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Overview of Multiple Sclerosis and Related Demyelinating Disorders

Demyelinating diseases are a group of disorders characterized by the loss of the myelin sheath surrounding axons in the central nervous system (CNS). Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating CNS disease of unknown etiology that affects females more frequently than males (approximately 2-3 times greater incidence), with typical onset between the ages of 20 and 40.311,  269  It is the most common disabling neurologic illness affecting young adults312  with up to 350,000 individuals in the United States affected.6655,  268  Although the etiology is unknown, MS is characterized by an immune-mediated inflammatory response against myelin, and perhaps other CNS proteins, leading to degenerative changes in the brain and spinal cord as well as concomitant sequelae.

Pathological Criteria for Multiple Sclerosis and Related Demyelinating Disorders

According to Victor and Ropper269  commonly accepted pathological criteria for demyelinating disorders include the following:

  1. Nerve fiber myelin sheath destruction

  2. Relative sparing of other elements of nervous tissue (axis cylinders, nerve cells, and supporting structures)

  3. Perivascular distribution of infiltrating inflammatory cells

  4. Specific lesion distribution, often perivenous and typically in white matter, either in multiple small disseminated foci or in larger foci spreading from 1 or more centers

  5. Relative lack of Wallerian, or secondary, fiber tract degeneration

Clinical Manifestations of Multiple Sclerosis and Related Demyelinating Disorders

Classic symptoms include motor weakness, paresthesias, monocular visual impairment with pain (optic neuritis), diplopia, nystagmus, dysarthria, ataxia, and intention tremor, as well as bladder and sexual dysfunction.269,  312  The early symptoms of MS can range from a transient single minor impairment to a constellation of debilitating primary symptoms that never fully remit.312  Symptom exacerbations are also unpredictable. Certain factors, however, reportedly aggravate symptoms or lead to an acute attack. These factors include heat (including fever), hyperventilation, stress, sleep deprivation, malnutrition, anemia, exertion, concomitant organ dysfunction, and childbirth. Many pregnant female patients experience a significant reduction in acute relapse during the third trimester, then an increase post partum.298  Overall, symptom exacerbations and the clinical course of MS are highly variable whereas outcome is not, with most MS patients eventually developing severe neurologic disability.319 

Diagnosis of Multiple Sclerosis and Related Demyelinating Disorders

The diagnosis of MS is based on an evaluation of a patient’s clinical symptoms, a brain and spinal magnetic resonance imaging (MRI), and often cerebrospinal fluid (CSF) examination. Additionally, it requires the clinician to rule out diseases (including other demyelinating disorders) that may mimic MS and its symptoms (see Fig.64). According to Miller, et al,319  85% of MS patients first present with a clinically isolated syndrome (CIS). These authors defined CIS as an acute or subacute episode of neurologic disturbance due to a single white matter lesion. A list of CIS characteristic of MS is found in Fig.65. Between 50% and 80% of individuals presenting with a CIS have MRI lesions consistent with prior disease activity. Outcome data on CIS and MS are available from 3 trials: The North American Optic Neuritis Treatment Trial (ONTT),303  Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS),311  and the Early Treatment of Multiple Sclerosis study (ETOMS).306  The probability of having a second CIS episode during the study periods ranged from 16.7% in ONTT, 38% in CHAMPS, and 45% in ETOMS. Overall, Miller, et al,319  concluded that baseline lesion number was predictive of conversion to clinically definite MS as well as the probability of developing mild-to-moderate disability.

Figure 64 – Differential Diagnosis of Multiple Sclerosis

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Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343(13):938-952, Massachusetts Medical Society (New Engl J Med) Copyright 2000 Massachusetts Medical Society. All rights reserved.

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Figure 65 – Clinically Isolated Syndromes Characteristic of Multiple Sclerosis


Frohman EM, Goodin DS, Calabresi PA, et al. The utility of MRI in suspected MS: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003;61(5):602-611. Copyright Lippincott Williams & Wilkins.

276

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Current Diagnostic Criteria for Multiple Sclerosis

Current diagnostic criteria for MS generally require at least 2 distinct events separated in time as well as involvement of at least 2 distinct areas of the CNS: the commonly referred to dissemination of time and space. This is why single clinical events (CIS) cannot establish a definite diagnosis of MS unless there is strong supportive MRI results or cerebrospinal fluid evidence.

Tools to Aid in Multiple Sclerosis Diagnosis

To date, there are no tests designed specifically to diagnosis MS. However, MRI, cerebrospinal fluid (CSF) evaluation, and evoked potential studies, in conjunction with a good clinical history, physical examination, and neurologic examination aid in the diagnosis of MS.

Magnetic resonance imaging has become a widely accepted tool in MS diagnosis.276  On T2-weighted MRI images, MS lesions appear as areas of hyperintensities, particularly in the spinal cord and cerebral white matter. In 2003, the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology examined the utility of MRI in suspected MS. The subcommittee’s recommendations were based on exclusion at baseline of appropriate alternative conditions that can mimic MS and/or the radiographic findings of MS. These recommendations include:

  1. On the basis of consistent Class I, II, and III evidence (see Fig.68) in patients with clinically isolated syndrome (CIS), the finding of 3 or more white matter lesions on a T2-weighted MRI scan is a very sensitive predictor (>80%) of the subsequent development of clinically definite MS (CDMS) within the next 7-10 years (Type A recommendation). It is possible that the presence of even a smaller number of white matter lesions (e.g., 1 to 3) may be equally predictive of future MS although this relationship requires better clarification.

  2. The presence of 2 or more gadolinium (Gd)-enhancing lesions at baseline is highly predictive of future development of CDMS (Type B recommendation).

  3. The appearance of new T2 lesions or new Gd enhancement 3 or more months after a clinically isolated demyelinating episode (and after a baseline MRI assessment) is highly predictive of subsequent development of CDMS in the near term (Type A recommendation).

  4. The probability of making a diagnosis other than MS in patients with CIS with any of the above MRI abnormalities is quite low, once alternative diagnoses that can mimic MS or can mimic the radiographic findings of MS have been excluded (Type A recommendation).

  5. The MRI features helpful in the diagnosis of primary progressive MS cannot be determined from the existing evidence (Type U recommendation).

Figure 68 – Classification of Evidence Definitions

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Frohman EM, Goodin DS, Calabresi PA, et al. The utility of MRI in suspected MS: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003;61(5):602-611. Copyright Lippincott Williams & Wilkins.

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CSF evaluation via lumbar puncture is another diagnostic tool used in the diagnosis of MS, although with advances in MRI scanning it is now typically reserved for atypical cases. CNS synthesis of immunoglobulin (Ig) G is increased in MS patients, whereas serum IgG levels remain normal. Electrophoretic studies of CSF demonstrate the IgG separation into oligoclonal bands, which is present in 90%-95% of patients with CDMS. However, this is significant only if oligoclonal banding is not found in the serum. CSF IgG elevations are not specific to MS, as they are seen in a variety of diseases. Moreover, early in the course of the disease, CSF may be positive in only 30%-50% of patients. Overall, CSF evaluation is sensitive but not specific to MS diagnosis, and diagnoses other than MS should be considered when the presence of more than 50 x 106 mononuclear cells is detected in the CSF.

Evoked potential studies can be useful in detecting asymptomatic demyelinated lesions. Visual, brain stem, and somatosensory evoked potential studies are designed to detect lesions in their respective areas, but the sensitivity and specificity of these tests is less than that found with MRI.312 

Multiple Sclerosis Clinical Courses

In addition to diagnosing a patient with clinically definite multiple sclerosis (CDMS), it is also important to differentiate the clinical course of a patient’s disease. The clinical course of MS has important implications for prognosis. Different clinical courses of MS include relapsing-remitting (RR) MS, secondary progressive (SP) MS, primary progressive (PP) MS, and progressive relapsing (PR) MS.276 

Approximately 85% of MS patients have the RRMS variant, which is typically characterized by self-limited attacks and new symptoms that last 24 hours or more. These symptoms are separated from other symptoms by at least 30 days, followed by complete or incomplete remissions. Recovery following an attack is traditionally quite good in the early course of the disease but deteriorates with incomplete symptom resolution later in the disease course. Of the 85% of MS patients with RRMS, less than 20% experience a benign course with an abrupt onset, few exacerbations, and no permanent disability. The majority of RRMS patients eventually enter a progressive phase of their disease characterized by acute attacks with incomplete symptom resolution referred to as SPMS. During this phase of the disease exacerbations and remissions are difficult to identify, and disability worsens.

Approximately 15% of MS patients have the PPMS variant, which has slow symptom onset, no attacks, but continually worsening disability over time. Consequently, PPMS patients have a poorer prognosis than those initially presenting with RRMS. A small percentage of MS patients can present with a mixture of progression and relapses; hence, this course is referred to as PRMS.

Epidemiology and Etiology of Multiple Sclerosis and Demyelinating Disorders

The prevalence of MS varies considerably worldwide. Multiple sclerosis is rare in tropical areas, with a reported prevalence of less than 1 per 100,000 persons in equatorial areas, which increases in prevalence as distance from the equator increases. Prevalence ranges from 6-14 per 100,000 persons in the southern United States and southern Europe to 30-80 per 100,000 persons in Canada, northern Europe, and the northern United States.269  Studies have demonstrated that individuals migrating from a high-risk to low-risk zone carry part of the risk from their country of origin. However, several studies have shown that this risk is mediated by age. Specifically, those emigrating before age 15 have similar risk to the natives of the area to which they emigrated, whereas those emigrating after that time carry the same risk as those from their birthplace. Overall, epidemiologic and other studies have shown that MS is associated with specific localities and not the ethnic groups from those localities. This emphasizes the importance of environmental factors in the development of MS.269 

The precise cause of MS remains undetermined, though the etiology of MS is thought to be a complex interplay of environmental and genetic factors. There is strong evidence for the role of genetics in the etiology of MS, but it is also clear that the disease does not arise from genetics alone. First- and second-degree relatives of MS patients are significantly more likely to develop MS than the general population.269  A large, population-based study in British Columbia examining the heritability of MS found that the risk of full siblings (both shared biologic parents) was 2-3 times greater than half siblings (1 shared biologic parent). Additional evidence of heritability comes from twin studies where 1 of each pair has MS. In one study (as cited in Ebers, et al269  ), a diagnosis of MS was verified in 12 of 35 pairs of monozygotic twins (34%), but only 2 of 49 pairs of dizygotic twins (4%). In addition, the concordance rate in dizygotic pairs is similar to that of nontwin siblings. The fact that the risk in monozygotic twins is not 100% clearly indicates that more than genetics is involved. Furthermore, increased familial incidence does not unequivocally implicate heritability, as it may simply reflect an exposure to a common environmental agent. However, the risk in individuals adopted as infants by a parent who goes on to develop MS is not increased compared with the background population, indicating that environment alone is probably not sufficient.323 

Other factors have been examined to help explain the likelihood of developing MS. Several studies in Europe and Canada looked at rural dwellers versus urban dwellers showing a higher MS rate for those living in rural settings. However, studies of US military personnel found the opposite. Studies in Great Britain found a link to socioeconomic status, though in the United States there is no clear relationship between socioeconomic status and MS. Other environmental factors, such as surgery, trauma, anesthesia, pet exposure, and mercury levels in amalgam teeth fillings, have been examined for their relationship with MS but are not supported by the evidence.269  The nature of environmental factors is unknown, but early childhood infections (especially viral infections), increased exposure to industrial toxins, decreased exposure to parasites and gram-negative organisms derived from farm animals (the “hygiene hypothesis”), and exposure to sunlight have all been postulated to play a role. However, the support for each of these theories is inconclusive at best.268,  316 

Immunology of Multiple Sclerosis

The pathological hallmark of clinically definite multiple sclerosis (MS) is the demyelinated (white matter) plaque. Acute lesions are characterized by inflammatory cell infiltration by T lymphocytes, B lymphocytes, macrophages filled with myelin debris, oligodendrocyte loss, breakdown of associated myelin sheaths and astrocyte proliferation (see Fig.72).

The immunologic basis for MS is not completely understood. However, a number of important insights have been gained from animal models, notably experimental models of autoimmune encephalitis, a disease induced in animals by immunization with myelin antigens.309  It is clear that T cells, especially CD4 cells, play a pivotal role. In studies where T cells activated against myelin basic protein were transferred to a different animal, marked demyelination was demonstrated. In contrast, administration of antibodies to myelin targets did not result in pathological changes.268  Additional cells, including CD8 cytotoxic T cells, also play a key role. In fact, CD8 cells show a more prominent clonal expansion in MS lesions, and the severity of lesions correlates with their concentration.323  Secreted pro-inflammatory cytokines, including interferon-α and tumor necrosis factor (TNF)-α, are also contributory. However, the role of TNF-α is complex. While signaling through the p55 TNF receptor appears to be pro-inflammatory in MS, signaling through the p75 TNF receptor may down-regulate autoimmune responses and induce reparative effects through oligodendrocyte proliferation.323  Thus, TNF-α may have both pro-inflammatory and anti-inflammatory roles in MS. This may help explain why anti-TNF treatment of MS appears to have a detrimental effect, a finding that at first was considered paradoxical.309,  322,  324 

Figure 72 – Possible Mechanisms for Injury and Repair in Multiple Sclerosis

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Noseworthy JH, Lucchinetti C, Rodriguez M, et al. Multiple sclerosis. N Engl J Med 2000;343(13):938-952. Copyright © 2000 Massachusetts Medical Society. All rights reserved.

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Possible Mechanisms for Injury and Repair in Multiple Sclerosis “Genetic and environmental factors (including viral infection, bacterial lipopolysaccharides, superantigens, reactive metabolites, and metabolite stress) may facilitate the movement of autoreactive T cells and demyelinating antibodies from the systemic circulation into the central nervous system through disruption of the blood-brain barrier. In the central nervous system, local factors (including viral infection and metabolic stress) may up-regulate the expression of endothelial adhesion molecules, such as intercellular adhesion molecule 1, vascular-cell adhesion molecule 1, and E-selectin, further facilitating the entry of T cells into the central nervous system. Proteases, including matrix metalloproteinases, may further enhance the migration of autoreactive immune cells by degrading extracellular-matrix macromolecules. Proinflammatory cytokines released by activated T cells, such as interferon-γ and tumor necrosis factor β (TNF-β), may up-regulate the expression of cell-surface molecules on neighboring lymphocytes and antigen-presenting cells. Binding of putative multiple sclerosis (MS) antigens, such as myelin basic protein, myelin-associated glycoprotein, myelin oligodendrocyte glycoprotein (MOG), proteolipid protein, αB-crystallin, phosphodiesterases, and S-100 protein, by the trimolecular complex—the T-cell receptor (TCR) and class II major histocompatibility complex (MHC) molecules on antigen-presenting cells—may trigger either an enhanced immune response against the bound antigen or anergy, depending on the type of signaling that results from interactions with surface costimulatory molecules (e.g., CD28 and CTLA-4) and their ligands (e.g., B7-1 and B7-2). Down-regulation of the immune response (anergy) may result in the release of antiinflammatory cytokines (interleukin-1, interleukin-4, and interleukin-10) from CD4+ T cells, leading to the proliferation of antiinflammatory CD4+ type 2 helper T (Th2) cells. Th2 cells may send antiinflammatory signals to the activated antigen-presenting cells and stimulate pathologic or repair-enhancing antibody-producing B cells. Alternatively, if antigen processing results in an enhanced immune response, proinflammatory cytokines (e.g., interleukin-12 and interferon-γ) may trigger a cascade of events, resulting in the proliferation of proinflammatory CD4+ type 1 helper T (Th1) cells and ultimately in immune-mediated injury to myelin and oligodendrocytes. Multiple mechanisms of immune-mediated injury of myelin have been postulated: cytokine-mediated injury of oligodendrocytes and myelin; digestion of surface myelin antigens by macrophages, including binding of antibodies against myelin and oligodendrocytes (i.e., antibody-dependent cytotoxicity); complement-mediated injury; and direct injury of oligodendrocytes by CD4+ and CD8+ T cells. This injury to the myelin membrane results in denuded axons that are no longer able to transmit action potentials efficiently with the central nervous system (loss of saltatory conduction). This slowing or blocking of the action potential results in the production of neurologic symptoms. The exposed axon segments may be susceptible to further injury from soluble mediators of injury (including cytokines, chemokines, complement, and proteases), resulting in irreversible axonal injury (such as axonal transection and terminal axon ovoids). There are several possible mechanisms of repair of the myelin membrane, including resolution of the inflammatory response followed by spontaneous remyelination, spread of sodium channels from the nodes of Ranvier to cover denuded axon segments and restore conduction, antibody-mediated remyelination, and remyelination resulting from the proliferation, migration, and differentiation of resident oligodendrocyte precursor cells.” Adapted from a drawing by the Mayo Foundation.280 

Content on this page was last reviewed on January 01, 2009.

Content on this page was last changed on December 22, 2009.

References:

268.  Lutton JD, Winston R, Rodman TC. Multiple sclerosis: etiological mechanisms and future directions. Exp Biol Med (Maywood). 2004;229(1):12-20. http://www.ebmonline.org/cgi/reprint/229/1/12 . Accessed August 14, 2006.
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276.  Frohman EM, Goodin DS, Calabresi PA, et al; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. The utility of MRI in suspected MS: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003;61(5):602-611.
280.  Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343(13):938-952.
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