Multiple sclerosis

Causes

MS is an autoimmune disease with a combination of genetic and environmental causes underlying it. Both T cells and B cells are involved. The causes of the disease are not fully understood. The Epstein-Barr Virus (EBV) very strongly increases the risk of MS.

Immune dysregulation

MS usually begins when immune cells known as T cells and B cells erroneously attack the body's own nervous system by releasing signals that cause inflammation in brain and other neurological tissues. This is supported by the presence of certain antibodies (oligoclonal IgG bands) commonly found in the spinal fluid of people with MS. Although T cells have been considered to be the major contributors to the inflammatory demyelination occurring in MS, recent studies indicate that B cells also play a significant role in the pathogenesis of this disease.

Epstein-Barr virus

The Epstein-Barr virus (EBV) infects about 90 to 95% of adults and can cause infectious mononucleosis. 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 is necessary for MS onset, although EBV alone may be insufficient to cause it.

The nuclear antigen of EBV, which is the most consistent marker of EBV infection across all strains, 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 EBV protein EBNA1 shares similarities with three human proteins, including the brain protein GlialCAM. Because of molecular mimicry, the immune system in MS mistakenly may attack these proteins. Two are part of the nervous system, while the third is a "guardian molecule" which protects the body against autoimmunity.

Genetics

MS is not considered a hereditary disease, but over 200 genetic variants have been shown to increase its risk. The probability of developing MS is higher in relatives of an affected person, with a greater risk among those more closely related. 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. MS is also more common in some ethnic groups than others.

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). The MHC is involved in how antigens are presented and how abundant different types of T cells are. The MHC allele (genetic variant) HLA-DRB1*15:01 which is present in 30% of the U.S. and Northern European population, produces the strongest association with higher risk of MS. Other allelles related to MHC exhibit a protective effect.

The contribution of HLA variants to MS susceptibility has been known since the 1980s, and it has also been implicated in the development of other autoimmune diseases. Genetic variants in autoimmune diseases are typically linked to T cells, but in MS (and lupus), many are linked to B cells too. In general, MS is associated more closely to autoimmune diseases than to other neurodegenerative diseases.

Vitamin D and sunlight

The prevalence of MS shows a geographic gradient: it is more common in people who live farther from the equator (e.g., those who live in northern regions of the world). Exceptions 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, and Canada's Inuit, as well as groups that have a relatively high risk and that live closer to the equator such as Sardinians, inland Sicilians, Palestinians, and Parsi.

The geographical gradient can, at least in part, be explained by exposure to sunlight and resulting vitamin D levels. Vitamin D plays various roles in the immune system, including helping the body get rid of pathogens and regulating immune tolerance. Low vitamin D levels are a risk factor for developing MS and for disease progression beyond the first attack. Sunlight exposure may reduce risk independently from vitamin D.

While there are dietary sources of vitamin D (e.g. fatty fish and some mushrooms), this usually is not enough to meet the body's need. The risk of MS tracks the sunlight exposure in childhood.

Other risks

Smoking is a risk factor for MS. Similarly, air pollution seems to increase MS risk, as well as the risk of relapses. Organic solvent exposure and night shift work are linked to increased risk of MS, but are not as established as other risk factors. Vaccinations were studied as causal factors; most studies, though, show no association.

The risk of developing MS is also weakly associated with obesity, and the presence of certain bacteria such as Akkermansia muciniphila in the intestines.

Pathophysiology

Multiple sclerosis is an autoimmune disease. 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. Damage is believed to be caused, at least in part, by attack on the nervous system by a person's own immune system.

Immune dysregulation

MS may stem from immune responses to activation of receptors for T-cells and B-cells involved in an inflammatory response. These T-cells produce substances called cytokines that induce an inflammatory response in the CNS, possibly leading to development of MS, according to a theory remaining under study, as of 2024.

Lesions

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. 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.

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). 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. 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. Repeated attacks lead to successively less effective remyelinations, until a scar-like plaque is built up around the damaged axons. These scars are the origin of the symptoms and during an attack magnetic resonance imaging (MRI) often shows more than 10 new plaques. This could indicate that some number of lesions exist, below which the brain is capable of repairing itself without producing noticeable consequences. Another process involved in the creation of lesions is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons. A number of lesion patterns have been described.

MS fatigue

The mechanisms causing MS fatigue are not well understood. MS fatigue can be affected by body heat. Fatigability, defined as "decline in physical performance over time", correlates with perceived fatigue, but the limited correlation suggests they are distinct constructs and warrant independent assessment in clinical studies.

Diagnosis

Multiple sclerosis is typically diagnosed based on the presenting signs and symptoms and MRI scans, in combination with supporting lab testing of the spinal fluid and measurement of nerve conduction velocities.

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.

The 2024 McDonald criteria states that patients with multiple sclerosis should have lesions which are disseminated in space (DIS) and, in many instances, disseminated in time (DIT), i.e. lesions which have appeared in different areas in the brain and at different times.

To show DIS, lesions typically need to be present in two out of five locations: spinal cord, optic nerve and three specific locations in the brain. These lesions can be detected on MRI. The optic nerve lesions can be detected with other tests too, which might be more wide available globally than MRI. For disease that has progressed over a period of 12 months or more, two spinal cord lesions are enough.

DIT can shown in repeat MRIs, among other methods. To reduce delays in diagnosis, DIS is no longer required for a diagnosis of MS. Alternatively, DIS can be combined with specific MRI findings such as the central vein sign to diagnose MS. Finally, DIS can be combined with specific tests of the cerebro-spinal fluid.

As of 2025, no single test (including biopsy) can provide a definitive diagnosis.

MRI

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.

The central vein sign, which shows as a dark line in the MRI through the bright white lesion, can help verify that the lesions are due to MS. Active MS lesions can have an inactive centre surrounded by microglia which contain iron. In specific MRI scans, these can be visible as paramagnetic rim lesions, which are another way to show that the lesions are likely due to MS.

Cerebrospinal fluid (lumbar puncture)

Testing of cerebrospinal fluid obtained from a lumbar puncture can provide evidence of chronic inflammation in the central nervous system. Two different biomarkers can show this inflammation with similar accuracy:

• Oligoclonal bands of IgG

• Kappa free-light chain (kFLC) concentrations

The measurement of oligoclonal bands requires specialists labs; it is easier to measure kFLC. These two biomarkers are not only elevated in MS, but also to a lesser extent in other diseases including NMOSD. They can be used instead of dissemination in time to diagnose MS where dissemination in space is demonstrated.

Differential diagnosis

Several diseases present similarly to MS. Medical professionals use the 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. They include individuals being younger than 11 or older than 50, signs of nerve damage outside of the central nervous system, severe vision loss, a very rapid onset, or atypical lab and exam findings.

A very rapid onset may indicate a stroke or seizure rather than MS. Intractable vomiting, severe optic neuritis, or bilateral optic neuritis raises suspicion for neuromyelitis optica spectrum disorder (NMOSD). 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 may also present in a similar way. Other rare diseases on the differential include CNS lymphoma, congenital leukodystrophies, and anti-MOG-associated myelitis.

Types and variants

Several disease courses (or types) of MS have been described. They are used to help predict the progression of MS for individuals, for clinical trials and for decisions on what medications to use. The International Advisory Committee on Clinical Trials of MS classifies MS courses into four disease courses in what is known as the Lublin-Reingold classification:

1. Relapsing-remitting MS (RRMS)
2. Primary progressive MS (PPMS)
3. Secondary progressive MS (SPMS)
4. Clinically isolated syndrome (CIS)

One other type is sometimes recognised

1. Radiologically isolated syndrome

CIS is a first episode of MS signs and symptoms, followed by a full or almost full recovery. To be classified as CIS, the attack must last at least a full day and be due to demyelination or inflammation of the central nervous system. Individuals with CIS can in some cases be diagnosed directly with MS, if they meet more strict criteria compared to people with a history of attacks. Radiologically isolated syndrome is diagnosed when an MRI for an unrelated issue shows MS-like lesions. Similarly, people can be diagnosed with MS if they meet more strict criteria.

RRMS is characterized by unpredictable relapses followed by periods of weeks to years of relative quiet (remission). Deficits that occur during attacks may either resolve fully or leave some problems. In between attacks, there is often silent progression of the disease (progression independent of relapse activity). RRMS describes the initial course of 85% of individuals with MS.

RRMS can sometimes develop into SPMS, as attack frequency declines and there is clear worsening between attacks. In practical terms, the diagnosis of SPMS is typically only made in people with a minimum amount of disability. Occasional relapses and minor remissions may appear. Less frequently, MS starts as PPMS, which is characterised by a progressive worsening in the absence of attacks, from disease onset. Symptoms may become slightly less severe temporarily.

Variants and subgroups

Regulators and clinical trials often use additional subgroups based on how active the disease is, even if there is no firm agreement on their definition. Examples are 'active MS', 'highly active MS' and 'rapidly evolving severe MS'. One definition of highly active MS is having an unchanged or increased number of relapses even after starting disease-modifying treatment. In addition, the term 'relapsing MS' is often used to denote people with relapsing-remitting MS as well as the subset of individuals with secondary progressive MS who still experience some relapses.

The terms "benign MS" is sometimes used for people who have had MS for a long time (15 years or so) with few attacks and little disability. As people may still get worse, the term is discouraged. On the other hand, the term aggressive multiple sclerosis (previously known as "malignant multiple sclerosis") is used to describe people with MS having reached a significant level of disability in a short period.

Atypical variants of MS have been described; these include tumefactive multiple sclerosis, Balo concentric sclerosis, and Marburg multiple sclerosis.

Treatment

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. 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.

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

Management of acute flare

During moderate or severe symptomatic attacks, a short course (usually 3–5 days) of high doses of corticosteriods is the usual approach. Initially, oral corticosteroids are used; if that is ineffective, an intravenous course can be tried. Milder attacks may not need treatment. Although targeted at acute attacks, they might also have a small longer-term benefit. Severe attacks that do not respond to corticosteroids might be treatable by plasma exchange.

Chronic management

Relapsing-remitting multiple sclerosis

Many disease-modifying medications have been approved for RRMS; and some are highly effective at decreasing the number of attacks. Highly effective medications include monoclonal antibodies directed at CD20-expressing B cells (administred by injection or infusion, e.g. rituximab), natalizumab (an integrin) or alemtuzumab, which depletes white blood cells more broadly.

Treatment of CIS with interferons decreases the chance of progressing to clinical MS. In general, aggressive treatment in the early stages of MS produces the best long-term outcomes.

The relative effectiveness of different treatments is unclear, as most have only been compared to placebo or a small number of other therapies. There is high confidence that natalizumab, cladribine, or alemtuzumab are decreasing relapses over two years for people with RRMS. 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. There is moderate confidence that a two-year treatment with natalizumab slows disability progression for people with RRMS. All medications are associated with adverse effects that may influence their risk-to-benefit profiles.

Ublituximab was approved for medical use in the United States in December 2022.

Medications

Overview of medications available for MS.

Progressive multiple sclerosis

In 2011, mitoxantrone was the first medication approved for secondary progressive MS. In this population, tentative evidence supports mitoxantrone moderately slowing the progression of the disease and decreasing rates of relapses over two years. In 2026, tolebrutinib, a BTK inhibitor, was approved for non-relapsing secondary MS in the EU. It reduces the activity of microglia, immune cells in the brain, as well as of B cells.

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. 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. 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.

In 2019, siponimod and cladribine were approved in the United States for the treatment of secondary progressive multiple sclerosis (SPMS). 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.

Ocrelizumab/hyaluronidase was approved for medical use in the United States in September 2024.

Adverse effects

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). Over time, a visible dent at the injection site, due to the local destruction of fat tissue, known as lipoatrophy, may develop. Interferons may produce flu-like symptoms; some people taking glatiramer experience a post-injection reaction with flushing, chest tightness, heart palpitations, and anxiety, which usually lasts less than thirty minutes. More dangerous but much less common are liver damage from interferons, systolic dysfunction (12%), infertility, and acute myeloid leukemia (0.8%) from mitoxantrone, and progressive multifocal leukoencephalopathy occurring with natalizumab (occurring in 1 in 600 people treated).

Fingolimod may give rise to hypertension and slowed heart rate, macular edema, elevated liver enzymes, or a reduction in lymphocyte levels. Tentative evidence supports the short-term safety of teriflunomide, with common side effects including headaches, fatigue, nausea, hair loss, and limb pain. There have also been reports of liver failure and PML with its use and it is dangerous for fetal development. Most common side effects of dimethyl fumarate are flushing and gastrointestinal problems. While dimethyl fumarate may lead to a reduction in the white blood cell count there were no reported cases of opportunistic infections during trials.

Symptom management

Alongside treatment that affects the disease itself, MS care includes symptom management with or without medication. Some symptoms have a good response to medication, such as bladder spasticity, while others are little changed. Equipment such as catheters for neurogenic bladder dysfunction or mobility aids can help improve functional status.

A 2022 Cochrane review found that nabiximols (a specific Cannabis extract first approved in the United Kingdom in 2010) likely reduces the severity of spasticity as an adjunctive therapy to standard anti-spasticity medication in the short term, but may have increased medication discontinuation to a small degree due to adverse events.

There is good evidence that specific approaches, such as exercise, and psychological therapies are effective. 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. The effectiveness of palliative approaches in addition to standard care is uncertain, due to lack of evidence. 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. Cognitive behavioral therapy has shown to be moderately effective for reducing MS fatigue. 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.

There is some evidence that aquatic therapy is a beneficial intervention.

The spasticity associated with MS can be difficult to manage because of the progressive and fluctuating course of the disease. 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.

Alternative treatments

Over 50% of people with MS may use complementary and alternative medicine, although percentages vary depending on how alternative medicine is defined. 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. The evidence for the effectiveness for such treatments in most cases is weak or absent. Treatments of unproven benefit used by people with MS include dietary supplementation and regimens, vitamin D, relaxation techniques such as yoga, herbal medicine (including medical cannabis), hyperbaric oxygen therapy, self-infection with hookworms, reflexology, acupuncture, and mindfulness. 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. There is insufficient evidence supporting high-dose biotin and some evidence for increased disease activity and higher risk of relapse with its use.

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. Before the advent of these medications, it took around 15 years before relapsing-remitting MS progressed to secondary progressive MS (which has associated mobility issues). With these medications, the progression is slower to 40 years.

The prognosis of MS depends on the subtype of the disease, and there is considerable individual variation in the progression of the disease. 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. With treatments available in the 2020s, relapses can be eliminated or substantially reduced. However, "silent progression" of the disease still occurs.

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. The prognosis for progressive MS is worse, with faster accumulation of disability, though with considerable individual variation. In untreated PPMS, the median time from onset to requiring a walking aid is estimated as seven years. 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.

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. Spinal cord lesions and a higher number of initial lesions on MRI are predictive of a worse course. Early treatment leads to a better prognosis, but a higher relapse frequency when treated with DMTs is associated with a poorer prognosis. 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.

Epidemiology

The total number of people with MS was 3.1 million globally in 2024, with a diagnosed prevalence of 38 per 100,000 people. Moreover, diagnosed prevalence varies widely in different regions around the world. In Africa, there are 4 people per 100,000 diagnosed with MS, compared to South East Asia where the prevalence is 8 per 100,000, 109 per 100,000 in the Americas, and 158 per 100,000 in Europe.

The higher number of cases in countries further from the equator can partially be explained by lower UV radiation and vitamin D production. However, the true difference between countries might be smaller, as richer countries have better resources for MS diagnosis. The prevalence of MS is slowly increasing, which might be explained by countries getting better at diagnosis the disease. In addition, improvements in treatment mean that people with MS live longer.

MS usually appears in adults in their twenties or thirties but it can also start in childhood and in individuals older than 40. Primary progressive MS typically starts after the age of 40. Similarly to many autoimmune disorders, the disease is more common in women, and the gender gap may have grown over time. Globally it is about two to three times more common in women than in men. In children under 12, it is only slightly more common in girls than boys, while in people with primary progressive MS, who are typically older, men and women are roughly equally affected.

History

Etymology

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.

Medical discovery

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. Specifically, Carswell described the injuries he found as "a remarkable lesion of the spinal cord accompanied with atrophy". Under the microscope, Swiss pathologist Georg Eduard Rindfleisch (1836–1908) noted in 1863 that the inflammation-associated lesions were distributed around blood vessels.

The French neurologist Jean-Martin Charcot (1825–1893) was the first person to recognize multiple sclerosis as a distinct disease in 1868. Summarizing previous reports and adding his own clinical and pathological observations, Charcot called the disease sclérose en plaques.

Improved diagnosis and treatment

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). Charcot also observed cognition changes, describing his patients as having a "marked enfeeblement of the memory" and "conceptions that formed slowly".

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". The DIT and DIS requirement was later inherited by the Poser and McDonald criteria.

During the 20th century, theories about the cause and pathogenesis were developed and effective treatments began to appear in the 1990s. 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).

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. 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". Other organizations have proposed later new clinical phenotypes, like HAMS (Highly Active MS).

Historical cases

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. Both cases have led to the proposal of a "Viking gene" hypothesis for the dissemination of the disease.

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. 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. His diary was published in 1919 as The Journal of a Disappointed Man. 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.

Research directions

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.

Biomarkers

Researchers are investigating biomarkers to help diagnose MS, to inform prognoses, and track response to medication. Ideally, biomarker would be detectable in blood, as cerebrospinal fluid is more difficult to access. Three biomarkers are emerging as candidates for real-world applications: Neurofilament light chain (NfL), chitinase-3-like protein 1 (CHI3L1) and glial fibrillary acidic protein (GFAP). NfL levels are elevated years before people typically get an MS diagnosis, and is of interest as a potential screening tool. GFAP and CHI3L1 may be able to track progression independent if relapse activity, and be used as disease progress markers.

Medications

Drugs that might promote remyelination are being studied. These drug may benefit individuals that have had myelin damage, but not yet widespread damage to exposed nerves. In general, these drugs stimulate oligodendrites in some form, which are the cells that produce myelin. Drugs under investigation include metformin (a diabetes drug), clemastine (an anti-histamine) and GSK239512. Metformin is tested in Belgium for individuals with non-active progressive MS, and Canada, for MS patients up to 25 years old. A separate trial in the UK investigates it in combination with clemastine for the treatment of relapsing-remitting MS.

One reason it has been challenging to find drugs for progressive MS is the intact blood–brain barrier, which makes it difficult to deliver drugs to the nervous system. During attacks in relapsing MS, the barrier is weakened. BTK inhibitors can cross this barrier to varying degrees, and many are studied for different types of MS. Therapies against EBV are of interest too. An EBV vaccine might help against MS, but there is also a risk the vaccine itself might trigger or worsen MS. Finally, CAR-T therapy is studied as a way to reset the immune system.

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.

In 2024, scientists shared research on their findings of ancient migration to northern Europe from the Yamnaya area of culture, tracing MS-risk gene variants dating back around 5,000 years. The MS-risk gene variants protected ancient cattle herders from animal diseases, but modern lifestyles, diets and better hygiene, have allowed the gene to develop, resulting in the higher risk of MS today.