Multiple Sclerosis 

Multiple sclerosis (MS) is an immune-mediated inflammatory disease that attacks myelinated axons in the central nervous system (CNS), destroying the myelin and the axon in variable degrees. The disease is characterized initially by episodes of reversible neurologic deficits. In most patients, these episodes are followed by progressive neurologic deterioration over time. The cause of the disease is not known, but it likely involves a combination of genetic susceptibility and a nongenetic trigger, such as a virus, low vitamin D levels, or environmental factors, that together result in a self-sustaining autoimmune disorder that leads to recurrent immune attacks on the CNS. (See Etiology.)

MS is diagnosed on the basis of clinical findings and supporting evidence from ancillary tests, such as magnetic resonance imaging (MRI) of the brain and cerebrospinal fluid examination. (See Workup.)

A common misconception is that any attack of demyelination means a diagnosis of acute MS. When a patient has a first attack of demyelination, the physician should not rush to diagnose MS, because the differential diagnosis includes a number of other diseases. MS must be distinguished from other neuroinflammatory disorders, including acute disseminated encephalomyelitis (ADEM), Schilder disease, and Baló concentric sclerosis. (See Diagnosis.)

Treatment consists of immunomodulatory therapy for the underlying immune disorder and management of symptoms, as well as nonpharmacologic treatments, such as physical and occupational therapy. (See Treatment and Management.)

Medications used to treat MS can be classified as immunomodulating or symptom-management medications. For acute exacerbations, methylprednisolone (Solu-Medrol) is given and has been shown to hasten recovery from the given attack, but it has uncertain long-term effects. In addition, plasma exchange (plasmapheresis) can be used short term for severe attacks if steroids are contraindicated or ineffective. The 2011 American Academy of Neurology (AAN) guideline for plasmapheresis in neurological diseases calls plasmapheresis “probably effective” as second-line treatment for relapsing MS exacerbations that do not respond to steroids.^[1]

The disease-modifying agents for MS (DMAMS) currently approved for use in relapsing forms of MS in the United States include interferon beta (Avonex, Betaseron, and Rebif), glatiramer acetate (Copaxone), natalizumab (Tysabri), and mitoxantrone (Novantrone). (See Medication.) FTY720 (fingolimod [Gilenya]) is now approved by the US Food and Drug Administration (FDA).

The drugs, which are available in injectable formand in an oral form for fingolimod,are currently FDA approved only for relapsing-remitting MS (RRMS). In a European study on secondary progressive MS (SPMS), patients in the interferon beta-1b group showed a highly significant delay in time to disease progression; however, FDA approval has not been granted yet for this indication.^{[2, 3, 4]}

MS is an inflammatory, demyelinating disease of the CNS. In pathologic specimens, the demyelinating lesions of MS, called plaques (see the image below), appear as indurated areas; hence the term sclerosis.

Examination of the demyelinating lesions in the spinal cord and brain of patients with MS shows myelin loss, destruction of oligodendrocytes, and reactive astrogliosis, often with relative sparing of the axon cylinder.^[5] In some MS patients, however, the axon is also aggressively destroyed. The location of lesions in the CNS dictates the type of deficit that results.

MS is characterized by perivenular infiltration of lymphocytes and macrophages in the parenchyma of the brain, brain stem, optic nerves, and spinal cord, as demonstrated in the image below.

Expression of adhesion molecules on the surface seems to underlie the ability of these inflammatory cells to penetrate the blood-brain barrier. The elevated immunoglobulin G (IgG) level in the cerebrospinal fluid (CSF), which can be demonstrated by an oligoclonal band pattern on electrophoresis, suggests an important humoral (ie, B-cell activation) component to MS. In fact, variable degrees of antibody-producing plasma cell infiltration have been demonstrated in MS lesions. The image below provides an overview of demyelination.

Immune cells in MS

Molecular studies of the white matter plaque tissue have shown that interleukin (IL)-12, a potent promoter of inflammation, is expressed at high levels in lesions that form early. A molecule required to stimulate lymphocytes to release proinflammatory cytokines, B7-1, is also expressed at high levels in early MS plaques.^[5] Evidence exists of higher frequencies of activated myelin-reactive T-cell clones in the circulation of patients with RRMS and higher IL-12 production in immune cells of patients with progressive MS, when compared with healthy controls.

Decreased function of immune cells with a regulatory role (Tregs) has been implicated in MS.^[6] These Tregs are CD4⁺ CD25⁺ T cells that can be identified by their expression of a transcription factor known as Foxp3. Conversely, the cytokine IL-23 has been shown to drive cells to commit to a pathogenic phenotype in autoimmune diseases, including MS. These pathogenic CD4⁺ T cells act reciprocally to counteract Treg function and can be identified by their high expression of the proinflammatory cytokine IL-17; they are therefore referred to as T_H 17 cells.^[7]

Tregs and T_H 17 cells are not the only critical immune cells in the pathogenesis of MS. Immune cells such as microglia (resident macrophages of the CNS), dendritic cells, natural killer (NK) cells, and B cells are gaining increased attention by MS researchers. In addition, nonimmune cells (ie, endothelial cells) have also been implicated in mechanisms that lead to CNS inflammation.^[8]

Spinal MS

As neural inflammation resolves in MS, some remyelination occurs, but most recovery of function that takes place in a patient may be due to cortical reorganization.

In 1988, MS was first described in the upper cervical spine using MRI. Spinal MS is often associated with concomitant brain lesions; however, as many as 20% of patients with spinal lesions do not have intracranial plaques. No strong correlation has been established between the extent of the plaques and the degree of clinical disability.

Spinal MS has a predilection for the cervical spinal cord (67% of cases), with preferential, eccentric involvement of the dorsal and lateral areas of the spinal cord abutting the subarachnoid space around the cord. The gray matter may be involved. Approximately 55-75% of patients with MS have spinal lesions at some point during the course of the disease.

Optic neuritis in MS

Approximately 20% of patients with MS present with optic neuritis (ON) as a first demyelinating event, and 40% of patients may present with ON during the course of their disease. (See History.)

Sequential episodes of optic nerve involvement and a longitudinally extensive myelopathy (ie, neuromyelitis optica [NMO], or Devic disease, as shown in the images below) are considered by some to be an MS variant.^[9] Others report that an identified antibody and the typical MS therapies are ineffective in Devic disease.

The cause of MS is unknown, but it is likely that multiple factors (not a single identifiable agent or event act in concert to trigger or perpetuate the disease. These factors are in part environmental and in part hereditary. The concordance rate for MS among monozygotic twins is only 20-35%, suggesting that genetic factors have only a modest effect. The presence of predisposing non-Mendelian factors (ie, epigenetic modification in 1 twin), along with environmental effects, plays an important role. For first-degree family members (children or siblings) of people affected with MS, the risk of developing the disorder is only 3-5%.

It has been hypothesized that MS results when an environmental agent or event (eg, virus, bacteria, chemicals, lack of sun exposure) acts in concert with a genetic predisposition to immune dysfunction.

Genetic and molecular factors

Different variants of genes normally found in the general population, commonly referred to as polymorphisms, may lead to different gradations of cellular expression of those genes and therefore of the proteins that they encode.

It may be that an individual with a polymorphism within the promoter region of a gene that is involved in immune reactivity generates an exaggerated response (eg, elevated gene expression of a proinflammatory gene) to a given antigen, leading to uncontrolled immune cell proliferation and autoimmunity. HLA-DRB1 is the only chromosomal locus that has been consistently associated with MS susceptibility.

Research on single nucleotide polymorphisms (SNIPS) that confer risk of more severe disease or risk of developing particular forms of MS will be of great interest to the clinicians treating this complex disorder in the early stages. (Genes that instead of conferring susceptibility to MS confer relative protection against it are also being investigated, and clues are emerging from within the MHC region. For example, it has been suggested that the HLA-C*05 allele confers disease protection.^[10] )

The molecular mimicry hypothesis refers to the possibility that peripheral blood T cells may become activated to attack a foreign antigen and then erroneously direct their attack toward brain proteins that share similar protein epitopes.

Viruses

Another hypothesis is that a virus may infect the immune system, activating self-reactive T cells (myelin reactive) that would otherwise remain quiescent.

A virus that infects cells of the immune and nervous systems can possibly be reactivated periodically and thus lead to acute exacerbations in MS. The Epstein-Barr virus (EBV) has been found to become periodically reactivated, but a causation role in MS has been difficult to prove. Arguments supporting this view include long-term studies showing a higher association with MS in individuals with early presence of serum antibodies against specific EBV antigens, and high expression of EBV antigens within MS plaques. Arguments against causation include the fact that MS is a highly heterogeneous disease (EBV might help to trigger some cases but not others, making associations in populations difficult), and the notion that disease manifestations could precede viral reactivation (ie, rather than being the trigger for MS, the virus might be reactivated as an epiphenomenon of a dysregulated immune system).

Environmental factors

Geography is clearly an important factor in the etiology of MS. The incidence of the disease is lower in the equatorial regions of the world than in the southernmost and northernmost regions. However, a systematic review by Alonso and Hernán found that this latitude gradient became attenuated after 1980, apparently due to an increased incidence of MS in lower latitudes.^[11] (See Epidemiology.)

Apparently, whatever environmental factor is involved must exert its effect in early childhood. If an individual lives in an area with low incidence of MS until age 15 years, that person's risk is low, and if an individual moves from an area of low incidence to an area of high incidence after age 15 years, his or her risk does not increase. Certain ethnic groups (eg, Eskimos), despite living in areas of higher incidence, do not have a high frequency of MS. Therefore, the exact role played by geography versus genetics is not clear. (See Epidemiology.)

Vitamin D levels

Low levels of vitamin D have been proposed as one environmental factor contributing to the development of MS. Vitamin D has a role in regulating immune response, by decreasing production of proinflammatory cytokines and increasing production of anti-inflammatory cytokines; also, high circulating levels of vitamin D appear to be associated with a reduced risk of MS.^[12] Thus, lower vitamin D levels due to lower sunlight exposure at higher latitudes may be one reason for the geographic variations in MS incidence, and the protective effect of traditional diets high in vitamin D could help explain why certain areas (eg, Norway) have a lower incidence of MS despite having limited sunlight.^[13] This hypothesis would also provide an explanation for the correlation between childhood sun exposure and MS in monozygotic twins discordant for MS.^[14]

Chronic cerebrospinal venous insufficiency

A controversial hypothesis proposes a vascular rather than an immunologic cause for some cases of MS. In 2008, Paolo Zamboni described an association between MS and chronic cerebrospinal venous insufficiency (CCSVI).^[15] In CCSVI, stenosis of the main extracranial venous outflow pathways results in compromised drainage and a high rate of cerebral venous reflux. CCSVI has been linked with iron deposition in the brain parenchyma, which is modestly to strongly predictive of disability progression, lesion volume accumulation, and atrophy in some patients with MS.^{[16, 17]}

A small, open-label study found that internal jugular vein and azygous vein angioplasty had a positive effect on MS symptoms in patients with CCSVI.^[18] Moreover, CCSVI has received widespread attention in the lay press and MS support groups, and physicians should be prepared for inquiries from patients on this subject.

Hepatitis B vaccine

Worldwide anecdotal reports suggesting a connection between hepatitis B vaccination and MS prompted the Centers for Disease Control and Prevention (CDC) to investigate this possibility. The CDC concluded that the weight of the available scientific evidence does not support the suggestion that hepatitis B vaccine causes or worsens MS.^[19] The National Multiple Sclerosis Society expert panel states: “P eople with MS should not be denied access to health-preserving and potentially-life saving vaccines because of their MS, and should follow the CDC guidelines for any given vaccine.”

United States statistics

Prevalence estimates for MS in the United States vary from 58 to 95 per 100,000 population.^[20] According to the National Multiple Sclerosis Society, 400,000 individuals in the United States are affected by MS.^[21] Misdiagnosis is common.

As is true of autoimmune diseases in general, MS is more common in women. The female-to-male ratio in MS incidence has increased since the mid-20^th century, from an estimated 1.4 in 1955 to 2.3 in 2000.^[11] MS is usually diagnosed in persons aged 15-45 years; however, it can occur in persons of any age. The average age at diagnosis is 29 years in women and 31 years in men.

International statistics

Worldwide, approximately 2.1 million people are affected by MS. The disease is seen in all parts of the world and in all races, but rates vary widely.^[21] In general, the prevalence of MS tends to increase with latitude (eg, lower rates in the tropics, higher rates in northern Europe), but there are many exceptions to this gradient (eg, low rates among Chinese, Japanese, and African blacks; high rates among Sardinians, Parsis, and Palestinians), which implies that racial and ethnic differences affect risk. In addition, a substantial increase in MS incidence has been reported from different regions, suggesting that environmental factors, as well as geographic and genetic ones, play an important role in MS.^[22] (See Etiology.)

If left untreated, more than 30% of patients with MS will develop significant physical disability within 20-25 years from onset. Several of the disease-modifying agents used in MS have slowed disability progression within the duration of research trials; whether these effects will be maintained over longer periods is not known.

Less than 5-10% of patients have a clinically milder MS phenotype, in which no significant physical disability accumulates despite several decades passing since onset (sometimes in spite of multiple new lesions seen on MRI). Detailed examination of these patients in many instances reveals some degree of cognitive deterioration.

Male patients with primary progressive MS have the worst prognosis, with less favorable response to treatment and rapidly accumulating disability. The higher incidence of spinal cord lesions in primary progressive MS is also a factor in the rapid development of disability.

Pain is a common occurrence in MS, with 30-50% of patients experiencing it at some time in the course of their illness.

Life expectancy is shortened only slightly in persons with MS, and the survival rate is linked to disability. Death usually results from secondary complications (50-66%), such as pulmonary or renal causes, but can also occur due to primary complications, suicide, and causes unrelated to MS.

Marburg variant of MS is an acute and clinically fulminant form of the disease that can lead to coma or death within days.

Include the family members or caregivers in any education provided, to ensure a successful outcome. Community agencies, such as the state chapters of the National Multiple Sclerosis Society, can provide valuable information concerning community resources, as well as social support and education. Patients should be educated on the purposes of medications, doses, and adverse effect management. Patients and caregivers need education on appropriate management of symptoms related to pain, fatigue, and spasticity, as well as on issues related to bowel, bladder, and sexual function. For patients with advanced disease, caregivers need hands-on training in transfer techniques, as well as in management of skin integrity, bowel programs, and urinary collection devices.

Patients may benefit from referral to comprehensive and professional organizations and Web sites that are dedicated to MS. Among these, the National Multiple Sclerosis Society is highly recommended for information on current hypotheses, ongoing research, general resources, and educational programs. Other highly recommended MS-related Web sites include MultipleSclerosis.com and Consortium of Multiple Sclerosis Centers.

For excellent patient education resources, visit eMedicine's Muscle Disorders Center. Also, see eMedicine's patient education article Multiple Sclerosis.