Multiple sclerosis (abbreviated MS, also known as disseminated sclerosis or encephalomyelitis disseminata) is a disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination 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 females. It has a prevalence that ranges between 2 and 150 per 100,000. MS was first described in 1868 by Jean-Martin Charcot.

MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other. Nerve cells communicate by sending electrical signals called action potentials down long fibers called axons, which are wrapped in an insulating substance called myelin. In MS, the body's own immune system 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) in the white matter 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 or infections. Different environmental risk factors have also been found.

Almost any neurological symptom can appear with the disease, and often progresses to physical and cognitive disability. 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 MS. 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 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 of patients is nearly the same as that of the unaffected population.

Classification

Progression of MS subtypes
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 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 85–90% of individuals with MS. When deficits always resolve between attacks, this is sometimes referred to as benign MS, although patients will still accrue some degree of disability in the long term.[citation needed] The relapsing-remitting subtype usually begins with a clinically isolated syndrome (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 have been described. These include Devic's disease, Balo concentric sclerosis, Schilder's diffuse sclerosis and Marburg multiple sclerosis; and 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

Main article: Multiple sclerosis signs and symptoms
Main symptoms of multiple sclerosis

The person with MS can suffer almost any neurological symptom or sign, including changes in sensation (hypoesthesia and paraesthesia), muscle weakness, muscle spasms, or difficulty in moving; difficulties with coordination and balance (ataxia); problems in speech (dysarthria) or swallowing (dysphagia), visual problems (nystagmus, optic neuritis, or diplopia), fatigue, acute or chronic pain, and bladder and bowel difficulties. Cognitive impairment of varying degrees and emotional symptoms of depression or unstable mood are also common. Uhthoff's phenomenon, an exacerbation of extant symptoms due to an exposure to higher than usual ambient temperatures, and Lhermitte's sign, 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 or EDSS.

Symptoms of MS usually appear in episodic acute periods of worsening (called relapses, 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 1 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 increase the risk of relapse. Stress 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 are relapse triggers.

Causes
Most likely MS occurs as a result of some combination of genetic, environmental and infectious factors. 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.

HLA region of Chromosome 6. Changes in this area increase the probability of suffering MS.

MS is not considered a hereditary disease. However, a number of genetic variations 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 siblings, parents, and children. The disease has an overall familial recurrence rate of 20%. In the case of monozygotic twins, 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 driven.

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

Apart from familial studies, specific genes have been linked with MS. Differences in the human leukocyte antigen (HLA) system a group of genes in chromosome 6 that serves as the major histocompatibility complex (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 and DQ6. Other loci have shown a protective effect, such as HLA-C554 and HLA-DRB

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 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 has also been shown to be an independent risk factor for developing MS. Association with occupational exposures and toxins mainly solvents 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 and hormone intake, have been investigated; however, more evidence is needed to confirm or refute their relation with the disease.

Gout occurs less than would statistically be expected in people with MS, and low levels 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 has 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 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 more common in regions of high MS prevalence. This pathogen is very common, causing in most individuals an asymptomatic 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, 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, mumps and rubella.