Multiple sclerosis (MS) is a chronic and neurodegenerative autoimmune disease in which the immune system attacks myelin, the insulating cover of nerve cells, causing damage to the central nervous system. This impairs the nervous system's ability to transmit signals. Symptoms include double vision, vision loss, eye pain, muscle weakness, loss of coordination, as well as cognitive issues like problems with memory.
MS may be a rare complication of an Epstein-Barr virus (EBV) infection. Genetics and environmental factors like exposure to sunlight also impact the risk of MS. MS can be diagnosed based on symptoms, MRI scans, and sometimes a lumbar puncture to investigate spinal fluid.
There is no cure for MS. Current treatments aim to manage symptoms during acute flares and prevent further attacks with disease-modifying therapies. With effective treatment, it is possible to reduce attacks strongly, but the disease progress is not fully stopped. In addition, symptoms of MS like balance issues can be managed with drugs and with non-drug treatments (e.g. physical therapy). On average, life expectancy is slightly lower than normal.
In 2024, about 3.1 million people were affected by MS globally, with rates much higher further from the equator. The disease usually begins between the ages of 20 and 40 and is almost three times more common in women than in men. MS was first described in 1868 by French neurologist Jean-Martin Charcot.*
Signs and symptoms
Because MS lesions can affect any part of the central nervous system, a person with MS can have almost any neurological signs or symptoms.
Fatigue is one of the most common symptoms of MS. Roughly 65% of people with MS experience fatigue. Of these, some 15–40% report fatigue as their most disabling symptom.
Autonomic, visual, motor, and sensory problems are also among the most common symptoms.
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, pronounced reflexes, muscle spasms, difficulty walking, or with coordination or balance (ataxia); problems with speech or swallowing, visual problems (optic neuritis manifesting as eye pain and vision loss, or nystagmus manifesting as double vision), fatigue, and bladder and bowel difficulties (such as urinary or fecal incontinence or retention), among others. When MS is more advanced, walking difficulties lead to a higher risk of falling.
Difficulties in thinking and emotional problems such as depression or unstable mood are also common. 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.
Uhthoff's phenomenon, a reversible exacerbation of 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. 60–80% of MS patients find that symptoms, such as fatigue, are affected by changes in body temperature. MS may also present with eye movement impairments, such as internuclear ophthalmoplegia or sixth nerve palsy.
Disease course
Prodromal phase MS may have a prodromal phase in the years leading up to its manifestation, characterized by psychiatric issues, cognitive impairment, and increased use of healthcare. People later diagnosed with MS may seek healthcare for fatigue, bladder issues, headaches and other pain disorders.
Onset 85% of cases begin as a clinically isolated syndrome (CIS) over a number of days with 45% having motor or sensory problems, 20% having optic neuritis, and 10% having symptoms related to brainstem dysfunction, while the remaining 25% have more than one of the aforementioned difficulties. 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. 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).
Relapses Relapses are usually unpredictable, occurring without warning. Exacerbations rarely occur more frequently than twice per year. Some relapses, however, are preceded by common triggers and they occur more frequently during spring and summer. Similarly, viral infections such as the common cold, influenza, or gastroenteritis increase their risk.Stress may also raise attack risk modestly, with the strongest evidence for severe stress like war or in PTSD.
Many events do not affect rates of relapse requiring hospitalization including vaccination, breast feeding, physical trauma, and Uhthoff's phenomenon.
Pregnancy Many women with MS who become pregnant experience lower symptoms during pregnancy, especially in the third trimester. During the period directly after delivery, the risk increases. Overall, pregnancy does not seem to influence long-term disability.
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. See lay summary:
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.