Multiple sclerosis
Overview
Multiple sclerosis is an inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

 disease in which the fatty myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...

 sheaths around the axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....

s of the brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...

 and spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...

 are damaged, leading to demyelination
Demyelinating disease
A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This impairs the conduction of signals in the affected nerves, causing impairment in sensation, movement, cognition, or other functions depending on which nerves are involved.The term...

 and scarring as well as a broad spectrum of signs and symptoms. Disease onset usually occurs in young adults, and it is more common in women. It has a prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...

 that ranges between 2 and 150 per 100,000. MS was first described in 1868 by Jean-Martin Charcot
Jean-Martin Charcot
Jean-Martin Charcot was a French neurologist and professor of anatomical pathology. He is known as "the founder of modern neurology" and is "associated with at least 15 medical eponyms", including Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis...

.

MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other effectively.
Encyclopedia
Multiple sclerosis is an inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

 disease in which the fatty myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...

 sheaths around the axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....

s of the brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...

 and spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...

 are damaged, leading to demyelination
Demyelinating disease
A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This impairs the conduction of signals in the affected nerves, causing impairment in sensation, movement, cognition, or other functions depending on which nerves are involved.The term...

 and scarring as well as a broad spectrum of signs and symptoms. Disease onset usually occurs in young adults, and it is more common in women. It has a prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...

 that ranges between 2 and 150 per 100,000. MS was first described in 1868 by Jean-Martin Charcot
Jean-Martin Charcot
Jean-Martin Charcot was a French neurologist and professor of anatomical pathology. He is known as "the founder of modern neurology" and is "associated with at least 15 medical eponyms", including Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis...

.

MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other effectively. Nerve cells communicate by sending electrical signals called action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...

s down long fibers called axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....

s, which are contained within an insulating substance called myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...

. In MS, the body's own immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

 attacks and damages the myelin. When myelin is lost, the axons can no longer effectively conduct signals. The name multiple sclerosis refers to scars (scleroses—better known as plaques or lesions) particularly in the white matter
White matter
White matter is one of the two components of the central nervous system and consists mostly of myelinated axons. White matter tissue of the freshly cut brain appears pinkish white to the naked eye because myelin is composed largely of lipid tissue veined with capillaries. Its white color is due to...

 of the brain and spinal cord, which is mainly composed of myelin. Although much is known about the mechanisms involved in the disease process, the cause remains unknown. Theories include genetics
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....

 or infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...

s. Different environmental risk factor
Risk factor
In epidemiology, a risk factor is a variable associated with an increased risk of disease or infection. Sometimes, determinant is also used, being a variable associated with either increased or decreased risk.-Correlation vs causation:...

s have also been found.

Almost any neurological symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...

 can appear with the disease, and often progresses to physical and cognitive disability
Disability
A disability may be physical, cognitive, mental, sensory, emotional, developmental or some combination of these.Many people would rather be referred to as a person with a disability instead of handicapped...

. MS takes several forms, with new symptoms occurring either in discrete attacks (relapsing forms) or slowly accumulating over time (progressive forms). Between attacks, symptoms may go away completely, but permanent neurological problems often occur, especially as the disease advances.

There is no known cure for multiple sclerosis. Treatments attempt to return function after an attack, prevent new attacks, and prevent disability. MS medications can have adverse effects or be poorly tolerated, and many patients pursue alternative treatments, despite the lack of supporting scientific study. The prognosis
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...

 is difficult to predict; it depends on the subtype of the disease, the individual patient's disease characteristics, the initial symptoms and the degree of disability the person experiences as time advances. Life expectancy
Life expectancy
Life expectancy is the expected number of years of life remaining at a given age. It is denoted by ex, which means the average number of subsequent years of life for someone now aged x, according to a particular mortality experience...

 of people with MS is 5 to 10 years lower than that of the unaffected population.

Classification

Several subtypes, or patterns of progression, have been described. Subtypes 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 therapeutic decisions. In 1996 the United States National Multiple Sclerosis Society
National Multiple Sclerosis Society
The National Multiple Sclerosis Society, a United States-based non-profit organization, and its network of chapters nationwide promote research, educate, advocate on issues relating to multiple sclerosis, and organize a wide range of programs, including support for the newly diagnosed and those...

 standardized four subtype definitions:
  1. relapsing remitting,
  2. secondary progressive,
  3. primary progressive, and
  4. progressive relapsing.


The relapsing-remitting subtype is characterized by unpredictable relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits suffered during attacks may either resolve or leave sequelae, the latter being more common as a function of time. This describes the initial course of 80% of individuals with MS. When deficits always resolve between attacks, this is sometimes referred to as benign
Benign
A benign tumor is a tumor that lacks the ability to metastasize. Common examples of benign tumors include moles and uterine fibroids.The term "benign" implies a mild and nonprogressive disease. Indeed, many kinds of benign tumors are harmless to human health...

 MS
, although patients will still accrue some degree of disability in the long term. The relapsing-remitting subtype usually begins with a clinically isolated syndrome
Clinically isolated syndrome
A clinically isolated syndrome is an individual's first neurological episode, caused by inflammation or demyelination of nerve tissue...

 (CIS). In CIS, a patient has an attack suggestive of demyelination, but does not fulfill the criteria for multiple sclerosis. However only 30 to 70% of persons experiencing CIS later develop MS.
Secondary progressive MS (sometimes called "galloping MS") describes around 65% of those with an initial relapsing-remitting MS, who then begin to have progressive neurologic decline between acute attacks without any definite periods of remission. Occasional relapses and minor remissions may appear. The median time between disease onset and conversion from relapsing-remitting to secondary progressive MS is 19 years.
The primary progressive subtype describes the approximately 10–15% of individuals who never have remission after their initial MS symptoms.
It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements. The age of onset for the primary progressive subtype is later than for the relapsing-remitting, but similar to mean age of progression between the relapsing-remitting and the secondary progressive. In both cases it is around 40 years of age.

Progressive relapsing MS describes those individuals who, from onset, have a steady neurologic decline but also suffer clear superimposed attacks. This is the least common of all subtypes.

Atypical variants of MS with non-standard behavior
Idiopathic inflammatory demyelinating diseases
Idiopathic inflammatory demyelinating diseases , sometimes known as borderline forms of multiple sclerosis, is a collection of multiple sclerosis variants, sometimes considered different diseases, but considered by others to form a spectrum differing only in terms of chronicity, severity, and...

 have been described; these include Devic's disease
Devic's disease
Neuromyelitis optica , also known as Devic's disease or Devic's syndrome, is an autoimmune, inflammatory disorder in which a person's own immune system attacks the optic nerves and spinal cord. This produces an inflammation of the optic nerve and the spinal cord...

, Balo concentric sclerosis
Balo concentric sclerosis
Balo concentric sclerosis is one of the borderline forms of multiple sclerosis.Balo concentric sclerosis is a demyelinating disease similar to standard multiple sclerosis, but with the particularity that the demyelinated tissues form concentric layers...

, Schilder's diffuse sclerosis
Diffuse myelinoclastic sclerosis
Diffuse myelinoclastic sclerosis, sometimes referred to as "Schilder's disease", is a very infrequent neurodegenerative disease that presents clinically as pseudotumoural demyelinating lesions, that make its diagnosis difficult...

 and Marburg multiple sclerosis
Marburg multiple sclerosis
Marburg multiple sclerosis, also known as fulminant multiple sclerosis, is considered one of the multiple sclerosis borderline diseases, which is a collection of diseases classified by some as MS variants and by others as different diseases. Other diseases in this group are Neuromyelitis optica ,...

. There is debate on whether they are MS variants or different diseases. Multiple sclerosis also behaves differently in children, taking more time to reach the progressive stage. Nevertheless they still reach it at a lower mean age than adults.

Signs and symptoms

A person with MS can suffer almost any neurological symptom or sign, including changes in sensation such as loss of sensitivity or tingling, pricking or numbness (hypoesthesia
Hypoesthesia
Hypoesthesia refers to a reduced sense of touch or sensation, or a partial loss of sensitivity to sensory stimuli....

 and paresthesia
Paresthesia
Paresthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"...

), muscle weakness, clonus
Clonus
Clonus is a series of involuntary muscular contractions and relaxations. Clonus is a sign of certain neurological conditions, and is particularly associated with upper motor neuron lesions such as in stroke, multiple sclerosis, spinal cord damage and hepatic encephalopathy...

, muscle spasms, or difficulty in moving; difficulties with coordination and balance (ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...

); problems in speech (dysarthria
Dysarthria
Dysarthria is a motor speech disorder resulting from neurological injury of the motor component of the motor-speech system and is characterized by poor articulation of phonemes...

) or swallowing (dysphagia
Dysphagia
Dysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....

), visual problems (nystagmus, optic neuritis
Optic neuritis
Optic neuritis is the inflammation of the optic nerve that may cause a complete or partial loss of vision.-Causes:The optic nerve comprises axons that emerge from the retina of the eye and carry visual information to the primary visual nuclei, most of which is relayed to the occipital cortex of the...

 including phosphene
Phosphene
A phosphene is a phenomenon characterized by the experience of seeing light without light actually entering the eye. The word phosphene comes from the Greek words phos and phainein...

s, or diplopia
Diplopia
Diplopia, commonly known as double vision, is the simultaneous perception of two images of a single object that may be displaced horizontally, vertically, or diagonally in relation to each other...

), fatigue
Fatigue (physical)
Fatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...

, acute or chronic pain
Chronic pain
Chronic pain has several different meanings in medicine. Traditionally, the distinction between acute and chronic pain has relied upon an arbitrary interval of time from onset; the two most commonly used markers being 3 months and 6 months since the initiation of pain, though some theorists and...

, and bladder and bowel difficulties. Cognitive impairment of varying degrees and emotional symptoms of depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...

 or unstable mood are also common. Uhthoff's phenomenon
Uhthoff's phenomenon
Uhthoff's phenomenon is the worsening of neurologic symptoms in multiple sclerosis and other neurological, demyelinating conditions when the body gets overheated from hot weather, exercise, fever, or saunas and hot tubs...

, an exacerbation of extant symptoms due to an exposure to higher than usual ambient temperatures, and Lhermitte's sign
Lhermitte's sign
Lhermitte's sign, sometimes called the Barber Chair phenomenon, is an electrical sensation that runs down the back and into the limbs. In many patients, it is elicited by bending the head forward...

, an electrical sensation that runs down the back when bending the neck, are particularly characteristic of MS although not specific. The main clinical measure of disability progression and symptom severity is the Expanded Disability Status Scale
Expanded Disability Status Scale
The Kurtzke Expanded Disability Status Scale is a method of quantifying disability in multiple sclerosis.The EDSS quantifies disability in eight Functional Systems and allows neurologists to assign a Functional System Score in each of these....

 or EDSS.

Symptoms of MS usually appear in episodic acute periods of worsening (called relapse
Relapse
Relapse, in relation to drug misuse, is resuming the use of a drug or a dependent substance after one or more periods of abstinence. The term is a landmark feature of both substance dependence and substance abuse, which are learned behaviors, and is maintained by neuronal adaptations that mediate...

s, exacerbations, bouts, attacks, or "flare-ups"), in a gradually progressive deterioration of neurologic function, or in a combination of both. Multiple sclerosis relapses are often unpredictable, occurring without warning and without obvious inciting factors with a rate rarely above one and a half per year. Some attacks, however, are preceded by common triggers. Relapses occur more frequently during spring and summer.
Viral infections such as the common cold, influenza, or gastroenteritis
Gastroenteritis
Gastroenteritis is marked by severe inflammation of the gastrointestinal tract involving both the stomach and small intestine resulting in acute diarrhea and vomiting. It can be transferred by contact with contaminated food and water...

 increase the risk of relapse. Stress
Stress (medicine)
Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...

 may also trigger an attack. Pregnancy affects the susceptibility to relapse, with a lower relapse rate at each trimester of gestation. During the first few months after delivery, however, the risk of relapse is increased. Overall, pregnancy does not seem to influence long-term disability. Many potential triggers have been examined and found not to influence MS relapse rates. There is no evidence that vaccination and breast feeding, physical trauma, or Uhthoff's phenomenon
Uhthoff's phenomenon
Uhthoff's phenomenon is the worsening of neurologic symptoms in multiple sclerosis and other neurological, demyelinating conditions when the body gets overheated from hot weather, exercise, fever, or saunas and hot tubs...

 are relapse triggers.

Causes

Most likely MS occurs as a result of some combination of genetic, environmental and infectious factors, and possibly other factors like vascular problems. Epidemiological studies of MS have provided hints on possible causes for the disease. Theories try to combine the known data into plausible explanations, but none has proved definitive.

Genetics

MS is not considered a hereditary disease. However, a number of genetic variations
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....

 have been shown to increase the risk of developing the disease.

The risk of acquiring MS is higher in relatives of a person with the disease than in the general population, especially in the case of sibling
Sibling
Siblings are people who share at least one parent. A male sibling is called a brother; and a female sibling is called a sister. In most societies throughout the world, siblings usually grow up together and spend a good deal of their childhood socializing with one another...

s, parents, and children. The disease has an overall familial recurrence rate of 20%. In the case of monozygotic twin
Twin
A twin is one of two offspring produced in the same pregnancy. Twins can either be monozygotic , meaning that they develop from one zygote that splits and forms two embryos, or dizygotic because they develop from two separate eggs that are fertilized by two separate sperm.In contrast, a fetus...

s, concordance occurs only in about 35% of cases, while it goes down to around 5% in the case of siblings and even lower in half-siblings. This indicates susceptibility is partly polygenically
Quantitative trait locus
Quantitative traits refer to phenotypes that vary in degree and can be attributed to polygenic effects, i.e., product of two or more genes, and their environment. Quantitative trait loci are stretches of DNA containing or linked to the genes that underlie a quantitative trait...

 driven.

It seems to be more common in some ethnic groups than others.

Apart from familial studies, specific gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

s have been linked with MS. Differences in the human leukocyte antigen
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...

 (HLA) system—a group of genes in chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...

 6
Chromosome 6 (human)
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 and represents between 5.5 and 6% of the total DNA in cells...

 that serves as the major histocompatibility complex
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...

 (MHC) in humans—increase the probability of suffering MS. The most consistent finding is the association between multiple sclerosis and alleles of the MHC defined as DR15
HLA-DR15
HLA-DR15 is a HLA-DR serotype that recognizes the DRB1*1501 to *1505 and *1507 gene products. DR15 is found at high levels from Ireland to Central Asia. frequencies...

 and DQ6
HLA-DQ6
HLA-DQ6 is a human leukocyte antigen serotype within HLA-DQ  serotype group. The serotype is determined by the antibody recognition of β6 subset of DQ β-chains. The β-chain of DQ isoforms are encoded by HLA-DQB1 locus and DQ6 are encoded by the HLA-DQB1*06 allele group. This group currently...

. Other loci have shown a protective effect, such as HLA-C554 and HLA-DRB1
HLA-DRB1
HLA class II histocompatibility antigen, DRB1-9 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.- Function :...

*11.

Environmental factors

Different environmental factors, both of infectious and non infectious origin have been proposed as risk factors for MS. Although some are partly modifiable, only further research—especially clinical trials—will reveal whether their elimination can help prevent MS.

MS is more common in people who live farther from the equator, although many exceptions exist. Decreased sunlight exposure has been linked with a higher risk of MS. Decreased vitamin D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....

 production and intake has been the main biological mechanism used to explain the higher risk among those less exposed to sun.

Severe stress may also be a risk factor although evidence is weak. Smoking
Tobacco smoking
Tobacco smoking is the practice where tobacco is burned and the resulting smoke is inhaled. The practice may have begun as early as 5000–3000 BCE. Tobacco was introduced to Eurasia in the late 16th century where it followed common trade routes...

 has also been shown to be an independent risk factor for developing MS. Association with occupational exposures and toxin
Toxin
A toxin is a poisonous substance produced within living cells or organisms; man-made substances created by artificial processes are thus excluded...

s—mainly solvent
Solvent
A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous solute, resulting in a solution that is soluble in a certain volume of solvent at a specified temperature...

s—has been evaluated, but no clear conclusions have been reached.Vaccinations were also considered as causal factors for the disease; however, most studies show no association between MS and vaccines. Several other possible risk factors, such as diet
Diet (nutrition)
In nutrition, diet is the sum of food consumed by a person or other organism. Dietary habits are the habitual decisions an individual or culture makes when choosing what foods to eat. With the word diet, it is often implied the use of specific intake of nutrition for health or weight-management...

 and hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...

 intake, have been investigated; however, evidence on their relation with the disease is "sparse and unpersuasive".

Gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...

 occurs less than would statistically be expected in people with MS, and low levels of uric acid
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 created when the body breaks down purine nucleotides. High blood concentrations of uric acid...

 have been found in MS patients as compared to normal individuals. This led to the theory that uric acid protects against MS, although its exact importance remains unknown.

Infections

Many microbes have been proposed as potential infectious triggers of MS, but none have been substantiated.

Genetic susceptibility can explain some of the geographic and epidemiological variations in MS incidence, like the high incidence of the disease among some families or the risk decline with genetic distance, but does not account for other phenomena, such as the changes in risk that occur with migration at an early age. An explanation for this epidemiological finding could be that some kind of infection, produced by a widespread microbe rather than a rare pathogen, is the origin of the disease. Different hypotheses have elaborated on the mechanism by which this may occur. The hygiene hypothesis
Hygiene hypothesis
In medicine, the Hygiene Hypothesis states that a lack of early childhood exposure to infectious agents, symbiotic microorganisms , and parasites increases susceptibility to allergic diseases by suppressing natural development of the immune system...

 proposes that exposure to several infectious agents early in life is protective against MS, the disease being a response to a later encounter with such agents. The prevalence hypothesis proposes that the disease is due to a pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...

 more common in regions of high MS prevalence. This pathogen is very common, causing in most individuals an asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...

 persistent infection. Only in a few cases, and after many years since the original infection, does it cause demyelination. The hygiene hypothesis has received more support than the prevalence hypothesis.

Evidence for viruses as a cause includes the presence of oligoclonal bands in the brain and cerebrospinal fluid of most patients, the association of several viruses with human demyelination encephalomyelitis
Encephalomyelitis
Encephalomyelitis is a general term for inflammation of the brain and spinal cord, describing a number of disorders:* Acute disseminated encephalomyelitis or postinfectious encephalomyelitis, a demyelinating disease of the brain and spinal cord, possibly triggered by vaccination or viral...

, and induction of demyelination in animals through viral infection. Human herpes viruses are a candidate group of viruses linked to MS. Individuals who have never been infected by the Epstein-Barr virus have a reduced risk of having the disease, and those infected as young adults have a greater risk than those who had it at a younger age. 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 at a later moment with the causative virus that is the trigger for the disease. Other diseases that have also been related with MS are measles
Measles
Measles, also known as rubeola or morbilli, is an infection of the respiratory system caused by a virus, specifically a paramyxovirus of the genus Morbillivirus. Morbilliviruses, like other paramyxoviruses, are enveloped, single-stranded, negative-sense RNA viruses...

, mumps
Mumps
Mumps is a viral disease of the human species, caused by the mumps virus. Before the development of vaccination and the introduction of a vaccine, it was a common childhood disease worldwide...

 and rubella
Rubella
Rubella, commonly known as German measles, is a disease caused by the rubella virus. The name "rubella" is derived from the Latin, meaning little red. Rubella is also known as German measles because the disease was first described by German physicians in the mid-eighteenth century. This disease is...

.

Blood-brain barrier breakdown

The blood–brain barrier is a capillary
Capillary
Capillaries are the smallest of a body's blood vessels and are parts of the microcirculation. They are only 1 cell thick. These microvessels, measuring 5-10 μm in diameter, connect arterioles and venules, and enable the exchange of water, oxygen, carbon dioxide, and many other nutrient and waste...

 system that should prevent entrance of T cells into the nervous system. The blood–brain barrier is normally not permeable to these types of cells, unless triggered by infection or a virus, which decreases the integrity of the tight junction
Tight junction
Tight junctions, or zonula occludens, are the closely associated areas of two cells whose membranes join together forming a virtually impermeable barrier to fluid. It is a type of junctional complex present only in vertebrates...

s forming the barrier. When the blood–brain barrier regains its integrity, usually after infection or virus has cleared, the T cells are trapped inside the brain.

Autoimmunology

MS is currently believed to be an immune-mediated disorder mediated by a complex interaction of the individual's genetics and as yet unidentified environmental insults. Damage is believed to be caused by the patient's own immune system. The immune system attacks the nervous system, possibly as a result of exposure to a molecule with a similar structure to one of its own.

Lesions
The name multiple sclerosis refers to the scars (scleroses – better known as plaques or lesions) that form in the nervous system. MS lesions most commonly involve white matter
White matter
White matter is one of the two components of the central nervous system and consists mostly of myelinated axons. White matter tissue of the freshly cut brain appears pinkish white to the naked eye because myelin is composed largely of lipid tissue veined with capillaries. Its white color is due to...

 areas close to the ventricles
Ventricular system
The ventricular system is a set of structures containing cerebrospinal fluid in the brain. It is continuous with the central canal of the spinal cord.-Components:The system comprises four ventricles:* right and left lateral ventricles* third ventricle...

 of the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...

, brain stem
Brain stem
In vertebrate anatomy the brainstem is the posterior part of the brain, adjoining and structurally continuous with the spinal cord. The brain stem provides the main motor and sensory innervation to the face and neck via the cranial nerves...

, basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...

 and spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...

; and the optic nerve
Optic nerve
The optic nerve, also called cranial nerve 2, transmits visual information from the retina to the brain. Derived from the embryonic retinal ganglion cell, a diverticulum located in the diencephalon, the optic nerve doesn't regenerate after transection.-Anatomy:The optic nerve is the second of...

. The function of white matter cells is to carry signals between grey matter
Grey matter
Grey matter is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil , glial cells and capillaries. Grey matter contains neural cell bodies, in contrast to white matter, which does not and mostly contains myelinated axon tracts...

 areas, where the processing is done, and the rest of the body. The peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...

 is rarely involved.

More specifically, MS destroys oligodendrocyte
Oligodendrocyte
Oligodendrocytes , or oligodendroglia , are a type of brain cell. They are a variety of neuroglia. Their main function is the insulation of axons in the central nervous system of some vertebrates...

s, the cells responsible for creating and maintaining a fatty layer—known as the myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...

 sheath—which helps the neurons carry electrical
Electricity
Electricity is a general term encompassing a variety of phenomena resulting from the presence and flow of electric charge. These include many easily recognizable phenomena, such as lightning, static electricity, and the flow of electrical current in an electrical wire...

 signals. MS results in a thinning or complete loss of myelin and, as the disease advances, the cutting (transection) of the neuron's extensions or axons. When the myelin is lost, a neuron can no longer effectively conduct electrical signals
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...

. A repair process, called remyelination
Remyelination
Remyelination is a term for the re-generation of the nerve's myelin sheath, damaged in many diseases such as multiple sclerosis and the leukodystrophies. Remyelination is a subject of active medical research.-External links:**...

, takes place in early phases of the disease, but the oligodendrocytes cannot completely rebuild the cell's myelin sheath. Repeated attacks lead to successively fewer effective remyelinations, until a scar-like plaque is built up around the damaged axons. Different lesion patterns have been described.

Inflammation
Apart from demyelination, the other pathologic hallmark of the disease is inflammation. According to a strictly immunological explanation of MS, the inflammatory process is caused by T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...

s, a kind of lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...

. Lymphocytes are cells that play an important role in the body's defenses. In MS, T cells gain entry into the brain via the previously described blood–brain barrier. Evidence from animal models also point to a role of B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...

s in addition to T cells in development of the disease.

The T cells recognize myelin as foreign and attack it as if it were an invading virus. This triggers inflammatory processes, stimulating other immune cells and soluble factors like cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

s and antibodies. Leaks form in the blood–brain barrier, which in turn cause a number of other damaging effects such as swelling
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...

, activation of macrophages, and more activation of cytokines and other destructive proteins.

Diagnosis

Multiple sclerosis can be difficult to diagnose
Medical diagnosis
Medical diagnosis refers both to the process of attempting to determine or identify a possible disease or disorder , and to the opinion reached by this process...

 since its signs and symptoms may be similar to other medical problems. Medical organizations have created diagnostic criteria to ease and standardize the diagnostic process especially in the first stages of the disease. Historically, the Schumacher
Schumacher criteria
Multiple sclerosis, understood as a CNS condition, can be difficult to diagnose since its signs and symptoms may be similar to other medical problems. Medical organizations have created diagnostic criteria to ease and standardize the diagnostic process especially in the first stages of the disease...

 and Poser criteria
Poser criteria
Poser criteria are diagnostic criteria for multiple sclerosis . They replaced the older Schumacker criteria, and now they are considered obsolete as McDonald criteria have superseded them...

 were both popular.

Currently, the McDonald criteria
McDonald criteria
The McDonald criteria are diagnostic criteria for multiple sclerosis . These criteria are named after neurologist W. Ian McDonald. In April 2001 an international panel in association with the National Multiple Sclerosis Society of America recommended revised diagnostic criteria for MS...

 focus on a demonstration with clinical, laboratory and radiologic data of the dissemination of MS lesions in time and space for non-invasive MS diagnosis, though some have stated that the only proved diagnosis of MS is autopsy, or occasionally biopsy, where lesions typical of MS can be detected through histopathological techniques.

Clinical data alone may be sufficient for a diagnosis of MS if an individual has suffered separate episodes of neurologic symptoms characteristic of MS. Since some people seek medical attention after only one attack, other testing may hasten and ease the diagnosis. The most commonly used diagnostic tools are neuroimaging
Neuroimaging
Neuroimaging includes the use of various techniques to either directly or indirectly image the structure, function/pharmacology of the brain...

, analysis of cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...

 and evoked potential
Evoked potential
An evoked potential is an electrical potential recorded from the nervous system of a human or other animal following presentation of a stimulus, as distinct from spontaneous potentials as detected by electroencephalography or electromyography .Evoked potential amplitudes tend to be low, ranging...

s. Magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...

 of the brain and spine shows areas of demyelination (lesions or plaques). Gadolinium
Gadolinium
Gadolinium is a chemical element with the symbol Gd and atomic number 64. It is a silvery-white, malleable and ductile rare-earth metal. It is found in nature only in combined form. Gadolinium was first detected spectroscopically in 1880 by de Marignac who separated its oxide and is credited with...

 can be administered intravenously as a contrast to highlight active plaques and, by elimination, demonstrate the existence of historical lesions not associated with symptoms at the moment of the evaluation. Testing of cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...

 obtained from a lumbar puncture
Lumbar puncture
A lumbar puncture is a diagnostic and at times therapeutic procedure that is performed in order to collect a sample of cerebrospinal fluid for biochemical, microbiological, and cytological analysis, or very rarely as a treatment to relieve increased intracranial pressure.-Indications:The...

 can provide evidence of chronic inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

 of the central nervous system. The cerebrospinal fluid is tested for oligoclonal band
Oligoclonal band
Oligoclonal bands are bands of immunoglobulins that are seen when a patient's blood serum, gained from blood plasma, or cerebrospinal fluid is analyzed....

s of IgG on electrophoresis, which are inflammation markers found in 75–85% of people with MS. The nervous system of a person with MS responds less actively to stimulation of the optic nerve
Optic nerve
The optic nerve, also called cranial nerve 2, transmits visual information from the retina to the brain. Derived from the embryonic retinal ganglion cell, a diverticulum located in the diencephalon, the optic nerve doesn't regenerate after transection.-Anatomy:The optic nerve is the second of...

 and sensory nerves
Sensory neuron
Sensory neurons are typically classified as the neurons responsible for converting external stimuli from the environment into internal stimuli. They are activated by sensory input , and send projections into the central nervous system that convey sensory information to the brain or spinal cord...

 due to demyelination of such pathways. These brain responses can be examined using visual and sensory evoked potential
Evoked potential
An evoked potential is an electrical potential recorded from the nervous system of a human or other animal following presentation of a stimulus, as distinct from spontaneous potentials as detected by electroencephalography or electromyography .Evoked potential amplitudes tend to be low, ranging...

s.

Management

Although there is no known cure for multiple sclerosis, several therapies have proven helpful. The primary aims of therapy are returning function after an attack, preventing new attacks, and preventing disability. As with any medical treatment, medications used in the management of MS have several adverse effects
Adverse effect (medicine)
In medicine, an adverse effect is a harmful and undesired 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. If it results from an unsuitable or incorrect dosage or...

. Alternative treatments
Alternative medicine
Alternative medicine is any healing practice, "that does not fall within the realm of conventional medicine." It is based on historical or cultural traditions, rather than on scientific evidence....

 are pursued by some patients, despite the shortage of supporting, comparable, replicated scientific study.

Acute attacks

During symptomatic attacks, administration of high doses of intravenous
Intravenous therapy
Intravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...

 corticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...

s, such as methylprednisolone
Methylprednisolone
Methylprednisolone is a synthetic glucocorticoid or corticosteroid drug. It is marketed in the USA and Canada under the brand names Medrol and Solu-Medrol. It is also available as a generic drug....

, is the routine therapy for acute relapses. Although generally effective in the short term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery. Oral and intravenous administration seem to have similar efficacy. Consequences of severe attacks which do not respond to corticosteroids might be treated by plasmapheresis
Plasmapheresis
Plasmapheresis is the removal, treatment, and return of blood plasma from blood circulation. It is thus an extracorporeal therapy...

.

Disease-modifying treatments

Fingolimod (trade name Gilenya) was approved for MS by the FDA in 2010, and in Europe in 2011. , after this approval, there are six disease-modifying treatments for MS approved by regulatory agencies of various countries, being the other five: Interferon beta-1a
Interferon beta-1a
Interferon beta-1a is a drug in the interferon family used to treat multiple sclerosis . It is produced by mammalian cells, while Interferon beta-1b is produced in modified E. coli. Interferons have been shown to produce about a 18–38% reduction in the rate of MS relapses, and to slow the...

 (trade names Avonex, CinnoVex
CinnoVex
CinnoVex is the trade name of recombinant Interferon beta 1-a, which is manufactured as biosimilar in Iran.- Description :An interferon-beta protein developed at the Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, Stuttgart, Germany, in collaboration with CinnaGen company,...

, ReciGen
ReciGen
ReciGen is the trade name of recombinant Interferon beta 1-a, which is manufactured as biosimilar as a liquid biomedicine in Iran.-Description:...

and Rebif) and interferon beta-1b
Interferon beta-1b
Interferon beta-1b is a drug in the interferon family used to treat the relapsing-remitting and secondary-progressive forms of multiple sclerosis . It is approved for use after the first MS event...

 (U.S. trade name Betaseron, in Europe and Japan Betaferon). A third medication is glatiramer acetate
Glatiramer acetate
Glatiramer acetate is an immunomodulator drug currently used to treat multiple sclerosis...

 (Copaxone), a non-interferon, non-steroidal immunomodulator
Immunomodulator
An immunomodulator, also known as an immunotherapy is a substance which has an effect on the immune system.- Immunosuppressants :Inhibits immune response in organ transplantation and autoimmune diseases.- Immunostimulants :...

. The fourth medication, mitoxantrone
Mitoxantrone
Mitoxantrone is an anthracenedione antineoplastic agent.-Uses:It is used in the treatment of certain types of cancer, mostly metastatic breast cancer, acute myeloid leukemia, and non-Hodgkin's lymphoma...

, is an immunosuppressant
Immunosuppressant
An immunosuppressant is any substance that performs immunosuppression of the immune system. They may be either exogenous, as immunosuppressive drugs, or endogenous, as ,e. g., testosterone...

 also used in cancer chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....

. The fifth is a humanized monoclonal antibody immunomodualtor, natalizumab
Natalizumab
Natalizumab is a humanized monoclonal antibody against the cellular adhesion molecule α4-integrin. Natalizumab is used in the treatment of multiple sclerosis and Crohn's disease. It is co-marketed by Biogen Idec and Élan as Tysabri, and was previously named Antegren. Natalizumab is administered by...

 (marketed as Tysabri). The interferons and glatiramer acetate are delivered by frequent injections, varying from once-per-day for glatiramer acetate to once-per-week (but intra-muscular) for Avonex. Natalizumab
Natalizumab
Natalizumab is a humanized monoclonal antibody against the cellular adhesion molecule α4-integrin. Natalizumab is used in the treatment of multiple sclerosis and Crohn's disease. It is co-marketed by Biogen Idec and Élan as Tysabri, and was previously named Antegren. Natalizumab is administered by...

 and mitoxantrone are given by IV infusion at monthly intervals.

All six kinds of medications are modestly effective at decreasing the number of attacks in relapsing-remitting MS (RRMS) while the capacity of interferons and glatiramer acetate is more controversial. Studies of their long-term effects are still lacking. Comparisons between immunomodulators (all but mitoxantrone) show that the most effective is natalizumab, both in terms of relapse rate reduction and halting disability progression. Mitoxantrone may be the most effective of them all; however, it is generally not considered as a long-term therapy, as its use is limited by severe secondary effects. The earliest clinical presentation of RRMS is the clinically isolated syndrome (CIS). Treatment with interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...

s during an initial attack can decrease the chance that a patient will develop clinical MS.

Treatment of progressive MS is more difficult than relapsing-remitting MS. Mitoxantrone has shown positive effects in patients with secondary progressive and progressive relapsing courses. It is moderately effective in reducing the progression of the disease and the frequency of relapses in patients in short-term follow-up. No treatment has been proven to modify the course of primary progressive MS.

As with many medical treatments, these treatments have several adverse effects. One of the most common is irritation at the injection site for glatiramer acetate and the interferon treatments. Over time, a visible dent at the injection site, due to the local destruction of fat tissue, known as lipoatrophy
Lipoatrophy
Lipoatrophy is the term describing the localized loss of fat tissue. This may occur as a result of subcutanous injections of insulin in the treatment of diabetes, from the use of human growth hormone or from subcutanous injections of Copaxone used for the treatment of multiple sclerosis. In the...

, may develop. Interferons produce symptoms similar to influenza; some patients taking glatiramer experience a post-injection reaction manifested by flushing, chest tightness, heart palpitations, breathlessness, and anxiety, which usually lasts less than thirty minutes. More dangerous but much less common are liver damage
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...

 from interferons, severe cardiotoxicity
Cardiotoxicity
Cardiotoxicity is the occurrence of heart electrophysiology dysfunction or/and muscle damage. The heart becomes weaker and is not as efficient in pumping and therefore circulating blood...

, infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...

, and acute myeloid leukemia
Acute myeloid leukemia
Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...

 of mitoxantrone, and the putative link between natalizumab and some cases of progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy , also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage or inflammation of the white matter of the brain at multiple locations .It occurs almost exclusively in...

.

Management of the effects of MS

Disease-modifying treatments reduce the progression rate of the disease, but do not stop it. As multiple sclerosis progresses, the symptomatology tends to increase. The disease is associated with a variety of symptoms and functional deficits that result in a range of progressive impairments and disability
Disability
A disability may be physical, cognitive, mental, sensory, emotional, developmental or some combination of these.Many people would rather be referred to as a person with a disability instead of handicapped...

. Management of these deficits is therefore very important. Both drug therapy and neurorehabilitation
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....

 have shown to ease the burden of some symptoms, though neither influences disease progression. Some symptoms have a good response to medication, such as unstable bladder and spasticity, while management of many others is much more complicated. As for any patient with neurologic deficits, a multidisciplinary approach is key to improving quality of life; however, there are particular difficulties in specifying a 'core team' because people with MS may need help from almost any health profession or service at some point. Multidisciplinary rehabilitation programs increase activity and participation of patients but do not influence impairment level.

Historically, individuals suffering from MS were advised against participation in physical activity due to worsening symptoms. However, under the direction of a physiotherapist, participation in physical activity can be safe and has been proven beneficial for patients with MS. Research has supported the rehabilitative role of physical activity in improving muscle power, mobility, mood, bowel health, general conditioning and quality of life. However, it is important to be cautious about not overworking or overheating the patient during the course of exercise. Physiotherapists have the expertise needed to adequately prescribe exercise programs that are suitable for the individual. The FITT equation (frequency of exercise, intensity of exercise, type of exercise and time/duration of exercise) is typically used to prescribe exercises. Depending on the patient, activities may include resistance training, walking, swimming, yoga, tai chi, and others. Determining an appropriate and safe exercise program is challenging and must be carefully individualized to each patient being sure to account for all contraindications and precautions.

Alternative treatments

As with most chronic diseases, alternative treatments for multiple sclerosis, which are unsupported by clinical or scientific evidence, are pursued by some patients. Examples are a dietary regimen, herbal medicine (including the use of medical cannabis
Medical cannabis
Medical cannabis refers to the use of parts of the herb cannabis as a physician-recommended form of medicine or herbal therapy, or to synthetic forms of specific cannabinoids such as THC as a physician-recommended form of medicine...

), hyperbaric oxygenation and self-infection with hookworm
Hookworm
The hookworm is a parasitic nematode that lives in the small intestine of its host, which may be a mammal such as a dog, cat, or human. Two species of hookworms commonly infect humans, Ancylostoma duodenale and Necator americanus. A. duodenale predominates in the Middle East, North Africa, India...

 (known generally as helminthic therapy
Helminthic therapy
Helminthic therapy, a type of immunotherapy, is the treatment of autoimmune diseases and immune disorders by means of deliberate infestation with a helminth or with the ova of a helminth. Helminths are parasitic worms such as hookworms and whipworms....

).

Prognosis

The prognosis
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...

 (the expected future course of the disease) for a person with multiple sclerosis depends on the subtype of the disease; the individual's sex, age, and initial symptoms; and the degree of disability
Disability
A disability may be physical, cognitive, mental, sensory, emotional, developmental or some combination of these.Many people would rather be referred to as a person with a disability instead of handicapped...

 the person experiences. The disease evolves and advances over decades, 30 being the mean years to death since onset.

Female sex, relapsing-remitting subtype, optic neuritis or sensory symptoms at onset, few attacks in the initial years and especially early age at onset, are associated with a better course.

The life expectancy
Life expectancy
Life expectancy is the expected number of years of life remaining at a given age. It is denoted by ex, which means the average number of subsequent years of life for someone now aged x, according to a particular mortality experience...

 of people with MS is 5 to 10 years lower than that of unaffected people. Almost 40% of patients reach the seventh decade of life. Nevertheless, two-thirds of the deaths in people with MS are directly related to the consequences of the disease. Suicide
Suicide
Suicide is the act of intentionally causing one's own death. Suicide is often committed out of despair or attributed to some underlying mental disorder, such as depression, bipolar disorder, schizophrenia, alcoholism, or drug abuse...

 also has a higher prevalence than in the healthy population, while infections and complications are especially hazardous for the more disabled ones.

Although most patients lose the ability to walk prior to death, 90% are still capable of independent walking at 10 years from onset, and 75% at 15 years.

Epidemiology

Two main measures are used in epidemiological
Epidemiology
Epidemiology is the study of health-event, health-characteristic, or health-determinant patterns in a population. It is the cornerstone method of public health research, and helps inform policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive...

 studies: incidence and prevalence. Incidence
Incidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...

 is the number of new cases per unit of person–time at risk (usually number of new cases per thousand person–years); while prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...

 is the total number of cases of the disease in the population at a given time.
Prevalence is known to depend not only on incidence, but also on survival rate and migrations of affected people. MS has a prevalence that ranges between 2 and 150 per 100,000 depending on the country or specific population.
Studies on populational and geographical patterns of epidemiological measures have been very common in MS, and have led to the proposal of different etiological
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....

 (causal) theories.

MS usually appears in adults in their thirties but it can also appear in children. The primary progressive subtype is more common in people in their fifties. As with many autoimmune disorders, the disease is more common in women, and the trend may be increasing. In children, the sex ratio difference is higher, while in people over fifty, MS affects males and females almost equally.

There is a north-to-south gradient in the northern hemisphere and a south-to-north gradient in the southern hemisphere, with MS being much less common in people living near the equator
Equator
An equator is the intersection of a sphere's surface with the plane perpendicular to the sphere's axis of rotation and containing the sphere's center of mass....

. Climate
Climate
Climate encompasses the statistics of temperature, humidity, atmospheric pressure, wind, rainfall, atmospheric particle count and other meteorological elemental measurements in a given region over long periods...

, sunlight
Sunlight
Sunlight, in the broad sense, is the total frequency spectrum of electromagnetic radiation given off by the Sun. On Earth, sunlight is filtered through the Earth's atmosphere, and solar radiation is obvious as daylight when the Sun is above the horizon.When the direct solar radiation is not blocked...

 and intake of vitamin D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....

 have been investigated as possible causes of the disease that could explain this latitude gradient. However, there are important exceptions to the north–south pattern and changes in prevalence rates over time; in general, this trend might be disappearing. This indicates that other factors such as environment or genetics have to be taken into account to explain the origin of MS. MS is also more common in regions with northern Europe populations. But even in regions where MS is common, some ethnic groups are at low risk of developing the disease, including the Samis
Sami people
The Sami people, also spelled Sámi, or Saami, are the arctic indigenous people inhabiting Sápmi, which today encompasses parts of far northern Sweden, Norway, Finland, the Kola Peninsula of Russia, and the border area between south and middle Sweden and Norway. The Sámi are Europe’s northernmost...

, Turkmen
Turkmen people
The Turkmen are a Turkic people located primarily in the Central Asian states of Turkmenistan, Afghanistan, and northeastern Iran. They speak the Turkmen language, which is classified as a part of the Western Oghuz branch of the Turkic languages family together with Turkish, Azerbaijani, Qashqai,...

, Amerindians
Indigenous peoples of the Americas
The indigenous peoples of the Americas are the pre-Columbian inhabitants of North and South America, their descendants and other ethnic groups who are identified with those peoples. Indigenous peoples are known in Canada as Aboriginal peoples, and in the United States as Native Americans...

, Canadian Hutterite
Hutterite
Hutterites are a communal branch of Anabaptists who, like the Amish and Mennonites, trace their roots to the Radical Reformation of the 16th century. Since the death of their founder Jakob Hutter in 1536, the beliefs of the Hutterites, especially living in a community of goods and absolute...

s, Africans, and New Zealand Māori.

Environmental factors during childhood may play an important role in the development of MS later in life. Several studies of migrants show that if migration occurs before the age of 15, the migrant acquires the new region's susceptibility to MS. If migration takes place after age 15, the migrant retains the susceptibility of his home country. However, the age–geographical risk for developing multiple sclerosis may span a larger timescale. A relationship between season of birth and MS has also been found which lends support to an association with sunlight and vitamin D. For example fewer people with MS are born in November as compared to May.

Medical discovery

The French neurologist
Neurologist
A neurologist is a physician who specializes in neurology, and is trained to investigate, or diagnose and treat neurological disorders.Neurology is the medical specialty related to the human nervous system. The nervous system encompasses the brain, spinal cord, and peripheral nerves. A specialist...

 Jean-Martin Charcot
Jean-Martin Charcot
Jean-Martin Charcot was a French neurologist and professor of anatomical pathology. He is known as "the founder of modern neurology" and is "associated with at least 15 medical eponyms", including Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis...

 (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. The three signs of MS now known as Charcot's triad 1 are nystagmus, intention tremor
Intention tremor
Intention tremor, also known as cerebellar tremor, is a dyskinetic disorder characterized by a broad, course, and low frequency tremor. The amplitude of an intention tremor increases as an extremity approaches the endpoint of deliberate and visually guided movement...

, and telegraphic speech
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....

, though these are not unique to MS. Charcot also observed cognition changes, describing his patients as having a "marked enfeeblement of the memory" and "conceptions that formed slowly".*

Prior to Charcot, Robert Carswell (1793–1857), a British professor of pathology
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....

, and Jean Cruveilhier
Jean Cruveilhier
Jean Cruveilhier was a French anatomist and pathologist.In 1816 he earned his doctorate in Paris, where in 1825 he succeeded Pierre Augustin Béclard as professor of anatomy...

 (1791–1873), a French professor of pathologic anatomy, had 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.

After Charcot's description, Eugène Devic
Eugène Devic
Eugène Devic was a French neurologist who was a native of Lyon. He studied medicine in Lyon under internist Léon Bouveret...

 (1858–1930), Jozsef Balo (1895–1979), Paul Ferdinand Schilder
Paul Ferdinand Schilder
Paul Ferdinand Schilder was an Austrian psychiatrist, psychoanalyst, researcher and author of numerous scientific publications. He was a pupil of Sigmund Freud...

 (1886–1940), and Otto Marburg
Otto Marburg
Dr. Otto Marburg was a doctor who was born in Austria Hungary.-Career:He was head of the University of Vienna's Neurological Institute for 19 years. He later went to the U.S...

 (1874–1948) described special cases of the disease. During all the 20th century there was an important development on the theories about the cause and pathogenesis of MS while efficacious treatments began to appear in 1990.

Historical cases

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

A young woman called Halldora, who lived in Iceland
Iceland
Iceland , described as the Republic of Iceland, is a Nordic and European island country in the North Atlantic Ocean, on the Mid-Atlantic Ridge. Iceland also refers to the main island of the country, which contains almost all the population and almost all the land area. The country has a population...

 around 1200, suddenly lost her vision and mobility, but after praying to the saints, recovered them seven days after. Saint Lidwina
Saint Lidwina
Saint Lidwina is a Dutch saint. At age 15, Lidwina was ice skating when she fell and broke a rib. She never recovered and became progressively disabled for the rest of her life...

 of Schiedam
Schiedam
Schiedam is a city and municipality in the province of South Holland in the Netherlands. It is part of the Rotterdam metropolitan area. The city is located west of Rotterdam, east of Vlaardingen and south of Delft...

 (1380–1433), a Dutch
Netherlands
The Netherlands is a constituent country of the Kingdom of the Netherlands, located mainly in North-West Europe and with several islands in the Caribbean. Mainland Netherlands borders the North Sea to the north and west, Belgium to the south, and Germany to the east, and shares maritime borders...

 nun
Nun
A nun is a woman who has taken vows committing her to live a spiritual life. She may be an ascetic who voluntarily chooses to leave mainstream society and live her life in prayer and contemplation in a monastery or convent...

, may be one of the first clearly identifiable MS patients. From the age of 16 until her death at 53, she suffered 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
Augustus d'Este
Sir Augustus Frederick d'Este KCB KCH was the son of Prince Augustus Frederick, Duke of Sussex and Lady Augusta Murray and the grandson of George III...

 (1794–1848), son of Prince Augustus Frederick, Duke of Sussex
Prince Augustus Frederick, Duke of Sussex
The Prince Augustus Frederick, Duke of Sussex , was the sixth son of George III of the United Kingdom and his consort, Charlotte of Mecklenburg-Strelitz. He was the only surviving son of George III who did not pursue an army or naval career.- Early life :His Royal Highness The Prince Augustus...

 and Lady Augusta Murray
Lady Augusta Murray
The Lady Augusta Murray was the first wife of Prince Augustus Frederick, Duke of Sussex, the sixth son of George III. As their marriage was in contravention of the Royal Marriages Act 1772, it was considered legally void, and she could not be styled as the Duchess of Sussex.-Early life:Lady...

 and the grandson of George III of the United Kingdom, almost certainly suffered from 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
Amaurosis fugax is a transient monocular visual loss.-Pathophysiology and etiology:...

) after the funeral of a friend. During the course of his disease, he developed weakness of the legs, clumsiness of the hands, numbness, dizziness, bladder disturbances, and erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....

. 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
W. N. P. Barbellion
Wilhelm Nero Pilate Barbellion was the nom-de-plume of Bruce Frederick Cummings , an English diarist who was responsible for The Journal of a Disappointed Man. Ronald Blythe called it "among the most moving diaries ever created" - Early life and education :Cummings was born in Barnstaple in 1889...

, nom-de-plume of Bruce Frederick Cummings (1889–1919), who maintained a detailed log of his diagnosis and struggle with MS. His diary was published in 1919 as The Journal of a Disappointed Man.

Therapies

Research directions on MS treatments include investigations of MS pathogenesis and heterogeneity; research of more effective, convenient, or tolerable new treatments for RRMS; creation of therapies for the progressive subtypes; neuroprotection strategies; and the search for effective symptomatic treatments.
A number of treatments that may curtail attacks or improve function are under investigation. Emerging agents for RRMS that have shown promise in phase 2 trials include alemtuzumab
Alemtuzumab
Alemtuzumab is a monoclonal antibody used in the treatment of chronic lymphocytic leukemia , cutaneous T-cell lymphoma and T-cell lymphoma...

 (trade name Campath), daclizumab
Daclizumab
Daclizumab is a therapeutic humanized monoclonal antibody to the alpha subunit of the IL-2 receptor of T cells. It is used to prevent rejection in organ transplantation, especially in kidney transplants....

 (trade name Zenapax), rituximab
Rituximab
Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...

, dirucotide, BHT-3009, cladribine
Cladribine
Cladribine is a drug used to treat hairy cell leukemia and multiple sclerosis. Its chemical name is 2-chlorodeoxyadenosine ....

, dimethyl fumarate
Dimethyl fumarate
Dimethyl fumarate is the methyl ester of fumaric acid.-Reactions:Dimethyl fumarate is an ester and an α,β-unsaturated electrophilic compound, undergoing reactions typical to them. It is also a diene acceptor in the ordinary Diels-Alder reaction, where the reactivity of its vinylidenic bond is...

, estriol
Estriol
Estriol is one of the three main estrogens produced by the human body.-Synthesis:Estriol is only produced in significant amounts during pregnancy as it is made by the placenta from 16-Hydroxydehydroepiandrosterone sulfate , an androgen steroid made in the fetal liver and adrenal glands.The human...

, fingolimod, laquinimod
Laquinimod
Laquinimod is an experimental immunomodulator developed by Active Biotech and Teva. It is currently being investigated as an oral treatment for multiple sclerosis ....

, minocycline
Minocycline
Minocycline is a broad-spectrum tetracycline antibiotic, and has a broader spectrum than the other members of the group. It is a bacteriostatic antibiotic, classified as a long-acting type...

, statins, temsirolimus
Temsirolimus
Temsirolimus is an intravenous drug for the treatment of renal cell carcinoma , developed by Wyeth Pharmaceuticals and approved by the U.S. Food and Drug Administration in late May 2007, and was also approved by the European Medicines Agency on November 2007...

 and teriflunomide
Teriflunomide
Teriflunomide is the active metabolite of leflunomide. Teriflunomide was investigated in the Phase III clinical trial TEMSO as a medication for multiple sclerosis . The study was completed in July 2010...

.

In 2010, an FDA committee recommended approving fingolimod for the treatment of MS attacks, and on , 2010, fingolimod (trade name Gilenya) became the first oral drug approved by the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 to reduce relapses and delay disability progression in patients with relapsing forms of multiple sclerosis. Clinical trials of fingolimod have demonstrated side effects in treated patients, including cardiovascular conditions, macular edema, infections, liver toxicity and malignancies.

Much interest has been focused on the prospect of utilizing vitamin D analogs in the prevention and management of CIS and MS, especially given its possible role in the pathogenesis of the disease.
While there is anecdotal evidence of benefit for low dose naltrexone
Low dose naltrexone
Low Dose Naltrexone describes the "off-label" use of the medication naltrexone, at low doses and for other diseases such as multiple sclerosis. Naltrexone is typically prescribed for opioid dependence or alcohol dependence as it is a strong opioid antogonist...

, only results from a pilot study in primary progressive MS have been published.

Disease biomarkers

The variable clinical presentation of MS and the lack of diagnostic laboratory tests lead to delays in diagnosis and the impossibility of predicting diagnosis. New diagnostic methods are being investigated. These include work with anti-myelin antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

, analysis of microarray
DNA microarray
A DNA microarray is a collection of microscopic DNA spots attached to a solid surface. Scientists use DNA microarrays to measure the expression levels of large numbers of genes simultaneously or to genotype multiple regions of a genome...

 gene expression and studies with serum and cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...

 but none of them has yielded reliable positive results.

Currently there are no clinically established laboratory investigations available that can predict prognosis. However, several promising approaches have been proposed. Investigations on the prediction of evolution have centered on monitoring disease activity. Disease activation biomarkers include interleukin-6, nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

 and nitric oxide synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...

, osteopontin
Osteopontin
Osteopontin , also known as bone sialoprotein I , early T-lymphocyte activation , secreted phosphoprotein 1 , 2ar and Rickettsia resistance , is a human gene product, which is also conserved in other species...

, and fetuin
Fetuin
Fetuins are blood proteins that are made in the liver and secreted into the blood stream. They belong to a large group of binding proteins mediating the transport and availability of a wide variety of cargo substances in the blood stream. The best known representative of these carrier proteins is...

-A. On the other hand since disease progression is the result of neurodegeneration the roles of proteins indicative of neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

al, axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....

al, and glial loss such as neurofilament
Neurofilament
Neurofilaments are the 10 nanometer intermediate filaments found specifically in neurons. They are a major component of the cell's cytoskeleton, and provide support for normal axonal radial growth...

s, tau
Tau protein
Tau proteins are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes...

 and N-acetylaspartate are under investigation.

A final investigative field is work with biomarkers that distinguish between medication responders and nonresponders.

Chronic cerebrospinal venous insufficiency

In 2008, Italian vascular surgeon Paolo Zamboni
Paolo Zamboni
Paolo Zamboni is an Italian doctor and vascular surgeon who found in a preliminary study that in over 90% of the participants afflicted with Multiple sclerosis there were several problems in veins draining their brain, like stenosis or defective valves...

 reported research suggesting that MS involves a vascular
Circulatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...

 disease process he referred to as chronic cerebrospinal venous insufficiency
Chronic cerebrospinal venous insufficiency
Chronic cerebrospinal venous insufficiency is a term developed by Italian researcher Paolo Zamboni in 2008 to describe compromised flow of blood in the veins draining the central nervous system...

 (CCSVI, CCVI), in which veins from the brain are constricted. He found CCSVI in the majority of MS patients, performed a surgical procedure to correct it and claimed that 73% of patients improved. Concern has been raised with Zamboni's research as it was neither blinded nor controlled and further studies have had variable results. This has raised serious objections to the hypothesis of CCSVI originating multiple sclerosis. The neurology community currently recommends not to use the proposed treatment until its effectiveness is confirmed by controlled studies, the need for which has been recognized by the scientific bodies engaged in MS research.

See also


External links

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