Multiple sclerosis

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Multiple sclerosis
Other namesMultiple cerebral sclerosis, multiple cerebro-spinal sclerosis, disseminated sclerosis, encephalomyelitis disseminata
CD68-stained tissue shows several macrophages in the area of a demyelinated lesion caused by MS.
SpecialtyNeurology
SymptomsVariable, including almost any neurological symptom or sign, with autonomic, visual, motor, and sensory problems being the most common.[1]
Usual onsetAge 20–50[2]
DurationLong term[3]
CausesUnknown[4]
Diagnostic methodBased on symptoms and medical tests[5]
TreatmentDisease-modifying therapies[6]

Physiotherapy[7]

Occupational therapy[7]
Frequency0.032% (world)

Multiple sclerosis (MS) is an

sensation or coordination.[3][10][11] MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms).[12][13] In the relapsing forms of MS, between attacks, symptoms may disappear completely, although some permanent neurological problems often remain, especially as the disease advances.[13] In the progressive forms of MS, bodily function slowly deteriorates and disability worsens once symptoms manifest and will steadily continue to do so if the disease is left untreated.[14]

While the cause is unclear, the underlying mechanism is thought to be either

viral infections.[15][16][8][17] MS is usually diagnosed based on the presenting signs and symptoms and the results of supporting medical tests.[5]

No cure for multiple sclerosis is known.[18] Current treatments are aimed at mitigating inflammation and resulting symptoms from acute flares and prevention of further attacks with disease-modifying medications.[8][19] Physical therapy[7] and occupational therapy,[20] 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.[21]

Multiple sclerosis is the most common immune-mediated disorder affecting the central nervous system.[22] Nearly one million people in the United States had MS in 2022,[23] and in 2020, about 2.8 million people were affected globally, with rates varying widely in different regions and among different populations.[24] The disease usually begins between the ages of 20 and 50 and is twice as common in women as in men.[2] MS was first described in 1868 by French neurologist Jean-Martin Charcot.[25]

The name "multiple

glial scars (or sclerae – essentially plaques or lesions) that develop on the white matter of the brain and spinal cord.[25]

Signs and symptoms

Main symptoms of multiple sclerosis

As MS lesions can affect any part of the central nervous system, a person with MS can have almost any neurological symptom or sign referable to the central nervous system.

Fatigue[26] is one of the most common symptoms of MS.[27][28] Some 65% of people with MS experience fatigue symptomatology, and of these some 15–40% report fatigue as their most disabling MS symptom.[29]

Autonomic, visual, motor, and sensory problems are also among the most common symptoms.[1]

The specific symptoms are determined by the locations of the lesions within the nervous system, and may include focal

muscle spasms, difficulty with ambulation, difficulties with coordination and balance (ataxia); problems with speech or swallowing, visual problems (optic neuritis manifesting as eye pain & vision loss,[31] or nystagmus manifesting as double vision), fatigue, and bladder and bowel difficulties (such as urinary and/or fecal incontinence or retention), among others.[1] When multiple sclerosis is more advanced, walking difficulties can occur and the risk of falling increases.[32][19][33]

Difficulties thinking and emotional problems such as depression or

unstable mood are also common.[1][34] 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.[35][36][37]

Uhthoff's phenomenon, a worsening of symptoms due to exposure to higher-than-usual temperatures, and Lhermitte's sign, an electrical sensation that runs down the back when bending the neck, are particularly characteristic of MS, although may not always be present.[1] 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.[38]

Some 60% or more of MS patients find their symptoms, particularly including fatigue,[39] are affected by changes in their body heat.[40][41][42]

Measures of disability

The main measure of disability and severity is the

expanded disability status scale (EDSS), with other measures such as the multiple sclerosis functional composite being increasingly used in research.[43][44][45] EDSS is also correlated with falls in people with MS.[10] While it is a popular measure, EDSS has been criticized for some of its limitations, such as relying too much on walking.[46][10]

Disease course

The condition begins in 85% of cases as a clinically isolated syndrome (CIS) over a number of days with 45% having motor or sensory problems, 20% having optic neuritis,[31] and 10% having symptoms related to brainstem dysfunction, while the remaining 25% have more than one of the previous difficulties.[5] 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).[2] A combination of these two patterns may also occur[13] or people may start in a relapsing and remitting course that then becomes progressive later on.[2]

Relapses

Relapses are usually not predictable, occurring without warning.

breast feeding,[1] physical trauma,[51] and Uhthoff's phenomenon.[47]

Prodromal phase

MS may have a

prodromal phase in the years leading up to MS manifestation, characterized by psychiatric issues, cognitive impairment, and increased use of healthcare.[52][53]

Causes

Multiple sclerosis 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 multiple sclerosis and the virus is transcriptionally active in the infected cells.[54][55] 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.[15] 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.[56]

Immune dysregulation

Failure of both central and peripheral nervous system clearance of autoreactive immune cells is implicated in the development of MS.[15] The thymus is responsible for the immune system's central tolerance, where autoreactive T-cells are killed without being released into circulation. Via a similar mechanism, autoreactive B-cells in the bone marrow are killed. Some autoreactive T-cells & B-cells are able to 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.[15][19] Further detail on immune dysregulation's role in MS is provided in the pathophysiology section of this article as well as here.

Infectious agents

One hypothesis is that infection by a widespread microbe contributes to disease development, and the geographic distribution of this organism influences the

oligoclonal bands in the brain and cerebrospinal fluid of most people with MS, the association of several viruses with human demyelinating encephalomyelitis, and the occurrence of demyelination in animals caused by some viral infections.[58]

Epstein-Barr herpes virus (EBV) can cause infectious mononucleosis and infects about 95% of adults. In combination with other genetic and environmental factors, there is "compelling epidemiological and mechanistic evidence for a causal role of EBV in multiple sclerosis", though only a small proportion of those infected with EBV later develop MS.[59][16][60][55] A study of individuals in the United States military between 1993 and 2013 (total population greater than 10 million) compared 801 people who developed MS on or after military service to 1,566 matched controls who did not develop MS during this observation period. The study found a 32-fold increased risk of developing MS after infection with EBV. It did not find an increased risk after infection with other viruses, including the similarly transmitted cytomegalovirus. The finding strongly suggests that EBV plays a role in the onset of MS, although EBV alone may be insufficient to cause it.[16][60]

The nuclear antigen of EBV, which is the most consistent marker of EBV infection across all strains,[61] has been identified as a direct source of autoreactivity in the human body. These antigens appear to be more likely to promote autoimmune responses in a person who also has a vitamin D deficiency. The exact nature of this relationship is poorly understood.[62][15]

Genetics

HLA region of chromosome 6: Changes in this area increase the probability of getting MS.

MS is not considered a

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.[1][8][65] If both parents are affected, the risk in their children is 10 times that of the general population.[2] MS is also more common in some ethnic groups than others.[66]

Specific

HLA-C554 and HLA-DRB1*11.[1] HLA differences account for an estimated 20 to 60% of the genetic predisposition.[67] Modern genetic methods (genome-wide association studies) have revealed at least 200 variants outside the HLA locus that modestly increase the probability of MS.[68]

Geography

Geographic risk distribution of MS

The prevalence of MS from a geographic standpoint resembles a gradient, with MS being more common in people who live farther from the

Parsi.[70] The cause of this geographical pattern is not clear, although exposure to ultraviolet B (UVB) radiation and vitamin D levels have been proposed as potential explanations.[71][15] As such, those who live in northern regions of the world are thought to have less exposure to UVB radiation and subsequently lower levels of vitamin D, which is a known risk factor for developing MS.[15] Inversely, those who live in areas of relatively higher sun exposure and subsequently increased UVB radiation have a decreased risk of developing MS.[15] While the north–south gradient of incidence is decreasing,[69] as of 2010 it is still present.[71]

MS is more common in regions with northern European populations,[1] so the geographic variation may simply reflect the global distribution of these high-risk populations.[2]

A relationship between season of birth and MS lends support to this idea, with fewer people born in the Northern Hemisphere in November compared to May being affected later in life.[73]

Environmental factors may play a role during childhood, 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 persons retain the risk of their home country.[1][74] Some evidence indicates that the effect of moving may still apply to people older than 15.[1]

Impact of heat or cold

MS symptoms may increase if body temperature is high or low.[75][76][77] Fatigue is particularly effected.[39][40][41][42][78][79][80][81]

Other

Stress may be a risk factor, although the evidence to support this is weak.[74] Association with occupational exposures and toxins—mainly organic solvents[83]—has been evaluated, but no clear conclusions have been reached.[74] Vaccinations were studied as causal factors; most studies, though, show no association.[74][84] 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".[82] 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.[85] Obesity during adolescence and young adulthood is a risk factor for MS.[86]

Pathophysiology

Multiple sclerosis

Multiple sclerosis is an autoimmune disease, primarily mediated by T-cells.

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.[1] Damage is believed to be caused, at least in part, by attack on the nervous system by a person's own immune system.[1]

Immune dysregulation

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.[15] 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.[15] 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.[15][19] The presence of these oligoclonal bands has been used as supportive evidence in clinching a diagnosis of MS.[87] As similarly described before, B-cells can also produce cytokines that induce an inflammatory immune response via activation of autoreactive T-cells.[15][88] As such, higher levels of these autoreactive B-cells is associated with increased number of lesions & neurodegeneration as well as worse disability.[15]

Another cell population that is becoming increasingly implicated in MS are microglia. These cells are resident to & keep watch over the CNS, responding to pathogens by shifting between pro- & anti-inflammatory states. Microglia have been shown to be involved in the formation of MS lesions and have been shown to be involved in other diseases that primarily affect the CNS white matter. Although, 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.[15] 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.[15]

Lesions

Klüver-Barrera
myelin staining, decoloration in the area of the lesion can be appreciated.

The name multiple sclerosis refers to the scars (sclerae – better known as plaques or lesions) that form in the nervous system. These lesions most commonly affect the

brain stem, basal ganglia, and spinal cord, or white matter tracts close to the lateral ventricles.[1] 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.[8]

MRI machine used as a tool for MS diagnosis

To be specific, MS involves the loss of

increase in the number of astrocytes due to the destruction of nearby neurons.[1] A number of lesion patterns have been described.[90]

Inflammation

Apart from demyelination, the other sign of the disease is

immunological explanation, the inflammatory process is caused by T cells, a kind of lymphocytes that plays an important role in the body's defenses.[8] 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".[1]

The attack on myelin starts inflammatory processes, which trigger other immune cells and the release of soluble factors like

macrophages, and more activation of cytokines and other destructive proteins.[8] Inflammation can potentially reduce transmission of information between neurons in at least three ways.[1] 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.[1]

Blood–brain barrier

The blood–brain barrier (BBB) is a part of the capillary system that prevents the entry of T cells into the central nervous system. 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.[8][91] Gadolinium cannot cross a normal BBB, so gadolinium-enhanced MRI is used to show BBB breakdowns.[92]

MS fatigue

The pathophysiology and mechanisms causing MS fatigue are not well understood.[93][94][95] MS fatigue can be affected by body heat,[75][77] and this may differentiate MS fatigue from other primary fatigue.[39][40][81] Fatigability (loss of strength) may increase perception of fatigue, but the two measures warrant independent assessment in clinical studies.[96]

Diagnosis

Animation showing dissemination of brain lesions in time and space as demonstrated by monthly MRI studies along a year
Multiple sclerosis as seen on MRI

Multiple sclerosis is typically diagnosed based on the presenting signs and symptoms, in combination with supporting medical imaging and laboratory testing.[5] It can be difficult to confirm, especially early on, since the signs and symptoms may be similar to those of other medical problems.[1][97]

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[98] with the Schumacher and Poser criteria being of mostly historical significance.[99] 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.[87] 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.[87]
  • 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.[87]
  • 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.[87]
  • 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.[87]
  • 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.[87]

As of 2017, no single test (including biopsy) can provide a definitive diagnosis.[100]

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.[101][102]

Central vein signs (CVSs) have been proposed as a good indicator of MS in comparison with other conditions causing white lesions.[103][104][105][106] One small study found fewer CVSs in older and hypertensive people.[107] Further research on CVS as a biomarker for MS is ongoing.[108]

Cerebrospinal fluid (lumbar puncture)

Testing of cerebrospinal fluid obtained from a lumbar puncture can provide evidence of chronic inflammation in the central nervous system. The cerebrospinal fluid is tested for oligoclonal bands of IgG on electrophoresis, which are inflammation markers found in 75–85% of people with MS.[101][109]

Differential diagnosis

Several diseases present similarly to MS.[110][111] 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.[110][111]

In an emergency setting, it is important to rule out a stroke or bleeding in the brain.[111] Intractable vomiting, severe optic neuritis,[31] or bilateral optic neuritis[31] raises suspicion for neuromyelitis optica spectrum disorder (NMOSD).[112] 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.[110][111]

Types and variants

MS progression types. From bottom to top: RRMS, PPMS, SPMS.

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:[113][114]

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

CIS can be characterised as a single lesion seen on MRI which is associated with signs and/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.[1][115] 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.[116]

RRMS is characterized by unpredictable relapses followed by periods of months to years of relative quiet (

problems, the latter in about 40% of attacks and being more common the longer a person has had the disease.[1][5] This describes the initial course of 80% of individuals with MS.[1]

PPMS occurs in roughly 10–20% of individuals with the disease, with no remission after the initial symptoms.[5][117] It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements.[13] The usual age of onset for the primary progressive subtype is later than of the relapsing-remitting subtype. It is similar to the age that secondary progressive usually begins in RRMS, around 40 years of age.[1]

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.[1][13] Occasional relapses and minor remissions may appear.[13] The most common length of time between disease onset and conversion from RRMS to SPMS is 19 years.[118]

Special courses

Independently of the types published by the MS associations, regulatory agencies such as the FDA often consider special courses, trying to reflect some clinical trials results on their approval documents. Some examples could be "highly active MS" (HAMS),[119] "active secondary MS" (similar to the old progressive-relapsing)[120] and "rapidly progressing PPMS".[121]

Also, deficits always resolving between attacks is sometimes referred to as "benign" MS,[122] although people still build up some degree of disability in the long term.[1] On the other hand, the term malignant multiple sclerosis is used to describe people with MS having reached significant level of disability in a short period.[123]

An international panel has published a standardized definition for the course HAMS.[119]

Variants

Atypical

Devic's disease, are now considered outside the MS spectrum.[125]

Management

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.[23] 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.[126]

The first approved medications used to treat MS were modestly effective, though were poorly tolerated and had many adverse effects.[3] Several treatment options with better safety and tolerability profiles have been introduced,[23] 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 flare

During symptomatic attacks, administration of high doses of intravenous corticosteroids, such as methylprednisolone, is the usual therapy,[1] with oral corticosteroids seeming to have a similar efficacy and safety profile.[127] Although effective in the short term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery.[128][129] The long-term benefit is unclear in optic neuritis as of 2020.[130][31] The consequences of severe attacks that do not respond to corticosteroids might be treatable by plasmapheresis.[1]

Chronic management

Relapsing remitting multiple sclerosis

Multiple

Interferons[132] and glatiramer acetate are first-line treatments[5] and are roughly equivalent, reducing relapses by approximately 30%.[133] Early-initiated long-term therapy is safe and improves outcomes.[134][135]

Treatment of CIS with interferons decreases the chance of progressing to clinical MS.[1][136][137] Efficacy of interferons and glatiramer acetate in children has been estimated to be roughly equivalent to that of adults.[138] The role of some newer agents such as fingolimod,[139] teriflunomide, and dimethyl fumarate,[140] is not yet entirely clear.[141] 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.[142]

The relative effectiveness of different treatments is unclear, as most have only been compared to placebo or a small number of other therapies.[143] Direct comparisons of interferons and glatiramer acetate indicate similar effects or only small differences in effects on relapse rate, disease progression, and MRI measures.[144] There is high confidence that natalizumab, cladribine, or alemtuzumab are decreasing relapses over a period of two years for people with RRMS.[145] 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.[143] Evidence on relative effectiveness in reducing disability progression is unclear.[143] There is moderate confidence that a two-year treatment with natalizumab slows disability progression for people with RRMS.[145] All medications are associated with adverse effects that may influence their risk to benefit profiles.[143][145]

Ublituximab was approved for medical use in the United States in December 2022.[146]

Medications

Overview of medications available for MS.[147]

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 [
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

Progressive multiple sclerosis

In 2011, mitoxantrone was the first medication approved for secondary progressive MS.[148] In this population, tentative evidence supports mitoxantrone moderately slowing the progression of the disease and decreasing rates of relapses over two years.[149][150]

New approved medications continue to emerge in modern medicine. In March 2017, the FDA approved ocrelizumab as a treatment for primary progressive MS in adults, the first drug to gain that approval,

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.[155]

In 2019, siponimod and cladribine were approved in the United States for the treatment of secondary progressive multiple sclerosis (SPMS).[151] 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.[156]

Adverse effects

Irritation zone after injection of glatiramer acetate

The

systolic dysfunction (12%), infertility, and acute myeloid leukemia (0.8%) from mitoxantrone,[149][161] and progressive multifocal leukoencephalopathy occurring with natalizumab (occurring in 1 in 600 people treated).[5][162]

Fingolimod may give rise to

reduction in lymphocyte levels.[139][141] Tentative evidence supports the short-term safety of teriflunomide, with common side effects including: headaches, fatigue, nausea, hair loss, and limb pain.[131] There have also been reports of liver failure and PML with its use and it is dangerous for fetal development.[141] Most common side effects of dimethyl fumarate are flushing and gastrointestinal problems.[140][163][141] While dimethyl fumarate may lead to a reduction in the white blood cell count there were no reported cases of opportunistic infections during trials.[164]

Associated symptoms

Both medications and neurorehabilitation have been shown to improve some symptoms, though neither changes the course of the disease.[165] Some symptoms have a good response to medication, such as bladder spasticity, while others are little changed.[1] Equipment such as catheters for neurogenic bladder dysfunction or mobility aids can be helpful in improving 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.[1] Multidisciplinary rehabilitation programs increase activity and participation of people with MS but do not influence impairment level.[166] 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.[167] There is limited evidence for the overall efficacy of individual therapeutic disciplines,[168][169] though there is good evidence that specific approaches, such as exercise,[170][171][172][173] and psychological therapies are effective.[174] 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.[175] The effectiveness of palliative approaches in addition to standard care is uncertain, due to lack of evidence.[176] 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.[177] Cognitive behavioral therapy has shown to be moderately effective for reducing MS fatigue.[178] 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.[179]

Non-pharmaceutical

There is some evidence that aquatic therapy is a beneficial intervention.[180]

The spasticity associated with MS can be difficult to manage because of the progressive and fluctuating course of the disease.[181] 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.[182]

Alternative treatments

Over 50% of people with MS may use

hyperbaric oxygen therapy,[190] self-infection with hookworms, reflexology, acupuncture,[183][191] and mindfulness.[192] 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.[193] There is insufficient evidence supporting high-dose biotin[194][195][196] and some evidence for increased disease activity and higher risk of relapse with its use.[197] A recent review of the effectiveness of Cannabis and Cannabinoids (2022) found that compared with placebo nabiximos probably reduce the severity of spasticity in the short term.[198]

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 as of 2022 there is no cure.[23][199]

The prognosis of MS depends on the subtype of the disease, and there is considerable individual variation in the progression of the disease.[200] 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.[23] With treatments available in the 2020s, relapses can be eliminated or substantially reduced. However, "silent progression" of the disease still occurs.[199][201]

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.[202][199][23] The prognosis for progressive MS is worse, with faster accumulation of disability, though with considerable individual variation.[202] In untreated PPMS, the median time from onset to requiring a walking aid is estimated as seven years.[23] In SPMS, a 2014 cohort study reported that people required a walking aid after an average of five years from onset of SPMS, and were chair or bed-bound after an average of fifteen years.[203]

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.[204] As of 2018, no biomarker can accurately predict disease progression in every patient.[200] 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 as of 2018.[204] Early treatment leads to a better prognosis, but a higher relapse frequency when treated with DMTs is associated with a poorer prognosis.[200][204] A 60-year longitudinal population study conducted in Norway found a 7-year shorter life expectancy in MS compared with the general population and a rise in survival in MS during the observation period. 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 5 years shorter than for women.[205]

Epidemiology

Deaths from multiple sclerosis per million persons in 2012
  0
  1
  2
  3–5
  6–12
  13–25

MS is the most common autoimmune disorder of the central nervous system.[22] 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.[24] In Africa, there are 5 people per 100,000 diagnosed with MS, compared to South East Asia where the prevalence is 9 per 100,000, 112 per 100,000 in the Americas, and 133 per 100,000 in Europe.[206]

Increasing rates of MS may be explained simply by better diagnosis.[2] Studies on populational and geographical patterns have been common[57] and have led to a number of theories about the cause.[17][74][82]

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.[2][98] The primary progressive subtype is more common in people in their fifties.[117] Similarly to many autoimmune disorders, the disease is more common in women, and the trend may be increasing.[1][207] 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.[208][medical citation needed] In children, it is even more common in females than males,[1] while in people over fifty, it affects males and females almost equally.[117]

History

Medical discovery

brain stem and spinal cord
(1838)

Georg Eduard Rindfleisch (1836–1908) noted in 1863 that the inflammation-associated lesions were distributed around blood vessels.[210][211]

The French

neurologist Jean-Martin Charcot (1825–1893) was the first person to recognize multiple sclerosis as a distinct disease in 1868.[209]
Summarizing previous reports and adding his own clinical and pathological observations, Charcot called the disease sclerose en plaques.

Diagnosis history

The first attempt to establish a set of diagnostic criteria was also due to Charcot in 1868. He published what now is known as the "

Charcot Triad", consisting in nystagmus, intention tremor, and telegraphic speech (scanning speech).[212] Charcot also observed cognition changes, describing his patients as having a "marked enfeeblement of the memory" and "conceptions that formed slowly".[25]

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".[212] The DIT and DIS requirement was later inherited by the Poser and McDonald criteria, whose 2017 revision is in use.[212][200]

During the 20th century, theories about the cause and pathogenesis were developed and effective treatments began to appear in the 1990s.[1] 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).[213]

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.[213] 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".[214] Other organizations have proposed later new clinical phenotypes, like HAMS (Highly Active MS).[215]

Historical cases

Muybridge

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

A young woman called Halldora who lived in

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.[216] Both cases have led to the proposal of a "Viking gene" hypothesis for the dissemination of the disease.[217]

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 of 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.[218][219] 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.[219] His diary was published in 1919 as The Journal of a Disappointed Man.[220] Charles Dickens, a keen observer, described possible bilateral optic neuritis with reduced contrast vision and Uhthoff phenomenon in the main female character of Bleak House (1852–1853), Esther Summerville.[221]

Research

Epstein-Barr virus

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.[16]

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

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 an pathophysiologocal 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.[225]

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 epignetically silent, but can be reactivated by exogenous viruses, proinflammatory conditions and/or oxidative stress.[226][227][228]

Medications

Medications that influence voltage-gated sodium ion channels are under investigation as a potential neuroprotective strategy because of hypothesized role of sodium in the pathological process leading to axonal injury and accumulating disability. There is insufficient evidence of an effect of sodium channel blockers for people with MS.[229]

Pathogenesis

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

anti-MOG demyelinating diseases.[230]

A third kind of auto-antibodies is accepted. They are several

combined central and peripheral demyelination (CCPD, which is considered another atypical MS presentation).[231]

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

Disease biomarkers

MRI brain scan produced using a Gradient-echo phase sequence showing an iron deposit in a white matter lesion (inside green box in the middle of the image; enhanced and marked by red arrow top-left corner)[233]

Since disease progression is the result of degeneration of neurons, the roles of proteins showing loss of nerve tissue such as

N-acetylaspartate are under investigation.[234][235]

Improvement in neuroimaging techniques such as

GABA, and GSH, observed for multiple sclerosis and its subtypes.[237] There are other techniques under development that include contrast agents capable of measuring levels of peripheral macrophages, inflammation, or neuronal dysfunction,[236] and techniques that measure iron deposition that could serve to determine the role of this feature in MS, or that of cerebral perfusion.[236]

COVID-19

The hospitalization rate was found to be higher among individuals with MS and COVID-19 infection, at 10%, while the pooled infection rate is estimated at 4%. The pooled prevalence of death in hospitalized individuals with MS is estimated as 4%.[238]

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.[239]

It has also been proposed that certain bacteria found in the gut use molecular mimicry to infiltrate the brain via the

better source needed
]

In 2024, scientists shared research on their findings of ancient migration to northern Europe from the Yamnaya area of culture, tracing DNA, MS gene variants dating back around 5,000 years.[244][245] The original gene 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.[246]

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External links