DEFINITION

As outlined in Figure 1, there are several different forms of MS. Because these classifications were based on clinical characteristics, they are empirical and do not reflect specific biologic pathophysiology. Nonetheless, they provide an organized framework for diagnosis and long-term management. Relapsing-remitting MS (RRMS) is the most common form of the disease, wherein symptoms appear for several days to weeks, after which they usually resolve spontaneously. After tissue damage accumulates over many years, patients typically enter the secondary progressive stage of MS (SPMS), in which pre-existing neurologic deficits gradually worsen over time. Relapses can be seen during the early stages of SPMS, but they become uncommon as the disease progresses. About 15% of patients have gradually worsening manifestations from the onset without clinical relapses, which defines primary progressive MS (PPMS). Patients with PPMS tend to be older, have fewer abnormalities on brain MRI, and generally respond less effectively to standard MS therapies.¹ Progressive relapsing MS is defined as gradual neurologic worsening from the onset with subsequent superimposed relapses. Progressive relapsing MS (and possibly a portion of PPMS) is suspected to represent secondary progressive MS, in which the initial relapses were unrecognized, forgotten, or clinically silent.

Figure 1 Illustration of different clinical courses of MS.

(Adapted from Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 1996;46:907–911.)

Neuromyelitis optica (NMO), or Devic’s disease, is an uncommon variant of MS.² NMO manifests as recurrent optic neuritis and longitudinally extensive transverse myelitis (extending over three or more vertebral segments). A relatively specific antibody, named NMO antibody, has been identified and recognizes the aquaporin-4 water channel in astrocyte foot processes located adjacent to capillary walls.^3,⁴ Recognition of the NMO antibody suggests the pathogenic role of autoantibodies in this form of MS, which has therapeutic implications.

PREVALENCE

MS affects more than 350,000 people in the United States and 2.5 million worldwide. In the United States, prevalence estimates are approximately 90 per 100,000 population. MS symptoms can start anywhere between 10 and 80 years of age, but they usually begin between 20 and 40 years, with a mean age of 32 years. Women outnumber men by a ratio of almost 2 to 1, although in PPMS the ratio is closer to equal. MS affects whites more than blacks, although blacks appear to become disabled earlier, suggesting more destructive tissue injury in blacks. The prevalence of MS varies by location, and it generally increases the farther one travels from the equator in either hemisphere. It remains unclear whether this altered incidence represents an environmental influence, genetic difference, or variable surveillance.

PATHOPHYSIOLOGY

Initially in the disease course, MS involves recurrent bouts of CNS inflammation that result in damage to both the myelin sheath surrounding axons and to the axons themselves. Histologic examination reveals foci of severe demyelination, decreased axonal and oligodendrocyte numbers, and gliotic scarring. The exact cause of inflammation remains unclear, but an autoimmune response directed against CNS antigens is suspected. Recent pathologic studies suggest that different patients might have different etiologies for inflammation: Some patients appear to have T cell–mediated or T cell–plus-antibody–mediated autoimmune responses, whereas others have a primary disorder within the myelin-producing oligodendrocyte cells.⁵ This latter mechanism is reminiscent of virus- or toxin-induced demyelination rather than autoimmunity in this subset of patients. Further research is needed to understand how these different pathologic subtypes affect prognosis and response to treatments. Currently, brain biopsy is the only method to determine pathologic subtype, but studies are under way to find blood, cerebrospinal fluid (CSF), or MRI markers.

In the past, inflammation was believed to involve only demyelination, but pathologic studies have found significant axonal pathology as well. In active MS lesions, observed transected axons were an average of more than 11,000/mm³, whereas control brain tissue had less than 1/mm³.⁶ Clearly, axonal injury is significant in the early stages of disease.

Later in the disease course, gradual progression of disability is observed. However, there is little active inflammation during this period, so this clinical progression probably involves significant degenerative changes. Nonetheless, oligodendrocyte progenitor cells capable of remyelinating axons have been observed, even in white matter plaques from patients with chronic MS (Fig. 2).⁷ This observation suggests that the potential for remyelination persists even very late in the disease course, which is an encouraging indicator for possible therapeutic targets at this late stage of disease.

Figure 2 Remyelinating oligodendrocyte in a demyelinated region of brain from a patient with chronic MS.

There are straight, healthy-appearing axons (green) and an oligodendrocyte (red) extending processes (arrowheads) to myelin internodes.

(Adapted from Chang A, Tourtellotte WW, Rudick R, Trapp BD: Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med 2002;346:165–173.)

Current concepts of the pathophysiology of MS are illustrated in Figure 3. On average, patients have clinical relapses every 1 to 2 years during the relapsing-remitting phase of the disease. Serial MRI studies have shown that lesions develop up to 10 to 20 times more frequently than clinical relapses. Thus, although relapsing-remitting MS appears to have clinically active and quiescent periods, inflammatory lesions are developing and evolving almost continuously. A current hypothesis states that overt progression of disability (secondary progressive MS) occurs when ongoing irreversible tissue injury exceeds a critical threshold beyond which the nervous system can no longer compensate. It is believed that at this point the disease has become essentially a degenerative process, with neurologic deterioration independent of ongoing inflammation.

Figure 3 Typical clinical and magnetic resonance imaging (MRI) course of multiple sclerosis.

MRI activity (vertical arrows) indicates an inflammatory process as measured on brain MRI by gadolinium enhancement or new T2 hyperintense brain lesions. MRI activity typically is more frequent than clinical relapses (spikes in clinical disability), which indicates that more disease activity is taking place than is clinically apparent. Loss of brain volume and increase in disease burden (total volume of lesions), both measured on MRI, indicate permanent tissue damage, which is present early in the disease and gradually progresses over time.

(Adapted from Fox RJ, Cohen JA: Multiple sclerosis: the importance of early recognition and treatment. Cleve Clin J Med 2001;68:175–171.)

An important implication of this hypothesis is that the accumulation of irreversible tissue damage limits the potential for benefit from disease-modifying immunomodulatory therapy as the disease progresses and becomes a degenerative process. To be maximally effective, disease-modifying immunomodulatory therapy should be started early in the relapsing-remitting phase and before permanent disability develops.

SIGNS AND SYMPTOMS

Because MS can affect any area of the brain, optic nerve, or spinal cord, MS can cause almost any neurologic symptom. Typical relapses of MS involve episodes of numbness, weakness, or dyscoordination affecting an arm, a leg, or both. Disease localized to the spinal cord can cause sensory or motor changes involving one side of the body or below a certain spinal cord level (i.e., hemiparesis or paraparesis). Brainstem involvement can manifest as diplopia, altered sensation in the face, or ataxia. Inflammation of the optic nerve (optic neuritis) usually manifests as blurry vision with painful eye movements.

Of all the lesions in MS, cerebral lesions are most common, but they cause the fewest symptoms. Very large cerebral lesions can manifest with weakness or numbness and rarely cause aphasia or other cortical dysfunction. Most cerebral lesions are not in eloquent regions and so are clinically silent and identified only by brain MRI. Lhermitte’s sign is a nonspecific sign, whereby flexion of the neck causes an electric shock–like shooting sensation extending into the arms or down the back. Lhermitte’s sign is believed to arise from partially demyelinated tissue, whereby mechanical stimulation leads to axonal activation.

Other common symptoms of MS include bladder and bowel dysfunction, decreased memory, fatigue, and affective disorders such as depression. Although these symptoms are not uncommon at the diagnosis of MS, they are also nonspecific and can be seen in a multitude of disorders.

DIAGNOSIS

There are no pathognomonic clinical, laboratory, or imaging findings in MS. The diagnosis ultimately is a clinical decision based on weighing the factors that support the diagnosis against those that fail to support it or point to the possibility of an alternative diagnosis.

The Schumacher criteria from 1965 capture the essence of the diagnosis of MS: CNS lesions disseminated in space and time, and the elimination of alternative diagnoses.⁸ These criteria render MS a diagnosis of exclusion, which continues today. However, the Schumacher criteria also required that the patient’s age be between 10 and 50 years and required the finding of objective abnormalities on examination, both of which are now outdated. However, the main concepts captured by these criteria remain relevant today.

Criteria from the Revised International Panel on MS Diagnosis, also called the Revised McDonald Criteria, is the latest attempt to clearly define diagnostic criteria for MS.⁹ Diagnostic classifications are reduced to definite MS and possible MS (Boxes 1 and 2). Advantages to the Revised International Panel criteria include the capability of making a definitive diagnosis of MS either after a monosymptomatic presentation or in the context of a primary progressive course. As the boxes illustrate, the diagnostic classification scheme and MRI criteria remain complicated and tedious, and this complexity limits their use in everyday practice. Furthermore, the specificity of these criteria is relatively low, emphasizing the importance of clinical judgment in excluding other diagnoses. Finally, studies have observed that standard MS disease-modifying medications can benefit patients who do not yet fulfill these diagnostic criteria.

Box 1 International Panel Criteria (McDonald Criteria) for the Diagnosis of Multiple Sclerosis

Adapted from Polman CH, Reingold SC, Edan G, et al: Diagnostic Criteria for Multiple Sclerosis: 2005 Revisions to the “McDonald Criteria.” Ann Neurol 2005;58:840-846.

Additional data needed for a diagnosis of multiple sclerosis for a given clinical presentation (in descending order of objective clinical evidence).