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Supplements Multiple Sclerosis: A Review of Diagnosis and Management

Current Strategies in the Treatment of Multiple Sclerosis


Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal degeneration.1-5 Although descriptions date back as far as the Middle Ages, MS was first recognized as a distinct disease in 1868 when Jean-Martin Charcot, professor of Neurology at the University of Paris, referred to the condition as sclérose en plaques.6-8 MS affects roughly 400,000 people in the United States and 2.5 million people worldwide.2,4 MS is associated with a heterogeneous array of signs and symptoms because of involvement of the motor, sensory, visual, and autonomic systems.1,3,5,9,10

Twenty-five years ago, the first disease-modifying treatment (DMT), interferon beta-1b, was approved by the US FDA for the treatment of MS.11 Since that time, and especially over the last 5 years, an increasing number of novel DMTs have been approved for the treatment of MS.3,12 These agents decrease but do not completely eliminate disease progression and/or disability in patients with MS.1,5,12,13

Overview of MS

MS is among the most common causes of neurological disability in young adults.4,15,16 The known prevalence of MS is increasing, which is most likely due to greater awareness and improved imaging techniques.17,18 The clinical presentation of MS is extremely variable and is largely unpredictable.10,18

Approximately half of all patients with MS require walking assistance within 15 years of disease onset.19 MS does not usually diminish life expectancy; however, the development of complications (eg, pneumonia, urosepsis) can lead to a shorter than average life expectancy.10,15 Suicide rates for patients diagnosed with MS are up to 7.5 times higher than those rates observed in the general population.16

Regarding pathogenesis of MS, both genetic and environmental factors are thought to play a role.3,6,9,10,15 Several causative factors appear to affect risk of developing MS, such as previous viral infections; distance from the equator prior to age 15 (ie, above the 37th parallel); family history (primarily first-degree relatives); cigarette smoking; and decreased sunlight exposure/vitamin D levels.3,9,10 Multiple studies of sunlight exposure and vitamin D levels suggest that increased vitamin D consumption in early life may decrease likelihood of MS.9

Although the disease can affect any ethnic group, individuals of Northern European descent are more likely to be affected than other ethnicities.3,10 MS typically presents in adults 20 to 45 years of age, but occasionally it presents in childhood or in later middle age.10,18,19 Women are more frequently diagnosed with MS compared with men by at least a 2:1 ratio and as high as 3:1.6,10,18,19 

MS is characterized by destruction of the myelin on neurons (demyelination) and subsequent damage to the underlying axon.20 The demyelinating plaque, the main pathologic hallmark of MS, contains a prominent immunologic response dominated by CD8+ and CD4+ T cells. When activated, these T cells (primarily TH1 cells) cross the blood–brain barrier into the CNS and attack the myelin sheath on the axons (see Figure). The resulting inflammation deteriorates the myelin, which slows or interrupts the conduction of nerve impulses along the axons.1,9

Demyelination leads to axonal damage, which can affect both white and gray matter. Recent data have highlighted the involvement of gray matter, which may be especially relevant to the irreversible disability that occurs in MS.18 Over time, demyelination can leave the underlying axon exposed and susceptible to damage.9,18,20 Axon loss is believed to be the major cause of permanent disability in patients with MS. B cells and their products also contribute to the pathogenesis of MS. B cells produce proinflammatory and anti-inflammatory cytokines, where proinflammatory cytokines activate T cells for T cell mediated demyelination.9,18,20 

Diagnosing Multiple Sclerosis

MS is a diagnosis of exclusion.10 The diagnosis is based on clinical expertise and involves obtaining evidence from a clinical examination, medical history, laboratory tests, and magnetic resonance imaging (MRI) scans of the brain and spinal cord.21 These tests are intended to gather data consistent with MS, while ruling out other possible causes not consistent with the disease.10

Despite the lack of a diagnostic test for MS, MRI scans are increasingly recognized as essential noninvasive tools for initial investigation of suspected disease.22 MRI scans show high sensitivity for detection of focal white matter lesions in the CNS and specifically for lesions disseminated in time and space. Dissemination in space is fulfilled by the presence of 1 or more lesions in 2 of 4 characteristic anatomic locations, while dissemination in time is demonstrated by simultaneous presence of gadolinium (Gd) enhancing and Gd non-enhancing lesions at follow-up MRI examination.22 Gray matter lesions are associated with cognitive impairment and are present in the brains of patients with MS. MRI sensitivity is much lower in detecting gray matter lesions compared with detecting white matter lesions.22 There is currently a lack of standardized image acquisition and analysis for gray matter lesions.

The McDonald criteria are the most widely accepted diagnostic criteria for MS.23 A diagnosis of MS requires that lesions are disseminated in time and space, referring to the occurrence of at least 2 episodes of neurological dysfunction reflecting distinct sites of CNS damage that cannot be explained by any other mechanisms.10,19 The goal of the McDonald criteria is to diagnose MS as soon as possible by allowing MRI-detected brain lesions, cerebrospinal fluid abnormalities, and visual-evoked potentials (VEPs) to substitute for clinical lesions in defining “separated by time and space.”  The original criteria were released in 2001,23 updated in 200524 and 2010,25 and revisions to the McDonald criteria in 2017 have further simplified the diagnosis of MS.26

Types of Multiple Sclerosis

Approximately 80% of MS cases present initially as clinically isolated syndrome (CIS),3 which refers to an acute clinical attack affecting 1 or more sites in the CNS, and can convert to clinically defined MS (CDMS).3 The rate of conversion to CDMS varies based on initial presentation. At baseline, 82% of patients with more than 1 clinically silent white matter MRI lesion eventually develop CDMS, as compared with only 21% of patients with normal MRIs who go on to develop CDMS.3 A majority of CDMS falls under the category of relapsing-remitting MS (RRMS), but other types include secondary progressive MS, primary progressive MS, and progressive relapsing MS.9

Less commonly, patients also present with radiologically isolated syndrome (RIS).10 In cases of RIS, individuals have clinical scenarios not typical of MS, yet obtain MRI scans for other reasons (eg, headache) and have radiological scans suggestive of MS. See Table 1 for additional information on types of MS.

Treating Multiple Sclerosis

The clinical management of MS should be considered as 3 distinct parallel pathways3,10:
  1. Relapses (acute exacerbations) should be treated with appropriate therapies.
  2. Symptomatic problems associated with MS should be managed with additional medications to prevent and/or treat complications and to preserve quality of life (QoL).
  3. Disease-modifying therapies should be used to decrease the number and severity of relapses, to decrease progression, and to prevent/minimize neuronal damage.

Treating Acute Exacerbations

Corticosteroids are considered the mainstay of treatment for acute exacerbations.10,28,29 Treatment with corticosteroids is associated with immunomodulation, anti-inflammatory effects, restoration of the blood–brain barrier, and reduction of edema.29 Numerous controlled clinical trials have found that corticosteroid therapy hastens recovery time from acute attacks, and that high-dose corticosteroids are significantly more effective than moderate-dose regimens.29 However, it is important to note that although high-dose corticosteroids have proven to shorten the duration of acute attacks, they have not demonstrated the ability to alter the progression of the disease.3 The American Academy of Neurology recommends intravenous methylprednisolone (500 to 1000 mg/day for 3 to 10 days) for the treatment of acute exacerbations.30 Some evidence suggests that equivalent doses of high-dose oral corticosteroids are comparable pharmacokinetically to intravenous methylprednisolone; definitive studies are lacking.10 Alternatives to corticosteroids, such as plasma exchange and intravenous immunoglobulin, should be considered for patients who do not respond or who are not considered viable candidates for corticosteroid therapy.3,10 See Table 2 for additional information on dosing and indications.

Symptom Management

The localization and severity of MS lesions within the brain and spinal cord are unpredictable and, therefore, a wide range of body systems can be adversely affected to varying degrees. Consequently, MS is associated with a host of symptoms and comorbidities that can negatively impact activities of daily living and QoL (see Table 3).31

Common symptomatic problems associated with MS include bladder dysfunction (various subtypes), bowel dysfunction (various subtypes), cognitive dysfunction, sexual dysfunction, depression, fatigue, gait disturbances, pain (various subtypes), and spasticity.3,7,10,31 Because no 2 patients with MS are alike, symptomatic problems tend to vary tremendously. Generally, symptomatic issues may be less severe or averted when patients are adherent to DMTs.

Disease-Modifying Therapies

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