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Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinTemplate:Sndthe insulating covers of nerve cellsTemplate:Sndin the brain and spinal cord.<ref name=NIH2015>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> As a demyelinating disease, MS disrupts the nervous system's ability to transmit signals, resulting in a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems.<ref name="pmid1897097722">Template:Cite journal</ref><ref name="pmid119555563">Template:Cite journal</ref><ref>Template:Cite book</ref> Symptoms include double vision, vision loss, eye pain, muscle weakness, and loss of sensation or coordination.<ref name=NIH2015 /><ref name="Piryonesi-2021">Template:Cite journal</ref><ref>Template:Cite journal</ref> MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms).<ref>Template:Cite journal</ref><ref name="pmid8780061">Template:Medical citation neededTemplate:Cite journal</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>Template:Cite journal</ref>
While its cause is unclear, the underlying mechanism is thought to be due to either 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 infections.<ref name="Ward 988–1005">Template:Cite journal</ref><ref name="Aloisi20222">Template:Cite journal</ref><ref name="pmid119555563"/><ref name="Ascherio_2007">Template:Cite journal</ref> The McDonald criteria are a frequently updated set of guidelines used to establish an MS diagnosis.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
There is no cure for MS.<ref name="NIH20152">{{#invoke:citation/CS1|citation |CitationClass=web }}</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">Template:Cite journal</ref> Physical therapy<ref name="Alphonsus_20192"/> and occupational therapy,<ref>Template:Cite journal</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">Template:Cite journal</ref>
MS is the most common immune-mediated disorder affecting the central nervous system (CNS).<ref name="pmid24746689">Template:Cite journal</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">Template:Cite journal</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">Template:Cite journal</ref> MS was first described in 1868 by French neurologist Jean-Martin Charcot.<ref name="Charcot1" />
The name "multiple sclerosis" is short for multiple cerebro-spinal sclerosis, which refers to the numerous glial scars (or sclerae – essentially plaques or lesions) that develop on the white matter of the brain and spinal cord.<ref name="Charcot1">Template:Cite journal
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Signs and symptomsEdit
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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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Fatigue is one of the most common symptoms of MS.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref> Roughly 65% of people with MS experience fatigue. Of these, some 15–40% report fatigue as their most disabling symptom.<ref name="pmid37602098">Template:Cite journal</ref>
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 loss of sensitivity or changes in sensation in the limbs, such as tingling, “pins and needles,” or numbness; limb motor weakness or pain, blurred vision,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> pronounced reflexes, muscle spasms, difficulty walking, or with coordination or balance (ataxia); problems with speech<ref>Template:Cite journal</ref> or swallowing, visual problems (optic neuritis manifesting as eye pain & vision loss,<ref name="Petzold_2022">Template:Cite journal</ref> or nystagmus manifesting as double vision), fatigue, and bladder and 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>Template:Cite book</ref><ref name="McGinley_2021" /><ref>Template:Cite journal</ref>
Difficulties in thinking and emotional problems such as depression or unstable mood are also common.<ref name="pmid1897097722"/><ref>Template:Cite journal</ref> The primary deficit in cognitive function that people with MS experience is slowed information-processing speed, with memory also commonly affected, and 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>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</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>Template:Cite journal</ref>
Some 60% or more of MS patients find their symptoms, particularly including fatigue,<ref name="Multiple Sclerosis Trust">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> are affected by changes in body temperature.<ref name="Christogianni-2018">Template:Cite journal</ref><ref name="Heat Sensitivity">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Multiple Sclerosis Trust-2">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Measures of disabilityEdit
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>Template:Cite journal</ref><ref name="pmid10467378">Template:Cite journal</ref><ref name="pmid12356200">Template:Cite journal</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>Template:Cite journal</ref><ref name="Piryonesi-2021" />
Disease courseEdit
Prodromal phaseEdit
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">Template:Cite journal</ref><ref name="Marrie2019_Prodrome">Template:Cite journal</ref>
OnsetEdit
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">Template:Cite journal</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 relapses, 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 />
RelapsesEdit
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">Template:Cite journal</ref> Similarly, viral infections such as the common cold, influenza, or gastroenteritis increase their risk.<ref name="pmid1897097722"/> Stress may also trigger an attack.<ref name="pmid17439878">Template:Cite journal</ref>
Many events do not affect rates of relapse requiring hospitalization including vaccination,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> breast feeding,<ref name="pmid1897097722"/> physical trauma,<ref name="pmid112053612">Template:Cite journal</ref> and Uhthoff's phenomenon.<ref name="pmid168043312"/>
PregnancyEdit
Many women with MS who become pregnant experience lower symptoms during pregnancy.<ref>Template:Cite journal</ref><ref name="Varytė-2020">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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"/>
CausesEdit
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 (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>Template:Cite journal</ref><ref name="Hassani-2018">Template:Cite journal</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 peptides 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>Template:Cite journal</ref>
Immune dysregulationEdit
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 pathophysiology section of this article as well as the standalone article on the pathophysiology of MS.
Infectious agentsEdit
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">Template:Cite journal</ref> One such virus, Epstein-Barr virus (EBV), can cause infectious mononucleosis and infects about 95% of adults, though only a small proportion of those infected later develop MS.<ref>Template:Cite journal</ref><ref name="Aloisi20222" /><ref name="Bjornevik2022">Template:Cite journal See lay summary: Template:Cite news</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 nuclear antigen of EBV, which is the most consistent marker of EBV infection across all strains,<ref>Template:Cite journal</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>Template:Cite journal</ref><ref name="Ward 988–1005" />
GeneticsEdit
MS is not considered a hereditary disease, but several genetic variations have been shown to increase its risk.<ref name="pmid14747002">Template:Cite journal</ref> Some of these genes appear to have higher expression levels in microglial cells than expected by chance.<ref name="SkeneGrant2016">Template:Cite journal</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>Template:Cite journal</ref> MS is also more common in some ethnic groups than others.<ref name="pmid11603614">Template:Cite journal</ref>
Specific genes linked with MS include differences in the human leukocyte antigen (HLA) system—a group of genes on 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">Template:Cite journal</ref> and it has also been implicated in the development of other autoimmune diseases, such as 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 DR15, which is present in 30% of the U.S. and Northern European population.<ref name="Ward 988–1005"/><ref name="pmid1897097722"/> Other 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 studies have revealed at least 200 MS-associated variants outside the HLA locus.<ref name="pmid31604244">Template:Cite journal</ref>
GeographyEdit
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 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">Template:Cite journal</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">Template:Cite journal</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, Amerindians, Canadian Hutterites, New Zealand Māori,<ref name="pmid121276522">Template:Cite journal</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 Sardinians,<ref name="Milo2010" /> inland Sicilians,<ref>Template:Cite journal</ref> Palestinians, and Parsi.<ref name="pmid121276522" />
Impact of temperatureEdit
MS symptoms may increase if body temperature is dysregulated.<ref name="Heat and cold sensitivity in multiple sclerosis">Template:Cite journal</ref><ref name="Davis-2010">Template:Cite journal</ref><ref name="Davis-2018">Template:Cite book</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">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Sumowski-2014">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Christogianni-2022">Template:Cite journal</ref>
OtherEdit
Smoking may be an independent risk factor for MS.<ref name="pmid17492755" /> 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">Template:Cite journal</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 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) (OR = 8.25, 95% 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" />
Vaccinations were studied as causal factors; most studies, though, show no association.<ref name="pmid15556803" /><ref>Template:Cite journal</ref> Several other possible risk factors, such as 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">Template:Cite book</ref> Obesity during adolescence and young adulthood is a risk factor for MS.<ref name="Nourbakhsh2019RisksPathogenesis">Template:Cite journal</ref>
PathophysiologyEdit
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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 sheaths of neurons. 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 dysregulationEdit
As briefly detailed in the 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 TH17 cells. These autoreactive T-cells produce substances called cytokines 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 IgG bands (antibodies produced by B-cells) in the 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">Template:Cite journal</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>Template:Cite journal</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 cells in early active MS lesions being proinflammatory microglia.<ref name="Ward 988–1005"/>
LesionsEdit
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 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"/>
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To be specific, MS involves the loss of oligodendrocytes, the cells responsible for creating and maintaining a fatty layer—known as the myelin sheath—which helps the neurons carry 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">Template:Cite book</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 increase in the number of astrocytes due to the destruction of nearby neurons.<ref name="pmid1897097722"/> A number of lesion patterns have been described.<ref name="pmid17351524">Template:Cite journal</ref>
InflammationEdit
Apart from demyelination, the other sign of the disease is inflammation. Fitting with an immunological explanation, the inflammatory process is caused by T cells, a kind of lymphocytes 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 cytokines and antibodies. A further breakdown of the blood-brain barrier, in turn, causes many other damaging effects, such as 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 barrierEdit
The blood-brain barrier (BBB) is a part of the capillary system that prevents the entry of T cells into the central nervous system. It may become permeable to these types of cells secondary to an infection by a virus or bacteria. After it repairs itself, typically once the infection has cleared, T cells may remain trapped inside the brain.<ref name="pmid119555563"/><ref>Template:Cite journal</ref> Gadolinium cannot cross a normal BBB, so gadolinium-enhanced MRI is used to show BBB breakdowns.<ref name="pmid23088946">Template:Cite journal</ref>
MS fatigueEdit
The pathophysiology and mechanisms causing MS fatigue are not well understood.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</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">Template:Cite journal</ref>
DiagnosisEdit
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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">Template:Cite journal</ref>
McDonald criteriaEdit
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>Template:Cite book</ref> with the Schumacher and Poser criteria being of mostly historical significance.<ref name="pmid15177763">Template:Cite journal</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" />
Template:As of, no single test (including biopsy) can provide a definitive diagnosis.<ref>Template:Cite journal</ref>
MRIEdit
Magnetic resonance imaging (MRI) of the brain and spine may show areas of demyelination (lesions or plaques). Gadolinium can be administered intravenously 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">Template:Cite journal</ref><ref name="pmid18256986">Template:Cite journal</ref>
Central vein signs (CVSs) have been proposed as a good indicator of MS in comparison with other conditions causing white lesions.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> One small study found fewer CVSs in older and hypertensive people.<ref>Template:Cite journal</ref> Further research on CVS as a biomarker for MS is ongoing.<ref>Template:Cite news</ref>
In vivo vs postmortem lesion visibility in MRI scansEdit
Only postmortem MRI allows visualization of sub-millimetric lesions in cortical layers and in the cerebellar cortex.<ref>Template:Cite journal</ref>
Cerebrospinal fluid (lumbar puncture)Edit
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 bands of IgG on electrophoresis, which are inflammation markers found in 75–85% of people with MS.<ref name="pmid11456302" /><ref name="pmid16945427">Template:Cite journal</ref>
Differential diagnosisEdit
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. 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">Template:Cite book</ref><ref name="Saguil-2022">Template:Cite journal</ref>
In an emergency setting, it is important to rule out a stroke or 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">Template:Cite journal</ref> Infectious diseases that may look similar to multiple sclerosis include HIV, Lyme disease, and syphilis. Autoimmune diseases include neurosarcoidosis, lupus, Guillain-Barré syndrome, acute disseminated encephalomyelitis, and Behçet's disease. Psychiatric conditions such as anxiety or conversion disorder may also present in a similar way. Other rare diseases on the differential include CNS lymphoma, congenital leukodystrophies, and anti-MOG-associated myelitis.<ref name="Loscalzo-2022" /><ref name="Saguil-2022" />
Types and variantsEdit
Several 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 Lublin classification:<ref name=Lublin>Template:Cite journal</ref><ref>Template:Cite journal</ref>
- Clinically isolated syndrome (CIS)
- 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 demyelination of the central nervous system.<ref name="pmid1897097722"/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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">Template:Cite journal</ref>
RRMS is characterized by unpredictable relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits that occur during attacks may either resolve or leave 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">Template:Cite journal</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">Template:Cite journal</ref>
Special coursesEdit
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">Template:Cite journal</ref> "active secondary MS" (similar to the old progressive-relapsing)<ref name="novartis.com">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and "rapidly progressing PPMS".<ref>Template:Cite journal</ref>
Also, deficits always resolving between attacks is sometimes referred to as "benign" MS,<ref name="pmid18219812">Template:Cite book</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>Template:Cite book</ref>
An international panel has published a standardized definition for the course HAMS.<ref name="sorensen" />
VariantsEdit
Atypical variants of MS have been described; these include tumefactive multiple sclerosis, Balo concentric sclerosis, Schilder's diffuse sclerosis, and Marburg multiple sclerosis. Debate remains on whether they are MS variants or different diseases.<ref name="pmid15727225">Template:Cite journal</ref> Some diseases previously considered MS variants, such as Devic's disease, are now considered outside the MS spectrum.<ref>Template:Cite journal</ref>
ManagementEdit
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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>Template:Cite journal</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 effects. Alternative treatments are pursued by some people, despite the shortage of supporting evidence of efficacy.
Initial management of acute flareEdit
During symptomatic attacks, administration of high doses of intravenous corticosteroids, such as methylprednisolone, is the usual therapy,<ref name="pmid1897097722"/> with oral corticosteroids seeming to have a similar efficacy and safety profile.<ref>Template:Cite journal</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>Template:Cite journal</ref><ref name="RCOP_acute">Template:Cite book</ref> The long-term benefit is unclear in optic neuritis as of 2020.<ref>Template:Cite journal</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 managementEdit
Relapsing-remitting multiple sclerosisEdit
Multiple disease-modifying medications were approved by regulatory agencies for RRMS; they are modestly effective at decreasing the number of attacks.<ref name=He2016>Template:Cite journal</ref> Interferons<ref name=Rice2001>Template:Cite journal</ref> and glatiramer acetate are first-line treatments<ref name="Tsang20112"/> and are roughly equivalent, reducing relapses by approximately 30%.<ref name=Hassan2011>Template:Cite journal</ref> Early-initiated long-term therapy is safe and improves outcomes.<ref name="pmid21205679">Template:Cite journal</ref><ref name="pmid22284996">Template:Cite journal</ref>
Treatment of CIS with interferons decreases the chance of progressing to clinical MS.<ref name="pmid1897097722"/><ref name="pmid21205678">Template:Cite journal</ref><ref>Template:Cite journal</ref> Efficacy of interferons and glatiramer acetate in children has been estimated to be roughly equivalent to that of adults.<ref name="pmid22642799">Template:Cite journal</ref> The role of some newer agents such as fingolimod,<ref name=LaMantia2016>Template:Cite journal</ref> teriflunomide, and dimethyl fumarate,<ref name=Xu2015>Template:Cite journal</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>Template:Cite journal</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>Template:Cite journal</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>Template:Cite journal</ref> There is high confidence that natalizumab, cladribine, or alemtuzumab are decreasing relapses over two years for people with RRMS.<ref name="Tramacere2015">Template:Cite journal</ref> Natalizumab and interferon beta-1a (Rebif) may reduce relapses compared to both placebo and interferon beta-1a (Avonex) while Interferon beta-1b (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>Template:Cite press release</ref>
MedicationsEdit
Overview of medications available for MS.<ref name="MSTrust">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
| Medication | Compound | Producer | Use | Efficacy (annualized relapse reduction rate) | Annualized relapse rate (ARR) |
|---|---|---|---|---|---|
| Avonex | Interferon beta-1a | Biogen | Intramuscular | 30% | 0.25 |
| Rebif | Interferon beta-1a | Merck Serono | Subcutaneous | 30% | 0.256 |
| Extavia | Interferon beta-1b | Bayer Schering | Subcutaneous | 30% | 0.256 |
| Copaxone | Glatiramer acetate | Teva Pharmaceuticals | Subcutaneous | 30% | 0.3 |
| Aubagio | Teriflunomide | Genzyme | Oral | 30% | 0.35 |
| Plegridy | Interferon beta-1a | Biogen | Subcutaneous | 30% | 0.12 |
| Tecfidera | Dimethyl fumarate | Biogen | Oral | 50% | 0.15 |
| Vumerity | Diroximel fumarate | Biogen | Oral | 50% | 0.11-0.15 |
| Gilenya | Fingolimod | Oral | 50% | 0.22-0.25 | |
| Zeposia | Ozanimod | Template:Better source needed | Oral | 0.18-0.24 | |
| Kesimpta | Ofatumumab | Subcutaneous | 70% | 0.09-0.14 | |
| Mavenclad | Cladribine | Oral | 70% | 0.1-0.14 | |
| Lemtrada | Alemtuzumab | Intravenous | 70% | 0.08 | |
| Ocrevus | Ocrelizumab | Intravenous | 70% | 0.09 | |
| Ocrevus Zunovo | Ocrelizumab/hyaluronidase | Subcutaneous |
Progressive multiple sclerosisEdit
In 2011, mitoxantrone was the first medication approved for secondary progressive MS.<ref name="BopeKellerman2011">Template:Cite book</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">Template:Cite journal</ref><ref>Template:Cite journal</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">Template:Cite journal</ref><ref name="STATapproval">Template:Cite news</ref><ref name="Ocrevus FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> with requirements for several Phase IV clinical trials.<ref name="FDABLAapproval">{{#invoke:citation/CS1|citation |CitationClass=web }}</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>Template:Cite journal</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>Template:Cite book</ref>
Ocrelizumab/hyaluronidase was approved for medical use in the United States in September 2024.<ref>Template:Cite press release</ref><ref>Template:Cite press release</ref>
Adverse effectsEdit
The disease-modifying treatments 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>Template:Cite journal</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">Template:Cite journal</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>Template:Cite journal</ref> More dangerous but much less common are liver damage from interferons,<ref name="pmid15592724">Template:Cite journal</ref> systolic dysfunction (12%), infertility, and acute myeloid leukemia (0.8%) from mitoxantrone,<ref name=CochMit2013 /><ref name="pmid19882365">Template:Cite journal</ref> and progressive multifocal leukoencephalopathy occurring with natalizumab (occurring in 1 in 600 people treated).<ref name="Tsang20112"/><ref>Template:Cite journal</ref>
Fingolimod may give rise to hypertension and slowed heart rate, macular edema, elevated liver enzymes, or a reduction in lymphocyte levels.<ref name=LaMantia2016 /><ref name="pmid22014437">Template:Cite journal</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 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>Template:Cite press release</ref><ref name="pmid22014437" /> While dimethyl fumarate may lead to a reduction in the white blood cell count there were no reported cases of opportunistic infections during trials.<ref name=fumarateNDA>{{#invoke:citation/CS1|citation
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Associated symptomsEdit
Both medications and neurorehabilitation have been shown to improve some symptoms, though neither changes the course of the disease.<ref name="pmid16168933">Template:Cite journal</ref> Some symptoms have a good response to medication, such as bladder spasticity, while others are little changed.<ref name="pmid1897097722"/> Equipment such as catheters 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">Template:Cite journal</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>Template:Cite journal</ref> There is limited evidence for the overall efficacy of individual therapeutic disciplines,<ref name="pmid15859525">Template:Cite journal</ref><ref name="pmid12917976">Template:Cite journal</ref> though there is good evidence that specific approaches, such as exercise,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="pmid17482708">Template:Cite journal</ref><ref>Template:Cite journal</ref> and psychological therapies are effective.<ref>Template:Cite journal</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>Template:Cite journal</ref> The effectiveness of palliative approaches in addition to standard care is uncertain, due to lack of evidence.<ref>Template:Cite journal</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>Template:Cite journal</ref> Cognitive behavioral therapy has shown to be moderately effective for reducing MS fatigue.<ref>Template:Cite journal</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>Template:Cite journal</ref>
Non-pharmaceuticalEdit
There is some evidence that aquatic therapy is a beneficial intervention.<ref>Template:Cite journal</ref>
The spasticity associated with MS can be difficult to manage because of the progressive and fluctuating course of the disease.<ref>Template:Cite journal</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>Template:Cite journal</ref>
Alternative treatmentsEdit
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">Template:Cite journal</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">Template:Cite journal</ref> Treatments of unproven benefit used by people with MS include dietary supplementation and regimens,<ref name="pmid16420779" /><ref>Template:Cite journal</ref><ref name="pmid21965673">Template:Cite journal</ref> vitamin D,<ref>Template:Cite journal</ref> relaxation techniques such as yoga,<ref name="pmid16420779" /> herbal medicine (including medical cannabis),<ref name="pmid16420779" /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> hyperbaric oxygen therapy,<ref name="pmid14974004">Template:Cite journal</ref> self-infection with hookworms, reflexology, acupuncture,<ref name="pmid16420779" /><ref>Template:Cite news</ref> and mindfulness.<ref>Template:Cite journal</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>Template:Cite journal</ref> There is insufficient evidence supporting high-dose biotin<ref name=Motte2020>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and some evidence for increased disease activity and higher risk of relapse with its use.<ref name=Goldschmidt2020>Template:Cite journal</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>Template:Cite journal</ref>
PrognosisEdit
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>Template:Cite journal</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>Template:Cite journal</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">Template:Cite journal</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>Template:Cite journal 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>Template:Cite journal</ref> Currently, no biomarker can accurately predict disease progression in every patient.<ref name=Oh2018/> Spinal cord lesions, abnormalities on MRI, and more 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>Template:Cite journal</ref>
EpidemiologyEdit
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 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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Nearly one million people in the United States had MS in 2022.<ref name="McGinley2021">Template:Cite journal</ref>
Increasing rates of MS may be explained simply by better diagnosis.<ref name=Milo2010 /> Studies on populational and geographical patterns have been common<ref name="pmid8269393">Template:Cite journal</ref> and have led to a number of theories about the cause.<ref name="Ascherio_2007"/><ref name="pmid15556803">Template:Cite journal</ref><ref name="pmid17492755">Template:Cite journal</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">Template:Cite journal</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>Template:Cite journal</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" />
HistoryEdit
Medical discoveryEdit
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">Template:Cite journal</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">Template:Cite journal</ref><ref>Template:Cite journal</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 historyEdit
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 triad", consisting of nystagmus, intention tremor, and telegraphic speech (scanning speech).<ref name="Milo">Template:Cite journal</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>Template:Cite journal</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>Template:Cite journal</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>Template:Cite journal</ref> Other organizations have proposed later new clinical phenotypes, like HAMS (Highly Active MS).<ref>Template:Cite journal</ref>
Historical casesEdit
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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">Template:Cite journal</ref> Both cases have led to the proposal of a "Viking gene" hypothesis for the dissemination of the disease.<ref name="pmid16479124">Template:Cite journal</ref>
Augustus Frederick d'Este (1794–1848), son of Prince Augustus Frederick, Duke of Sussex and Lady Augusta Murray and a grandson of George 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>Template:Cite book</ref><ref name="pmid16103678">Template:Cite journal</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>Template:Cite book</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>Template:Cite journal</ref>
ResearchEdit
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Epstein-Barr virusEdit
As of 2022, the pathogenesis of MS, as it relates to 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 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-cells (B lymphocytes)<ref>Template:Cite journal</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>Template:Cite journal</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>Template:Cite journal</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 EBNA1 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>Template:Cite journal</ref>
Human endogenous retrovirusesEdit
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>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
MedicationsEdit
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>Template:Cite journal</ref>
PathogenesisEdit
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.
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">Template:Cite journal</ref> Some cases of MS were presenting 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 demyelinating diseases.<ref name="Misu" />
A third kind of auto-antibodies is accepted. There are several 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">Template:Cite journal</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">Template:Cite journal</ref>
BiomarkersEdit
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Since disease progression is the result of degeneration of neurons, the roles of proteins showing loss of nerve tissue such as neurofilaments, tau, and N-acetylaspartate are under investigation.<ref>Template:Cite journal</ref><ref>Template:Cite journal</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 tensor, and functional magnetic resonance imaging.<ref name="pmid22159052">Template:Cite journal</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, GABA, and GSH, observed for multiple sclerosis and its subtypes.<ref>Template:Cite journal</ref> There are other techniques under development that include contrast agents capable of measuring levels of peripheral macrophages, 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-19Edit
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>Template:Cite journal</ref>
MetforminEdit
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>Template:Cite journal</ref><ref>Template:Cite journal</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Currently, clinical trials on humans are ongoing in Belgium, for patients with non-active progressive MS,<ref>Template:Cite journal</ref> in the U.K., in combination with clemastine for the treatment of relapsing-remitting MS,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and Canada, for MS patients up to 25 years old.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Other emerging theoriesEdit
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>Template:Cite journal</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>Template:Cite journal</ref> MS mechanisms begin when peripheral autoreactive effector CD4+ T cells get activated and move into the CNS. Antigen-presenting cells 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>Template:Cite journal</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>Template:Cite journal</ref> Astrocytes generate neurotoxic chemicals like nitric oxide and TNFα, attract neurotoxic inflammatory monocytes to the CNS, and are responsible for astrogliosis, the scarring that prevents the spread of neuroinflammation and kills neurons inside the scarred area.<ref>Template:Cite book</ref>Template:Better source needed
In 2024, scientists shared research on their findings of ancient migration to northern Europe from the Yamnaya area of culture,<ref>Template:Cite journal</ref> tracing MS-risk gene variants dating back around 5,000 years.<ref>Template:Cite news</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The MS-risk gene variants protected ancient cattle herders from animal diseases,<ref>Template:Cite bioRxiv</ref> but modern lifestyles, diets and better hygiene, have allowed the gene to develop, resulting in the higher risk of MS today.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
See alsoEdit
ReferencesEdit
External linksEdit
Template:Medical condition classification and resources Template:Multiple sclerosis Template:Diseases of the nervous system Template:Autoimmune diseases Template:Authority control