, Reguraman N, Shehab S, Khan G | title = Primary Peripheral Epstein-Barr Virus Infection Can Lead to CNS Infection and Neuroinflammation in a Rabbit Model: Implications for Multiple Sclerosis Pathogenesis | journal = Frontiers in Immunology | volume = 12 | pages = 764937 | date = 2021 | pmid = 34899715 | pmc = 8656284 | doi = 10.3389/fimmu.2021.764937 | doi-access = free }}</ref> As such, higher levels of these autoreactive B-cells are associated with an increased number of lesions & neurodegeneration as well as worse disability.<ref name="Ward 988–1005"/>

Another cell population that is becoming increasingly implicated in MS is [[microglia]]. These cells are resident to & keep watch over the CNS, responding to pathogens by shifting between pro- & anti-inflammatory states. Microglia are involved in the formation of MS lesions and be involved in other diseases that primarily affect the CNS white matter. However, because of their ability to switch between pro- & anti-inflammatory states, microglia have also been shown to be able to assist in remyelination & subsequent neuron repair.<ref name="Ward 988–1005"/> As such, microglia are thought to be participating in both acute & chronic MS lesions, with 40% of [[phagocytic cell]]s in early active MS lesions being proinflammatory microglia.<ref name="Ward 988–1005"/>

=== Lesions ===
[[File:MS Demyelinisation KB 10x.jpg|thumb|Demyelination in MS: On [[Klüver-Barrera]] myelin staining, decoloration in the area of the lesion can be appreciated.]]
The name multiple sclerosis refers to the scars (sclerae – better known as plaques or lesions) that form in the nervous system. These lesions most commonly affect the [[white matter]] in the [[optic nerve]], [[brain stem]], [[basal ganglia]], and [[spinal cord]], or white matter tracts close to the lateral [[Ventricular system|ventricles]].<ref name="pmid1897097722"/> The function of white matter cells is to carry signals between [[grey matter]] areas, where the processing is done, and the rest of the body. The [[peripheral nervous system]] is rarely involved.<ref name="pmid119555563"/>

[[File:MRI machine with patient (23423505123).jpg|thumb|MRI machine used as a tool for MS diagnosis]]

To be specific, MS involves the loss of [[oligodendrocyte]]s, the cells responsible for creating and maintaining a fatty layer—known as the [[myelin]] sheath—which helps the neurons carry [[Action potential|electrical signals]] (action potentials).<ref name="pmid1897097722"/> This results in a thinning or complete loss of myelin, and as the disease advances, the breakdown of the [[axons]] of neurons. When the myelin is lost, a neuron can no longer effectively conduct electrical signals.<ref name="pmid119555563"/> A repair process, called [[remyelination]], takes place in the early phases of the disease, but the oligodendrocytes are unable to completely rebuild the cell's myelin sheath.<ref name="pmid17531860">{{cite book | vauthors = Chari DM  |chapter=Remyelination in Multiple Sclerosis | veditors = Minagar A |title=The Neurobiology of Multiple Sclerosis |series=International Review of Neurobiology |date=2007 |volume=79 |pages=589–620 |pmid=17531860 |pmc=7112255 |isbn=978-0-12-373736-6 |doi=10.1016/S0074-7742(07)79026-8 }}</ref> Repeated attacks lead to successively less effective remyelinations, until a scar-like plaque is built up around the damaged axons.<ref name="pmid17531860" /> These scars are the origin of the symptoms and during an attack [[magnetic resonance imaging]] (MRI) often shows more than 10 new plaques.<ref name="pmid1897097722"/> This could indicate that some number of lesions exist, below which the brain is capable of repairing itself without producing noticeable consequences.<ref name="pmid1897097722"/> Another process involved in the creation of lesions is an abnormal [[astrocytosis|increase in the number of astrocytes]] due to the destruction of nearby neurons.<ref name="pmid1897097722"/> A number of [[pathophysiology of multiple sclerosis#Demyelination patterns|lesion patterns]] have been described.<ref name="pmid17351524">{{cite journal | vauthors = Pittock SJ, Lucchinetti CF | title = The pathology of MS: new insights and potential clinical applications | journal = The Neurologist | volume = 13 | issue = 2 | pages = 45–56 | date = March 2007 | pmid = 17351524 | doi = 10.1097/01.nrl.0000253065.31662.37 | s2cid = 2993523 }}</ref>

=== Inflammation ===
Apart from demyelination, the other sign of the disease is [[inflammation]]. Fitting with an [[immunological]] explanation, the inflammatory process is caused by [[T cell]]s, a kind of [[lymphocyte]]s that plays an important role in the body's defenses.<ref name="pmid119555563"/> T cells gain entry into the brain as a result of disruptions in the [[blood–brain barrier]]. The T cells recognize myelin as foreign and attack it, explaining why these cells are also called "autoreactive lymphocytes".<ref name="pmid1897097722"/>

The attack on myelin starts inflammatory processes, which trigger other immune cells and the release of soluble factors like [[cytokine]]s and [[antibodies]]. A further breakdown of the blood-brain barrier, in turn, causes many other damaging effects, such as [[oedema|swelling]], activation of [[macrophages]], and more activation of cytokines and other destructive proteins.<ref name="pmid119555563"/> Inflammation can potentially reduce transmission of information between neurons in at least three ways.<ref name="pmid1897097722"/> The soluble factors released might stop neurotransmission by intact neurons. These factors could lead to or enhance the loss of myelin, or they may cause the axon to break down completely.<ref name="pmid1897097722"/>

=== Blood-brain barrier ===
The blood-brain barrier (BBB) is a part of the [[capillary]] system that prevents the entry of T cells into the central nervous system.<!--<ref name="pmid11955556" /> --> It may become permeable to these types of cells secondary to an infection by a virus or bacteria.<!--<ref name="pmid11955556" /> --> After it repairs itself, typically once the infection has cleared, T cells may remain trapped inside the brain.<ref name="pmid119555563"/><ref>{{cite journal | vauthors = Huang X, Hussain B, Chang J | title = Peripheral inflammation and blood-brain barrier disruption: effects and mechanisms | journal = CNS Neuroscience & Therapeutics | volume = 27 | issue = 1 | pages = 36–47 | date = January 2021 | pmid = 33381913 | doi = 10.1111/cns.13569 | pmc = 7804893 }}</ref> [[Gadolinium]] cannot cross a normal BBB, so gadolinium-enhanced MRI is used to show BBB breakdowns.<ref name="pmid23088946">{{cite journal | vauthors = Ferré JC, Shiroishi MS, Law M | title = Advanced techniques using contrast media in neuroimaging | journal = Magnetic Resonance Imaging Clinics of North America | volume = 20 | issue = 4 | pages = 699–713 | date = November 2012 | pmid = 23088946 | pmc = 3479680 | doi = 10.1016/j.mric.2012.07.007 }}</ref>

===MS fatigue===
The pathophysiology and mechanisms causing MS [[fatigue]] are not well understood.<ref>{{cite journal | vauthors = Manjaly ZM, Harrison NA, Critchley HD, Do CT, Stefanics G, Wenderoth N, Lutterotti A, Müller A, Stephan KE| title = Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 90 | issue = 6 | pages = 642–651 | date = June 2019 | pmid = 30683707 | pmc = 6581095 | doi = 10.1136/jnnp-2018-320050 }}</ref><ref>{{cite journal | vauthors = Ellison PM, Goodall S, Kennedy N, Dawes H, Clark A, Pomeroy V, Duddy M, Baker MR, Saxton JM|title = Neurostructural and Neurophysiological Correlates of Multiple Sclerosis Physical Fatigue: Systematic Review and Meta-Analysis of Cross-Sectional Studies | journal = Neuropsychology Review | volume = 32 | issue = 3 | pages = 506–519 | date = September 2022 | pmid = 33961198 | pmc = 9381450 | doi = 10.1007/s11065-021-09508-1 }}</ref><ref>{{cite journal | pmc=5102292 | date=2016 | title=Central fatigue in multiple sclerosis: A review of the literature | journal=The Journal of Spinal Cord Medicine | volume=39 | issue=4 | pages=386–399 | doi=10.1080/10790268.2016.1168587 | pmid=27146427 | vauthors = Newland P, Starkweather A, Sorenson M }}</ref> MS fatigue can be affected by body heat,<ref name="Heat and cold sensitivity in multiple sclerosis"/><ref name="Davis-2018"/> and this may differentiate MS fatigue from other primary fatigue.<ref name="Multiple Sclerosis Trust"/><ref name="Christogianni-2018"/><ref name="Christogianni-2022"/> Fatigability (loss of strength) may increase perception of fatigue, but the two measures warrant independent assessment in clinical studies.<ref name="loy">{{cite journal |vauthors=Loy BD, Taylor RL, Fling BW, Horak FB |title=Relationship between perceived fatigue and performance fatigability in people with multiple sclerosis: A systematic review and meta-analysis |journal=Journal of Psychosomatic Research |volume=100 |issue= |pages=1–7 |date=September 2017 |pmid=28789787 |pmc=5875709 |doi=10.1016/j.jpsychores.2017.06.017}}</ref>

== Diagnosis ==
{{Main|Multiple sclerosis diagnosis}}
[[File:Monthly multiple sclerosis anim cropped no text.gif|thumb|Animation showing dissemination of brain lesions in time and space as demonstrated by monthly MRI studies along a year]] [[File:MSMRIMark.png|thumb|Multiple sclerosis as seen on MRI]]
Multiple sclerosis is typically diagnosed based on the presenting signs and symptoms, in combination with supporting [[medical imaging]] and laboratory testing.<ref name="Tsang20112"/> It can be difficult to confirm, especially early on, since the signs and symptoms may be similar to those of other medical problems.<ref name="pmid1897097722"/><ref name="pmid11794488">{{cite journal | vauthors = Trojano M, Paolicelli D | title = The differential diagnosis of multiple sclerosis: classification and clinical features of relapsing and progressive neurological syndromes | journal = Neurological Sciences | volume = 22 | issue = Suppl 2 | pages = S98-102 | date = November 2001 | pmid = 11794488 | doi = 10.1007/s100720100044| s2cid = 3057096 }}</ref>

===McDonald criteria===
The [[McDonald criteria]], which focus on clinical, laboratory, and radiologic evidence of lesions at different times and in different areas, is the most commonly used method of diagnosis<ref name=Atlas2008>{{cite book |author=World Health Organization |title=Atlas: Multiple Sclerosis Resources in the World 2008 |publisher=World Health Organization |location=Geneva |year=2008 |pages=15–16 |isbn=978-92-4-156375-8 |hdl=10665/43968 |hdl-access=free }}</ref> with the [[Schumacher criteria|Schumacher]] and [[Poser criteria]] being of mostly historical significance.<ref name="pmid15177763">{{cite journal | vauthors = Poser CM, Brinar VV | title = Diagnostic criteria for multiple sclerosis: an historical review | journal = Clinical Neurology and Neurosurgery | volume = 106 | issue = 3 | pages = 147–58 | date = June 2004 | pmid = 15177763 | doi = 10.1016/j.clineuro.2004.02.004 | s2cid = 23452341 }}</ref> The McDonald criteria states that patients with multiple sclerosis should have lesions which are disseminated in time (DIT) and disseminated in space (DIS), i.e. lesions which have appeared in different areas in the brain and at different times.<ref name="Thompson-2018"/> Below is an abbreviated outline of the 2017 McDonald Criteria for diagnosis of MS.
* At least 2 clinical attacks with MRI showing 2 or more lesions characteristic of MS.<ref name="Thompson-2018" />
* At least 2 clinical attacks with MRI showing 1 lesion characteristic of MS with clear historical evidence of a previous attack involving a lesion at a distinct location in the CNS.<ref name="Thompson-2018" />
* At least 2 clinical attacks with MRI showing 1 lesion characteristic of MS, with DIT established by an additional clinical attack at a distinct CNS site or by MRI showing an old MS lesion.<ref name="Thompson-2018" />
* 1 clinical attack with MRI showing at least 2 lesions characteristic of MS, with DIT established by an additional attack, by MRI showing old MS lesion(s), or presence of oligoclonal bands in CSF.<ref name="Thompson-2018" />
* 1 clinical attack with MRI showing 1 lesion characteristic of MS, with DIS established by an additional attack at a different CNS site or by MRI showing old MS lesion(s), and DIT established by an additional attack, by MRI showing old MS lesion(s), or presence of oligoclonal bands in CSF.<ref name="Thompson-2018" />

{{as of|2017}}, no single test (including biopsy) can provide a definitive diagnosis.<ref>{{cite journal | vauthors = Rovira À | title = Diagnosis of Multiple Sclerosis| journal = Journal of the Belgian Society of Radiology | volume = 101 | issue = S1 | pages = 12 | date = November 2017 | doi = 10.5334/jbr-btr.1426| doi-access = free }}</ref>

===MRI===
Magnetic resonance imaging (MRI) of the brain and spine may show areas of demyelination (lesions or plaques). Gadolinium can be administered [[intravenous]]ly as a [[contrast agent]] to highlight active plaques, and by elimination, demonstrate the existence of historical lesions not associated with symptoms at the moment of the evaluation.<ref name="pmid11456302">{{cite journal | vauthors = McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS | author1-link=W. Ian McDonald | author16-link=Jerry Wolinsky | title = Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis | journal = Annals of Neurology | volume = 50 | issue = 1 | pages = 121–7 | date = July 2001 | pmid = 11456302 | doi = 10.1002/ana.1032 | s2cid=13870943 | doi-access = free }}</ref><ref name="pmid18256986">{{cite journal | vauthors = Rashid W, Miller DH | title = Recent advances in neuroimaging of multiple sclerosis | journal = Seminars in Neurology | volume = 28 | issue = 1 | pages = 46–55 | date = February 2008 | pmid = 18256986 | doi = 10.1055/s-2007-1019127 | s2cid = 260317568 }}</ref>

Central vein signs (CVSs) have been proposed as a good indicator of MS in comparison with other conditions causing white lesions.<ref>{{cite journal | vauthors = Sinnecker T, Clarke MA, Meier D, Enzinger C, Calabrese M, De Stefano N, Pitiot A, Giorgio A, Schoonheim MM, Paul F, Pawlak MA, Schmidt R, Kappos L, Montalban X, Rovira À, Evangelou N, Wuerfel J | title = Evaluation of the Central Vein Sign as a Diagnostic Imaging Biomarker in Multiple Sclerosis | journal = JAMA Neurology | volume = 76 | issue = 12 | pages = 1446–1456 | date = December 2019 | pmid = 31424490 | pmc = 6704746 | doi = 10.1001/jamaneurol.2019.2478 | collaboration = MAGNIMS Study Group }}</ref><ref>{{cite journal |vauthors=Bernitsas E |title=The Central Vein Sign |journal=Practical Neurology |date=February 2020 |url=https://practicalneurology.com/articles/2020-feb/the-central-vein-sign |access-date=5 October 2021 |archive-date=5 October 2021 |archive-url=https://web.archive.org/web/20211005141611/https://practicalneurology.com/articles/2020-feb/the-central-vein-sign |url-status=live }}</ref><ref>{{cite journal | vauthors = Castellaro M, Tamanti A, Pisani AI, Pizzini FB, Crescenzo F, Calabrese M | title = The Use of the Central Vein Sign in the Diagnosis of Multiple Sclerosis: A Systematic Review and Meta-analysis | journal = Diagnostics | volume = 10 | issue = 12 | pages = 1025 | date = November 2020 | pmid = 33260401 | pmc = 7760678 | doi = 10.3390/diagnostics10121025 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Al-Zandi SH, Fayadh NA, Al-Waely NK |title=Central vein sign detected by SWI at 3 T MRI as a discriminator between multiple sclerosis and leukoaraiosis |journal=The Egyptian Journal of Radiology and Nuclear Medicine |date=1 March 2018 |volume=49 |issue=1 |pages=158–164 |doi=10.1016/j.ejrnm.2017.09.003 |doi-access=free }}</ref> One small study found fewer CVSs in older and hypertensive people.<ref>{{cite journal | vauthors = Guisset F, Lolli V, Bugli C, Perrotta G, Absil J, Dachy B, Pot C, Théaudin M, Pasi M, van Pesch V, Maggi P | title = The central vein sign in multiple sclerosis patients with vascular comorbidities | journal = Multiple Sclerosis | volume = 27 | issue = 7 | pages = 1057–1065 | date = June 2021 | pmid = 32749948 | doi = 10.1177/1352458520943785 | hdl-access = free | hdl = 2078.1/239849 }}</ref> Further research on CVS as a biomarker for MS is ongoing.<ref>{{cite news |vauthors=Chapman M |title=$7.2M NIH Grant Supports Study of MS Diagnostic Biomarker |url=https://multiplesclerosisnewstoday.com/news-posts/2020/06/16/cleveland-clinic-given-7-million-nih-grant-study-diagnostic-cvs-biomarker/ |agency=BioNews Services |date=16 June 2020 |access-date=5 October 2021 |archive-date=5 October 2021 |archive-url=https://web.archive.org/web/20211005173348/https://multiplesclerosisnewstoday.com/news-posts/2020/06/16/cleveland-clinic-given-7-million-nih-grant-study-diagnostic-cvs-biomarker/ |url-status=live }}</ref>

====In vivo vs postmortem lesion visibility in MRI scans====
Only postmortem MRI allows visualization of sub-millimetric lesions in cortical layers and in the cerebellar cortex.<ref>{{cite journal | vauthors = Weigel M, Dechent P, Galbusera R, Bahn E, Nair G, Lu PJ, Kappos L, Brück W, Stadelmann C, Granziera C | title = Imaging multiple sclerosis pathology at 160 μm isotropic resolution by human whole-brain ex vivo magnetic resonance imaging at 3 T | journal = Scientific Reports | volume = 11 | issue = 1 | pages = 15491 | date = July 2021 | pmid = 34326420 | pmc = 8322069 | doi = 10.1038/s41598-021-94891-1 }}</ref>

===Cerebrospinal fluid (lumbar puncture)===
Testing of cerebrospinal fluid obtained from a [[lumbar puncture]] can provide evidence of chronic inflammation in the central nervous system. The cerebrospinal fluid is tested for [[oligoclonal band]]s of IgG on [[electrophoresis]], which are inflammation markers found in 75–85% of people with MS.<ref name="pmid11456302" /><ref name="pmid16945427">{{cite journal | vauthors = Link H, Huang YM | title = Oligoclonal bands in multiple sclerosis cerebrospinal fluid: an update on methodology and clinical usefulness | journal = Journal of Neuroimmunology | volume = 180 | issue = 1–2 | pages = 17–28 | date = November 2006 | pmid = 16945427 | doi = 10.1016/j.jneuroim.2006.07.006 | s2cid = 22724352 }}</ref>

=== Differential diagnosis ===
Several diseases present similarly to MS.<ref name="Loscalzo-2022" /><ref name="Saguil-2022" /> Medical professionals use a patient's specific presentation, history, and exam findings to make an individualized [[Differential diagnosis|differential]]. Red flags are findings that suggest an alternate diagnosis, although they do not rule out MS. Red flags include a patient younger than 15 or older than 60, less than 24 hours of symptoms, involvement of multiple [[cranial nerves]], involvement of organs outside of the [[nervous system]], and atypical lab and exam findings.<ref name="Loscalzo-2022">{{Cite book | vauthors = Hauser SL | chapter = Chapter 442: Diseases of the Spinal Cord | veditors = Loscalzo J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL  |title=Harrison's principles of internal medicine |date=2022 |isbn=978-1-264-26849-8 |edition=21st |location=New York | publisher = McGraw-Hill |oclc=1282172709 | page = 3466 }}</ref><ref name="Saguil-2022">{{cite journal | vauthors = Saguil A, Farnell IV EA, Jordan TS | title = Multiple Sclerosis: A Primary Care Perspective | journal = American Family Physician | volume = 106 | issue = 2 | pages = 173–183 | date = August 2022 | pmid = 35977131 | url = https://www.aafp.org/pubs/afp/issues/2022/0800/multiple-sclerosis.html }}</ref>

In an emergency setting, it is important to rule out a stroke or [[Intracranial hemorrhage|bleeding]] in the brain.<ref name="Saguil-2022" /> Intractable vomiting, severe optic neuritis,<ref name="Petzold_2022" /> or bilateral optic neuritis<ref name="Petzold_2022" /> raises suspicion for [[neuromyelitis optica spectrum disorder]] (NMOSD).<ref name="Solomon2019DiagnosisReview">{{cite journal | vauthors = Solomon AJ | title = Diagnosis, Differential Diagnosis, and Misdiagnosis of Multiple Sclerosis | journal = Continuum | volume = 25 | issue = 3 | pages = 611–635 | date = June 2019 | pmid = 31162308 | doi = 10.1212/CON.0000000000000728 | s2cid = 173991777 }}</ref> Infectious diseases that may look similar to multiple sclerosis include HIV, [[Lyme disease]], and [[Neurosyphilis|syphilis]]. Autoimmune diseases include [[neurosarcoidosis]], [[lupus]], [[Guillain–Barré syndrome|Guillain-Barré syndrome]], [[acute disseminated encephalomyelitis]], and [[Behçet's disease]]. Psychiatric conditions such as [[Generalized anxiety disorder|anxiety]] or [[conversion disorder]] may also present in a similar way. Other rare diseases on the differential include [[Primary central nervous system lymphoma|CNS lymphoma]], [[Leukodystrophy|congenital leukodystrophies]], and [[MOG antibody disease|anti-MOG-associated myelitis]].<ref name="Loscalzo-2022" /><ref name="Saguil-2022" />

== Types and variants ==
[[File:Ms progression types.svg|thumb|MS progression types. From bottom to top: RRMS, PPMS, SPMS.]]
Several [[Phenotype (clinical medicine)|phenotypes]] (commonly termed "types"), or patterns of progression, have been described. Phenotypes use the past course of the disease in an attempt to predict the future course. They are important not only for prognosis but also for treatment decisions.

The International Advisory Committee on Clinical Trials of MS describes four types of MS (revised in 2013) in what is known as the [[Multiple sclerosis research#Lublin classification|Lublin classification]]:<ref name=Lublin>{{cite journal| title = Defining the clinical course of multiple sclerosis, The 2013 revisions | journal = Neurology | volume = 83 | issue = 3 | pages = 278–286 |vauthors=Lublin FD, etal | date = 15 July 2014| doi = 10.1212/WNL.0000000000000560 | pmid = 24871874 | pmc = 4117366}}</ref><ref>{{cite journal |vauthors=Lublin FD, Coetzee T, Cohen JA, Marrie RA, Thompson AJ |title=The 2013 clinical course descriptors for multiple sclerosis: A clarification |journal=Neurology |volume=94 |issue=24 |pages=1088–1092 |date=June 2020 |pmid=32471886 |pmc=7455332 |doi=10.1212/WNL.0000000000009636}}</ref>

# [[Clinically isolated syndrome]] (CIS)
# [[Relapsing–remitting|Relapsing-remitting]] MS (RRMS)
# Primary progressive MS (PPMS)
# Secondary progressive MS (SPMS)
CIS can be characterised as a single lesion seen on MRI which is associated with signs or symptoms found in MS. Due to the McDonald criteria, it does not completely fit the criteria to be diagnosed as MS, hence being named "clinically isolated syndrome". CIS can be seen as the first episode of demyelination in the central nervous system. To be classified as CIS, the attack must last at least 24 hours and be caused by [[inflammation]] or [[Demyelinating disease|demyelination]] of the [[central nervous system]].<ref name="pmid1897097722"/><ref>{{Cite web |title=Clinically Isolated Syndrome (CIS) |url=https://www.nationalmssociety.org/What-is-MS/Types-of-MS/Clinically-Isolated-Syndrome-(CIS) |access-date=4 October 2023 |website=National MS Society |archive-date=30 September 2023 |archive-url=https://web.archive.org/web/20230930160029/https://www.nationalmssociety.org/What-is-MS/Types-of-MS/Clinically-Isolated-Syndrome-(CIS) |url-status=dead }}</ref> Patients who suffer from CIS may or may not go on to develop MS, but 30 to 70% of persons who experience CIS will later develop MS.<ref name="pmid15847841">{{cite journal |vauthors=Miller D, Barkhof F, Montalban X, Thompson A, Filippi M |date=May 2005 |title=Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis |journal=The Lancet. Neurology |volume=4 |issue=5 |pages=281–8 |doi=10.1016/S1474-4422(05)70071-5 |pmid=15847841 |s2cid=36401666}}</ref>

RRMS is characterized by unpredictable relapses followed by periods of months to years of relative quiet ([[remission (medicine)|remission]]) with no new signs of disease activity. Deficits that occur during attacks may either resolve or leave [[sequelae|problems]], the latter in about 40% of attacks and being more common the longer a person has had the disease.<ref name="pmid1897097722"/><ref name="Tsang20112"/> This describes the initial course of 80% of individuals with MS.<ref name="pmid1897097722"/>

PPMS occurs in roughly 10–20% of individuals with the disease, with no remission after the initial symptoms.<ref name="Tsang20112"/><ref name="pmid17884680">{{cite journal | vauthors = Miller DH, Leary SM | title = Primary-progressive multiple sclerosis | journal = The Lancet. Neurology | volume = 6 | issue = 10 | pages = 903–12 | date = October 2007 | pmid = 17884680 | doi = 10.1016/S1474-4422(07)70243-0 | s2cid = 31389841 | hdl = 1871/24666 | hdl-access = free }}</ref> It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements.<ref name="pmid8780061" /> The usual age of onset for the primary progressive subtype is later than that of the relapsing-remitting subtype. It is similar to the age that secondary progressive usually begins in RRMS, around 40 years of age.<ref name="pmid1897097722"/>

SPMS occurs in around 65% of those with initial RRMS, who eventually have progressive neurologic decline between acute attacks without any definite periods of remission.<ref name="pmid1897097722"/><ref name="pmid8780061" /> Occasional relapses and minor remissions may appear.<ref name="pmid8780061" /> The most common length of time between disease onset and conversion from RRMS to SPMS is 19 years.<ref name="pmid16545751">{{cite journal | vauthors = Rovaris M, Confavreux C, Furlan R, Kappos L, Comi G, Filippi M | title = Secondary progressive multiple sclerosis: current knowledge and future challenges | journal = The Lancet. Neurology | volume = 5 | issue = 4 | pages = 343–54 | date = April 2006 | pmid = 16545751 | doi = 10.1016/S1474-4422(06)70410-0 | s2cid = 39503553 }}</ref>

=== Special courses ===
Independently of the types published by the MS associations, regulatory agencies such as the FDA often consider special courses, trying to reflect some clinical trial results on their approval documents. Some examples could be "highly active MS" (HAMS),<ref name="sorensen">{{cite journal |vauthors=Sørensen PS, Centonze D, Giovannoni G, et al. |title=Expert opinion on the use of cladribine tablets in clinical practice |journal=Ther Adv Neurol Disord |volume=13 |pages=1756286420935019 |year=2020 |pmid=32636933 |pmc=7318823 |doi=10.1177/1756286420935019 |type= Review}}</ref> "active secondary MS" (similar to the old progressive-relapsing)<ref name="novartis.com">{{Cite web|url=https://www.novartis.com/news/media-releases/novartis-receives-fda-approval-mayzent-siponimod-first-oral-drug-treat-secondary-progressive-ms-active-disease|title=Novartis receives FDA approval for Mayzent® (siponimod), the first oral drug to treat secondary progressive MS with active disease|website=Novartis.com|access-date=12 November 2021|archive-date=20 November 2020|archive-url=https://web.archive.org/web/20201120002815/https://www.novartis.com/news/media-releases/novartis-receives-fda-approval-mayzent-siponimod-first-oral-drug-treat-secondary-progressive-ms-active-disease|url-status=live}}</ref> and "rapidly progressing PPMS".<ref>{{cite journal |vauthors=Saida T |title=多発性硬化症: 再燃時の治療と再発予防 |trans-title=Multiple sclerosis: treatment and prevention of relapses and progression in multiple sclerosis |language=ja |journal=臨床神経学 |trans-journal=Rinsho Shinkeigaku |volume=44 |issue=11 |pages=796–8 |date=November 2004 |pmid=15651294 |type= Review}}</ref>

Also, deficits always resolving between attacks is sometimes referred to as "benign" MS,<ref name="pmid18219812">{{cite book | vauthors = Pittock SJ, Rodriguez M | chapter = Benign Multiple Sclerosis: A Distinct Clinical Entity with Therapeutic Implications | veditors = Rodriguez M | title = Advances in multiple Sclerosis and Experimental Demyelinating Diseases | series = Current Topics in Microbiology and Immunology | volume = 318 | pages = 1–17 | year = 2008 | pmid = 18219812 | doi = 10.1007/978-3-540-73677-6_1 | isbn = 978-3-540-73676-9 }}</ref> although people still build up some degree of disability in the long term.<ref name="pmid1897097722"/> On the other hand, the term [[malignant multiple sclerosis]] is used to describe people with MS having reached a significant level of disability in a short period.<ref>{{cite book | vauthors = Feinstein A | chapter = Chapter 1 - Multiple sclerosis: diagnosis and definitions |title=The Clinical Neuropsychiatry of Multiple Sclerosis |date=2007 |isbn=978-0-521-85234-0 | pages = 1–27 |doi=10.1017/CBO9780511543760 }}</ref>

An international panel has published a standardized definition for the course HAMS.<ref name="sorensen" />

=== Variants ===
Atypical [[Idiopathic inflammatory demyelinating diseases|variants]] of MS have been described; these include [[tumefactive multiple sclerosis]], [[Balo concentric sclerosis]], [[Diffuse myelinoclastic sclerosis|Schilder's diffuse sclerosis]], and [[Marburg multiple sclerosis]]. Debate remains on whether they are MS variants or different diseases.<ref name="pmid15727225">{{cite journal | vauthors = Stadelmann C, Brück W | title = Lessons from the neuropathology of atypical forms of multiple sclerosis | journal = Neurological Sciences | volume = 25 | issue = Suppl 4 | pages = S319–S322 | date = November 2004 | pmid = 15727225 | doi = 10.1007/s10072-004-0333-1 | s2cid = 21212935 }}</ref> Some diseases previously considered MS variants, such as [[Devic's disease]], are now considered outside the MS spectrum.<ref>{{cite journal | vauthors = Fujihara K | title = Neuromyelitis optica spectrum disorders: still evolving and broadening | journal = Current Opinion in Neurology | volume = 32 | issue = 3 | pages = 385–394 | date = June 2019 | pmid = 30893099 | pmc = 6522202 | doi = 10.1097/WCO.0000000000000694 | type = Review }}</ref>

== Management ==
{{Main|Management of multiple sclerosis}}

Although no cure for multiple sclerosis has been found, several therapies have proven helpful. Several effective treatments can decrease the number of attacks and the rate of progression.<ref name=McGinley2021/> The primary aims of therapy are returning function after an attack, preventing new attacks, and preventing disability. Starting medications is generally recommended in people after the first attack when more than two lesions are seen on MRI.<ref name=Neurology2018>{{cite journal | vauthors = Rae-Grant A, Day GS, Marrie RA, Rabinstein A, Cree BA, Gronseth GS, Haboubi M, Halper J, Hosey JP, Jones DE, Lisak R, Pelletier D, Potrebic S, Sitcov C, Sommers R, Stachowiak J, Getchius TS, Merillat SA, Pringsheim T | title = Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology | journal = Neurology | volume = 90 | issue = 17 | pages = 777–788 | date = April 2018 | pmid = 29686116 | doi = 10.1212/WNL.0000000000005347 | doi-access = free }}</ref>

The first approved medications used to treat MS were modestly effective, though were poorly tolerated and had many adverse effects.<ref name=NIH2015 /> Several treatment options with better safety and tolerability profiles have been introduced,<ref name=McGinley2021/> improving the prognosis of MS.

As with any medical treatment, medications used in the management of MS have several [[adverse effect (medicine)|adverse effects]]. [[Alternative medicine|Alternative treatments]] are pursued by some people, despite the shortage of supporting evidence of efficacy.

=== Initial management of acute flare ===
During symptomatic attacks, administration of high doses of [[intravenous therapy|intravenous]] [[corticosteroid]]s, such as [[methylprednisolone]], is the usual therapy,<ref name="pmid1897097722"/> with oral corticosteroids seeming to have a similar efficacy and safety profile.<ref>{{cite journal | vauthors = Burton JM, O'Connor PW, Hohol M, Beyene J | title = Oral versus intravenous steroids for treatment of relapses in multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | volume = 12 | pages = CD006921 | date = December 2012 | pmid = 23235634 | doi = 10.1002/14651858.CD006921.pub3 }}</ref> Although effective in the short term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery.<ref>{{cite journal |vauthors=Filippini G, Brusaferri F, Sibley WA, et al. |title=Corticosteroids or ACTH for acute exacerbations in multiple sclerosis |journal=Cochrane Database Syst Rev |issue=4 |pages=CD001331 |year=2000 |volume=2013 |pmid=11034713 |doi=10.1002/14651858.CD001331 |pmc=11391333 }}</ref><ref name="RCOP_acute">{{cite book|author=The National Collaborating Centre for Chronic Conditions|title=Multiple sclerosis: national clinical guideline for diagnosis and management in primary and secondary care|year=2004|publisher=Royal College of Physicians|location=London|isbn=1-86016-182-0|chapter=Treatment of acute episodes|pages=54–58|url=https://www.ncbi.nlm.nih.gov/books/NBK48921/|pmid=21290636|access-date=5 October 2021|archive-date=10 February 2023|archive-url=https://web.archive.org/web/20230210212932/https://www.ncbi.nlm.nih.gov/books/NBK48921/|url-status=live}}</ref> The long-term benefit is unclear in optic neuritis as of 2020.<ref>{{cite journal |vauthors=Petzold A, Braithwaite T, van Oosten BW  |title=Case for a new corticosteroid treatment trial in optic neuritis: review of updated evidence |journal=J. Neurol. Neurosurg. Psychiatry |volume=91 |issue=1 |pages=9–14 |date=January 2020 |pmid=31740484 |pmc=6952848 |doi=10.1136/jnnp-2019-321653 |type= Review}}</ref><ref name="Petzold_2022" /> The consequences of severe attacks that do not respond to corticosteroids might be treatable by [[plasmapheresis]].<ref name="pmid1897097722"/>

=== Chronic management ===
==== Relapsing-remitting multiple sclerosis ====
Multiple [[Management of multiple sclerosis#Disease-modifying treatments|disease-modifying]] medications were approved by regulatory agencies for RRMS; they are modestly effective at decreasing the number of attacks.<ref name=He2016>{{cite journal | vauthors = He D, Zhang C, Zhao X, Zhang Y, Dai Q, Li Y, Chu L | title = Teriflunomide for multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | pages = CD009882 | date = March 2016 | issue = 3 | pmid = 27003123 | doi = 10.1002/14651858.CD009882.pub3 | pmc = 10493042 }}</ref> [[Interferons]]<ref name=Rice2001>{{cite journal |vauthors=Rice GP, Incorvaia B, Munari L, et al. |title=Interferon in relapsing-remitting multiple sclerosis |journal=Cochrane Database Syst Rev |issue=4 |pages=CD002002 |year=2001 |volume=2001 |pmid=11687131 |pmc=7017973 |doi=10.1002/14651858.CD002002 }}</ref> and [[glatiramer acetate]] are first-line treatments<ref name="Tsang20112"/> and are roughly equivalent, reducing relapses by approximately 30%.<ref name=Hassan2011>{{cite journal | vauthors = Hassan-Smith G, Douglas MR | title = Management and prognosis of multiple sclerosis | journal = British Journal of Hospital Medicine | volume = 72 | issue = 11 | pages = M174-6 | date = November 2011 | pmid = 22082979 | doi = 10.12968/hmed.2011.72.Sup11.M174 }}</ref> Early-initiated long-term therapy is safe and improves outcomes.<ref name="pmid21205679">{{cite journal | vauthors = Freedman MS | title = Long-term follow-up of clinical trials of multiple sclerosis therapies | journal = Neurology | volume = 76 | issue = 1 Suppl 1 | pages = S26-34 | date = January 2011 | pmid = 21205679 | doi = 10.1212/WNL.0b013e318205051d | s2cid = 16929304 }}</ref><ref name="pmid22284996">{{cite journal | vauthors = Qizilbash N, Mendez I, Sanchez-de la Rosa R | title = Benefit-risk analysis of glatiramer acetate for relapsing-remitting and clinically isolated syndrome multiple sclerosis | journal = Clinical Therapeutics | volume = 34 | issue = 1 | pages = 159–176.e5 | date = January 2012 | pmid = 22284996 | doi = 10.1016/j.clinthera.2011.12.006 }}</ref>

Treatment of CIS with interferons decreases the chance of progressing to clinical MS.<ref name="pmid1897097722"/><ref name="pmid21205678">{{cite journal | vauthors = Bates D | title = Treatment effects of immunomodulatory therapies at different stages of multiple sclerosis in short-term trials | journal = Neurology | volume = 76 | issue = 1 Suppl 1 | pages = S14-25 | date = January 2011 | pmid = 21205678 | doi = 10.1212/WNL.0b013e3182050388 | s2cid = 362182 }}</ref><ref>{{cite journal |vauthors=Clerico M, Faggiano F, Palace J, et al. |title=Recombinant interferon beta or glatiramer acetate for delaying conversion of the first demyelinating event to multiple sclerosis |journal=Cochrane Database Syst Rev |issue=2 |pages=CD005278 |date=April 2008 |pmid=18425915 |doi=10.1002/14651858.CD005278.pub3}}</ref> Efficacy of interferons and glatiramer acetate in children has been estimated to be roughly equivalent to that of adults.<ref name="pmid22642799">{{cite journal | vauthors = Johnston J, So TY | title = First-line disease-modifying therapies in paediatric multiple sclerosis: a comprehensive overview | journal = Drugs | volume = 72 | issue = 9 | pages = 1195–211 | date = June 2012 | pmid = 22642799 | doi = 10.2165/11634010-000000000-00000 | s2cid = 20323687 }}</ref> The role of some newer agents such as [[fingolimod]],<ref name=LaMantia2016>{{cite journal |vauthors=La Mantia L, Tramacere I, Firwana B, et al. |title=Fingolimod for relapsing-remitting multiple sclerosis |journal=Cochrane Database Syst Rev |volume=2016 |pages=CD009371 |date=April 2016 |issue=4 |pmid=27091121 |doi=10.1002/14651858.CD009371.pub2 |pmc=10401910 }}</ref> [[teriflunomide]], and [[dimethyl fumarate]],<ref name=Xu2015>{{cite journal |vauthors=Xu Z, Zhang F, Sun F, et al. |title=Dimethyl fumarate for multiple sclerosis |journal=Cochrane Database Syst Rev |issue=4 |pages=CD011076 |date=April 2015 |volume=2015 |pmid=25900414 |doi=10.1002/14651858.CD011076.pub2 |pmc=10663978 }}</ref> is not yet entirely clear.<ref name="pmid22014437" /> Making firm conclusions about the best treatment is difficult, especially regarding the long‐term benefit and safety of early treatment, given the lack of studies directly comparing disease-modifying therapies or long-term monitoring of patient outcomes.<ref>{{cite journal |vauthors=Filippini G, Del Giovane C, Clerico M, et al. |title=Treatment with disease-modifying drugs for people with a first clinical attack suggestive of multiple sclerosis |journal=Cochrane Database Syst Rev |volume=2017 |pages=CD012200 |date=April 2017 |issue=4 |pmid=28440858 |pmc=6478290 |doi=10.1002/14651858.CD012200.pub2 }}</ref>

The relative effectiveness of different treatments is unclear, as most have only been compared to placebo or a small number of other therapies.<ref name=Filippini2013>{{cite journal |vauthors=Filippini G, Del Giovane C, Vacchi L, et al. |title=Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis |journal=Cochrane Database Syst Rev |issue=6 |pages=CD008933 |date=June 2013 |pmid=23744561 |doi=10.1002/14651858.CD008933.pub2 |pmc=11627144 }}</ref> Direct comparisons of interferons and glatiramer acetate indicate similar effects or only small differences in effects on relapse rate, disease progression, and MRI measures.<ref>{{cite journal |vauthors=La Mantia L, Di Pietrantonj C, Rovaris M, et al |title=Interferons-beta versus glatiramer acetate for relapsing-remitting multiple sclerosis |journal=Cochrane Database Syst Rev |volume=2016 |pages=CD009333 |date=November 2016 |issue=11 |pmid=27880972 |pmc=6464642 |doi=10.1002/14651858.CD009333.pub3}}</ref> There is high confidence that [[natalizumab]], [[cladribine]], or [[alemtuzumab]] are decreasing relapses over two years for people with RRMS.<ref name="Tramacere2015">{{cite journal |vauthors=Gonzalez-Lorenzo M, Ridley B, Minozzi S, Del Giovane C, Peryer G, Piggott T, Foschi M, Filippini G, Tramacere I, Baldin E, Nonino F |date=January 2024 |title=Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis |journal=Cochrane Database Syst Rev |volume= 2024|issue= 1|pages= CD011381|doi=10.1002/14651858.CD011381.pub3 |pmc= 10765473|pmid=38174776 |hdl-access=}}</ref> Natalizumab and [[interferon beta-1a]] ([[Interferon beta-1a#Brand names|Rebif]]) may reduce relapses compared to both placebo and interferon beta-1a (Avonex) while [[Interferon beta-1b]] ([[Interferon beta-1b#Commercial formulations|Betaseron]]), glatiramer acetate, and [[mitoxantrone]] may also prevent relapses.<ref name=Filippini2013 /> Evidence on relative effectiveness in reducing disability progression is unclear.<ref name=Filippini2013 /> There is moderate confidence that a two-year treatment with natalizumab slows disability progression for people with RRMS.<ref name=Tramacere2015 /> All medications are associated with adverse effects that may influence their risk-to-benefit profiles.<ref name=Filippini2013 /><ref name=Tramacere2015 />

[[Ublituximab]] was approved for medical use in the United States in December 2022.<ref>{{cite press release | title=TG Therapeutics Announces FDA Approval of Briumvi (ublituximab-xiiy) | publisher=TG Therapeutics | via=GlobeNewswire | date=28 December 2022 | url=https://www.globenewswire.com/news-release/2022/12/28/2580377/8790/en/TG-Therapeutics-Announces-FDA-Approval-of-BRIUMVI-ublituximab-xiiy.html | access-date=29 December 2022 | archive-date=28 December 2022 | archive-url=https://web.archive.org/web/20221228194153/https://www.globenewswire.com/news-release/2022/12/28/2580377/8790/en/TG-Therapeutics-Announces-FDA-Approval-of-BRIUMVI-ublituximab-xiiy.html | url-status=live }}</ref>

=== Medications ===

Overview of medications available for MS.<ref name="MSTrust">{{Cite web|date=2023-12-03|title=MS Decisions aid|url=https://mstrust.org.uk/information-support/ms-drugs-treatments/ms-decisions-aid|access-date=2023-12-03|location=Letchworth Garden City, United Kingdom|publisher=Multiple Sclerosis Trust|language=en|archive-date=3 December 2023|archive-url=https://web.archive.org/web/20231203213822/https://mstrust.org.uk/information-support/ms-drugs-treatments/ms-decisions-aid|url-status=live}}</ref>

{| class="wikitable"
! Medication
! Compound
! Producer
! Use
! Efficacy (annualized relapse reduction rate)
! Annualized relapse rate (ARR)
|-
| Avonex
| [[Interferon beta-1a]]
| [[Biogen]]
| [[Intramuscular injection|Intramuscular]]
| 30%
| 0.25
|-
| Rebif
| [[Interferon beta-1a]]
| [[Merck Serono]]
| [[Subcutaneous administration|Subcutaneous]]
| 30%
| 0.256
|-
| Extavia
| [[Interferon beta-1b]]
| [[Bayer Schering]]
| [[Subcutaneous administration|Subcutaneous]]
| 30%
| 0.256
|-
| Copaxone
| [[Glatiramer acetate]]
| [[Teva Pharmaceuticals]]
| [[Subcutaneous administration|Subcutaneous]]
| 30%
| 0.3
|-
| Aubagio
| [[Teriflunomide]]
| [[Genzyme]]
| [[Oral administration|Oral]]
| 30%
| 0.35
|-
| Plegridy
| [[Interferon beta-1a]]
| Biogen
| [[Subcutaneous administration|Subcutaneous]]
| 30%
| 0.12
|-
| Tecfidera
| [[Dimethyl fumarate]]
| Biogen
| [[Oral administration|Oral]]
| 50%
| 0.15
|-
| Vumerity
| [[Diroximel fumarate]]
| Biogen
| [[Oral administration|Oral]]
| 50%
| 0.11-0.15
|-
| Gilenya
| [[Fingolimod]]
|
| [[Oral administration|Oral]]
| 50%
| 0.22-0.25
|-
| Zeposia
| [[Ozanimod]]
| {{Better source needed|date=November 2023}}
| [[Oral administration|Oral]]
|
| 0.18-0.24
|-
| Kesimpta
| [[Ofatumumab]]
|
| [[Subcutaneous administration|Subcutaneous]]
| 70%
| 0.09-0.14
|-
| Mavenclad
| [[Cladribine]]
|
| [[Oral administration|Oral]]
| 70%
| 0.1-0.14
|-
| Lemtrada
| [[Alemtuzumab]]
|
| [[Intravenous therapy|Intravenous]]
| 70%
| 0.08
|-
| Ocrevus
| [[Ocrelizumab]]
|
| [[Intravenous therapy|Intravenous]]
| 70%
| 0.09
|-
| Ocrevus Zunovo
| [[Ocrelizumab/hyaluronidase]]
|
| [[Subcutaneous administration|Subcutaneous]]
|
|
|-

|}

==== Progressive multiple sclerosis ====
In 2011, mitoxantrone was the first medication approved for secondary progressive MS.<ref name="BopeKellerman2011">{{cite book | vauthors = Keegan BM | chapter = Multiple Sclerosis | veditors = Bope ET, Kellerman RD |title=Conn's Current Therapy 2012: Expert Consult – Online and Print|chapter-url=https://books.google.com/books?id=pyKjGU5JdqQC&pg=PT662|date=22 December 2011|publisher=Elsevier Health Sciences|isbn=978-1-4557-0738-6|pages=626 }}</ref> In this population, tentative evidence supports mitoxantrone moderately slowing the progression of the disease and decreasing rates of relapses over two years.<ref name="CochMit2013">{{cite journal | vauthors = Martinelli Boneschi F, Vacchi L, Rovaris M, Capra R, Comi G | title = Mitoxantrone for multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | volume = 5 | issue = 5 | pages = CD002127 | date = May 2013 | pmid = 23728638 | doi = 10.1002/14651858.CD002127.pub3 | pmc = 11745300 | hdl = 2434/533488 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Marriott JJ, Miyasaki JM, Gronseth G, O'Connor PW | title = Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology | journal = Neurology | volume = 74 | issue = 18 | pages = 1463–70 | date = May 2010 | pmid = 20439849 | pmc = 2871006 | doi = 10.1212/WNL.0b013e3181dc1ae0 }}</ref>

New approved medications continue to emerge. In March 2017, the FDA approved ocrelizumab as a treatment for primary progressive MS in adults, the first drug to gain that approval,<ref name="pmid31598138">{{cite journal | vauthors = Faissner S, Gold R | title = Progressive multiple sclerosis: latest therapeutic developments and future directions | journal = Therapeutic Advances in Neurological Disorders | volume = 12 | pages = 1756286419878323 | year = 2019 | pmid = 31598138 | pmc = 6764045 | doi = 10.1177/1756286419878323 | doi-access = free }}</ref><ref name="STATapproval">{{cite news |title=After 40-year odyssey, first drug for aggressive MS wins FDA approval |url=https://www.statnews.com/2017/03/28/multiple-sclerosis-ms-drug-ocrelizumab/ |date=28 March 2017 | vauthors = Winslow R |publisher=STAT |url-status=live |archive-url=https://web.archive.org/web/20170401151407/https://www.statnews.com/2017/03/28/multiple-sclerosis-ms-drug-ocrelizumab/ |archive-date=1 April 2017 }}</ref><ref name="Ocrevus FDA label">{{cite web | title=Ocrevus- ocrelizumab injection | website=DailyMed | date=13 December 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9da42362-3bb5-4b83-b4bb-b59fd4e55f0d | access-date=26 March 2020 | archive-date=27 June 2020 | archive-url=https://web.archive.org/web/20200627100425/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9da42362-3bb5-4b83-b4bb-b59fd4e55f0d | url-status=live }}</ref> with requirements for several [[Phases of clinical research#Phase IV|Phase IV]] clinical trials.<ref name="FDABLAapproval">{{cite web|title=BLA Approval Letter|url=https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/761053Orig1s000ltr.pdf|publisher=FDA|date=28 March 2017|url-status=dead|archive-url=https://web.archive.org/web/20170402081250/https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/761053Orig1s000ltr.pdf|archive-date=2 April 2017}}</ref> It is also used for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults.<ref name="Ocrevus FDA label" /> According to a 2021 [[Cochrane review]], ocrelizumab may reduce worsening of symptoms for primary progressive MS and probably increases unwanted effects but makes little or no difference to the number of serious unwanted effects.<ref>{{cite journal | vauthors = Lin M, Zhang J, Zhang Y, Luo J, Shi S | title = Ocrelizumab for multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | volume = 2022 | issue = 5 | pages = CD013247 | date = May 2022 | pmid = 35583174 | pmc = 9115862 | doi = 10.1002/14651858.CD013247.pub2 | collaboration = Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group }}</ref>

In 2019, [[siponimod]] and [[cladribine]] were approved in the United States for the treatment of secondary progressive multiple sclerosis (SPMS).<ref name="pmid31598138" /> Subsequently, [[ozanimod]] was approved in 2020, and [[ponesimod]] was approved in 2021, which were both approved for management of CIS, relapsing MS, and SPMS in the U.S., and RRMS in Europe.<ref>{{Cite book | vauthors = Penner IK, Schreiber H | chapter = Disease Modifying Immunotherapies and Fatigue | veditors = Penner IK |title=Fatigue in Multiple Sclerosis |publisher=Springer, Cham |year=2023 |isbn=978-3-031-13498-2 | pages = 161–177 }}</ref>

[[Ocrelizumab/hyaluronidase]] was approved for medical use in the United States in September 2024.<ref>{{cite press release | title=FDA Approves Ocrevus Zunovo as the First and Only Twice-A-Year 10-Minute Subcutaneous Injection for People With Relapsing and Progressive Multiple Sclerosis | website=Genentech | date=13 September 2024 | url=https://www.gene.com/media/press-releases/15036/2024-09-13/fda-approves-ocrevus-zunovo-as-the-first | access-date=13 September 2024 | archive-date=14 September 2024 | archive-url=https://web.archive.org/web/20240914061044/https://www.gene.com/media/press-releases/15036/2024-09-13/fda-approves-ocrevus-zunovo-as-the-first | url-status=live }}</ref><ref>{{cite press release | title=Halozyme Announces FDA Approval of Roche's Subcutaneous Ocrevus Zunovo with Enhanze for People with Relapsing and Primary Progressive Multiple Sclerosis | publisher=Halozyme Therapeutics | via=PR Newswire | date=13 September 2024 | url=https://www.prnewswire.com/news-releases/halozyme-announces-fda-approval-of-roches-subcutaneous-ocrevus-zunovo-with-enhanze-for-people-with-relapsing-and-primary-progressive-multiple-sclerosis-302247928.html | access-date=13 September 2024 | archive-date=14 September 2024 | archive-url=https://web.archive.org/web/20240914061013/https://www.prnewswire.com/news-releases/halozyme-announces-fda-approval-of-roches-subcutaneous-ocrevus-zunovo-with-enhanze-for-people-with-relapsing-and-primary-progressive-multiple-sclerosis-302247928.html | url-status=live }}</ref>

==== Adverse effects ====
[[File:Copaxone Injection Site Reaction.JPG|thumb|Irritation zone after injection of glatiramer acetate]]
The [[disease-modifying treatment]]s have several adverse effects. One of the most common is irritation at the injection site for glatiramer acetate and the interferons (up to 90% with subcutaneous injections and 33% with intramuscular injections).<ref name=Rice2001 /><ref name=Balak2012>{{cite journal | vauthors = Balak DM, Hengstman GJ, Çakmak A, Thio HB | title = Cutaneous adverse events associated with disease-modifying treatment in multiple sclerosis: a systematic review | journal = Multiple Sclerosis | volume = 18 | issue = 12 | pages = 1705–17 | date = December 2012 | pmid = 22371220 | doi = 10.1177/1352458512438239 | hdl = 1765/73097 | hdl-access = free }}</ref> Over time, a visible dent at the injection site, due to the local destruction of fat tissue, known as [[lipoatrophy]], may develop.<ref name=Balak2012 /> Interferons may produce [[flu-like symptoms]];<ref name="pmid17131933">{{cite journal | vauthors = Sládková T, Kostolanský F | title = The role of cytokines in the immune response to influenza A virus infection | journal = Acta Virologica | volume = 50 | issue = 3 | pages = 151–62 | year = 2006 | pmid = 17131933 }}</ref> some people taking glatiramer experience a post-injection reaction with flushing, chest tightness, heart palpitations, and anxiety, which usually lasts less than thirty minutes.<ref>{{cite journal | vauthors = La Mantia L, Munari LM, Lovati R | title = Glatiramer acetate for multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | issue = 5 | pages = CD004678 | date = May 2010 | pmid = 20464733 | doi = 10.1002/14651858.CD004678.pub2 }}</ref> More dangerous but much less common are [[hepatotoxicity|liver damage]] from interferons,<ref name="pmid15592724">{{cite journal | vauthors = Tremlett H, Oger J | title = Hepatic injury, liver monitoring and the beta-interferons for multiple sclerosis | journal = Journal of Neurology | volume = 251 | issue = 11 | pages = 1297–303 | date = November 2004 | pmid = 15592724 | doi = 10.1007/s00415-004-0619-5 | s2cid = 12529733 }}</ref> [[systolic dysfunction]] (12%), [[infertility]], and [[acute myeloid leukemia]] (0.8%) from mitoxantrone,<ref name=CochMit2013 /><ref name="pmid19882365">{{cite journal | vauthors = Comi G | title = Treatment of multiple sclerosis: role of natalizumab | journal = Neurological Sciences | volume = 30 | issue = S2 | pages = S155-8 | date = October 2009 | pmid = 19882365 | doi = 10.1007/s10072-009-0147-2 | series = 30 | s2cid = 25910077 }}</ref> and [[progressive multifocal leukoencephalopathy]] occurring with natalizumab (occurring in 1 in 600 people treated).<ref name="Tsang20112"/><ref>{{cite journal | vauthors = Hunt D, Giovannoni G | title = Natalizumab-associated progressive multifocal leucoencephalopathy: a practical approach to risk profiling and monitoring | journal = Practical Neurology | volume = 12 | issue = 1 | pages = 25–35 | date = February 2012 | pmid = 22258169 | doi = 10.1136/practneurol-2011-000092 | s2cid = 46326042 }}</ref>

Fingolimod may give rise to [[hypertension]] and [[bradycardia|slowed heart rate]], [[macular edema]], elevated liver enzymes, or a [[lymphopenia|reduction in lymphocyte levels]].<ref name=LaMantia2016 /><ref name="pmid22014437">{{cite journal | vauthors = Killestein J, Rudick RA, Polman CH | title = Oral treatment for multiple sclerosis | journal = The Lancet. Neurology | volume = 10 | issue = 11 | pages = 1026–34 | date = November 2011 | pmid = 22014437 | doi = 10.1016/S1474-4422(11)70228-9 | s2cid = 206160178 }}</ref> Tentative evidence supports the short-term safety of teriflunomide, with common side effects including headaches, fatigue, nausea, hair loss, and limb pain.<ref name=He2016 /> There have also been reports of liver failure and PML with its use and it is [[Teratology|dangerous for fetal development]].<ref name="pmid22014437" /> Most common side effects of dimethyl fumarate are flushing and gastrointestinal problems.<ref name=Xu2015 /><ref name=fumarate>{{cite press release|url=http://www.biogenidec.com/press_release_details.aspx?ID=5981&ReqId=1801165|title=Biogen Idec's TECFIDERA™ (Dimethyl Fumarate) Approved in US as a First-Line Oral Treatment for Multiple Sclerosis|publisher=Biogen Idec|date=27 March 2013|access-date=4 June 2013|url-status=dead|archive-url=https://web.archive.org/web/20130512021453/http://www.biogenidec.com/press_release_details.aspx?ID=5981&ReqId=1801165|archive-date=12 May 2013}}</ref><ref name="pmid22014437" /> While dimethyl fumarate may lead to a [[neutropenia|reduction in the white blood cell count]] there were no reported cases of opportunistic infections during trials.<ref name=fumarateNDA>{{cite web |title=NDA 204063 – FDA Approved Labeling Text |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204063lbl.pdf |date=27 March 2013 |access-date=5 April 2013 |publisher=US Food and Drug Agency |url-status=live |archive-url=https://web.archive.org/web/20131004220910/http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204063lbl.pdf |archive-date=4 October 2013 }}<br />{{cite web |title=NDA Approval |date=27 March 2013 |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/204063Orig1s000ltr.pdf |access-date=5 April 2013 |publisher=US Food and Drug Agency |url-status=dead |archive-url=https://web.archive.org/web/20131004220451/http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/204063Orig1s000ltr.pdf |archive-date=4 October 2013 }}</ref>

=== Associated symptoms ===
Both medications and neurorehabilitation have been shown to improve some symptoms, though neither changes the course of the disease.<ref name="pmid16168933">{{cite journal | vauthors = Kesselring J, Beer S | title = Symptomatic therapy and neurorehabilitation in multiple sclerosis | journal = The Lancet. Neurology | volume = 4 | issue = 10 | pages = 643–52 | date = October 2005 | pmid = 16168933 | doi = 10.1016/S1474-4422(05)70193-9 | s2cid = 28253186 }}</ref> Some symptoms have a good response to medication, such as bladder [[spasticity]], while others are little changed.<ref name="pmid1897097722"/> Equipment such as [[catheter]]s for [[neurogenic bladder dysfunction]] or mobility aids can help improve functional status.

A [[multidisciplinary]] approach is important for improving quality of life; however, it is difficult to specify a 'core team' as many health services may be needed at different points in time.<ref name="pmid1897097722"/> Multidisciplinary rehabilitation programs increase activity and participation of people with MS but do not influence impairment level.<ref name="pmid17443610">{{cite journal | vauthors = Khan F, Turner-Stokes L, Ng L, Kilpatrick T | title = Multidisciplinary rehabilitation for adults with multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD006036 | date = April 2007 | volume = 2011 | pmid = 17443610 | doi = 10.1002/14651858.CD006036.pub2 | pmc = 8992048 | veditors = Khan F }}</ref> Studies investigating information provision in support of patient understanding and participation suggest that while interventions (written information, decision aids, coaching, educational programmes) may increase knowledge, the evidence of an effect on decision making and quality of life is mixed and low certainty.<ref>{{cite journal | vauthors = Köpke S, Solari A, Rahn A, Khan F, Heesen C, Giordano A | title = Information provision for people with multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | pages = CD008757 | date = October 2018 | issue = 10 | pmid = 30317542 | pmc = 6517040 | doi = 10.1002/14651858.CD008757.pub3 }}</ref> There is limited evidence for the overall efficacy of individual therapeutic disciplines,<ref name="pmid15859525">{{cite journal | vauthors = Steultjens EM, Dekker J, Bouter LM, Leemrijse CJ, van den Ende CH | title = Evidence of the efficacy of occupational therapy in different conditions: an overview of systematic reviews | journal = Clinical Rehabilitation | volume = 19 | issue = 3 | pages = 247–54 | date = May 2005 | pmid = 15859525 | doi = 10.1191/0269215505cr870oa | hdl = 1871/26505 | url = https://research.vu.nl/en/publications/6f3a1a11-d73e-42e6-a372-79aa1a265df3 }}</ref><ref name="pmid12917976">{{cite journal | vauthors = Steultjens EM, Dekker J, Bouter LM, Cardol M, Van de Nes JC, Van den Ende CH | title = Occupational therapy for multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | issue = 3 | pages = CD003608 | year = 2003 | volume = 2010 | pmid = 12917976 | doi = 10.1002/14651858.CD003608 | pmc = 9022193 | veditors = Steultjens EE }}</ref> though there is good evidence that specific approaches, such as exercise,<ref>{{cite journal | vauthors = Amatya B, Khan F, Galea M | title = Rehabilitation for people with multiple sclerosis: an overview of Cochrane Reviews | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD012732 | date = January 2019 | issue = 1 | pmid = 30637728 | pmc = 6353175 | doi = 10.1002/14651858.CD012732.pub2 }}</ref><ref>{{cite journal | vauthors = Heine M, van de Port I, Rietberg MB, van Wegen EE, Kwakkel G | title = Exercise therapy for fatigue in multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | issue = 9 | pages = CD009956 | date = September 2015 | volume = 2015 | pmid = 26358158 | doi = 10.1002/14651858.CD009956.pub2 | pmc = 9554249 }}</ref><ref name="pmid17482708">{{cite journal | vauthors = Gallien P, Nicolas B, Robineau S, Pétrilli S, Houedakor J, Durufle A | title = Physical training and multiple sclerosis | journal = Annales de Réadaptation et de Médecine Physique | volume = 50 | issue = 6 | pages = 373–6, 369–72 | date = July 2007 | pmid = 17482708 | doi = 10.1016/j.annrmp.2007.04.004 }}</ref><ref>{{cite journal | vauthors = Rietberg MB, Brooks D, Uitdehaag BM, Kwakkel G | title = Exercise therapy for multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD003980 | date = January 2005 | volume = 2005 | pmid = 15674920 | pmc = 6485797 | doi = 10.1002/14651858.CD003980.pub2 | veditors = Kwakkel G }}</ref> and psychological therapies are effective.<ref>{{cite journal | vauthors = Thomas PW, Thomas S, Hillier C, Galvin K, Baker R | title = Psychological interventions for multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD004431 | date = January 2006 | volume = 2010 | pmid = 16437487 | doi = 10.1002/14651858.CD004431.pub2 | veditors = Thomas PW | pmc = 8406851 }}</ref> Cognitive training, alone or combined with other neuropsychological interventions, may show positive effects for memory and attention though firm conclusions are not possible given small sample numbers, variable methodology, interventions and outcome measures.<ref>{{cite journal | vauthors = Rosti-Otajärvi EM, Hämäläinen PI | title = Neuropsychological rehabilitation for multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD009131 | date = February 2014 | volume = 2014 | pmid = 24515630 | doi = 10.1002/14651858.CD009131.pub3 | pmc = 10966661 }}</ref> The effectiveness of [[Palliative care|palliative approaches]] in addition to standard care is uncertain, due to lack of evidence.<ref>{{cite journal | vauthors = Latorraca CO, Martimbianco AL, Pachito DV, Torloni MR, Pacheco RL, Pereira JG, Riera R | title = Palliative care interventions for people with multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | pages = CD012936 | date = October 2019 | issue = 10 | pmid = 31637711 | pmc = 6803560 | doi = 10.1002/14651858.CD012936.pub2 }}</ref> The effectiveness of interventions, including exercise, specifically for the prevention of falls in people with MS is uncertain, while there is some evidence of an effect on balance function and mobility.<ref>{{cite journal | vauthors = Hayes S, Galvin R, Kennedy C, Finlayson M, McGuigan C, Walsh CD, Coote S | title = Interventions for preventing falls in people with multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | pages = CD012475 | date = November 2019 | issue = 11 | pmid = 31778221 | pmc = 6953359 | doi = 10.1002/14651858.CD012475.pub2 }}</ref> [[Cognitive behavioral therapy]] has shown to be moderately effective for reducing MS fatigue.<ref>{{cite journal | vauthors = van den Akker LE, Beckerman H, Collette EH, Eijssen IC, Dekker J, de Groot V | title = Effectiveness of cognitive behavioral therapy for the treatment of fatigue in patients with multiple sclerosis: A systematic review and meta-analysis | journal = Journal of Psychosomatic Research | volume = 90 | pages = 33–42 | date = November 2016 | pmid = 27772557 | doi = 10.1016/j.jpsychores.2016.09.002 }}</ref> The evidence for the effectiveness of non-pharmacological interventions for chronic pain is insufficient to recommend such interventions alone, however their use in combination with medications may be reasonable.<ref>{{cite journal | vauthors = Amatya B, Young J, Khan F | title = Non-pharmacological interventions for chronic pain in multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | volume = 12 | pages = CD012622 | date = December 2018 | issue = 12 | pmid = 30567012 | pmc = 6516893 | doi = 10.1002/14651858.CD012622.pub2 | doi-access = free }}</ref>

=== Non-pharmaceutical ===

There is some evidence that [[aquatic therapy]] is a beneficial intervention.<ref>{{cite journal |vauthors=Corvillo I, Varela E, Armijo F, Alvarez-Badillo A, Armijo O, Maraver F |title=Efficacy of aquatic therapy for multiple sclerosis: a systematic review |journal=Eur J Phys Rehabil Med |volume=53 |issue=6 |pages=944–952 |date=December 2017 |pmid=28215060 |doi=10.23736/S1973-9087.17.04570-1 |type=Review}}</ref>

The spasticity associated with MS can be difficult to manage because of the progressive and fluctuating course of the disease.<ref>{{cite journal |vauthors=Khan F, Amatya B, Bensmail D, Yelnik A |title=Non-pharmacological interventions for spasticity in adults: An overview of systematic reviews |journal=Ann Phys Rehabil Med |volume=62 |issue=4 |pages=265–273 |date=July 2019 |pmid=29042299 |doi=10.1016/j.rehab.2017.10.001 |s2cid=207497395 |doi-access=free }}</ref> Although there is no firm conclusion on the efficacy in reducing spasticity, PT interventions can be a safe and beneficial option for patients with multiple sclerosis. Physical therapy including vibration interventions, electrical stimulation, exercise therapy, standing therapy, and radial shock wave therapy (RSWT), were beneficial for limiting spasticity, helping limit excitability, or increasing range of motion.<ref>{{cite journal |vauthors=Etoom M, Khraiwesh Y, Lena F, et al |title=Effectiveness of Physiotherapy Interventions on Spasticity in People With Multiple Sclerosis: A Systematic Review and Meta-Analysis |journal=Am J Phys Med Rehabil |volume=97 |issue=11 |pages=793–807 |date=November 2018 |pmid=29794531 |doi=10.1097/PHM.0000000000000970 |s2cid=44156766 }}</ref>

=== Alternative treatments ===
Over 50% of people with MS may use [[complementary and alternative medicine]], although percentages vary depending on how alternative medicine is defined.<ref name="pmid16420779">{{cite journal |vauthors=Huntley A |date=January 2006 |title=A review of the evidence for efficacy of complementary and alternative medicines in MS |journal=International MS Journal |volume=13 |issue=1 |pages=5–12, 4 |pmid=16420779}}</ref> Regarding the characteristics of users, they are more frequently women, have had MS for a longer time, tend to be more disabled and have lower levels of satisfaction with conventional healthcare.<ref name="pmid16420779" /> The evidence for the effectiveness for such treatments in most cases is weak or absent.<ref name="pmid16420779" /><ref name="pmid19222053">{{cite journal|vauthors=Olsen SA|year=2009|title=A review of complementary and alternative medicine (CAM) by people with multiple sclerosis|journal=Occupational Therapy International|volume=16|issue=1|pages=57–70|doi=10.1002/oti.266|pmid=19222053}}</ref> Treatments of unproven benefit used by people with MS include dietary supplementation and regimens,<ref name="pmid16420779" /><ref>{{cite journal | vauthors = Parks NE, Jackson-Tarlton CS, Vacchi L, Merdad R, Johnston BC | title = Dietary interventions for multiple sclerosis-related outcomes | journal = The Cochrane Database of Systematic Reviews | volume = 2020 | pages = CD004192 | date = May 2020 | issue = 5 | pmid = 32428983 | doi = 10.1002/14651858.CD004192.pub4 | pmc = 7388136 }}</ref><ref name="pmid21965673">{{cite journal | vauthors = Grigorian A, Araujo L, Naidu NN, Place DJ, Choudhury B, Demetriou M | title = N-acetylglucosamine inhibits T-helper 1 (Th1)/T-helper 17 (Th17) cell responses and treats experimental autoimmune encephalomyelitis | journal = The Journal of Biological Chemistry | volume = 286 | issue = 46 | pages = 40133–41 | date = November 2011 | pmid = 21965673 | pmc = 3220534 | doi = 10.1074/jbc.M111.277814 | doi-access = free }}</ref> [[vitamin D]],<ref>{{cite journal | vauthors = Pozuelo-Moyano B, Benito-León J, Mitchell AJ, Hernández-Gallego J | title = A systematic review of randomized, double-blind, placebo-controlled trials examining the clinical efficacy of vitamin D in multiple sclerosis | journal = Neuroepidemiology | volume = 40 | issue = 3 | pages = 147–53 | year = 2013 | pmid = 23257784 | pmc = 3649517 | doi = 10.1159/000345122 | type = Systematic review | quote = the available evidence substantiates neither clinically significant benefit nor harm from vitamin D in the treatment of patients with MS }}</ref> [[relaxation technique]]s such as [[yoga as exercise|yoga]],<ref name="pmid16420779" /> [[herbal medicine]] (including [[medical cannabis]]),<ref name="pmid16420779" /><ref>{{cite journal | vauthors = Chong MS, Wolff K, Wise K, Tanton C, Winstock A, Silber E | title = Cannabis use in patients with multiple sclerosis | journal = Multiple Sclerosis | volume = 12 | issue = 5 | pages = 646–51 | date = October 2006 | pmid = 17086912 | doi = 10.1177/1352458506070947 | s2cid = 34692470 }}</ref><ref>{{cite journal | vauthors = Torres-Moreno MC, Papaseit E, Torrens M, Farré M | title = Assessment of Efficacy and Tolerability of Medicinal Cannabinoids in Patients With Multiple Sclerosis: A Systematic Review and Meta-analysis | journal = JAMA Network Open | volume = 1 | issue = 6 | pages = e183485 | date = October 2018 | pmid = 30646241 | pmc = 6324456 | doi = 10.1001/jamanetworkopen.2018.3485 }}</ref> [[hyperbaric oxygen therapy]],<ref name="pmid14974004">{{cite journal | vauthors = Bennett M, Heard R | title = Hyperbaric oxygen therapy for multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD003057 | year = 2004 | volume = 2011 | pmid = 14974004 | doi = 10.1002/14651858.CD003057.pub2 | veditors = Bennett MH | pmc = 8407327 }}</ref> [[helminthic therapy|self-infection with hookworms]], [[reflexology]], [[acupuncture]],<ref name="pmid16420779" /><ref>{{cite news | vauthors = Adams T | title=Gut instinct: the miracle of the parasitic hookworm | url=https://www.theguardian.com/lifeandstyle/2010/may/23/parasitic-hookworm-jasper-lawrence-tim-adams | newspaper=The Observer | date=23 May 2010 | url-status=live | archive-url= https://web.archive.org/web/20141024051021/http://www.theguardian.com/lifeandstyle/2010/may/23/parasitic-hookworm-jasper-lawrence-tim-adams | archive-date=24 October 2014 | df=dmy-all }}</ref> and [[mindfulness]].<ref>{{cite journal | vauthors = Simpson R, Booth J, Lawrence M, Byrne S, Mair F, Mercer S | title = Mindfulness based interventions in multiple sclerosis—a systematic review | journal = BMC Neurology | volume = 14 | pages = 15 | date = January 2014 | pmid = 24438384 | pmc = 3900731 | doi = 10.1186/1471-2377-14-15 | doi-access = free }}</ref> Evidence suggests vitamin D supplementation, irrespective of the form and dose, provides no benefit for people with MS; this includes for measures such as relapse recurrence, disability, and MRI lesions while effects on health‐related quality of life and fatigue are unclear.<ref>{{cite journal | vauthors = Jagannath VA, Filippini G, Di Pietrantonj C, Asokan GV, Robak EW, Whamond L, Robinson SA | title = Vitamin D for the management of multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | volume = 9 | issue = 9 | pages = CD008422 | date = September 2018 | pmid = 30246874 | pmc = 6513642 | doi = 10.1002/14651858.CD008422.pub3 }}</ref> There is insufficient evidence supporting high-dose [[biotin]]<ref name=Motte2020>{{cite journal |vauthors=Motte J, Gold R |title=High-dose biotin in multiple sclerosis: the end of the road |journal=Lancet Neurol |volume=19 |issue=12 |pages=965–966 |date=December 2020 |pmid=33222766 |doi=10.1016/S1474-4422(20)30353-7 |s2cid=225049079 }}</ref><ref>{{cite journal |vauthors=Tryfonos C, Mantzorou M, Fotiou D, Vrizas M, Vadikolias K, Pavlidou E, Giaginis C |title=Dietary Supplements on Controlling Multiple Sclerosis Symptoms and Relapses: Current Clinical Evidence and Future Perspectives |journal=Medicines  |volume=6 |issue=3 |date=September 2019 |page=95 |pmid=31547410 |pmc=6789617 |doi=10.3390/medicines6030095 |doi-access=free }}</ref><ref>{{cite journal |vauthors=Sedel F, Bernard D, Mock DM, Tourbah A |title=Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis |journal=Neuropharmacology |volume=110 |issue=Pt B |pages=644–653 |date=November 2016 |pmid=26327679 |doi=10.1016/j.neuropharm.2015.08.028 |doi-access=free }}</ref> and some evidence for increased disease activity and higher risk of relapse with its use.<ref name=Goldschmidt2020>{{cite journal |vauthors=Goldschmidt CH, Cohen JA |title=The Rise and Fall of High-Dose Biotin to Treat Progressive Multiple Sclerosis |journal=Neurotherapeutics |volume=17 |issue=3 |pages=968–970 |date=July 2020 |pmid=32761325 |doi=10.1007/s13311-020-00907-5 |pmc=7609671 |doi-access=free }}</ref> A 2022 review found that [[nabiximols]] ([[tetrahydrocannabinol]] and [[cannabidiol]]) can reduce the severity of spasticity in the short term, but may have unwanted neurological effects.<ref>{{cite journal | vauthors = Filippini G, Minozzi S, Borrelli F, Cinquini M, Dwan K | title = Cannabis and cannabinoids for symptomatic treatment for people with multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | volume = 5 | issue = 5 | pages = CD013444 | date = May 2022 | pmid = 35510826 | pmc = 9069991 | doi = 10.1002/14651858.CD013444.pub2 }}</ref>

== Prognosis ==
The availability of treatments that modify the course of multiple sclerosis beginning in the 1990s, known as disease-modifying therapies (DMTs), has improved prognosis. These treatments can reduce relapses and slow progression, but there is no cure.<ref name=McGinley2021/><ref name=Cree2022>{{cite journal |vauthors=Cree BA, Hartung HP, Barnett M |title=New drugs for multiple sclerosis: new treatment algorithms |journal=Curr Opin Neurol |volume=35 |issue=3 |pages=262–270 |date=June 2022 |pmid=35674067 |doi=10.1097/WCO.0000000000001063 |s2cid=249438715 |url=|doi-access=free }}</ref>

The prognosis of MS depends on the subtype of the disease, and there is considerable individual variation in the progression of the disease.<ref name=Oh2018/> In relapsing MS, the most common subtype, a 2016 cohort study found that after a median of 16.8 years from onset, one in ten needed a walking aid, and almost two in ten transitioned to secondary progressive MS, a form characterized by more progressive decline.<ref name=McGinley2021/> With treatments available in the 2020s, relapses can be eliminated or substantially reduced. However, "silent progression" of the disease still occurs.<ref name=Cree2022/><ref>{{cite journal |vauthors=Hauser SL, Cree BA |title=Treatment of Multiple Sclerosis: A Review |journal=Am J Med |volume=133 |issue=12 |pages=1380–1390.e2 |date=December 2020 |pmid=32682869 |doi=10.1016/j.amjmed.2020.05.049 |pmc=7704606 |url=}}</ref>

In addition to secondary progressive MS (SPMS), a small proportion of people with MS (10–15%) experience progressive decline from the onset, known as primary progressive MS (PPMS). Most treatments have been approved for use in relapsing MS; there are fewer treatments with lower efficacy for progressive forms of MS.<ref name="Continuum">{{cite journal |vauthors=Ontaneda D |title=Progressive Multiple Sclerosis |journal=Continuum |volume=25 |issue=3 |pages=736–752 |date=June 2019 |pmid=31162314 |doi=10.1212/CON.0000000000000727 |s2cid=174808956 |url=}}</ref><ref name=Cree2022/><ref name="McGinley2021" /> The prognosis for progressive MS is worse, with faster accumulation of disability, though with considerable individual variation.<ref name=Continuum/> In untreated PPMS, the median time from onset to requiring a walking aid is estimated as seven years.<ref name=McGinley2021/> In SPMS, a 2014 cohort study reported that people required a walking aid after an average of five years from the onset of SPMS, and were chair or bed-bound after an average of fifteen years.<ref>{{cite journal |vauthors=Inojosa H, Proschmann U, Akgün K, Ziemssen T |title=A focus on secondary progressive multiple sclerosis (SPMS): challenges in diagnosis and definition |journal=J Neurol |volume=268 |issue=4 |pages=1210–1221 |date=April 2021 |pmid=31363847 |doi=10.1007/s00415-019-09489-5 |s2cid=198999832 |url=}} [[Expanded Disability Status Scale]] (EDSS) 6.0 is equivalent to requiring a walking aid, and EDSS 8.0 equivalent to chair or bedbound</ref>

After diagnosis of MS, characteristics that predict a worse course are male sex, older age, and greater disability at the time of diagnosis; female sex is associated with a higher relapse rate.<ref name=lancet2018>{{cite journal |vauthors=Thompson AJ, Baranzini SE, Geurts J, Hemmer B, Ciccarelli O |title=Multiple sclerosis |journal=Lancet |volume=391 |issue=10130 |pages=1622–1636 |date=April 2018 |pmid=29576504 |doi=10.1016/S0140-6736(18)30481-1 |s2cid=4313310 }}</ref> Currently, no biomarker can accurately predict disease progression in every patient.<ref name=Oh2018/> Spinal cord lesions, abnormalities on MRI, and more [[Cerebral atrophy|brain atrophy]] are predictive of a worse course, though brain atrophy as a predictor of disease course is experimental and not used in clinical practice.<ref name="lancet2018" /> Early treatment leads to a better prognosis, but a higher relapse frequency when treated with DMTs is associated with a poorer prognosis.<ref name=Oh2018/><ref name=lancet2018/> A 60-year longitudinal population study conducted in Norway found that those with MS had a [[life expectancy]] seven years shorter than the general population. Median life expectancy for RRMS patients was 77.8 years and 71.4 years for PPMS, compared to 81.8 years for the general population. Life expectancy for men was five years shorter than for women.<ref>{{cite journal | vauthors = Lunde HM, Assmus J, Myhr KM, Bø L, Grytten N | title = Survival and cause of death in multiple sclerosis: a 60-year longitudinal population study | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 88 | issue = 8 | pages = 621–625 | date = August 2017 | pmid = 28365589 | pmc = 5537547 | doi = 10.1136/jnnp-2016-315238 }}</ref>

== Epidemiology ==
{{Update|section|date=July 2022}}
[[File:Multiple sclerosis world map-Deaths per million persons-WHO2012.svg|thumb|left|upright=1.3|Deaths from multiple sclerosis per million persons in 2012 {{Div col|small=yes|colwidth=10em}}{{legend|#ffff20|0}}{{legend|#ffc020|1}}{{legend|#f08015|2}}{{legend|#e06815|3–5}}{{legend|#d85010|6–12}}{{legend|#d02010|13–25}}{{div col end}}]]

MS is the most common autoimmune disorder of the central nervous system.<ref name="pmid24746689" /> The latest estimation of the total number of people with MS was 2.8&nbsp;million globally, with a [[prevalence]] of 36 per 100,000 people. Moreover, prevalence varies widely in different regions around the world.<ref name="Lane2022" /> In Africa, there are five people per 100,000 diagnosed with MS, compared to South East Asia where the prevalence is nine per 100,000, 112 per 100,000 in the Americas, and 133 per 100,000 in Europe.<ref>{{Cite web | work = Multiple Sclerosis International Federation |date=September 2020 |title=Atlas of MS |url=https://www.msif.org/wp-content/uploads/2020/12/Atlas-3rd-Edition-Epidemiology-report-EN-updated-30-9-20.pdf}}</ref> Nearly one million people in the United States had MS in 2022.<ref name="McGinley2021">{{cite journal |vauthors=McGinley MP, Goldschmidt CH, Rae-Grant AD |title=Diagnosis and Treatment of Multiple Sclerosis: A Review |journal=JAMA |volume=325 |issue=8 |pages=765–779 |date=February 2021 |pmid=33620411 |doi=10.1001/jama.2020.26858|s2cid=232019589 }}</ref>

Increasing rates of MS may be explained simply by better diagnosis.<ref name=Milo2010 /> Studies on populational and [[#Geography|geographical patterns]] have been common<ref name="pmid8269393">{{cite journal | vauthors = Kurtzke JF | title = Epidemiologic evidence for multiple sclerosis as an infection | journal = Clinical Microbiology Reviews | volume = 6 | issue = 4 | pages = 382–427 | date = October 1993 | pmid = 8269393 | pmc = 358295 | doi = 10.1128/CMR.6.4.382 }}</ref> and have led to a number of theories about the cause.<ref name="Ascherio_2007"/><ref name="pmid15556803">{{cite journal | vauthors = Marrie RA | title = Environmental risk factors in multiple sclerosis aetiology | journal = The Lancet. Neurology | volume = 3 | issue = 12 | pages = 709–18 | date = December 2004 | pmid = 15556803 | doi = 10.1016/S1474-4422(04)00933-0 | s2cid = 175786 }}</ref><ref name="pmid17492755">{{cite journal | vauthors = Ascherio A, Munger KL | title = Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors | journal = Annals of Neurology | volume = 61 | issue = 6 | pages = 504–13 | date = June 2007 | pmid = 17492755 | doi = 10.1002/ana.21141 | s2cid = 36999504 | doi-access = free }}</ref>

MS usually appears in adults in their late twenties or early thirties but it can rarely start in childhood and after 50 years of age.<ref name=Milo2010 /><ref name=Atlas2008 /> The primary progressive subtype is more common in people in their fifties.<ref name="pmid17884680" /> Similarly to many autoimmune disorders, the disease is more common in women, and the trend may be increasing.<ref name="pmid1897097722"/><ref name="pmid18606967">{{cite journal | vauthors = Alonso A, Hernán MA | title = Temporal trends in the incidence of multiple sclerosis: a systematic review | journal = Neurology | volume = 71 | issue = 2 | pages = 129–135 | date = July 2008 | pmid = 18606967 | pmc = 4109189 | doi = 10.1212/01.wnl.0000316802.35974.34 }}</ref> As of 2020, globally it is about two times more common in women than in men, and the ratio of women to men with MS is as high as 4:1 in some countries.<ref>{{cite journal | vauthors = Walton C, King R, Rechtman L, Kaye W, Leray E, Marrie RA, Robertson N, La Rocca N, Uitdehaag B, van der Mei I, Wallin M, Helme A, Angood Napier C, Rijke N, Baneke P | title = Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition | journal = Multiple Sclerosis | volume = 26 | issue = 14 | pages = 1816–1821 | date = December 2020 | pmid = 33174475 | pmc = 7720355 | doi = 10.1177/1352458520970841 }}</ref> In children, it is even more common in females than males,<ref name="pmid1897097722"/> while in people over fifty, it affects males and females almost equally.<ref name="pmid17884680" />

== History ==
=== Medical discovery ===
[[File:Carswell-Multiple Sclerosis2.jpg|thumb|Detail of Carswell's drawing of MS lesions in the [[brain stem]] and [[spinal cord]] (1838)]]
[[Robert Carswell (pathologist)|Robert Carswell]] (1793–1857), a British professor of [[pathology]], and [[Jean Cruveilhier]] (1791–1873), a French professor of pathologic anatomy, described and illustrated many of the disease's clinical details, but did not identify it as a separate disease.<ref name="pmid3066846">{{cite journal | vauthors = Compston A | title = The 150th anniversary of the first depiction of the lesions of multiple sclerosis | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 51 | issue = 10 | pages = 1249–52 | date = October 1988 | pmid = 3066846 | pmc = 1032909 | doi = 10.1136/jnnp.51.10.1249 }}</ref> Specifically, Carswell described the injuries he found as "a remarkable lesion of the spinal cord accompanied with atrophy".<ref name="pmid1897097722"/> Under the microscope, Swiss pathologist [[Georg Eduard Rindfleisch]] (1836–1908) noted in 1863 that the inflammation-associated lesions were distributed around blood vessels.<ref name="pmid10603616">{{cite journal | vauthors = Lassmann H | title = The pathology of multiple sclerosis and its evolution | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 354 | issue = 1390 | pages = 1635–40 | date = October 1999 | pmid = 10603616 | pmc = 1692680 | doi = 10.1098/rstb.1999.0508 }}</ref><ref>{{cite journal | vauthors = Lassmann H | title = Multiple sclerosis pathology: evolution of pathogenetic concepts | journal = Brain Pathology | volume = 15 | issue = 3 | pages = 217–22 | date = July 2005 | pmid = 16196388 | doi = 10.1111/j.1750-3639.2005.tb00523.x | s2cid = 8342303 | pmc = 8095927 }}</ref>

The French [[neurologist]] [[Jean-Martin Charcot]] (1825–1893) was the first person to recognize multiple sclerosis as a distinct disease in 1868.<ref name="pmid3066846" /> Summarizing previous reports and adding his own clinical and pathological observations, Charcot called the disease ''sclerose en plaques''.

=== Diagnosis history ===
The first attempt to establish a set of diagnostic criteria was also due to Charcot in 1868. He published what now is known as the "[[Charcot's neurologic triad|Charcot triad]]", consisting of nystagmus, [[intention tremor]], and [[telegraphic speech]] (scanning speech).<ref name="Milo">{{cite journal | vauthors = Milo R, Miller A | title = Revised diagnostic criteria of multiple sclerosis | journal = Autoimmunity Reviews | volume = 13 | issue = 4–5 | pages = 518–524 | date = April 2014 | pmid = 24424194 | doi = 10.1016/j.autrev.2014.01.012 }}</ref> Charcot also observed cognition changes, describing his patients as having a "marked enfeeblement of the memory" and "conceptions that formed slowly".<ref name="Charcot1" />

The diagnosis was based on Charcot triad and clinical observation until Schumacher made the first attempt to standardize criteria in 1965 by introducing some fundamental requirements: Dissemination of the lesions in time (DIT) and space (DIS), and that "signs and symptoms cannot be explained better by another disease process".<ref name="Milo" /> The DIT and DIS requirement was later inherited by the Poser and McDonald criteria, whose 2017 revision is in use.<ref name="Milo" /><ref name=Oh2018>{{cite journal |vauthors=Oh J, Vidal-Jordana A, Montalban X |title=Multiple sclerosis: clinical aspects |journal=Curr Opin Neurol |volume=31 |issue=6 |pages=752–759 |date=December 2018 |pmid=30300239 |doi=10.1097/WCO.0000000000000622 |url=https://repositorio.ufms.br/handle/123456789/4900 |archive-date=25 November 2024 |access-date=2 June 2024 |archive-url=https://web.archive.org/web/20241125061549/https://repositorio.ufms.br/handle/123456789/4900 |url-status=live }}</ref>

During the 20th century, theories about the cause and pathogenesis were developed and effective treatments began to appear in the 1990s.<ref name="pmid1897097722"/> Since the beginning of the 21st century, refinements of the concepts have taken place.  The 2010 revision of the McDonald criteria allowed for the diagnosis of MS with only one proved lesion (CIS).<ref name=mcdonald2010>{{cite journal | vauthors = Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O'Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS | title = Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria | journal = Annals of Neurology | volume = 69 | issue = 2 | pages = 292–302 | date = February 2011 | pmid = 21387374 | pmc = 3084507 | doi = 10.1002/ana.22366 }}</ref>

In 1996, the US National Multiple Sclerosis Society (NMSS) (Advisory Committee on Clinical Trials) defined the first version of the clinical phenotypes that is in use. In this first version, they provided standardized definitions for four MS clinical courses: relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP), and progressive relapsing (PR). In 2010, PR was dropped and CIS was incorporated.<ref name=mcdonald2010 /> Three years later, the 2013 revision of the "phenotypes for the disease course" were forced to consider CIS as one of the phenotypes of MS, making obsolete some expressions like "conversion from CIS to MS".<ref>{{cite journal | vauthors = Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ, Wolinsky JS, Balcer LJ, Banwell B, Barkhof F, Bebo B, Calabresi PA, Clanet M, Comi G, Fox RJ, Freedman MS, Goodman AD, Inglese M, Kappos L, Kieseier BC, Lincoln JA, Lubetzki C, Miller AE, Montalban X, O'Connor PW, Petkau J, Pozzilli C, Rudick RA, Sormani MP, Stüve O, Waubant E, Polman CH | title = Defining the clinical course of multiple sclerosis: the 2013 revisions | journal = Neurology | volume = 83 | issue = 3 | pages = 278–86 | date = July 2014 | pmid = 24871874 | pmc = 4117366 | doi = 10.1212/WNL.0000000000000560 }}</ref> Other organizations have proposed later new clinical phenotypes, like HAMS (Highly Active MS).<ref>{{cite journal | vauthors = Sørensen PS, Centonze D, Giovannoni G, Montalban X, Selchen D, Vermersch P, Wiendl H, Yamout B, Salloukh H, Rieckmann P | title = Expert opinion on the use of cladribine tablets in clinical practice | journal = Therapeutic Advances in Neurological Disorders | volume = 13 | pages = 1756286420935019 | date = 24 June 2020 | pmid = 32636933 | doi = 10.1177/1756286420935019 | pmc = 7318823 | doi-access = free }}</ref>

=== Historical cases ===
[[File:Animal locomotion. Plate 541 (Boston Public Library).jpg|thumb|Photographic study of locomotion of a woman with MS with walking difficulties created in 1887 by [[Muybridge]]]]

There are several historical accounts of people who probably had MS and lived before or shortly after the disease was described by Charcot.

A young woman called Halldora who lived in [[Iceland]] around 1200 suddenly lost her vision and mobility but recovered them seven days after. [[Saint Lidwina]] of [[Schiedam]] (1380–1433), a Dutch [[nun]], may be one of the first clearly identifiable people with MS. From the age of 16 until her death at 53, she had intermittent pain, weakness of the legs and vision loss: symptoms typical of MS.<ref name="pmid390966">{{cite journal | vauthors = Medaer R | title = Does the history of multiple sclerosis go back as far as the 14th century? | journal = Acta Neurologica Scandinavica | volume = 60 | issue = 3 | pages = 189–92 | date = September 1979 | pmid = 390966 | doi = 10.1111/j.1600-0447.1979.tb08970.x | s2cid = 221422840 }}</ref> Both cases have led to the proposal of a "Viking gene" hypothesis for the dissemination of the disease.<ref name="pmid16479124">{{cite journal | vauthors = Holmøy T | title = A Norse contribution to the history of neurological diseases | journal = European Neurology | volume = 55 | issue = 1 | pages = 57–8 | year = 2006 | pmid = 16479124 | doi = 10.1159/000091431 | doi-access = free }}</ref>

[[Augustus d'Este|Augustus Frederick d'Este]] (1794–1848), son of [[Prince Augustus Frederick, Duke of Sussex]] and [[Lady Augusta Murray]] and a grandson of [[George&nbsp;III of the United Kingdom]], almost certainly had MS. D'Este left a detailed diary describing his 22 years living with the disease. His diary began in 1822 and ended in 1846, although it remained unknown until 1948. His symptoms began at age 28 with a sudden transient visual loss ([[amaurosis fugax]]) after the funeral of a friend. During his disease, he developed weakness in the legs, clumsiness of the hands, numbness, dizziness, bladder disturbance and [[erectile dysfunction]]. In 1844, he began to use a wheelchair. Despite his illness, he kept an optimistic view of life.<ref>{{cite book| vauthors = Firth D |title= The Case of August D'Esté |year=1948|publisher=Cambridge University Press|location=Cambridge}}</ref><ref name="pmid16103678">{{cite journal | vauthors = Pearce JM | title = Historical descriptions of multiple sclerosis | journal = European Neurology | volume = 54 | issue = 1 | pages = 49–53 | year = 2005 | pmid = 16103678 | doi = 10.1159/000087387 | doi-access = free }}</ref> Another early account of MS was kept by the British diarist [[W. N. P. Barbellion]], pen name of Bruce Frederick Cummings (1889–1919), who maintained a detailed log of his diagnosis and struggle.<ref name="pmid16103678" /> His diary was published in 1919 as ''[[The Journal of a Disappointed Man]]''.<ref>{{cite book| vauthors = Barbellion WN |title= The Journal of a Disappointed Man |url= https://archive.org/details/journaladisappo00wellgoog|year=1919|publisher=George H. Doran|location=New York|isbn= 0-7012-1906-8}}</ref> [[Charles Dickens]], a keen observer, described possible bilateral [[optic neuritis]] with reduced contrast vision and [[Uhthoff's phenomenon]] in the main female character of ''[[Bleak House]]'' (1852–1853), Esther Summerson.<ref>{{cite journal | vauthors = Petzold A | title = Optic Neuritis: Another Dickensian Diagnosis | journal = Neuro-Ophthalmology | volume = 37 | issue = 6 | pages = 247–250 | date = 2013 | pmid = 28167994 | pmc = 5291069 | doi = 10.3109/01658107.2013.830313 }}</ref>

== Research ==
{{Main|Research in multiple sclerosis}}

=== Epstein-Barr virus ===
As of 2022, the pathogenesis of MS, as it relates to [[Epstein–Barr virus|Epstein-Barr virus (EBV)]], is actively investigated, as are disease-modifying therapies; understanding of how risk factors combine with EBV to initiate MS is sought. Whether EBV is the only cause of MS might be better understood if an [[Epstein–Barr virus vaccine|EBV vaccine]] is developed and shown to prevent MS as well.<ref name="Aloisi20222"/>

Even though a variety of studies showed the connection between an EBV infection and a later development of multiple sclerosis, the mechanisms behind this correlation are not completely clear, and several theories have been proposed to explain the relationship between the two diseases. It is thought that the involvement of EBV-infected [[B cell|B-cells]] (B lymphocytes)<ref>{{cite journal | vauthors = Bar-Or A, Pender MP, Khanna R, Steinman L, Hartung HP, Maniar T, Croze E, Aftab BT, Giovannoni G, Joshi MA | title = Epstein-Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies | journal = Trends in Molecular Medicine | volume = 26 | issue = 3 | pages = 296–310 | date = March 2020 | pmid = 31862243 | pmc = 7106557 | doi = 10.1016/j.molmed.2019.11.003 }}</ref> and the involvement of anti-[[EBNA]] antibodies, which appear to be significantly higher in multiple sclerosis patients, play a crucial role in the development of the disease.<ref>{{cite journal | vauthors = DeLorenze GN, Munger KL, Lennette ET, Orentreich N, Vogelman JH, Ascherio A | title = Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up | journal = Archives of Neurology | volume = 63 | issue = 6 | pages = 839–844 | date = June 2006 | pmid = 16606758 | doi = 10.1001/archneur.63.6.noc50328 | doi-access = free }}</ref> This is supported by the fact that treatment against B-cells, e.g. [[ocrelizumab]], reduces the symptoms of multiple sclerosis: annual relapses appear less frequently and the disability progression is slower.<ref>{{cite journal | vauthors = Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Montalban X, Rammohan KW, Selmaj K, Traboulsee A, Wolinsky JS, Arnold DL, Klingelschmitt G, Masterman D, Fontoura P, Belachew S, Chin P, Mairon N, Garren H, Kappos L | title = Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis | journal = The New England Journal of Medicine | volume = 376 | issue = 3 | pages = 221–234 | date = January 2017 | pmid = 28002679 | doi = 10.1056/NEJMoa1601277 | s2cid = 205099904 | hdl = 2445/178507 | hdl-access = free }}</ref> A 2022 [[Stanford University]] study has shown that during an EBV infection, molecular mimicry can occur, where the immune system will produce antibodies against the [[EBNA]]1 protein, which at the same time is able to bind to GlialCAM in the myelin. Additionally, they observed a phenomenon which is uncommon in healthy individuals but often detected in multiple sclerosis patients – B-cells are trafficking to the brain and spinal cord, where they are producing oligoclonal antibody bands. A majority of these oligoclonal bands do have an affinity to the viral protein EBNA1, which is cross-reactive to GlialCAM. These antibodies are abundant in approximately 20–25% of multiple sclerosis patients and worsen the autoimmune demyelination which leads consequently to a pathophysiological exacerbation of the disease. Furthermore, the intrathecal oligoclonal expansion with a constant somatic hypermutation is unique in multiple sclerosis when compared to other neuroinflammatory diseases. In the study, there was also the abundance of antibodies with IGHV 3–7 genes measured, which appears to be connected to the disease progress. Antibodies which are IGHV3–7-based are binding with a high affinity to EBNA1 and GlialCAM. This process is actively thriving the demyelination. It is probable that B-cells, expressing IGHV 3–7 genes entered the CSF and underwent affinity maturation after facing GlialCAM, which led consequently to the production of high-affinity anti-GlialCAM antibodies. This was additionally shown in the EAE mouse model where immunization with EBNA1 lead to a strong B-cell response against GlialCAM, which worsened the EAE.<ref>{{cite journal | vauthors = Lanz TV, Brewer RC, Ho PP, Moon JS, Jude KM, Fernandez D, Fernandes RA, Gomez AM, Nadj GS, Bartley CM, Schubert RD, Hawes IA, Vazquez SE, Iyer M, Zuchero JB, Teegen B, Dunn JE, Lock CB, Kipp LB, Cotham VC, Ueberheide BM, Aftab BT, Anderson MS, DeRisi JL, Wilson MR, Bashford-Rogers RJ, Platten M, Garcia KC, Steinman L, Robinson WH | title = Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM | journal = Nature | volume = 603 | issue = 7900 | pages = 321–327 | date = March 2022 | pmid = 35073561 | pmc = 9382663 | doi = 10.1038/s41586-022-04432-7 | bibcode = 2022Natur.603..321L }}</ref>

=== Human endogenous retroviruses ===
Two members of the human endogenous retroviruses-W ([[HERV]]-W) family, namely, ERVWE1 and MS-associated retrovirus (MSRV), may be co-factors in MS immunopathogenesis. HERVs constitute up to 8% of the human genome; most are epigenetically silent, but can be reactivated by exogenous viruses, proinflammatory conditions or oxidative stress.<ref>{{cite journal | vauthors = Morandi E, Tanasescu R, Tarlinton RE, Constantinescu CS, Zhang W, Tench C, Gran B | title = The association between human endogenous retroviruses and multiple sclerosis: A systematic review and meta-analysis | journal = PLOS ONE | volume = 12 | issue = 2 | pages = e0172415 | date = 2017-02-16 | pmid = 28207850 | pmc = 5313176 | doi = 10.1371/journal.pone.0172415 | bibcode = 2017PLoSO..1272415M | veditors = Ruprecht K | doi-access = free }}</ref><ref>{{Cite journal |vauthors=Li Y, Fan T, Cui J |date=March 2022 |title=Human endogenous retroviruses in viral disease and therapy |journal=Clinical and Translational Discovery |language=en |volume=2 |issue=1 |doi=10.1002/ctd2.38 |s2cid=247750447 |doi-access=free }}</ref><ref>{{cite journal | vauthors = Rangel SC, da Silva MD, da Silva AL, Dos Santos JM, Neves LM, Pedrosa A, Rodrigues FM, Trettel CD, Furtado GE, de Barros MP, Bachi AL, Romano CM, Nali LH | title = Human endogenous retroviruses and the inflammatory response: A vicious circle associated with health and illness | journal = Frontiers in Immunology | volume = 13 | pages = 1057791 | date = 2022-11-23 | pmid = 36518758 | pmc = 9744114 | doi = 10.3389/fimmu.2022.1057791 | doi-access = free }}</ref>

=== Medications ===
Medications that influence voltage-gated sodium ion channels are under investigation as a potential neuroprotective strategy because of hypothesized role of sodium in the pathological process leading to axonal injury and accumulating disability. There is insufficient evidence of an effect of sodium channel blockers for people with MS.<ref>{{cite journal | vauthors = Yang C, Hao Z, Zhang L, Zeng L, Wen J | title = Sodium channel blockers for neuroprotection in multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | issue = 10 | pages = CD010422 | date = October 2015 | volume = 2015 | pmid = 26486929 | doi = 10.1002/14651858.CD010422.pub2 | pmc = 9242538 }}</ref>

=== Pathogenesis ===
MS is a clinically defined entity with several atypical presentations. Some auto-antibodies have been found in atypical MS cases, giving birth to separate disease families and restricting the previously wider concept of MS.

[[Aquaporin 4|Anti-AQP4 autoantibodies]] were found in [[neuromyelitis optica]] (NMO), which was previously considered a MS variant. A spectrum of diseases named NMOSD (NMO spectrum diseases) or anti-AQP4 diseases has been accepted.<ref name="Misu">{{cite journal | vauthors = Misu T, Fujihara K | title = Neuromyelitis optica spectrum and myelin oligodendrocyte glycoprotein antibody-related disseminated encephalomyelitis. | journal = Clinical and Experimental Neuroimmunology | date = February 2019 | volume = 10 | issue = 1 | pages= 9–17 | doi = 10.1111/cen3.12491 | doi-access = free }}</ref> Some cases of MS were presenting [[myelin oligodendrocyte glycoprotein|anti-MOG autoantibodies]], mainly overlapping with the Marburg variant. Anti-MOG autoantibodies were found to be also present in ADEM, and a second spectrum of separated diseases is being considered. This spectrum is named inconsistently across different authors, but it is normally something similar to [[Anti-MOG associated encephalomyelitis|anti-MOG demyelinating diseases]].<ref name="Misu" />

A third kind of auto-antibodies is accepted. There are several [[neurofascin|anti-neurofascin]] auto-antibodies that damage the Ranvier nodes of the neurons. These antibodies are more related to the peripheral nervous demyelination, but they were also found in chronic progressive PPMS and [[combined central and peripheral demyelination]] (CCPD, which is considered another atypical MS presentation).<ref name="Kira">{{cite journal | vauthors = Kira JI, Yamasaki R, Ogata H | title = Anti-neurofascin autoantibody and demyelination | journal = Neurochemistry International | volume = 130| pages = 104360| pmid = 30582947 | doi = 10.1016/j.neuint.2018.12.011 | year = 2019 | doi-access = free }}</ref>

In addition to the significance of auto-antibodies in MS, four different patterns of demyelination have been reported, opening the door to consider MS as a [[heterogeneous disease]].<ref name="pmid23917093">{{cite journal | vauthors = Popescu BF, Pirko I, Lucchinetti CF | title = Pathology of multiple sclerosis: where do we stand? | journal = Continuum | volume = 19 | issue = 4 Multiple Sclerosis | pages = 901–21 | date = August 2013 | pmid = 23917093 | pmc = 3915566 | doi = 10.1212/01.CON.0000433291.23091.65 }}</ref>

=== Biomarkers ===
{{Main|Biomarkers of multiple sclerosis}}
[[File:Journal.pone.0057573.g005 cropped.png|thumb|upright|[[Magnetic resonance imaging|MRI]] brain scan produced using a ''Gradient-echo phase sequence'' showing an iron deposit in a white matter lesion (inside green box in the middle of the image; enhanced and marked by red arrow top-left corner)<ref name="pmid23516409">{{cite journal | vauthors = Mehta V, Pei W, Yang G, Li S, Swamy E, Boster A, Schmalbrock P, Pitt D | title = Iron is a sensitive biomarker for inflammation in multiple sclerosis lesions | journal = PLOS ONE | volume = 8 | issue = 3 | pages = e57573 | year = 2013 | pmid = 23516409 | pmc = 3597727 | doi = 10.1371/journal.pone.0057573 | bibcode = 2013PLoSO...857573M | doi-access = free }}</ref>]]

Since disease progression is the result of degeneration of neurons, the roles of proteins showing loss of nerve tissue such as [[neurofilament]]s, [[Tau protein|tau]], and [[N-acetylaspartate]] are under investigation.<ref>{{cite journal | vauthors = Khalil M, Teunissen CE, Otto M, Piehl F, Sormani MP, Gattringer T, Barro C, Kappos L, Comabella M, Fazekas F, Petzold A, Blennow K, Zetterberg H, Kuhle J | title = Neurofilaments as biomarkers in neurological disorders | journal = Nature Reviews. Neurology | volume = 14 | issue = 10 | pages = 577–589 | date = October 2018 | pmid = 30171200 | doi = 10.1038/s41582-018-0058-z | url = https://discovery.ucl.ac.uk/id/eprint/10057189/ }}</ref><ref>{{cite journal | vauthors = Petzold A | title = Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss | journal = Journal of the Neurological Sciences | volume = 233 | issue = 1–2 | pages = 183–98 | date = June 2005 | pmid = 15896809 | doi = 10.1016/j.jns.2005.03.015 | url = https://discovery.ucl.ac.uk/id/eprint/18928/ }}</ref>

Improvement in neuroimaging techniques such as [[positron emission tomography]] (PET) or MRI carry a promise for better diagnosis and prognosis predictions. Regarding MRI, there are several techniques that have already shown some usefulness in research settings and could be introduced into clinical practice, such as double-inversion recovery sequences, [[magnetization transfer]], [[Diffusion MRI#Diffusion tensor imaging|diffusion tensor]], and [[functional magnetic resonance imaging]].<ref name="pmid22159052">{{cite journal | vauthors = Filippi M, Rocca MA, De Stefano N, Enzinger C, Fisher E, Horsfield MA, Inglese M, Pelletier D, Comi G | title = Magnetic resonance techniques in multiple sclerosis: the present and the future | journal = Archives of Neurology | volume = 68 | issue = 12 | pages = 1514–20 | date = December 2011 | pmid = 22159052 | doi = 10.1001/archneurol.2011.914 | doi-access = free }}</ref> These techniques are more specific for the disease than existing ones, but still lack some standardization of acquisition protocols and the creation of normative values.<ref name="pmid22159052" /> This is particularly the case for [[proton magnetic resonance spectroscopy]], for which a number of methodological variations observed in the literature may underlie continued inconsistencies in central nervous system metabolic abnormalities, particularly in [[N-acetyl aspartate]], [[myoinositol]], [[choline]], [[Glutamate (neurotransmitter)|glutamate]], [[GABA]], and [[Glutathione|GSH]], observed for multiple sclerosis and its subtypes.<ref>{{cite journal | vauthors = Swanberg KM, Landheer K, Pitt D, Juchem C | title = Quantifying the Metabolic Signature of Multiple Sclerosis by ''in vivo'' Proton Magnetic Resonance Spectroscopy: Current Challenges and Future Outlook in the Translation From Proton Signal to Diagnostic Biomarker | language = English | journal = Frontiers in Neurology | volume = 10 | pages = 1173 |year = 2019 | pmid = 31803127 | pmc = 6876616 | doi = 10.3389/fneur.2019.01173 | doi-access = free }}</ref> There are other techniques under development that include contrast agents capable of measuring levels of peripheral [[macrophage]]s, inflammation, or neuronal dysfunction,<ref name="pmid22159052" /> and techniques that measure iron deposition that could serve to determine the role of this feature in MS, or that of cerebral perfusion.<ref name="pmid22159052" />

=== COVID-19 ===
The hospitalization rate was found to be higher among individuals with MS and COVID-19 infection, at 10%, while the pooled infection rate is estimated at 4%. The pooled prevalence of death in hospitalized individuals with MS is estimated as 4%.<ref>{{cite journal |vauthors=Moghadasi AN, Mirmosayyeb O, Barzegar M, Sahraian MA, Ghajarzadeh M |title=The prevalence of COVID-19 infection in patients with multiple sclerosis (MS): a systematic review and meta-analysis |journal=Neurol Sci |volume=42 |issue=8 |pages=3093–3099 |date=August 2021 |pmid=34100130 |pmc=8184129 |doi=10.1007/s10072-021-05373-1 }}</ref>

=== Metformin ===
A 2019 study on rats and a 2024 study on mice showed that a first-line medication for the treatment of [[type 2 diabetes]], [[metformin]], could promote [[remyelination]].<ref>{{cite journal | vauthors = Neumann B, Baror R, Zhao C, Segel M, Dietmann S, Rawji KS, Foerster S, McClain CR, Chalut K, van Wijngaarden P, Franklin RJ | title = Metformin Restores CNS Remyelination Capacity by Rejuvenating Aged Stem Cells | journal = Cell Stem Cell | volume = 25 | issue = 4 | pages = 473–485.e8 | date = October 2019 | pmid = 31585093 | pmc = 6863391 | doi = 10.1016/j.stem.2019.08.015 }}</ref><ref>{{cite journal | vauthors = Gilbert EA, Livingston J, Flores EG, Khan M, Kandavel H, Morshead CM | title = Metformin treatment reduces inflammation, dysmyelination and disease severity in a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis | journal = Brain Research | volume = 1822 | pages = 148648 | date = January 2024 | pmid = 37890574 | doi = 10.1016/j.brainres.2023.148648 | doi-access = free }}</ref> The promising drug is currently being researched on humans in the Octopus trials, a multi-arm, multi-stage trial, focussed on testing existing drugs for other conditions on patients with MS.<ref>{{Cite web |date=2023-06-06 |title=New treatment hope as world-first MS mega-trial opens site in Northern Ireland |url=https://www.qub.ac.uk/News/Allnews/featured-research/new-treatment-world-first-ms-mega-trial-opens-site-northern-ireland.html |access-date=2024-07-30 |website=www.qub.ac.uk |language=en |archive-date=30 July 2024 |archive-url=https://web.archive.org/web/20240730074954/https://www.qub.ac.uk/News/Allnews/featured-research/new-treatment-world-first-ms-mega-trial-opens-site-northern-ireland.html |url-status=live }}</ref> Currently, clinical trials on humans are ongoing in [[Belgium]], for patients with non-active progressive MS,<ref>{{cite journal | vauthors = De Keersmaecker AV, Van Doninck E, Popescu V, Willem L, Cambron M, Laureys G, D' Haeseleer M, Bjerke M, Roelant E, Lemmerling M, D'hooghe MB, Derdelinckx J, Reynders T, Willekens B | title = A metformin add-on clinical study in multiple sclerosis to evaluate brain remyelination and neurodegeneration (MACSiMiSE-BRAIN): study protocol for a multi-center randomized placebo controlled clinical trial | language = English | journal = Frontiers in Immunology | volume = 15 | pages = 1362629 | date = 2024-02-21 | pmid = 38680485 | pmc = 11046490 | doi = 10.3389/fimmu.2024.1362629 | doi-access = free }}</ref> in the [[United Kingdom|U.K.]], in combination with [[clemastine]] for the treatment of relapsing-remitting MS,<ref>{{Cite web |title=Can metformin and clemastine repair myelin in people with MS? |url=https://www.mssociety.org.uk/research/explore-our-research/search-our-research-projects/can-metformin-clemastine-repair-myelin-people-MS |access-date=July 30, 2024 |website=MS Society UK |archive-date=30 July 2024 |archive-url=https://web.archive.org/web/20240730074950/https://www.mssociety.org.uk/research/explore-our-research/search-our-research-projects/can-metformin-clemastine-repair-myelin-people-MS |url-status=live }}</ref> and [[Canada]], for MS patients up to 25 years old.<ref>{{Cite web |title=Visual & Neurocognitive Outcomes |url=https://lab.research.sickkids.ca/neuroinflamm/research/visual-neurocognitive-outcomes/ |access-date=2024-07-30 |website=Paediatric Neuroinflammatory Disorders Program |language=en-CA |archive-date=30 July 2024 |archive-url=https://web.archive.org/web/20240730074959/https://lab.research.sickkids.ca/neuroinflamm/research/visual-neurocognitive-outcomes/ |url-status=live }}</ref><ref>{{cite web |title=Metformin |url=https://www.mssociety.org.uk/research/explore-our-research/emerging-research-and-treatments/explore-treatments-in-trials/metformin |website=Multiple Sclerosis Society |access-date=30 July 2024 |archive-date=30 July 2024 |archive-url=https://web.archive.org/web/20240730074951/https://www.mssociety.org.uk/research/explore-our-research/emerging-research-and-treatments/explore-treatments-in-trials/metformin |url-status=live }}</ref>

=== Other emerging theories ===
One emerging hypothesis, referred to as the hygiene hypothesis, suggests that early-life exposure to infectious agents helps to develop the immune system and reduces susceptibility to allergies and autoimmune disorders. The hygiene hypothesis has been linked with MS and [[microbiome]] hypotheses.<ref>{{cite journal | vauthors = Wasko NJ, Nichols F, Clark RB | title = Multiple sclerosis, the microbiome, TLR2, and the hygiene hypothesis | journal = Autoimmunity Reviews | volume = 19 | issue = 1 | pages = 102430 | date = January 2020 | pmid = 31734400 | doi = 10.1016/j.autrev.2019.102430 | doi-access = free }}</ref>

It has also been proposed that certain bacteria found in the gut use molecular mimicry to infiltrate the brain via the [[gut–brain axis]], initiating an inflammatory response and increasing blood-brain barrier permeability. [[Vitamin D]] levels have also been correlated with MS; lower levels of vitamin D correspond to an increased risk of MS, suggesting a reduced prevalence in the tropics – an area with more Vitamin D-rich sunlight – strengthening the impact of geographical location on MS development.<ref>{{cite journal | vauthors = Aranow C | title = Vitamin D and the immune system | journal = Journal of Investigative Medicine | volume = 59 | issue = 6 | pages = 881–886 | date = August 2011 | pmid = 21527855 | pmc = 3166406 | doi = 10.2310/jim.0b013e31821b8755 }}</ref> MS mechanisms begin when peripheral [[Autoreactive lymphocyte|autoreactive]] effector [[CD4+ T cells]] get activated and move into the CNS. [[Antigen-presenting cell]]s localize the reactivation of autoreactive effector CD4-T cells once they have entered the CNS, attracting more T cells and macrophages to form the inflammatory lesion.<ref>{{cite journal | vauthors = Tada T, Takemori T, Okumura K, Nonaka M, Tokuhisa T | title = Two distinct types of helper T cells involved in the secondary antibody response: independent and synergistic effects of Ia- and Ia+ helper T cells | journal = The Journal of Experimental Medicine | volume = 147 | issue = 2 | pages = 446–458 | date = February 1978 | pmid = 415110 | pmc = 2184496 | doi = 10.1084/jem.147.2.446 }}</ref> In MS patients, macrophages and microglia assemble at locations where demyelination and neurodegeneration are actively occurring, and microglial activation is more apparent in the normal-appearing white matter of MS patients.<ref>{{cite journal | vauthors = Lassmann H | title = Multiple Sclerosis Pathology | journal = Cold Spring Harbor Perspectives in Medicine | volume = 8 | issue = 3 | pages = a028936 | date = March 2018 | pmid = 29358320 | pmc = 5830904 | doi = 10.1101/cshperspect.a028936 }}</ref> [[Astrocyte]]s generate neurotoxic chemicals like [[nitric oxide]] and [[TNFα]], attract neurotoxic inflammatory [[monocyte]]s to the CNS, and are responsible for [[astrogliosis]], the scarring that prevents the spread of neuroinflammation and kills neurons inside the scarred area.<ref>{{cite book | vauthors = Minagar A, Shapshak P, Alexander JS | chapter = Pathogenesis of HIV-Associated Dementia and Multiple Sclerosis: Role of Microglia and Astrocytes |date=28 December 2004 | veditors = Aschner M, Costa LG | title = The Role of Glia in Neurotoxicity | edition = 2nd |pages=283–298 |publisher=CRC Press |doi=10.1201/9781420039740-21 |isbn=978-0-429-12860-8 }}</ref>{{Better source needed|reason=Not very recent|date=December 2022}}

In 2024, scientists shared research on their findings of ancient migration to northern Europe from the [[Yamnaya culture|Yamnaya area of culture]],<ref>{{cite journal |vauthors = Allentoft ME, Sikora M, Refoyo-Martínez A, Irving-Pease EK, Fischer A, Barrie W, Ingason A, Stenderup J, Sjögren KG, Pearson A, Sousa da Mota B, Schulz Paulsson B, Halgren A, Macleod R, Jørkov ML, Demeter F, Sørensen L, Nielsen PO, Henriksen RA, Vimala T, McColl H, Margaryan A, Ilardo M, Vaughn A, Fischer Mortensen M, Nielsen AB, Ulfeldt Hede M, Johannsen NN, Rasmussen P, Vinner L, Renaud G, Stern A, Jensen TZ, Scorrano G, Schroeder H, Lysdahl P, Ramsøe AD, Skorobogatov A, Schork AJ, Rosengren A, Ruter A, Outram A, Timoshenko AA, Buzhilova A, Coppa A, Zubova A, Silva AM, Hansen AJ, Gromov A, Logvin A, Gotfredsen AB, Henning Nielsen B, González-Rabanal B, Lalueza-Fox C, McKenzie CJ, Gaunitz C, Blasco C, Liesau C, Martinez-Labarga C, Pozdnyakov DV, Cuenca-Solana D, Lordkipanidze DO, En'shin D, Salazar-García DC, Price TD, Borić D, Kostyleva E, Veselovskaya EV, Usmanova ER, Cappellini E, Brinch Petersen E, Kannegaard E, Radina F, Eylem Yediay F, Duday H, Gutiérrez-Zugasti I, Merts I, Potekhina I, Shevnina I, Altinkaya I, Guilaine J, Hansen J, Aura Tortosa JE, Zilhão J, Vega J, Buck Pedersen K, Tunia K, Zhao L, Mylnikova LN, Larsson L, Metz L, Yepiskoposyan L, Pedersen L, Sarti L, Orlando L, Slimak L, Klassen L, Blank M, González-Morales M, Silvestrini M, Vretemark M, Nesterova MS, Rykun M, Rolfo MF, Szmyt M, Przybyła M, Calattini M, Sablin M, Dobisíková M, Meldgaard M, Johansen M, Berezina N, Card N, Saveliev NA, Poshekhonova O, Rickards O, Lozovskaya OV, Gábor O, Uldum OC, Aurino P, Kosintsev P, Courtaud P, Ríos P, Mortensen P, Lotz P, Persson P, Bangsgaard P, de Barros Damgaard P, Vang Petersen P, Martinez PP, Włodarczak P, Smolyaninov RV, Maring R, Menduiña R, Badalyan R, Iversen R, Turin R, Vasilyev S, Wåhlin S, Borutskaya S, Skochina S, Sørensen SA, Andersen SH, Jørgensen T, Serikov YB, Molodin VI, Smrcka V, Merts V, Appadurai V, Moiseyev V, Magnusson Y, Kjær KH, Lynnerup N, Lawson DJ, Sudmant PH, Rasmussen S, Korneliussen TS, Durbin R, Nielsen R, Delaneau O, Werge T, Racimo F, Kristiansen K, Willerslev E | title=Population genomics of post-glacial western Eurasia |doi-access=free|journal=Nature |date=11 January 2024 |volume=625 |issue=7994 |pages=301–311 |doi=10.1038/s41586-023-06865-0| pmid=38200295 | pmc=10781627 | bibcode=2024Natur.625..301A }}</ref> tracing MS-risk gene variants dating back around 5,000 years.<ref>{{Cite news |vauthors=Johnson CY |date=2024-01-10 |title=Ancient DNA helps trace multiple sclerosis origins in European descendants |url=https://www.washingtonpost.com/science/2024/01/10/ancient-dna-multiple-sclerosis-european-ancestry/ |access-date=2024-01-11 |newspaper=Washington Post |archive-date=17 August 2024 |archive-url=https://web.archive.org/web/20240817130847/https://www.washingtonpost.com/science/2024/01/10/ancient-dna-multiple-sclerosis-european-ancestry/ |url-status=live }}</ref><ref>{{Cite web |vauthors=Roxby P |date=10 January 2024 |title=Scientists crack mystery of how MS gene spread |url=https://www.bbc.com/news/health-67917294 |access-date=2024-01-11 |website=BBC News |language=en-GB |archive-date=11 January 2024 |archive-url=https://web.archive.org/web/20240111083346/https://www.bbc.com/news/health-67917294 |url-status=live }}</ref> The MS-risk gene variants protected ancient cattle herders from animal diseases,<ref>{{cite bioRxiv |vauthors= Barrie W, Yang Y, Irving-Pease E, Attfield KE, Scorrano G, Jensen LT, Armen AP, Dimopoulos EA, Stern A, Refoyo-Martinez A, Pearson A | title =  Elevated genetic risk for multiple sclerosis originated in Steppe Pastoralist populations.  |date=October 6, 2023 |biorxiv=10.1101/2023.10.06.561165|quote=Our findings also support the interpretation of increased pathogen pressure as a driver of positive selection on immunogenetic variants associated with risk of the autoimmune disease multiple sclerosis in Steppe populations around 5,000 years ago[[doi:10.1101/2022.09.23.509097|[59]<nowiki/>]]}}</ref> but modern lifestyles, diets and better hygiene, have allowed the gene to develop, resulting in the higher risk of MS today.<ref>{{Cite web|url=https://www.nationalmssociety.org/About-the-Society/News/Novel-Study-Suggests-that-MS-was-Brought-to-Northe|title=Novel Study Suggests that MS was Brought to Northern Europe 5,000 Years Ago|date=10 January 2024|work=National MS Society|access-date=11 January 2024|archive-date=11 January 2024|archive-url=https://web.archive.org/web/20240111083629/https://www.nationalmssociety.org/About-the-Society/News/Novel-Study-Suggests-that-MS-was-Brought-to-Northe|url-status=live}}</ref>

== See also ==
{{Portal|Medicine}}
* [[List of multiple sclerosis organizations]]
* [[List of people with multiple sclerosis]]

== References ==
{{Reflist}}

== External links ==
{{Commons category|Multiple sclerosis}}

{{Medical condition classification and resources
 | DiseasesDB = 8412
 | ICD11 = {{ICD11|8A40}}
 | ICD10 = {{ICD10|G35}}
 | ICD9 = {{ICD9|340}}
 | OMIM = 126200
 | MedlinePlus = 000737
 | eMedicineSubj = neuro
 | eMedicineTopic = 228
 | eMedicine_mult = {{eMedicine2|oph|179}} {{eMedicine2|emerg|321}} {{eMedicine2|pmr|82}} {{eMedicine2|radio|461}}
 | MeshID = D009103
 | GeneReviewsNBK = NBK1316
 | GeneReviewsName = Overview
}}
{{Multiple sclerosis|state=expanded}}
{{Diseases of the nervous system}}
{{Autoimmune diseases}}
{{Authority control}}

[[Category:Multiple sclerosis| ]]
[[Category:Ailments of unknown cause]]
[[Category:Epstein–Barr virus–associated diseases]]
[[Category:Myelin disorders]]
[[Category:Wikipedia medicine articles ready to translate (full)]]
[[Category:Wikipedia neurology articles ready to translate]]