Multiple sclerosis
   HOME

TheInfoList



OR:

Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common
demyelinating disease A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This damage impairs the conduction of signals in the affected nerves. In turn, the reduction in conduction ability causes deficiency i ...
, in which the insulating covers of
nerve cells A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
in the
brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...
and
spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spi ...
are damaged. This damage disrupts the ability of parts of the nervous system to transmit signals, resulting in a range of
signs and symptoms Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...
, including physical, mental, and sometimes psychiatric problems. Specific symptoms can include
double vision Diplopia is the simultaneous perception of two images of a single object that may be displaced horizontally or vertically in relation to each other. Also called double vision, it is a loss of visual focus under regular conditions, and is often v ...
,
blindness Visual impairment, also known as vision impairment, is a medical definition primarily measured based on an individual's better eye visual acuity; in the absence of treatment such as correctable eyewear, assistive devices, and medical treatment ...
in one eye, muscle weakness, and trouble with
sensation Sensation (psychology) refers to the processing of the senses by the sensory system. Sensation or sensations may also refer to: In arts and entertainment In literature * Sensation (fiction), a fiction writing mode * Sensation novel, a Britis ...
or coordination. MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms). In the relapsing forms of MS, between attacks, symptoms may disappear completely, although some permanent neurological problems often remain, especially as the disease advances. While the cause is unclear, the underlying mechanism is thought to be either destruction by the immune system or failure of the
myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...
-producing cells. Proposed causes for this include
genetics Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian friar wor ...
and environmental factors, such as
viral infection A viral disease (or viral infection) occurs when an organism's body is invaded by pathogenic viruses, and infectious virus particles (virions) attach to and enter susceptible cells. Structural Characteristics Basic structural characteristics, ...
s. MS is usually diagnosed based on the presenting signs and symptoms and the results of supporting medical tests. There is no known cure for multiple sclerosis. Treatments attempt to improve function after an attack and prevent new attacks. Physical therapy and occupational therapy can help with people's ability to function. Many people pursue
alternative treatments Alternative medicine is any practice that aims to achieve the healing effects of medicine despite lacking biological plausibility, testability, repeatability, or evidence from clinical trials. Complementary medicine (CM), complementary and alt ...
, despite a lack of evidence of benefit. 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. Multiple sclerosis is the most common immune-mediated disorder affecting the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
. There are nearly one million people with MS in the United States in 2022, and in 2020, about 2.8 million people were affected globally, with rates varying widely in different regions and among different populations. The disease usually begins between the ages of twenty and fifty and is twice as common in women as in men. MS was first described in 1868 by French neurologist Jean-Martin Charcot. The name ''multiple sclerosis'' refers to the numerous
glial scars Glial scar formation (gliosis) is a reactive cellular process involving astrogliosis that occurs after injury to the central nervous system. As with scarring in other organs and tissues, the glial scar is the body's mechanism to protect and begin ...
(or sclerae – essentially plaques or lesions) that develop on the
white matter White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distributi ...
of the brain and spinal cord.
*


Signs and symptoms

A person with MS can have almost any neurological symptom or sign, with autonomic, visual, motor, and sensory problems being the most common. The specific symptoms are determined by the locations of the lesions within the nervous system, and may include loss of sensitivity or changes in sensation such as tingling, pins and needles or numbness, muscle weakness, blurred vision, pronounced reflexes,
muscle spasms A spasm is a sudden involuntary contraction of a muscle, a group of muscles, or a hollow organ such as the bladder. A spasmodic muscle contraction may be caused by many medical conditions, including dystonia. Most commonly, it is a muscle c ...
, or difficulty in moving; difficulties with coordination and balance (
ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
); problems with speech or swallowing, visual problems (
nystagmus Nystagmus is a condition of involuntary (or voluntary, in some cases) eye movement. Infants can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in reduced or limited vision. Due to the invol ...
,
optic neuritis Optic neuritis describes any condition that causes inflammation of the optic nerve; it may be associated with demyelinating diseases, or infectious or inflammatory processes. It is also known as optic papillitis (when the head of the optic nerv ...
or
double vision Diplopia is the simultaneous perception of two images of a single object that may be displaced horizontally or vertically in relation to each other. Also called double vision, it is a loss of visual focus under regular conditions, and is often v ...
), feeling tired,
acute Acute may refer to: Science and technology * Acute angle ** Acute triangle ** Acute, a leaf shape in the glossary of leaf morphology * Acute (medicine), a disease that it is of short duration and of recent onset. ** Acute toxicity, the adverse eff ...
or
chronic pain Chronic pain is classified as pain that lasts longer than three to six months. In medicine, the distinction between acute and chronic pain is sometimes determined by the amount of time since onset. Two commonly used markers are pain that continue ...
, and bladder and bowel difficulties (such as
neurogenic bladder Neurogenic bladder dysfunction, or neurogenic bladder, refers to urinary bladder problems due to disease or injury of the central nervous system or peripheral nerves involved in the control of urination. There are multiple types of neurogenic bladde ...
), among others. When multiple sclerosis is more advanced, walking difficulties can occur and the risk of falling increases. Difficulties 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 In cognitive science and neuropsychology, executive functions (collectively referred to as executive function and cognitive control) are a set of cognitive processes that are necessary for the cognitive control of behavior: selecting and succ ...
less commonly. Intelligence, language, and
semantic memory Semantic memory refers to general world knowledge that humans have accumulated throughout their lives. This general knowledge (word meanings, concepts, facts, and ideas) is intertwined in experience and dependent on culture. We can learn about n ...
are usually preserved, and the level of cognitive impairment varies significantly between people with MS.
Uhthoff's phenomenon Uhthoff's phenomenon (also known as Uhthoff's syndrome, Uhthoff's sign, and Uhthoff's symptom) is the worsening of neurologic symptoms in multiple sclerosis (MS) and other demyelinating diseases when the body is overheated. This may occur due to ...
, a worsening of symptoms due to exposure to higher than usual temperatures, and
Lhermitte's sign Lhermitte phenomenon, also called the barber chair phenomenon, is an uncomfortable "electrical" sensation that runs through the back and into the limbs. The sensation can feel like it goes up or down the spine. It is painful for some, although oth ...
, an electrical sensation that runs down the back when bending the neck, are particularly characteristic of MS. The main measure of disability and severity is the expanded disability status scale (EDSS), with other measures such as the
multiple sclerosis functional composite The Multiple Sclerosis Functional Composite (MSFC) is a clinical trial outcome measure of assessing the severity of multiple sclerosis primarily used in research. The score is based on a combination of timed tests of walking, arm function, and cog ...
being increasingly used in research. EDSS is also correlated with falls in people with MS. While it is a popular measure, EDSS has been criticized for some of its limitations, such as relying too much on walking. The condition begins in 85% of cases as a
clinically isolated syndrome A clinically isolated syndrome (CIS) is a clinical situation of an individual's first neurological episode, caused by inflammation or demyelination of nerve tissue. An episode may be monofocal, in which symptoms present at a single site in the cen ...
(CIS) over a number of days with 45% having motor or sensory problems, 20% having
optic neuritis Optic neuritis describes any condition that causes inflammation of the optic nerve; it may be associated with demyelinating diseases, or infectious or inflammatory processes. It is also known as optic papillitis (when the head of the optic nerv ...
, and 10% having symptoms related to brainstem dysfunction, while the remaining 25% have more than one of the previous difficulties. The course of symptoms occurs in two main patterns initially: either as episodes of sudden worsening that last a few days to months (called
relapse In internal medicine, relapse or recidivism is a recurrence of a past (typically medical) condition. For example, multiple sclerosis and malaria often exhibit peaks of activity and sometimes very long periods of dormancy, followed by relapse or ...
s, exacerbations, bouts, attacks, or flare-ups) followed by improvement (85% of cases) or as a gradual worsening over time without periods of recovery (10–15% of cases). A combination of these two patterns may also occur or people may start in a relapsing and remitting course that then becomes progressive later on. Relapses are usually not predictable, 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 The common cold or the cold is a viral infectious disease of the upper respiratory tract that primarily affects the respiratory mucosa of the nose, throat, sinuses, and larynx. Signs and symptoms may appear fewer than two days after exposu ...
, influenza, or gastroenteritis increase their risk.
Stress Stress may refer to: Science and medicine * Stress (biology), an organism's response to a stressor such as an environmental condition * Stress (linguistics), relative emphasis or prominence given to a syllable in a word, or to a word in a phrase ...
may also trigger an attack. Women with MS who become pregnant experience fewer relapses; however, during the first months after delivery the risk increases. Overall, pregnancy does not seem to influence long-term disability. Many events have been found not to affect relapse rates including
vaccination Vaccination is the administration of a vaccine to help the immune system develop immunity from a disease. Vaccines contain a microorganism or virus in a weakened, live or killed state, or proteins or toxins from the organism. In stimulating ...
,
breast feeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that brea ...
, physical trauma, and
Uhthoff's phenomenon Uhthoff's phenomenon (also known as Uhthoff's syndrome, Uhthoff's sign, and Uhthoff's symptom) is the worsening of neurologic symptoms in multiple sclerosis (MS) and other demyelinating diseases when the body is overheated. This may occur due to ...
.


Prodromal phase

MS may have a
prodromal In medicine, a prodrome is an early sign or symptom (or set of signs and symptoms) that often indicates the onset of a disease before more diagnostically specific signs and symptoms develop. It is derived from the Greek word ''prodromos'', meaning ...
phase in the years leading up to MS manifestation, characterized by psychiatric issues, cognitive impairment, and increased utilization of healthcare.


Causes

The cause of MS is unknown; however, it is believed to occur as a result of some combination of genetic and environmental factors such as infectious agents.


Infectious agents

Many
microbes A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...
have been proposed as triggers of MS. One hypothesis is that infection by a widespread microbe contributes to disease development, and the geographic distribution of this organism significantly influences the epidemiology of MS. Two opposing versions of this hypothesis include the
hygiene hypothesis In medicine, the hygiene hypothesis states that early childhood exposure to particular microorganisms (such as the gut flora and helminth parasites) protects against allergic diseases by contributing to the development of the immune system. In pa ...
and the prevalence hypothesis, the former being more favored. The hygiene hypothesis proposes that exposure to certain infectious agents early in life is protective; the disease is a response to a late encounter with such agents. The prevalence hypothesis proposes that an early, persistent, and silent infection increases risk of disease, and thus the disease is more common where the infectious agent is more common. Only in a few cases and after many years does it cause demyelination.
Human herpes virus ''Herpesviridae'' is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word ''ἕρπειν ...
es are a candidate group of viruses. Epstein-Barr virus (EBV), a herpes virus that can cause
infectious mononucleosis Infectious mononucleosis (IM, mono), also known as glandular fever, is an infection usually caused by the Epstein–Barr virus (EBV). Most people are infected by the virus as children, when the disease produces few or no symptoms. In young adult ...
and infects approximately 95% of adults, has been increasingly suspected to be an initiating cause of MS, in combination with other genetic and environmental factors, even though only a small proportion of those infected with EBV will later develop MS. Se
BBC lay summary
of 13 April 2022.
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 insufficent to cause MS. Although some consider that this goes against the hygiene hypothesis, since the non-infected have probably experienced a more hygienic upbringing, others believe that there is no contradiction, since it is a first encounter with the causative virus relatively late in life that is the trigger for the disease. Other diseases that may be related include measles, mumps and rubella. Evidence for a virus as a cause include the presence of
oligoclonal bands Oligoclonal bands (OCBs) are bands of immunoglobulins that are seen when a patient's blood serum, or cerebrospinal fluid (CSF) is analyzed. They are used in the diagnosis of various neurological and blood diseases, especially in multiple sclerosis. ...
in the brain and
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...
of most people with MS, the association of several viruses with human demyelinating
encephalomyelitis Encephalomyelitis is inflammation of the brain and spinal cord. Various types of encephalomyelitis include: * '' Acute disseminated encephalomyelitis'' or ''postinfectious encephalomyelitis'', a demyelinating disease of the brain and spinal cord, ...
, and the occurrence of demyelination in animals caused by some viral infections.


Genetics

MS is not considered a
hereditary disease A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
; however, a number of genetic variations have been shown to increase the risk. Some of these genes appear to have higher levels of expression in
microglial cells Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune ...
than expected by chance. The probability of developing the disease is higher in relatives of an affected person, with a greater risk among those more closely related. An
identical twin Twins are two offspring produced by the same pregnancy.MedicineNet > Definition of TwinLast Editorial Review: 19 June 2000 Twins can be either ''monozygotic'' ('identical'), meaning that they develop from one zygote, which splits and forms two ...
of an affected individual has a 30% chance of developing MS, 5% for a non-identical twin, 2.5% for a sibling, and an even lower chance for a half-sibling. If both parents are affected the risk in their children is 10 times that of the general population. MS is also more common in some ethnic groups than others. Specific
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
s that have been linked with MS include differences in the
human leukocyte antigen The human leukocyte antigen (HLA) system or complex is a complex of genes on chromosome 6 in humans which encode cell-surface proteins responsible for the regulation of the immune system. The HLA system is also known as the human version of th ...
(HLA) system—a group of genes on
chromosome 6 Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs (the building material of DNA) and represents between 5.5 and 6% of the total ...
that serves as the major histocompatibility complex (MHC). That differences in the HLA region are related to susceptibility has been known since the 1980s, and this same region has also been implicated in the development of other autoimmune diseases such as
diabetes type I Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar f ...
and
systemic lupus erythematosus Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...
. The most consistent finding is the association between multiple sclerosis and
allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chro ...
s of the MHC defined as DR15 and DQ6. Other loci have shown a protective effect, such as HLA-C554 and
HLA-DRB1 HLA class II histocompatibility antigen, DRB1 beta chain is a protein that in humans is encoded by the ''HLA-DRB1'' gene. DRB1 encodes the most prevalent beta subunit of HLA-DR. DRB1 alleles, especially those encoding amino acid sequence changes at ...
*11. Overall, it has been estimated that HLA differences account for between 20% and 60% of the genetic predisposition. Modern genetic methods (
genome-wide association studies In genomics, a genome-wide association study (GWA study, or GWAS), also known as whole genome association study (WGA study, or WGAS), is an observational study of a genome-wide set of genetic variants in different individuals to see if any varian ...
) have revealed at least 200 variants outside the HLA
locus Locus (plural loci) is Latin for "place". It may refer to: Entertainment * Locus (comics), a Marvel Comics mutant villainess, a member of the Mutant Liberation Front * ''Locus'' (magazine), science fiction and fantasy magazine ** ''Locus Award' ...
that modestly increase the probability of MS.


Geography

MS is more common in people who live farther from the
equator The equator is a circle of latitude, about in circumference, that divides Earth into the Northern and Southern hemispheres. It is an imaginary line located at 0 degrees latitude, halfway between the North and South poles. The term can als ...
, although exceptions exist. These exceptions include ethnic groups that are at low risk and that live far from the equator such as the
Sami Acronyms * SAMI, ''Synchronized Accessible Media Interchange'', a closed-captioning format developed by Microsoft * Saudi Arabian Military Industries, a government-owned defence company * South African Malaria Initiative, a virtual expertise ...
,
Amerindians The Indigenous peoples of the Americas are the inhabitants of the Americas before the arrival of the European settlers in the 15th century, and the ethnic groups who now identify themselves with those peoples. Many Indigenous peoples of the Ame ...
, Canadian
Hutterite Hutterites (german: link=no, Hutterer), also called Hutterian Brethren (German: ), are a communal ethnoreligious branch of Anabaptists, who, like the Amish and Mennonites, trace their roots to the Radical Reformation of the early 16th century ...
s, New Zealand
Māori Māori or Maori can refer to: Relating to the Māori people * Māori people of New Zealand, or members of that group * Māori language, the language of the Māori people of New Zealand * Māori culture * Cook Islanders, the Māori people of the C ...
, and Canada's
Inuit Inuit (; iu, ᐃᓄᐃᑦ 'the people', singular: Inuk, , dual: Inuuk, ) are a group of culturally similar indigenous peoples inhabiting the Arctic and subarctic regions of Greenland, Labrador, Quebec, Nunavut, the Northwest Territories ...
, as well as groups that have a relatively high risk and that live closer to the equator such as
Sardinians The Sardinians, or Sards ( sc, Sardos or ; Italian and Sassarese: ''Sardi''; Gallurese: ''Saldi''), are a Romance language-speaking ethnic group native to Sardinia, from which the western Mediterranean island and autonomous region of Italy de ...
, inland
Sicilians Sicilians or the Sicilian people are a Romance speaking people who are indigenous to the island of Sicily, the largest island in the Mediterranean Sea, as well as the largest and most populous of the autonomous regions of Italy. Origin and i ...
,
Palestinians Palestinians ( ar, الفلسطينيون, ; he, פָלַסְטִינִים, ) or Palestinian people ( ar, الشعب الفلسطيني, label=none, ), also referred to as Palestinian Arabs ( ar, الفلسطينيين العرب, label=non ...
, and
Parsi Parsis () or Parsees are an ethnoreligious group of the Indian subcontinent adhering to Zoroastrianism. They are descended from Persians who migrated to Medieval India during and after the Arab conquest of Iran (part of the early Muslim conq ...
. The cause of this geographical pattern is not clear. While the north–south gradient of incidence is decreasing, as of 2010 it is still present. MS is more common in regions with northern European populations and the geographic variation may simply reflect the global distribution of these high-risk populations. 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. 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, however, the person retains the risk of their home country. There is some evidence that the effect of moving may still apply to people older than 15.


Other

Smoking Smoking is a practice in which a substance is burned and the resulting smoke is typically breathed in to be tasted and absorbed into the bloodstream. Most commonly, the substance used is the dried leaves of the tobacco plant, which have bee ...
may be an independent risk factor for MS.
Stress Stress may refer to: Science and medicine * Stress (biology), an organism's response to a stressor such as an environmental condition * Stress (linguistics), relative emphasis or prominence given to a syllable in a word, or to a word in a phrase ...
may be a risk factor, although the evidence to support this is weak. Association with occupational exposures and
toxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849 ...
s—mainly organic
solvent A solvent (s) (from the Latin '' solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a solution. A solvent is usually a liquid but can also be a solid, a gas, or a supercritical fluid. Water is a solvent for ...
s—has been evaluated, but no clear conclusions have been reached.
Vaccinations Vaccination is the administration of a vaccine to help the immune system develop immunity from a disease. Vaccines contain a microorganism or virus in a weakened, live or killed state, or proteins or toxins from the organism. In stimulating ...
were studied as causal factors; however, most studies show no association. Several other possible risk factors, such as
diet Diet may refer to: Food * Diet (nutrition), the sum of the food consumed by an organism or group * Dieting, the deliberate selection of food to control body weight or nutrient intake ** Diet food, foods that aid in creating a diet for weight loss ...
and
hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are require ...
intake, have been looked at; however, evidence on their relation with the disease is "sparse and unpersuasive".
Gout Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by deposition of monosodium urate monohydrate crystals. Pain typically comes on rapidly, reaching maximal intens ...
occurs less than would be expected and lower levels of
uric acid Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown ...
have been found in people with MS. This has led to the theory that uric acid is protective, although its exact importance remains unknown. Obesity during adolescence and young adulthood is a risk factor for MS.


Pathophysiology

The three main characteristics of MS are the formation of lesions in the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
(also called plaques), inflammation and the destruction of
myelin sheath Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...
s of
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s. These features interact in a complex and not yet fully understood manner to produce the breakdown of nerve tissue and in turn the signs and symptoms of the disease. Cholesterol crystals are believed both to impair myelin repair and to aggravate inflammation. MS is believed to be an
immune-mediated An immune disorder is a dysfunction of the immune system. These disorders can be characterized in several different ways: * By the component(s) of the immune system affected * By whether the immune system is overactive or underactive * By whether ...
disorder that develops from an interaction of the individual's genetics and as yet unidentified environmental causes. Damage is believed to be caused, at least in part, by attack on the nervous system by a person's own immune system.


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 White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distributi ...
in the
optic nerve In neuroanatomy, the optic nerve, also known as the second cranial nerve, cranial nerve II, or simply CN II, is a paired cranial nerve that transmits visual information from the retina to the brain. In humans, the optic nerve is derived fro ...
,
brain stem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is co ...
,
basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an exter ...
, and
spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spi ...
, or white matter tracts close to the lateral ventricles. The function of white matter cells is to carry signals between
grey matter Grey matter is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil (dendrites and unmyelinated axons), glial cells (astrocytes and oligodendrocytes), synapses, and capillaries. Grey matter is distingu ...
areas, where the processing is done, and the rest of the body. The
peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...
is rarely involved. To be specific, MS involves the loss of
oligodendrocyte Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the ...
s, the cells responsible for creating and maintaining a fatty layer—known as the
myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...
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 Remyelination is the process of propagating oligodendrocyte precursor cells to form oligodendrocytes to create new myelin sheaths on demyelinated axons in the CNS. This is a process naturally regulated in the body and tends to be very efficient i ...
, takes place in 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 ten new plaques. This could indicate that there are a number of lesions 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.


Inflammation

Apart from demyelination, the other sign of the disease is
inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
. Fitting with an
immunological Immunology is a branch of medicineImmunology for Medical Students, Roderick Nairn, Matthew Helbert, Mosby, 2007 and biology that covers the medical study of immune systems in humans, animals, plants and sapient species. In such we can see there ...
explanation, the inflammatory process is caused by
T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s, a kind of
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
that plays an important role in the body's defenses. 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." The attack on myelin starts inflammatory processes, which trigger other immune cells and the release of soluble factors like
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s and antibodies. A further breakdown of the blood-brain barrier, in turn, causes a number of other damaging effects such as swelling, activation of
macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
, and more activation of cytokines and other destructive proteins. Inflammation can potentially reduce transmission of information between neurons in at least three ways. 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.


Blood–brain barrier

The blood–brain barrier (BBB) is a part of the
capillary A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the bod ...
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.
Gadolinium Gadolinium is a chemical element with the symbol Gd and atomic number 64. Gadolinium is a silvery-white metal when oxidation is removed. It is only slightly malleable and is a ductile rare-earth element. Gadolinium reacts with atmospheric oxygen ...
cannot cross a normal BBB and, therefore, gadolinium-enhanced MRI is used to show BBB breakdowns.


Diagnosis

Multiple sclerosis is typically diagnosed based on the presenting signs and symptoms, in combination with supporting medical imaging and laboratory testing. It can be difficult to confirm, especially early on, since the signs and symptoms may be similar to those of other medical problems. The
McDonald criteria The McDonald criteria are diagnostic criteria for multiple sclerosis (MS). These criteria are named after neurologist W. Ian McDonald who directed an international panel in association with the National Multiple Sclerosis Society (NMSS) of America ...
, 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 with the Schumacher and Poser criteria being of mostly historical significance. , there is no single test (including biopsy) that can provide a definitive diagnosis. Magnetic resonance imaging (MRI) of the brain and spine may show areas of demyelination (lesions or plaques).
Gadolinium Gadolinium is a chemical element with the symbol Gd and atomic number 64. Gadolinium is a silvery-white metal when oxidation is removed. It is only slightly malleable and is a ductile rare-earth element. Gadolinium reacts with atmospheric oxygen ...
can be administered intravenously as a
contrast agent A contrast agent (or contrast medium) is a substance used to increase the contrast of structures or fluids within the body in medical imaging. Contrast agents absorb or alter external electromagnetism or ultrasound, which is different from radiop ...
to highlight active plaques and, by elimination, demonstrate the existence of historical lesions not associated with symptoms at the moment of the evaluation. Central vein signs (CVS) have been proposed as a good indicator of MS in comparison with other conditions causing white lesions. One small study found fewer CVS in older and hypertensive people. Further research on CVS as a biomarker for MS is ongoing. Brain atrophy is seen as an indicator of MS. Testing of cerebrospinal fluid obtained from a lumbar puncture can provide evidence of chronic
inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
in the central nervous system. The cerebrospinal fluid is tested for
oligoclonal band Oligoclonal bands (OCBs) are bands of immunoglobulins that are seen when a patient's blood serum, or cerebrospinal fluid (CSF) is analyzed. They are used in the diagnosis of various neurological and blood diseases, especially in multiple sclerosis ...
s of IgG on electrophoresis, which are inflammation markers found in 75–85% of people with MS.


Differential diagnosis

There are several diseases that present similarly to multiple sclerosis. Intractable vomiting, severe optic neuritis, or bilateral optic neuritis raises suspicion for
neuromyelitis optica spectrum disorder Neuromyelitis optica spectrum disorders (NMOSD), including neuromyelitis optica (NMO), are autoimmune diseases characterized by acute inflammation of the optic nerve (optic neuritis, ON) and the spinal cord (myelitis). Episodes of ON and myelitis ...
(NMOSD). Involvement of multiple cranial nerves raises suspicion for
neurosarcoidosis Neurosarcoidosis (sometimes shortened to neurosarcoid) refers to a type of sarcoidosis, a condition of unknown cause featuring granulomas in various tissues, in this type involving the central nervous system (brain and spinal cord). Neurosarcoidosi ...
. Longitudinally extensive transverse myelitis (LETM), in which spinal cord damage spans three or more vertebral segments, raises suspicion for NMOSD, neurosarcoidosis, anti-MOG–associated myelitis, systemic
rheumatologic disease Rheumatism or rheumatic disorders are conditions causing chronic, often intermittent pain affecting the joints or connective tissue. Rheumatism does not designate any specific disorder, but covers at least 200 different conditions, including a ...
, or a
paraneoplastic disorder A paraneoplastic syndrome is a syndrome (a set of signs and symptoms) that is the consequence of a tumor in the body (usually a cancerous one), specifically due to the production of chemical signaling molecules (such as hormones or cytokines) by ...
.


Types and variants

Several
phenotypes In genetics, the phenotype () is the set of observable characteristics or phenotypic trait, traits of an organism. The term covers the organism's morphology (biology), morphology or physical form and structure, its Developmental biology, dev ...
(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: # Clinically isolated syndrome (CIS) # Relapsing-remitting MS (RRMS) # Primary progressive MS (PPMS) # Secondary progressive MS (SPMS) Relapsing-remitting MS is characterized by unpredictable relapses followed by periods of months to years of relative quiet ( remission) with no new signs of disease activity. Deficits that occur during attacks may either resolve or leave
problems A problem is a difficulty which may be resolved by problem solving. Problem(s) or The Problem may also refer to: People * Problem (rapper), (born 1985) American rapper Books * ''Problems'' (Aristotle), an Aristotelian (or pseudo-Aristotelian) co ...
, the latter in about 40% of attacks and being more common the longer a person has had the disease. This describes the initial course of 80% of individuals with MS. The relapsing-remitting subtype usually begins with a clinically isolated syndrome (CIS). In CIS, a person has an attack suggestive of demyelination, but does not fulfill the criteria for multiple sclerosis. 30 to 70% of persons who experience CIS, later develop MS. Primary progressive MS occurs in approximately 10–20% of individuals with the disease, with no remission after the initial symptoms. It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements. 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 relapsing-remitting MS, around 40 years of age. Secondary progressive MS occurs in around 65% of those with initial relapsing-remitting MS, who eventually have progressive neurologic decline between acute attacks without any definite periods of remission. Occasional relapses and minor remissions may appear. The most common length of time between disease onset and conversion from relapsing-remitting to secondary progressive MS is 19 years.


Special courses

Independently of the types published by the MS associations, regulatory agencies like 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), "Active Secondary MS" (similar to the old Progressive-Relapsing) and "Rapidly progressing PPMS". Also, when deficits always resolve between attacks, this is sometimes referred to as ''benign MS'', although people will still build up some degree of disability in the long term. 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. An international panel has published a standardized definition for the course HAMS.


Variants

Atypical
variants Variant may refer to: In arts and entertainment * ''Variant'' (magazine), a former British cultural magazine * Variant cover, an issue of comic books with varying cover art * ''Variant'' (novel), a novel by Robison Wells * " The Variant", 2021 e ...
of MS have been described; these include
tumefactive multiple sclerosis Tumefactive multiple sclerosis is a condition in which the central nervous system of a person has multiple demyelinating lesions with atypical characteristics for those of standard multiple sclerosis (MS). It is called tumefactive as the lesions ...
,
Balo concentric sclerosis Baló's concentric sclerosis is a disease in which the white matter of the brain appears damaged in concentric layers, leaving the axis cylinder intact. It was described by József Mátyás Baló who initially named it "leuko-encephalitis periaxial ...
, Schilder's diffuse sclerosis, and
Marburg multiple sclerosis Marburg acute multiple sclerosis, also known as Marburg multiple sclerosis or acute fulminant multiple sclerosis, is considered one of the multiple sclerosis borderline diseases, which is a collection of diseases classified by some as MS variants ...
. There is debate on whether they are MS variants or different diseases. Some diseases previously considered MS variants like
Devic's disease Neuromyelitis optica spectrum disorders (NMOSD), including neuromyelitis optica (NMO), are autoimmune diseases characterized by acute inflammation of the optic nerve (optic neuritis, ON) and the spinal cord (myelitis). Episodes of ON and myelitis ...
are now considered outside the MS spectrum.


Management

Although there is no known cure for multiple sclerosis, several therapies have proven helpful. Several effective treatments can significantly 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. Older medications used to treat MS were modestly effective, could have side effects, and were poorly tolerated. However, several treatment options with better safety and tolerability profiles have been introduced, changing the prognosis of MS. In the treatment era, 16% of people with relapsing MS went on to need a cane to walk after 20 years. As with any medical treatment, medications used in the management of MS have several
adverse effects An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complica ...
.
Alternative treatments Alternative medicine is any practice that aims to achieve the healing effects of medicine despite lacking biological plausibility, testability, repeatability, or evidence from clinical trials. Complementary medicine (CM), complementary and alt ...
are pursued by some people, despite the shortage of supporting evidence of efficacy.


Acute attacks

During symptomatic attacks, administration of high doses of intravenous
corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...
s, such as
methylprednisolone Methylprednisolone (Depo-Medrol, Medrol, Solu-Medrol) is a synthetic glucocorticoid, primarily prescribed for its anti-inflammatory and immunosuppressive effects. It is either used at low doses for chronic illnesses or used concomitantly at hig ...
, is the usual therapy, with oral corticosteroids seeming to have a similar efficacy and safety profile. Although effective in the short term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery. The long-term benefit is unclear in optic neuritis as of 2020. The consequences of severe attacks that do not respond to corticosteroids might be treatable by
plasmapheresis Plasmapheresis (from the Greek πλάσμα, ''plasma'', something molded, and ἀφαίρεσις ''aphairesis'', taking away) is the removal, treatment, and return or exchange of blood plasma or components thereof from and to the blood circulati ...
.


Disease-modifying treatments


Relapsing remitting multiple sclerosis

As of 2021, multiple disease-modifying medications were approved by regulatory agencies for relapsing-remitting multiple sclerosis (RRMS). In RRMS they are modestly effective at decreasing the number of attacks. The interferons and glatiramer acetate are first-line treatments and are roughly equivalent, reducing relapses by approximately 30%. Early-initiated long-term therapy is safe and improves outcomes. Treatment of clinically isolated syndrome (CIS) with interferons decreases the chance of progressing to clinical MS. Efficacy of interferons and glatiramer acetate in children has been estimated to be roughly equivalent to that of adults. The role of some newer agents such as fingolimod, teriflunomide, and dimethyl fumarate, is not yet entirely clear. It is difficult to make firm conclusions about the best treatment, 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. The relative effectiveness of different treatments is unclear, as most have only been compared to placebo or a small number of other therapies. Direct comparisons of interferons and
glatiramer acetate Glatiramer acetate (also known as Copolymer 1, Cop-1), sold under the brand name Copaxone among others, is an immunomodulator medication used to treat multiple sclerosis. Glatiramer acetate is approved in the United States to reduce the frequenc ...
indicate similar effects or only small differences in effects on relapse rate, disease progression and magnetic resonance imaging measures. Alemtuzumab, natalizumab, and fingolimod may be more effective than other drugs in reducing relapses over the short term in people with RRMS.
Natalizumab Natalizumab, sold under the brand name Tysabri among others, is a medication used to treat multiple sclerosis and Crohn's disease. It is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin. It is given by intravenou ...
and
interferon beta-1a Interferon beta-1a (also interferon beta 1-alpha) is a cytokine in the interferon family used to treat multiple sclerosis (MS). It is produced by mammalian cells, while interferon beta-1b is produced in modified '' E. coli''. Some research indic ...
( Rebif) may reduce relapses compared to both placebo and
interferon beta-1a Interferon beta-1a (also interferon beta 1-alpha) is a cytokine in the interferon family used to treat multiple sclerosis (MS). It is produced by mammalian cells, while interferon beta-1b is produced in modified '' E. coli''. Some research indic ...
( Avonex) while Interferon beta-1b (
Betaseron Interferon beta-1b is a cytokine in the interferon family used to treat the relapsing-remitting and secondary-progressive forms of multiple sclerosis (MS). It is approved for use after the first MS event. Closely related is interferon beta 1a, ...
),
glatiramer acetate Glatiramer acetate (also known as Copolymer 1, Cop-1), sold under the brand name Copaxone among others, is an immunomodulator medication used to treat multiple sclerosis. Glatiramer acetate is approved in the United States to reduce the frequenc ...
, and mitoxantrone may also prevent relapses. Evidence on relative effectiveness in reducing disability progression is unclear. All medications are associated with adverse effects that may influence their risk to benefit profiles.


Progressive multiple sclerosis

, only one medication, mitoxantrone, had been 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. As of 2013, review of 9
immunomodulator Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
s and
immunosuppressant Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system. Classification Immunosuppressive drugs can be classified in ...
s found no evidence of any being effective in preventing disability progression in people with progressive MS. In March 2017 the FDA approved ocrelizumab as a treatment for primary progressive MS in adults, the first drug to gain that approval, with requirements for several Phase IV clinical trials. 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. In 2019,
siponimod Siponimod, sold under the brand name Mayzent, is a selective sphingosine-1-phosphate receptor modulator for oral use that is used for multiple sclerosis (MS). It is intended for once-daily oral administration. In March 2019, it was approved in ...
and
cladribine Cladribine, sold under the brand name Leustatin, among others, is a medication used to treat hairy cell leukemia (leukemic reticuloendotheliosis) and B-cell chronic lymphocytic leukemia. Cladribine, sold under the brand name Mavenclad, is indicat ...
were approved in the United States for the treatment of secondary progressive multiple sclerosis.


Adverse effects

The
disease-modifying treatment A disease-modifying treatment, disease-modifying drug, or disease-modifying therapy is a treatment that delays or slows the progression of a disease by targeting its underlying cause. They are distinguished from symptomatic treatments that treat th ...
s have several adverse effects. One of the most common is irritation at the injection site for glatiramer acetate and the interferons (up to 90% with subcutaneous injections and 33% with intramuscular injections). Over time, a visible dent at the injection site, due to the local destruction of fat tissue, known as
lipoatrophy Lipoatrophy is the term describing the localized loss of fat tissue. This may occur as a result of subcutaneous injections of insulin in the treatment of diabetes, from the use of human growth hormone or from subcutaneous injections of copaxone us ...
, may develop. Interferons may produce
flu-like symptoms Influenza-like illness (ILI), also known as flu-like syndrome or flu-like symptoms, is a medical diagnosis of possible influenza or other illness causing a set of common symptoms. These include fever, shivering, chills, malaise, dry cough, loss ...
; 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 Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Signs and symptoms Some of the si ...
from interferons, systolic dysfunction (12%), infertility, and
acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may inclu ...
(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 Macular edema occurs when fluid and protein deposits collect on or under the macula of the eye (a yellow central area of the retina) and causes it to thicken and swell (edema). The swelling may distort a person's central vision, because the macul ...
, 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.


Associated symptoms

Both medications and
neurorehabilitation Neurorehabilitation is a complex medical process which aims to aid recovery from a nervous system injury, and to minimize and/or compensate for any functional alterations resulting from it. Features In case of a serious disability, such as caused ...
have been shown to improve some symptoms, though neither changes the course of the disease. Some symptoms have a good response to medication, such as bladder
spasticity Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles ...
, while others are little changed. Equipment such as
catheter In medicine, a catheter (/ˈkæθətər/) is a thin tubing (material), tube made from medical grade materials serving a broad range of functions. Catheters are medical devices that can be inserted in the body to treat diseases or perform a surgi ...
s for
neurogenic bladder Neurogenic bladder dysfunction, or neurogenic bladder, refers to urinary bladder problems due to disease or injury of the central nervous system or peripheral nerves involved in the control of urination. There are multiple types of neurogenic bladde ...
or mobility aids can be helpful in improving functional status. A
multidisciplinary Interdisciplinarity or interdisciplinary studies involves the combination of multiple academic disciplines into one activity (e.g., a research project). It draws knowledge from several other fields like sociology, anthropology, psychology, ec ...
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. Multidisciplinary rehabilitation programs increase activity and participation of people with MS but do not influence impairment level. 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. There is limited evidence for the overall efficacy of individual therapeutic disciplines, though 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.


Non-pharmaceutical

There is some evidence that
aquatic therapy Aquatic therapy refers to treatments and exercises performed in water for relaxation, fitness, physical rehabilitation, and other therapeutic benefit. Typically a qualified aquatic therapist gives constant attendance to a person receiving treat ...
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 Alternative medicine is any practice that aims to achieve the healing effects of medicine despite lacking biological plausibility, testability, repeatability, or evidence from clinical trials. Complementary medicine (CM), complementary and al ...
, 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 technique A relaxation technique (also known as relaxation training) is any method, process, procedure, or activity that helps a person to relax; to attain a state of increased calmness; or otherwise reduce levels of pain, anxiety, stress or anger. Rela ...
s such as
yoga Yoga (; sa, योग, lit=yoke' or 'union ) is a group of physical, mental, and spiritual practices or disciplines which originated in ancient India and aim to control (yoke) and still the mind, recognizing a detached witness-consci ...
,
herbal medicine Herbal medicine (also herbalism) is the study of pharmacognosy and the use of medicinal plants, which are a basis of traditional medicine. With worldwide research into pharmacology, some herbal medicines have been translated into modern remed ...
(including
medical cannabis Medical cannabis, or medical marijuana (MMJ), is cannabis and cannabinoids that are prescribed by physicians for their patients. The use of cannabis as medicine has not been rigorously tested due to production and governmental restrictions ...
),
hyperbaric oxygen therapy Hyperbaric medicine is medical treatment in which an ambient pressure greater than sea level atmospheric pressure is a necessary component. The treatment comprises hyperbaric oxygen therapy (HBOT), the medical use of oxygen at an ambient pressure ...
, self-infection with hookworms,
reflexology Reflexology, also known as zone therapy, is an alternative medical practice involving the application of pressure to specific points on the feet, ears, and hands. This is done using thumb, finger, and hand massage techniques without the use of ...
,
acupuncture Acupuncture is a form of alternative medicine and a component of traditional Chinese medicine (TCM) in which thin needles are inserted into the body. Acupuncture is a pseudoscience; the theories and practices of TCM are not based on scientif ...
, 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 as of 2022 there is no cure. The prognosis of MS depends on the subtype of the disease, and there is also great individual variation in the progression of the disease. For relapsing MS, which is the most common subtype, approximately one of every five people later transition to secondary progressive MS, a form characterized by more progressive decline. A 2016 cohort study found that after a median of 16.8 years from onset, one in ten of those with relapsing MS needed a walking aid, and almost two in ten transitioned to secondary progressive MS. 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 limited effective treatments for progressive forms of MS, and treatments aren't as effective. The prognosis for progressive MS is worse, with faster accumulation of disability, though the rate of decline varies considerably between people. 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 onset of SPMS, and were chair or bedbound after average 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, though, is associated with a higher relapse rate. As of 2018, no biomarker can accurately predict disease progression in every patient. Spinal cord lesions, abnormalities on MRI, and more
brain atrophy Cerebral atrophy is a common feature of many of the diseases that affect the brain. Atrophy of any tissue means a decrement in the size of the cell, which can be due to progressive loss of cytoplasmic proteins. In brain tissue, atrophy describes ...
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. Early treatment leads to a better prognosis, but a higher relapse frequency when treated with DMTs is associated with a poorer prognosis.


Epidemiology

MS is the most common autoimmune disorder of the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
. As of 2022, there are nearly one million known cases of multiple sclerosis in the United States. In 2020, the number of people with MS was 2.8 million globally, with rates varying widely in different regions. In Africa rates are less than 0.5 per 100,000, while they are 2.8 per 100,000 in South East Asia, 8.3 per 100,000 in the Americas, and 80 per 100,000 in Europe. Rates surpass 200 per 100,000 in certain populations of Northern European descent. The number of new cases that develop per year is about 2.5 per 100,000. Increasing rates of MS may be explained simply by better diagnosis. Studies on populational and geographical patterns have been common and have led to a number of theories about the cause. 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. The primary progressive subtype is more common in people in their fifties. Similarly to many autoimmune disorders, the disease is more common in women, and the trend may be increasing. As of 2008, globally it is about two times more common in women than in men. In children, it is even more common in females than males, while in people over fifty, it affects males and females almost equally.


History


Medical discovery

Robert Carswell (1793–1857), a British professor of
pathology Pathology is the study of the causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in ...
, and
Jean Cruveilhier Jean Cruveilhier (; 9 February 1791 – 7 March 1874) was a French anatomist and pathologist. Academic career Cruveilhier was born in Limoges, France. As a student in Limoges, he planned to enter the priesthood. He later developed an inte ...
(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 Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...
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 ''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 Nystagmus is a condition of involuntary (or voluntary, in some cases) eye movement. Infants can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in reduced or limited vision. Due to the invol ...
,
intention tremor Intention tremor is a dyskinetic disorder characterized by a broad, coarse, and low frequency (below 5 Hz) tremor evident during deliberate and visually-guided movement (hence the name intention tremor). An intention tremor is usually perpendi ...
, and
telegraphic speech Telegraphic speech, according to linguistics and psychology, is speech during the two-word stage of language acquisition in children, which is laconic and efficient. Background The name derives from the fact that someone sending a telegram was ...
(scanning speech). Charcot also observed cognition changes, describing his patients as having a "marked enfeeblement of the memory" and "conceptions that formed slowly". 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 Poser criteria and
McDonald criteria The McDonald criteria are diagnostic criteria for multiple sclerosis (MS). These criteria are named after neurologist W. Ian McDonald who directed an international panel in association with the National Multiple Sclerosis Society (NMSS) of America ...
, whose 2017 revision is in use. 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 Iceland ( is, Ísland; ) is a Nordic island country in the North Atlantic Ocean and in the Arctic Ocean. Iceland is the most sparsely populated country in Europe. Iceland's capital and largest city is Reykjavík, which (along with its s ...
around 1200 suddenly lost her vision and mobility but recovered them seven days after. Saint Lidwina of Schiedam (1380–1433), a
Dutch Dutch commonly refers to: * Something of, from, or related to the Netherlands * Dutch people () * Dutch language () Dutch may also refer to: Places * Dutch, West Virginia, a community in the United States * Pennsylvania Dutch Country People E ...
nun A nun is a woman who vows to dedicate her life to religious service, typically living under vows of poverty, chastity, and obedience in the enclosure of a monastery or convent.''The Oxford English Dictionary'', vol. X, page 599. The term is o ...
, 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 Prince Augustus Frederick, Duke of Sussex, (27 January 1773 – 21 April 1843) was the sixth son and ninth child of King George III and his queen consort, Charlotte of Mecklenburg-Strelitz. He was the only surviving son of George III who did not ...
and
Lady Augusta Murray Lady Augusta De Ameland (''born'' Murray; 27 January 1761 – 4 March 1830) was the first wife of Prince Augustus Frederick, Duke of Sussex, the sixth son of George III. They married on 4 April 1793 in Rome. Their union was in contravention of t ...
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 Amaurosis fugax (Greek ''amaurosis'' meaning ''darkening'', ''dark'', or ''obscure'', Latin '' fugax'' meaning ''fleeting'') is a painless temporary loss of vision in one or both eyes. Signs and symptoms The experience of amaurosis fugax is clas ...
) 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. 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''.


Research


Epstein-Barr virus ongoing studies

As of 2022, the pathogenesis of MS as it relates to 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.


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.


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-AQP4 autoantibodies were found in
neuromyelitis optica Neuromyelitis optica spectrum disorders (NMOSD), including neuromyelitis optica (NMO), are autoimmune diseases characterized by acute inflammation of the optic nerve (optic neuritis, ON) and the spinal cord (myelitis). Episodes of ON and myelitis ...
(NMO), which was previously considered a MS variant. A spectrum of diseases named NMOSD (NMO spectrum diseases) or anti-AQP4 diseases has been accepted. Some cases of MS were presenting anti-MOG autoantibodies, mainly overlapping with the Marburg variant. Anti-MOG autoantibodies were found to be also present in ADEM, and a second spectrum of separated diseases is being considered. This spectrum is named inconsistently across different authors, but it is normally something similar to anti-MOG demyelinating diseases. A third kind of auto-antibodies is accepted. They are several anti-neurofascin auto-antibodies which damage the Ranvier nodes of the neurons. These antibodies are more related to the peripheral nervous demyelination, but they were also found in chronic progressive PPMS and
combined central and peripheral demyelination Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired autoimmune disease of the peripheral nervous system characterized by progressive weakness and impaired sensory function in the legs and arms. The disorder is sometimes called ...
(CCPD, which is considered another atypical MS presentation). In addition to the significance of auto-antibodies in MS, four different patterns of demyelination have been reported, opening the door to consider MS as a
heterogeneous disease A heterogeneous medical condition or heterogeneous disease is a medical term referring to a medical condition with several etiologies (root causes), such as hepatitis or diabetes. Medical conditions are normally defined pathologically (i.e. based ...
.


Disease biomarkers

Since disease progression is the result of degeneration of neurons, the roles of proteins showing loss of nerve tissue such as
neurofilament Neurofilaments (NF) are classed as type IV intermediate filaments found in the cytoplasm of neurons. They are protein polymers measuring 10 nm in diameter and many micrometers in length. Together with microtubules (~25 nm) and mi ...
s,
tau Tau (uppercase Τ, lowercase τ, or \boldsymbol\tau; el, ταυ ) is the 19th letter of the Greek alphabet, representing the voiceless dental or alveolar plosive . In the system of Greek numerals, it has a value of 300. The name in English ...
, and
N-acetylaspartate ''N''-Acetylaspartic acid, or ''N''-acetylaspartate (NAA), is a derivative of aspartic acid with a formula of C6H9NO5 and a molecular weight of 175.139. NAA is the second-most-concentrated molecule in the brain after the amino acid glutamate. ...
are under investigation. Improvement in neuroimaging techniques such as positron emission tomography (PET) or magnetic resonance imaging (MRI) carry a promise for better diagnosis and prognosis predictions. Regarding MRI, there are several techniques that have already shown some usefulness in research settings and could be introduced into clinical practice, such as double-inversion recovery sequences,
magnetization transfer Magnetization transfer (MT), in NMR and MRI, refers to the transfer of nuclear spin polarization and/or spin coherence from one population of nuclei to another population of nuclei, and to techniques that make use of these phenomena. There is some ...
, diffusion tensor, and functional magnetic resonance imaging. These techniques are more specific for the disease than existing ones, but still lack some standardization of acquisition protocols and the creation of normative values. This is particularly the case for proton magnetic resonance spectroscopy, for which a number of methodological variations observed in the literature may underlie continued inconsistencies in central nervous system metabolic abnormalities, particularly in N-acetyl aspartate,
myoinositol Inositol, or more precisely ''myo''-inositol, is a carbocyclic sugar that is abundant in the brain and other mammalian tissues; it mediates cell signal transduction in response to a variety of hormones, neurotransmitters, and growth factors an ...
,
choline Choline is an essential nutrient for humans and many other animals. Choline occurs as a cation that forms various salts (X− in the depicted formula is an undefined counteranion). Humans are capable of some ''de novo synthesis'' of choline but r ...
, glutamate, GABA, and GSH, observed for multiple sclerosis and its subtypes. There are other techniques under development that include contrast agents capable of measuring levels of peripheral macrophages, inflammation, or neuronal dysfunction, and techniques that measure iron deposition that could serve to determine the role of this feature in MS, or that of cerebral perfusion.


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%.


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, including MS. Germ-free mice infected with transplanted fecal matter from MS patients exhibit an increased risk of developing EAE, an animal model of MS. It has also been proposed that certain bacteria found in the gut use molecular mimicry to infiltrate the brain via the gut-brain axis, initiating an inflammatory response and increasing blood-brain barrier permeability.
Vitamin D Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 (c ...
levels have also been correlated with MS; lower levels of vitamin D correspond to an increased risk of MS, suggesting a reduced prevalence in the tropics - an area with more Vitamin D-rich sunlight - strengthening the impact of geographical location on MS development. MS mechanisms begin when peripheral autoreactive effector
CD4+ T cells The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are consider ...
get activated and move into the CNS. Antigen-presenting cells localize the reactivation of autoreactive effector CD4-T cells once they have entered the CNS, attracting more T cells and
macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
to form the inflammatory lesion. In MS patients, macrophages and microglia assemble at locations where demyelination and neurodegeneration are actively occurring, and microglial activation is more apparent in the normal-appearing white matter of MS patients.
Astrocytes Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...
generate neurotoxic chemicals like nitric oxide and
TNFα Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
, attract neurotoxic inflammatory monocytes to the CNS, and are responsible for
astrogliosis Astrogliosis (also known as astrocytosis or referred to as reactive astrogliosis) is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from central nervous system (CNS) trauma, infection, ischemia, stroke, a ...
, the scarring that prevents the spread of neuroinflammation and kills neurons inside the scarred area.


See also

*
List of multiple sclerosis organizations List of multiple sclerosis organizations in different countries around the world. International *Multiple Sclerosis International Federation Australasia Australia * MS Research Australia Europe United Kingdom *Multiple Sclerosis S ...
* List of people with multiple sclerosis


References


External links

*
Database for analysis and comparison of global data on the epidemiology of MS
{{Authority control Ailments of unknown cause Epstein–Barr virus–associated diseases Myelin disorders Wikipedia neurology articles ready to translate Wikipedia medicine articles ready to translate (full)