Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) pathologically characterized by CNS inflammation, demyelination, and axonal loss (Compston & Coles, 2008). Clinically, the disease is most often characterized by early relapses and remissions of neurological symptoms referable to the CNS, a clinical course known as relapsing-remitting MS (RRMS). After early relapses with characteristic inflammation and demyelination, there is some functional reorganization and remyelination that occurs early in the disease and helps to restore function. Over time, RRMS often transitions to a disease course characterized by a progressive decline in function. Although relapses may still occur, they occur less often; this course of MS is known as secondary progressive MS. In individuals with secondary progressive MS, early repair mechanisms fail and more axonal loss occurs (Hagemeier, Bruck, & Kuhlmann, 2012). Approximately 10%-15% of all patients with MS will have a progressive course of the disease from onset, known as primary progressive MS (Lublin & Reingold, 1996).

The etiology of MS is unknown; however, it is thought to be because of a complex interplay of factors including genetic risk for autoimmunity, immune system dysregulation, and environmental factors (i.e., viral exposure, particularly Epstein Barr, vitamin D deficiency, and smoking; Ascherio & Munger, 2007; Giovannoni & Ebers, 2007; Shirani & Tremlett, 2010). Immunologically, the inflammatory process is thought to be mediated by T-cell and B-cell responses to CNS autoantigens. The inflammation that occurs within the CNS is also responsible, at least in part, for degenerative changes, including axonal loss and damage to oligodendrocytes that lead to irreversible damage in the brain and spinal cord.

Symptoms of MS vary widely in type and severity. Common symptoms include generalized and frequently overwhelming fatigue; depression; unilateral visual blurring or loss; diplopia; sensory symptoms, such as numbness, tingling, or pain; incoordination; spasticity; weakness; ataxia; and elimination dysfunction, such as urgency, frequency, and incontinence of bladder or bowel. Cognitive impairment, such as short-term memory loss and slowed processing, is also possible.

Diagnostics

Making the diagnosis of MS can be quite challenging because there is no specific diagnostic test. Traditionally, the diagnosis is made if there are at least two neurological events referable to the CNS, separated or disseminated in space (different areas of the CNS) and time (events occur at different points in time), with objective evidence of CNS involvement and all other possible causes of the symptoms are excluded. The diagnosis is mostly based on history of neurological symptoms and neurological examination findings. More recently, magnetic resonance imaging (MRI) findings and other paraclinical testing, such as spinal fluid analysis, have been used to establish dissemination in space and time when two clinical events have not occurred but MS is believed to be the most likely diagnosis.

Since the mid-1960s, there have been published diagnostic criteria developed by MS experts that have helped with the diagnosis of MS. In 2001, an international panel of MS experts convened and developed criteria that utilized both clinical and MRI findings, including the criteria of dissemination in space and time (McDonald et al., 2001). Since 2001, these criteria, known as the McDonald criteria, have been revised, both in 2005 (Polman et al., 2005) and in 2010 (Polman et al., 2011). In each of the revisions, the MRI criteria have been modified to reflect increased evidence of MRI changes consistent with MS.

One of the goals of these criteria is to expedite the diagnosis of MS. Therefore, the McDonald diagnostic criteria have traditionally been applied to those individuals who present with a clinically isolated syndrome (CIS). The CIS is a term that describes the first onset of neurological symptoms in an individual, which usually involve the optic nerve, brainstem, or spinal cord and are characteristic of MS (Miller et al., 2008). Symptoms should last a minimum of 24 hours in the absence of infection. Individuals who have symptoms and an MRI suggestive of inflammation and demyelination or spinal fluid with findings consistent with MS are considered at high risk to develop additional symptoms and would then be considered to have MS. The diagnostic criteria utilize paraclinical evidence of MRI and/or cerebrospinal fluid abnormalities to establish dissemination in space and/or time when only a single clinical event has occurred. Imaging criteria for the 2010 McDonald criteria revision were based on recent publications from the MAGNIMS research group (Montalban et al., 2010; Rovira et al., 2009; Swanton et al., 2007). Fluid-attenuated inversion recovery and T2-weighted sequences are the MRI techniques that are currently of greatest clinical interest in MS, along with postcontrast T1-weighted scans. These sequences provide information about active inflammatory and subclinical MS activity. Subclinical activity occurs much more frequently than do clinical symptoms (Filippi et al., 2011).

On the basis of the McDonald criteria, the criterion for dissemination in space can be met by the presence of an MRI lesion in at least two of four areas of the CNS, which include juxtacortical, periventricular, infratentorial, or spinal cord (Figure 1). The criterion of dissemination in time can be met with an additional T2 lesion and/or gadolinium (Gd)-enhancing lesion on a subsequent MRI, performed at any time after the initial MRI, or the simultaneous presence of asymptomatic Gd-enhancing lesions and nonenhancing lesions in an individual with CIS (Polman et al., 2011). If the criteria for dissemination in space and time are met in the absence of additional clinical symptoms and other causes of the symptoms have been completely excluded, the diagnosis of MS can be made (Polman et al., 2011). Other possible causes of neurological symptoms that must be excluded include other inflammatory conditions, CNS infections, metabolic conditions, vascular conditions, and inherited conditions. Table 1 lists some of the diagnostic mimics of MS.

TABLE 1 MS Mimics (Cohen & Rensel, 2000)

FIGURE 1. MRI in Multiple Sclerosis

Although not part of the MRI diagnostic criteria nor part of the conventional imaging of clinical practice, nonconventional imaging techniques have been utilized to identify additional CNS pathology in MS. These techniques have added to the overall understanding of the disease. Although traditionally thought to be a white matter disease, gray matter abnormalities have been identified through the use of high-field-strength MRI (Stadelmann, Albert, Wegner, & Bruck, 2008). Calabrese and colleagues examined 59 patients with CIS and showed that gray matter atrophy in the superior frontal gyrus, thalamus, and cerebellum were independent predictors of conversion from CIS to MS (Calabrese et al., 2011). In addition, gray matter atrophy in patients with MS is associated with progression of MS (Fisniku et al., 2008).

Imaging techniques, such as brain parenchymal fraction and structural image evaluation using normalization of atrophy, provide different methods to quantify brain atrophy. These techniques have shown that brain atrophy measurements correlate better with disability than do conventional MRI techniques. It has been suggested that atrophy measurements may be a useful way of measuring the ability of disease-modifying treatments (DMTs) to provide neuroprotection (Barkhof, Calabresi, Miller, & Reingold, 2009).

Other MRI techniques utilized in the research arena are magnetic transfer imaging (MT-MRI) and MR spectroscopy. MT-MRI is a technique that measures the interaction of free water protons and bound protons and provides information about areas of MS damage as well as normal-appearing white matter (Filippi & Rocca, 2007). MR spectroscopy provides quantification of chemical changes found in lesions and normal-appearing white matter. Considered a marker of axonal integrity, N-acetyl aspartate can be measured using MR spectroscopy and provides evidence of the extent of axonal damage (Poloni, Minagar, Haacke, & Zivadinov, 2011).

Optical coherence tomography (OCT), a non-MRI imaging tool, is a noninvasive method to observe and quantify the retinal nerve fiber layer thickness. The retinal nerve is unmyelinated; thus, OCT is able to quantify axonal integrity and damage. Gordon-Lipkin and colleagues showed that OCT correlated with brain atrophy in MS (Gordon-Lipkin et al., 2007). This imaging tool may be an important outcome measurement in clinical trials of neuroprotection because it provides information about axonal integrity.

DMTs

Once the diagnosis of CIS or MS is made, treatment can be considered. DMTs, available since the early 1990s, are able to alter the natural history of RRMS because of their anti-inflammatory effect on the immune system. These agents have shown efficacy in the reduction of relapse frequency and reduction in CNS inflammation and have a variable ability to reduce the progression of disability. Emerging treatments in the research pipeline promise alternate mechanisms of action from the currently approved treatments as well as efficacy in relapse reduction, inflammatory events, and progression of disability.

Currently, there are 10 Food and Drug Administration (FDA)-approved treatments for MS, including four interferon beta preparations, glatiramer acetate, natalizumab, fingolimod, mitoxantrone, teriflunomide, and dimethyl fumarate (DMF; Table 2). The interferons, glatiramer acetate, natalizumab, teriflunomide, fingolimod, and DMF are indicated for RRMS. Mitoxantrone is indicated for secondary progressive MS, worsening relapsing MS, and progressive relapsing MS. In well-designed clinical trials, the interferon preparations and glatiramer acetate have been shown to delay the conversion of CIS to MS (Comi et al., 2009, 2012a; Jacobs et al., 2000; Kappos et al., 2006a). Two separate head-to-head trials showed superiority in reducing relapses and improving MRI outcomes for high-dose/high-frequency interferon beta compared with weekly interferon beta-1a (Durelli et al., 2002; Panitch et al., 2005). Two other separate head-to-head trials of interferon beta and glatiramer acetate showed a similar effect on relapse outcomes (Mikol et al., 2008; O'Connor et al., 2009).

TABLE 2 FDA-Approved Disease-Modifying Treatments for MS (

Unfortunately, in secondary progressive MS and primary progressive MS, the clinical trial results of the available agents were not as positive. Only the European trial of interferon beta-1b showed a favorable effect on progression in secondary progressive MS (PRISMS [Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis] Study Group, 1998). The North American trial of interferon beta-1b in secondary progressive MS was unable to corroborate those results (Panitch et al., 2004). Upon further evaluation of the two trials, it was apparent that the populations studied in the two trials were slightly different, with the European cohort having more inflammatory activity (Derwenskus, 2011). A study of glatiramer acetate in primary progressive MS was stopped after the interim analysis showed that the drug failed to affect progression (Wolinsky et al., 2007). A trial in secondary progressive MS of interferon beta-1a subcutaneous injection was also negative with respect to effect on progression (Kappos, Polman, Pozzilli, Thompson, & Dahlke, 1998).

The interferon preparations are slightly different in that interferon beta-1b is produced in modified E. coli cells and interferon beta-1a is produced in mammalian cells. Both interferon beta-1b and interferon beta-1a work similarly by reducing peripheral antigen presentation and T-cell proliferation. Furthermore, interferon beta may downregulate adhesion molecules at the level of the blood brain barrier. All interferon preparations have shown efficacy in relapse reduction and disability outcomes. In addition, whether in phase 3 regulatory trials or subsequent trials, interferon preparations have shown efficacy for improving MRI outcome measures and have indicated favorable long-term safety (Herndon et al., 2005; Kappos et al., 2006b; Reder et al., 2010).

Glatiramer acetate is a synthetic polypeptide similar to myelin basic protein. It is thought to work by provoking the immune system to shift to a less inflammatory response. In several clinical trials, glatiramer acetate has shown a favorable effect on relapses and MRI outcomes. An open-label extension of the original phase 3 trial is ongoing and has established the long-term safety of glatiramer acetate (Ford et al., 2010).

More recent additions to the MS treatment armamentarium are natalizumab, fingolimod, teriflunomide, and DMF. Natalizumab is indicated for RRMS and is recommended in patients who have had a suboptimal response to injectable treatments or cannot tolerate other treatments. Natalizumab blocks VLA-4, an adhesion molecule found on activated lymphocytes. Without adhesion to the blood vessel wall, activated lymphocytes are unable to traffic into the CNS. Natalizumab was studied in two large clinical trials and, in both, was shown to have a statistically significant effect on relapses, disability progression, and MRI outcomes (Polman et al., 2006; Rudick et al., 2006). Natalizumab is associated with progressive multifocal leukoencephalopathy (PML), a rare infection of the CNS caused by the John Cunningham virus (JCV). JCV infects approximately one half of the adult population and, as a primary infection, is not associated with clinical symptoms. The virus becomes latent after the initial exposure and can become reactivated under certain conditions, such as untreated human immunodeficiency virus, immunosuppressant treatment, and treatment with certain monoclonal antibodies, including rituximab and natalizumab. Reactivated JCV can infect the CNS and causes widespread damage to myelin and oligodendrocytes, ultimately resulting in death if the causative agent is not promptly removed or eliminated (Monaco & Major, 2012). Over 300 individuals on natalizumab for MS have developed PML since 2006, and 22% of them have died. Previous exposure to JCV provokes the development of antibodies to JCV. Individuals with antibodies to JCV are more likely to develop PML. By 24 months of treatment, in antibody-positive patients with JCV, the risk of developing PML is approximately 1:200 (Monaco & Major, 2012). If an individual is JCV antibody-positive and has had previous immunosuppressant treatment, the risk of PML increases to approximately 1:100 (Monaco & Major, 2012).

Approved in 2010, fingolimod is the first FDA-approved oral agent for the treatment of RRMS. Fingolimod is a sphingosine 1-phosphate inhibitor that works by depriving naive and central memory T-cells of a signal to egress from secondary lymph organs. Results from two large phase 3 trials indicated that a 0.5-mg daily dose of fingolimod significantly reduced annualized relapse rate, MRI activity, and disability progression (Cohen et al., 2010; Kappos et al., 2010). Sphingosine 1-phosphate receptors are found on many different cells, and thus, unwanted side effects from fingolimod may occur. Fingolimod is associated with bradycardia, particularly on the first dose. Patients must be observed for 6 hours after the first dose for any heart rate or blood pressure issues (Ginsberg et al., 1995). An electrocardiogram is to be obtained before dosing and at the completion of the observation period. In May 2012, the FDA revised the labeling of fingolimod to include the following contraindications (Ginsberg et al., 1995):

* Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III/IV heart failure.

* History or presence of Mobitz Type II second-degree or third-degree atrioventricular block or sick sinus syndrome, unless patient has a functioning pacemaker.

* Baseline QTc interval of >=500 milliseconds.

* Treatment with Class IA or Class III anti-arrhythmic drugs.

Lymphopenia and hepatic enzyme elevations are possible side effects, and laboratory monitoring is necessary. Herpes infections, including varicella zoster, were seen in clinical trials, and it is recommended that all patients have a varicella-zoster titer before the initiation of treatment and vaccination before treatment if no titer is detected. Macular edema has been observed in patients receiving fingolimod (Cohen et al., 2010; Kappos et al., 2010). Blood pressure elevations have also been observed with fingolimod use (Ginsberg et al., 1995).

Teriflunomide was approved for relapsing MS in September 2012. Teriflunomide is an oral treatment administered once daily. The approved doses are 7 mg once daily and 14 mg once daily. It is a derivative of leflunomide, which is FDA approved for the treatment of rheumatoid arthritis. This agent works by inhibiting dihydroorotate dehydrogenase, which is necessary for deoxyribonucleic acid replication. It reduces T-cell and B-cell activation, proliferation, and response to autoantigens. Two randomized, double-blind, placebo-controlled clinical trials met the relapse rate and disability end points (14-mg dose; Freedman et al., 2013; O'Connor et al., 2011). Both approved doses (7 and 14 mg) were shown to be superior compared with placebo for the MRI outcomes of total lesion volume and Gd enhancement (O'Connor et al., 2011). In a separate randomized, double-blind trial, teriflunomide (14 mg) was shown to be comparable with interferon beta-1a for the annualized relapse rate outcome (Vermersch et al., 2012). Adverse events reported with teriflunomide have included gastrointestinal upset, temporary hair thinning, hepatic enzyme elevation, mild neutropenia, and mild blood pressure elevations (O'Connor et al., 2011). Teriflunomide is contraindicated in pregnant patients and patients with severe hepatic impairment (Aubagio, 2013).

DMF, an oral treatment administered twice daily, was approved for relapsing MS in March 2013. DMF is thought to work in MS by several potential mechanisms. It has been found to induce T-cell apoptosis, potentially protect against oxidative stress, inhibit adhesion molecules, and potentially shift the immune response toward a Th-2 (helper T-cell) response (Gold, 2011; Kappos et al., 2008; Killestein et al., 2011). Results of a large, randomized, placebo-controlled, phase 3 trial of DMF in patients with RRMS showed that DMF (240 mg) was associated with significant reductions in the annualized relapse rate, a significant reduction in the probability of disability progression (based on the Expanded Disability Status Scale) and a reduction in MRI measures of disease progression (Abad, Gomez-Outes, Martinez-Gonzales, & Rocha, 2006). Side effects of DMF include flushing, bloating, diarrhea, lymphopenia, and eosinophilia (Kappos et al., 2008).

Emerging Therapies

There are numerous new treatments in late-stage development in the MS research pipeline. Those agents that have completed or are in phase 3 trials include laquinimod, alemtuzumab, and daclizumab. Laquinimod is an oral treatment, alemtuzumab is administered intravenously once yearly over several days, and daclizumab is administered subcutaneously every 2 or 4 weeks. Alemtuzumab is currently under FDA review for potential approval as a DMT for MS.

Laquinimod

Laquinimod is a small molecule related to linomide, which was tested in MS. Linomide appeared promising as an MS treatment; however, serious cardiac events resulted in the termination of clinical trials. Laquinimod, although structurally similar, has not been associated with cardiac events. The mechanism of action of laquinimod is not known, but it is believed to shift the immune response to a less inflammatory response (Gasperini & Ruggieri, 2011). Additional investigations have shown the inhibition of adhesion molecules at the level of the blood brain barrier with laquinimod (Wegner et al., 2010). Laquinimod may also affect the CNS. Laquinimod was evaluated in two large phase 3 trials of RRMS (Comi et al., 2012b; Vollmer, 2011). The first phase 3 trial, known as the ALLEGRO trial, showed a reduction in the annualized relapse rate of 23% in the laquinimod group relative to placebo (p < .0024). In addition, there was a 36% decrease in the risk for disability progression, as measured by the Expanded Disability Status Scale compared with placebo (p = .0122) and a 32.8% reduction in brain volume loss (p < .0001; Comi et al., 2012b).

The second phase 3 trial of laquinimod, known as the BRAVO trial, included 1,106 patients with RRMS. That trial consisted of a laquinimod arm, a placebo arm, and a rater-blinded comparator arm of interferon beta-1a. The trial failed to meet the primary end point of relapse rate reduction. It was determined that the baseline MRI characteristics of the treated and placebo groups were different, which may have accounted for the missed end point. After adjusting for the differences, the results were statistically significant, with a 21% reduction in relapses (p = .26), a 33.5% decrease in risk of disability progression (p = .044), and a 27.5% reduction in brain volume loss (p < .0001; Vollmer, 2011).

Side effects of laquinimod were mild and included mild liver function test elevations, mild arthralgia, elevated erythrocyte sedimentation rate, and increased rates of infection in the treated groups. There were no cardiac events reported with laquinimod treatment (Comi et al., 2010; Gasperini & Ruggieri, 2011). At this time, laquinimod will not be submitted to the FDA for approval. However, plans are underway for regulatory approval in Europe.

Alemtuzumab

Alemtuzumab is a humanized anti-CD52 monoclonal antibody. It has been used and is FDA approved for the treatment of chronic lymphoid leukemia. CD-52 is expressed on a variety of cell types, including T and B lymphocytes, monocytes, and macrophages; alemtuzumab depletes these cells rapidly after infusion. Alemtuzumab is dosed once yearly by intravenous infusion daily for 5 days. In the second year of clinical trials, the dosing was daily for 3 consecutive days. Alemtuzumab was evaluated in two large phase 3 trials (Comi et al., 2010; Jeffrey, 2011). Of note, both trials compared alemtuzumab with interferon beta-1a three times weekly, and there was no placebo arm in either trial. The first trial included 581 DMT-naive patients, and the results showed a 55% reduction in relapses in the alemtuzumab group relative to the interferon group (p < .0001). The disability end point was not met in that trial (Comi et al., 2010). In the second phase 3 trial, 840 patients who had breakthrough disease were eligible for participation, and again, the comparator arm was interferon beta-1a by subcutaneous injection three times a week. In this trial, there was a 49% reduction in the annualized relapse rate in the alemtuzumab arm compared with interferon beta-1a (p < .0001). The disability end point was met with a 43% reduction in sustained disability (p = .008; Jeffrey, 2011). Adverse events, including idiopathic thrombocytopenia purpura, autoimmune thyroid disease, infusion-related reactions, and increased risk for infections, were observed in the clinical trials (Jeffrey, 2011).

Daclizumab

Daclizumab is a monoclonal antibody against the interleukin-2 receptor that binds to CD-25. It has been found to decrease abnormal T-cell activation and may also increase the population of regulatory natural killer cells. Daclizumab has been administered by intravenous infusion and, more recently, by subcutaneous injection. Two phase 2 trials have been completed that indicate efficacy in relapse reduction and MRI outcomes (Giovannoni et al., 2011; Wynn et al., 2010). The SELECT trial was a 1-year, randomized, double-blind trial that compared 150 and 300 mg of monthly subcutaneous daclizumab to placebo. Both treatment groups reduced annual relapse rate by approximately 50% (p = .0002). New and enlarging T2 MRI lesions were reduced by 70%-78% (p < .0001; Giovannoni et al., 2011). A second phase 2 trial, the CHOICE trial, was a 24-week study of 230 patients with RRMS who had at least one relapse or Gd-enhancing lesion in the brain or spinal cord while on stable interferon beta therapy. Patients were randomized to receive high-dose daclizumab (2 mg/kg every 2 weeks subcutaneously plus interferon beta), low-dose daclizumab (1 mg/kg every 4 weeks subcutaneously plus interferon beta), or interferon beta plus placebo. The primary outcome was new or enhancing MRI lesions, and a significant 72% reduction was observed in the number of new or enlarging T2 MRI lesions in the high-dose daclizumab plus interferon beta group compared with the interferon beta plus placebo group (p = .004). Adverse events included rash and infections consisting mainly of urinary tract and respiratory tract infections (Wynn et al., 2010). Mild lymphopenia and mild elevations in hepatic enzymes have also been observed with daclizumab treatment (Martin, 2012). A phase 3 trial of daclizumab is currently in progress.

Summary

MS is a complex disease that causes widespread demyelination and axonal damage of white and gray matter, leading to often irreversible damage and disabling neurological symptoms. Diagnosis of MS is often difficult and requires clinical and paraclinical information, along with the exclusion of other possible causes of symptoms. An international panel has developed and revised diagnostic criteria for MS to expedite the diagnosis and to improve diagnostic accuracy.

Since 1993, 10 medications have received FDA approval for MS: nine for RRMS and mitoxantrone for worsening relapsing and secondary progressive MS. Interferon beta-1a weekly injections and interferon beta-1b subcutaneous injections, as well as glatiramer acetate, are approved for CIS and RRMS. These injectable treatments have shown long-term efficacy and long-term safety. The more recent treatments natalizumab, fingolimod, teriflunomide, and DMF have shown efficacy in RRMS, but their use is or may be associated with greater potential risks. The MS treatment pipeline has several treatments that have been recently submitted to the FDA for approval and in clinical development.

The treatment landscape for MS has expanded over the past 20 years and will likely undergo further expansion over the next several years. Although new treatments have shown efficacy in relapse reduction and MRI outcomes, treatment side effects and potential risks associated with these treatments will become important points of discussion with patients. Treatments continue to be directed toward the inflammatory response seen in MS, with outcomes of relapse reduction and reduction in new MRI activity. Some also show a positive effect on progression of disability and may have neuroprotective properties.

Nurses will need to understand the immunological basis of MS as well as the diagnostic criteria to help patients understand their disease and diagnosis. In addition, with the ever-growing treatment options, nurses will need to understand the mechanisms of action of MS treatments; their effects on relapses, MRI, and progression; and the risks and tolerability of these treatments to help patients make informed decisions. Nurses will also play a role in the long-term monitoring of the safety and efficacy of MS treatments to allow for the identification of patients with worsening MS who may need potential adjustments to their treatment plan.

Acknowledgments

Editorial support for the writing of this manuscript was provided by Megan Knagge, PhD, of MedErgy and was funded by Sanofi-Aventis. The author retained full editorial control over the content of this manuscript.

References