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Key Clinical Questions

  • image What are the major disease manifestations and complications of multiple sclerosis?

  • image How are exacerbations of multiple sclerosis treated?

  • image What are treatment options for complicating symptoms of multiple sclerosis, such as fatigue, bladder dysfunction, and spasticity?

  • image What disease-modifying agents are available to treat multiple sclerosis? What are their major toxicities and long-term risks?

Multiple sclerosis (MS) in its most typical form is an autoimmune, T-cell-driven disease of the central nervous system characterized initially by demyelination and, eventually, by axonal destruction and neuronal loss. It is the most common neurologic disease of young adults.


The peak age of onset is between 20 and 40 years with a twofold higher incidence in women. It has long been observed that latitude of residence in childhood is a risk factor for the development of the disease. Multiple sclerosis is rare in equatorial areas, and the prevalence rises sharply with increasing distance from the equator. Potential explanations for this phenomenon include geographical clustering of susceptibility genes, effects of ultraviolet light exposure in childhood on immune development, and latitudinal variation in vitamin D levels. Low vitamin D levels early in the course of multiple sclerosis are associated with increased size and number of lesions on MRI, and a higher risk of relapse and disability.

Genetic factors play a major role in the development of MS, and a family history is present in 15% of patients and 3% to 5% in first degree relatives. The major histocompatibility complex alleles, among them HLA-DRB1*1501, and two cytokine receptor genes, the interleukin 7 receptor alpha chain gene (IL7RA) and the interleukin 2 receptor alpha chain gene (IL2RA), have been implicated. Susceptibility to MS is likely polygenic, with the contribution of any single locus being small. Clusters of MS cases have suggested an infectious trigger, with limited data to implicate EBV. Smoking, obesity, and high salt intake have inconsistently been implicated as MS risk factors.



Multiple sclerosis is characteristically a relapsing and remitting disease, but there is great variation in its course. Common presenting symptoms of MS are summarized in Table 212-1. Weakness, numbness, or both in one or more limbs are common first symptoms. Patients may have paresthesias in the extremities or a band-like tightness around the trunk or limbs. The legs may feel heavy or difficult to control. Neck flexion may cause a sensation of electric shocks in the shoulders, back, and occasionally in the thighs. This finding, known as the Lhermitte sign, may also be present in cervical spondylosis, vitamin B12 deficiency, radiation myelopathy, and other conditions affecting the cervical spine.

TABLE 212-1Predominant Presenting Symptoms of Multiple Sclerosis

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