Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system that most commonly affects young to middle-aged adults. It is characterized by multiple white matter plaques of demyelination that pose major threats to function by producing impairments to cognition, vision, speech, swallowing, muscle function, and bowel and bladder function. Because of its chronic, progressive nature, disability may evolve throughout the course of a patient’s lifetime. The costs of disease, both direct and indirect, are immense. Direct medical costs have been estimated to be in excess of $10 billion per year in the United States. Indirect costs include those related to employment (reduced, or unemployment), disability-related assistive devices and home modifications, and personal care. Physiatric and rehabilitative intervention is crucial to ensure functional and symptomatic improvement over the course of a patient’s life, to improve quality of life, and to decrease the burden of disease.

Most patients with MS are diagnosed while in their 20s and 30s, traditionally prime working and childbearing years. Although the incidence of disease is difficult to ascertain, it is estimated that 400,000 people in the United States are living with MS. Worldwide, prevalence probably exceeds 2.5 million people. Areas with the highest prevalence include northern Europe, southern Australia, and the middle portion of North America. Additionally, MS is one of the most common causes of nontraumatic disability in young adults. The disease is more common in women, with a female-to-male ratio of approximately 2–3:1. Caucasians also tend to be affected more than blacks and Asians.

Although the cause of MS remains unknown, several different factors appear to play a role. One theory focuses on environmental factors associated with geographic location. Living farther away from the equator has been found to convey a higher risk of developing MS, although the Inuit population is an exception. A second notable difference relates to migration patterns. Researchers have noted that the risk of MS decreases when individuals migrate from areas of high to low geographic risk, but the opposite is not true. Although the relationship between distance from the equator and MS is unclear, the significance of vitamin D–promoting sun exposure in relation to development of MS has gained prominence. There is a known increased risk of development of MS in those with low levels of vitamin D. Research is ongoing to determine the effect of vitamin D levels on symptoms in patients previously diagnosed with the disease. Giving additional credence to the environmental influence is the variability seen in disease manifestations and age of onset. This variability implies that while individuals may have a genetic predisposition to develop the disease, environmental factors may continue to mitigate susceptibility. It remains unclear whether a critical period for physiologically necessary sun exposure exists during the lifespan.

The most prominent theories of causation focus on a postinfectious etiology and an autoimmune process, with the latter influenced by genetic predisposition. Numerous research studies have investigated the possibility that an infectious agent initiates the disease process in MS. Viruses that have been studied include rabies, herpes simplex virus 6 (HSV-6), measles, coronavirus, canine distemper virus, human T-lymphotropic virus 1 (HTLV-1), and Epstein-Barr virus (EBV). Chlamydia pneumoniae, a bacterium, has also been studied. Although none of these agents has been proven to cause MS, many experts believe, based on cerebrospinal fluid studies, that an infectious agent does play a role. The persistence of oligoclonal immunoglobulin G (IgG) in the cerebrospinal fluid of patients with MS is consistent with infectious or parainfectious disorders of the central nervous system; however, the specificity of IgG in cerebrospinal fluid remains unknown. Of the viral candidates, the relationship between EBV and MS has been established most strongly, as individuals who are seronegative for EBV have a very low risk of developing MS. Exposure to EBV may be most important during adolescence or early adulthood, as there are many more adults who are seropositive for EBV but do not have MS. Moreover, infectious mononucleosis has been determined to be a risk factor for MS. Again, it remains unclear at which point of exposure any of these factors could ignite the inflammatory cascade.

A genetic predisposition, in combination with environmental triggers, has also been proposed as a mechanism for MS. Multiple genetic linkage studies have confirmed a linkage with the major histocompatibility (MHC) region, as well as less well-defined linkages to other zones that code for interleukins. The presence of serotype HLA-DR2 in DR-positive families is associated with a greater chance of developing the disease. The risk of concordant MS is 30% with monozygotic twins, 5% with dizygotic twins, and between 2% and 4% for first-degree family members of people with MS.

Despite many theories and ongoing research, no clear single etiology has been elucidated, and the disease likely represents a combination of environmental, infectious, and genetic factors.

MS was first defined as its own disease entity by French neurologist Jean-Martin Charcot in 1868. Historically, MS has also been known as disseminated sclerosis or encephalomyelitis disseminata, based on descriptions of affected brains and spinal cords. Charcot called the disease sclerose en plaques, based on his own clinical findings and those of others. Charcot also noticed a triad of symptoms similar among patients with the disease: diplopia, dysarthria, and ataxia.

The disease is characterized by multiple lesions occurring in the white matter of the brain and spinal cord, causing demyelination. Typically these lesions are found adjacent to the lateral ventricles, corpus callosum, periaqueductal region, optic nerves, optic chiasm, and optic tracts, as well as white matter tracts of the spinal cord. The process is believed to be autoimmune mediated, whereby an individual’s immune system attacks the nervous system in response to some unknown trigger. This process is believed to occur in genetically susceptible individuals. The plaques consist of inflammatory infiltrates composed of lymphocytes and macrophages, and there is evidence of astrocytic proliferation and gliosis. This inflammatory process is caused by T cells. T cells cross the blood–brain barrier through leaks, and begin to attack the myelin. An additional release of other inflammatory cytokines, such as interleukin-2, γ interferon, and tumor necrosis factor, also occurs.

T cells specifically attack oligodendrocytes, the cells responsible for production and maintenance of myelin. Myelin helps to insulate axons, and if damaged, results in loss of impulse strength between nodes of Ranvier. This slows or blocks nerve conduction, thus impeding normal nerve impulses and compromising related functions. As the disease worsens, transection of the axons may occur, correlated with irreversible disability. An additional insult to the axon is mediated not only by demyelination, but also by the proliferation of sodium channels localized within the membrane. In an attempt to reestablish normal conduction, there is an increased entry of sodium, slowing of nerve conduction, and potentially, even conduction block.

In between exacerbations, a repair process occurs, or remyelination. However, oligodendrocytes cannot completely rebuild the cell’s myelin sheath, and repeated attacks lead to successively fewer effective remyelinations. The myelin segments become thinner and shorter until a scarlike plaque is built up around the damaged axons. Return of function depends on the degree of remyelination, although this can be altered by fatigue, heat, or additional comorbidities.

Researchers have recently described four different pathologic subtypes of MS. They are: cell-mediated destruction of myelin, cell-mediated myelin destruction with immunoglobulin and activated complement, primary oligodendrogliopathy with apoptosis, and finally neurodegenerative oligodendrogliopathy.

Symptoms and Signs

MS remains a clinical diagnosis. Patient presentations are varied and complex, occasionally making the diagnosis a challenge to the practitioner. The first presenting symptoms are commonly optic neuritis or sensory disturbance. Other symptoms that may prompt patients to seek evaluation are tremor, ataxia, cognitive problems, and dysarthria. Many patients report symptoms of weakness, bowel and bladder dysfunction, fatigue, balance deficits, and pain, for which the differential diagnosis is broad (see later discussion).

The National Multiple Sclerosis Society classifies MS into four main clinical patterns, which are contrasted in Table 15–1. This classification system is helpful in clarifying prognostic and therapeutic decisions. Of the four patterns, the last two are far less common than the first two.

A. Relapsing-Remitting MS

This is the most common pattern of MS, affecting approximately 55–65% of patients. Affected individuals have discrete attacks of new or worsened neurologic symptoms that emerge over a few days and may resolve over a 4–8-week period with or without corticosteroid treatment. The most common initial complaint is tingling or weakness of a limb. Others may complain of visual disturbances or optic neuritis—transient unilateral visual impairment lasting days to weeks, which may be associated with retrobulbar pain. In general, patients with sensory symptoms, and patients whose symptoms fully remit after early exacerbations, demonstrate better long-term prognosis. All relapsing-remitting patients remit after an exacerbation, but they may have residual disability.

B. Secondary-Progressive MS

About 25% of patients are in the secondary progressive category. This pattern begins as relapsing-remitting MS; however, patients deteriorate between attacks and, overtime, functional deficits accumulate. Many patients who have a relapsing-remitting pattern of disease initially eventually develop the secondary-progressive type. The reason for this is not known. These patients also tend to have fewer attacks and show less gadolinium enhancement on magnetic resonance imaging (MRI) than during the relapsing-remitting phase (see later discussion).

C. Primary-Progressive MS