Key Concepts
A chronic, degenerative, inflammatory disease of the central nervous system that affects neuromuscular function and characteristically involves the destruction of myelin, the insulating material around nerve fibers. The best early description of multiple sclerosis (MS) was that of Jean-Martin Charcot in 1868, who called the disease sclerose en plaques. He noted three cardinal symptoms of MS, known as Charcot's triad—ataxia (coordination problems), dysarthria (slurred speech), and tremor—and associated these symptoms with gray discolorations distributed throughout the brain (Fig. 1) and spinal cord. Today, MS is recognized as causing a variety of potentially disabling neurological symptoms, including diminished strength, coordination, or sensation; visual changes; mood and cognitive problems; and loss of bowel or bladder control. See also: Central nervous system; Nerve; Nervous system disorders; Nervous system (vertebrate); Neuroimmunology

Pathophysiology
MS appears to be an autoimmune disease in which the immune system attacks myelin in the central nervous system. Myelin is a fatty substance that is wrapped around axons, the nerve cables connecting neurons to each other, and enhances the conduction of nerve impulses. In MS, an inflammatory cascade is initiated that causes breakdown of the blood-brain barrier, a layer of endothelial cells that normally prevents large molecules or cells from entering the central nervous system. This allows activated T (thymus-derived) lymphocytes (T cells), other inflammatory cells, and signaling molecules known as cytokines to enter the central nervous system. Ultimately, by mechanisms that are not completely understood, these inflammatory cells or their products damage both the myelin wrapping and, to a variable extent, the axons themselves. Earlier in the disease course, remyelination leads to some clinical improvement. Unfortunately, remyelination is limited and is generally not as effective as the original myelin. Over time, the scars referred to as plaques accumulate, and patients are no longer able to recover well from attacks. See also: Autoimmunity; Cytokine
Common symptoms
The plaques in MS may occur in many locations in the white matter (myelin is yellowish-white) of the central nervous system (Fig. 2). Typical locations include the spinal cord (causing numbness, tingling, weakness, and bowel and bladder disturbance), optic nerves (painful loss of vision), brain stem (vertigo and double vision), cerebellum (incoordination and slurred speech), and the areas next to the ventricles, deep in the brain (Fig. 1). Thus, a wide variety of symptoms is possible. Later in the disease course, muscle spasms, emotional lability, mood disorders, short-term memory and other cognitive difficulties, and fatigue often become prominent symptoms. See also: Brain

Geographical distribution
In North America, northern Europe, and Australia, about 1 in 1000 people suffers from MS. Disease frequency is much lower in Asia, Africa, and the Middle East. This disparity is not well understood. However, with notable exceptions, there appears to be a geographical gradient worldwide, whereby people closer to the Equator (warmer climates) have a significantly lower chance of developing MS than those farther away (colder climates). This gradient has been attributed to several environmental factors, including sun exposure, vitamin D metabolism, diet, toxins, and viral illnesses, although none of these potential links has been conclusively established. Interestingly, these geographic tendencies seem to be most important in childhood. If a patient moves to a different climate after the age of 15, that patient retains the risk for the geographic area from which he or she moved. In addition, as with most autoimmune diseases, about twice as many women as men have MS. See also: Seasons
Disease subtypes
The disease course in MS is highly variable, but most patients fall into one of four categories of disease progression. About 85% of patients, especially young women, initially have attacks (also called relapses or exacerbations) of symptoms lasting days to weeks, followed by complete or incomplete remission of symptoms—so-called relapsing-remitting MS (RRMS). These patients may be relatively stable until they have a new attack, which could happen weeks, months, or years later. After a variable number of years (3–20), a significant proportion of these patients will make the transition into secondary progressive MS (SPMS), when they stop having new attacks but gradually decline neurologically. Much of the disability that accrues over time occurs during SPMS. Primary progressive MS (PPMS) is described in about 10–15% of patients, with no clear attacks but slowly worsening progression of symptoms, often with significant leg weakness and bowel and bladder dysfunction from the onset of the disease. A small number of patients have a combination of both progressive and rare superimposed attacks, referred to as progressive relapsing MS (PRMS). Prognosis is variable, but MS patients generally do somewhat better overall if they are young at diagnosis and female, and if they have few attacks, mostly sensory problems, and fewer lesions seen on imaging studies. Less favorable prognosis is associated with those diagnosed at a later age, males, African Americans, and those with many attacks or PPMS, motor problems, and more lesions seen on imaging studies. In general, MS does not limit life span, but may result in significant disability over time. However, various therapies have been useful in the treatment of MS.
Relapses
Patients may have new symptoms (a new attack) or often will have a recurrence of old symptoms (a pseudoattack) with elevation of body temperature, infection, or stress. An example of a pseudoattack is a patient with previous optic neuritis transiently losing visual function (Uhthoff's phenomenon) with exercise and raised core body temperature. Also, when large populations of MS patients are studied, true attacks seem to be more prevalent during the warmer months. Most attacks, however, appear randomly and with no apparent cause. There is no evidence that vaccinations, such as influenza, varicella (chickenpox), tetanus, hepatitis B, or other commonly given vaccines, increase the risk of MS attacks. Interestingly, the third trimester of pregnancy is associated with a decrease in relapse rate, suggesting a protective hormonal effect. See also: Hormone
Diagnosis
Although formal diagnostic criteria have changed over time, the diagnosis of MS has always required “dissemination of lesions in time and space” within the central nervous system, with objective abnormalities on the neurological examination, and no other cause identified to account for the symptoms. The role of laboratory testing for MS has evolved significantly over the last half-century, first with the identification of abnormal production of immunoglobulins (referred to as oligoclonal bands) in the cerebrospinal fluid. Later, it was found that stimulation of the visual, auditory, or somatosensory systems was slowed in MS patients, and identification of slowing confirmed the lesions as demyelinating in nature. In the last few decades, neuroimaging, especially magnetic resonance imaging (MRI) of the brain and spinal cord, has not only enhanced our ability to diagnose MS, but also altered our view of the nature of the illness. MRI has reinforced the concept that many pathological lesions in the brain are unaccompanied by new clinical symptoms, that brain atrophy is common and important early in the disease, and that the number of lesions and brain atrophy correlate with the progression of disability over time. Adopted in 2001 and updated since then, the newest diagnostic MS criteria (McDonald criteria) explicitly allow the use of laboratory tests, especially MRI, to assist in determining dissemination in space and time, and this allows for earlier diagnosis and treatment of MS. See also: Immunoglobulin; Magnetic resonance; Medical imaging
Differential diagnosis
Many diseases may mimic MS, including systemic lupus erythematosus, Sjögren's syndrome, antiphospholipid antibody syndrome, neurosarcoidosis, Behçet's disease, Lyme disease, other central nervous system infections, and degenerative disorders such as amyotrophic lateral sclerosis (Lou Gehrig's disease). Although all of these diseases can have a variety of neurological manifestations, many mimics of MS also have symptoms outside of the central nervous system; MS symptoms, on the other hand, are restricted to the central nervous system. The paraclinical data such as MRI and the cerebrospinal fluid profile also point to the diagnosis of MS, and laboratory studies in blood often eliminate other potential causes.
Treatment
Various approaches are used in treating MS. Chronic MS symptoms, including fatigue, incontinence, spasticity, and depression, are treated with drugs for those specific problems. Physical, occupational, and speech therapies are often helpful in maximizing activities of daily living, especially gait. Acute attacks of relapsing-remitting MS are treated with high-dose corticosteroids, generally intravenous methylprednisolone (IVMP) for 3–5 days, which will hasten the recovery of neurological function. If IVMP fails to shorten the duration of a severe, disabling attack, plasma exchange over a 2-week period is frequently helpful.
A number of therapies have been approved by the U.S. Food and Drug Administration (FDA) and are used to prevent new attacks and slow the onset of disability in relapsing forms of MS. Some therapeutic drugs are injected by patients at home, including interferons—interferon β-1a and interferon β-1b. These medications are derived from human cytokines, that is, naturally occurring proteins produced by white blood cells, which are induced in the human body in response to infection and other biological factors. It is not entirely understood how these drugs work, but they have an immunomodulatory function and decrease the inflammation involved in the pathogenesis of MS. Another important drug is glatiramer acetate, which is a mixture of polypeptides that is thought to work by shifting the T lymphocyte response away from attacking myelin. The aforementioned drugs are injected at home by the patient and are modestly effective at preventing new attacks (about a one-third reduction) and slowing the progression of disability in MS patients (shown convincingly only in the interferon products). They are distinguished from one another primarily by frequency of dosing and side effects, and there is some evidence that higher dose and frequency of administration of interferon may be slightly more efficacious than lower dose and less frequent administration.
Another chemotherapy drug, mitoxantrone, is helpful in secondary progressive MS and severe relapsing-remitting MS. However, it is limited in its use because of the risks of damaging heart muscle and inducing leukemia. Another drug, natalizumab, is a monoclonal antibody that prevents trafficking of white blood cells across the blood-brain barrier, and is used in the treatment of relapsing-remitting MS. As a result of side effects, it too is restricted in practice to those patients who were nonresponsive to or intolerant of one or more standard MS medications and/or those patients with bad prognosis. In addition, other infused medications (for example, alemtuzumab and ocrelizumab) and oral medications (for example, teriflunomide, fingolimod, dimethyl fumarate, and siponimod) are utilized in various regimens to treat MS.