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Overview of the Epidemiology, Diagnosis, and Disease Progression Associated With Multiple Sclerosis
Mark J. Tullman, MD
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A. Scott Mathis, PharmD
Participating Faculty: Improving Clinical and Economic Outcomes in Multiple Sclerosis
Improving Clinical and Economic Outcomes in Multiple Sclerosis

Overview of the Epidemiology, Diagnosis, and Disease Progression Associated With Multiple Sclerosis

Mark J. Tullman, MD
Lucchinetti and colleagues identified 4 distinct pathological patterns in an immunohistopathological study of actively demyelinating MS lesions from 83 cases, which included 51 biopsies and 32 autopsies.14 All 4 patterns contained an inflammatory infiltrate consisting of T lymphocytes and macrophages. The most common type, pattern II, was characterized by the deposition of immunoglobulin and complement. Pattern I was characterized by macrophage-associated demyelination. In patterns III and IV, demyelination was due to an oligodendrogliopathy. Pattern III was differentiated from pattern IV by a preferential loss of myelin-associated glycoprotein. The same lesion pattern was observed within each patient, but there was marked heterogeneity between patients, suggesting that MS might have multiple pathogenic mechanisms. However, the results of this study were challenged by another autopsy series of 12 patients with relapsing-remitting MS (RRMS) who died in the setting of an acute relapse. Most cases, including 1 patient who died 17 hours after an exacerbation, included lesions characterized by extensive oligodendrocyte apoptosis with intact myelin sheaths and slight or no inflammatory infiltrate. More than 1 of the aforementioned patterns were observed in some patients.14 The investigators concluded that pattern III lesions represent an early stage of lesion formation that precedes inflammation and demyelination. Recent evidence from another biopsy study indicates that the cortical demyelinating lesions are present in 81% of patients with early MS, and are associated with meningeal inflammation.13 These data suggest that the cortical lesions may be associated with acute MS, and not just progressive forms, and may contribute to cognitive impairment and irreversible disability.14 However, biopsy and some autopsy studies are susceptible to inherent selection bias and the findings may not be representative of typical MS.


The clinical manifestations of MS are highly variable, but an attack of neurologic dysfunction (eg, optic neuritis, incomplete transverse myelitis, brain stem or cerebelar syndrome), referred to as a clinically isolated syndrome (CIS), heralds the onset of the disease in approximately 90% of patients.1,15 A relapsing-remitting course ensues and may be followed by a progressive phase of the disease. MS begins insidiously and gradually worsens in about 10% of patients. Symptoms, which depend on lesion location and extent of tissue destruction, range from mild to severe.15 Common symptoms of an MS exacerbation (relapse or attack) include numbness, tingling, weakness, impaired balance, blurred vision, double vision, vertigo, and bladder or bowel dysfunction.2,16,17 Facial weakness, trigeminal neuralgia, hearing loss, and slurred speech are less common.

Disease Course

The current MS classification system is based on consensus and relies on the clinical course of the disease. RRMS is the initial form of the disease in approximately 90% of patients.1 It is characterized by acute relapses interspersed with periods of clinical remission that are characterized by a lack of disease progression. When MS is left untreated, the majority of patients with RRMS enter a progressive phase known as secondary-progressive MS, which is characterized by the gradual accumulation of disability with or without occasional superimposed relapses.18 Approximately 10% of patients have primary-progressive MS. In this form of the disease, there is continuous and usually gradual deterioration of neurologic function. There may be occasional plateaus and slight fluctuations, but relapses do not occur.18 Approximately 15% to 40% of patients with an initial primary-progressive course experience at least 1 subsequent relapse, which may not occur until many years after the onset of their original symptoms.18 This type of MS is referred to as progressive-relapsing MS and is the least common form of the disease.


The diagnostic criteria for MS have evolved over time.16,19-21 New MS diagnostic criteria, which are often referred to as the McDonald criteria, were established in 2001 and revised in 2005 and 2010 (Table).16 A diagnosis of RRMS requires at least 1 episode of neurologic dysfunction consistent with inflammation and demyelination that occurs in the absence of fever or infection and lasts for at least 24 hours along with objective evidence of lesions disseminated in space and time.16 Dissemination in space and time may be demonstrated clinically or by magnetic resonance imaging (MRI) (see Table). The new diagnostic criteria allow for an earlier MS diagnosis, which is of considerable importance as disease-modifying drugs appear to be most effective when initiated early in the course of the disease. Furthermore, a delay in treatment may result in irreversible neurologic deficit.


MS is an extremely variable illness. Therefore, counseling patients with CIS and early MS poses a major challenge for clinicians. However, brain MRI abnormalities after an initial clinical demyelinating event provide important prognostic information regarding the development of MS. Approximately 50% of patients who initially have optic neuritis and at least 3 T2 hyperintense lesions experience a second clinical attack disseminated in space and time within 5 years, compared with only 16% who have normal brain MRI.22 A second exacerbation separated in space and time occurs within 20 years in 82% of patients with CIS with at least 1 T2 lesion, compared with just 21% with a normal baseline brain MRI.22 Interestingly, individuals with only 1 to 3 lesions have a risk of MS similar to those with at least 10 lesions. In recent CIS studies which required patients to have at least 2 or 3 asymptomatic brain lesions for entry, 41% to 50% of patients given placebo developed a second exacerbation disseminated in space and time within 2 to 3 years. In those studies, the risk of MS at 18 to 24 months was greatest in patients with more than 8 T2 hyperintense lesions or at least 1 or 2 gadolinium-enhancing lesions on a baseline brain MRI. In general, the higher the number of baseline brain MRI lesions at the time of a CIS, the greater the risk of long-term disability. There is also a modest correlation between the change in MRI T2 lesion volume in the first 5 years and long-term disability.22

Although the course of MS is essentially impossible to predict in an individual patient, female sex, younger age at onset, and little disability 5 years after onset are generally favorable prognostic signs. Male sex, older age at onset, frequent attacks early in the course of the disease, a short interval between the first 2 attacks, incomplete recovery from the first attack, rapidly accumulating disability, cerebellar involvement as a first symptom, and progressive disease from onset are associated with worse outcomes. Optic neuritis as a first attack is associated with a favorable short- and intermediate-term outcome, but 20-year disability is similar among patients who present with optic neuritis, brain stem, or spinal cord syndromes. African Americans have a lower prevalence of MS than Caucasians, but tend to accumulate disability more rapidly.22

In 1 natural history study, 24% of patients with a CIS who were followed for an average of 4 years reached an Expanded Disability Status Scale (EDSS) score of at least 6 (a score of 6 is defined as unable to walk 100 meters without unilateral assistance) and 40% of those followed for 6 to 15 years entered the secondary-progressive phase of the disease.23 In another study, the natural course of the disease was less aggressive, with only 24% of patients reaching an EDSS score of at least 6 and 39% developing secondary-progressive MS 20 years after the onset of their first clinical demyelinating event.23

Some patients have a very mild form of RRMS, with minimal or no disability at least 10 years after disease onset, which is often referred to as benign MS. Although natural history studies have yielded conflicting results, most suggest that many of these patients will develop significant disability and enter the secondary-progressive phase of the disease within 20 years. There are no reliable predictors to identify which patients will continue to have a mild course. Furthermore, neuropsychological testing reveals cognitive impairment in approximately 20% to 45% of patients considered to have benign MS. Therefore, the diagnosis of benign MS should include an assessment of cognitive function and only be considered in retrospect and after prolonged follow-up.


The etiology of MS is unknown, but it is likely due to complex interactions between environmental and genetic factors and the immune system. The clinical manifestations and the course of MS are extremely variable, but most patients accumulate disability over time. To optimize treatment outcomes, clinicians need to be familiar with the immunopathogenesis, symptoms, and natural course of the disease, and the recently revised MS diagnostic criteria.

Author affiliation: MS Center for Innovations in Care, Missouri Baptist Medical Center, St. Louis, Missouri.
Funding source: This activity is supported by educational grants from EMD Serono, Inc, and Teva Pharmaceuticals, Ltd.
Author disclosure: Dr Tullman reports consultancy/advisory board membership with with Acorda Therapeutics, Allergan, Biogen Idec, Genzyme, Novartis, and Teva Pharmaceuticals. He also reports grant support from Acorda Therapeutics and honoraria from Acorda Therapeutics, Biogen Idec, EMD Serono, Novartis, Pfizer, and Teva Pharmaceuticals.
Authorship information: Analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and supervision.
Address correspondence to: E-mail:
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