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Multiple Sclerosis Research: Diagnostics, Disease-Modifying

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Multiple Sclerosis Research: Diagnostics, Disease-Modifying S14 Journal of Neuroscience Nursing Multiple Sclerosis Research: Diagnostics, Disease-Modifying Treatments, and Emerging Therapies Kathleen Costello ABSTRACT Multiple sclerosis (MS) is a complex disease that affects the central nervous system. It is believed to be an immune mediated disease, and although the etiology remains unknown, it is believed to occur from a combination of genetic risk factors and environmental risk factors. There is no single diagnostic test for MS, and diagnostic criteria have been developed to aid the provider in making an accurate and timely diagnosis. Once a diagnosis of MS is made, treatments directed toward the inflammatory immune response should be initiated. Currently, there are 10 treatments for MS: four interferon beta products; one glatiramer acetate; one monoclonal antibodyVnatalizumab; three oral treatmentsVfingolimod, teriflunomide, and dimethyl fumarate; and one immunosuppressant agentVmitoxantrone. Each of these agents has a different administration and different risks and side effects. Numerous agents are in late stage development, and it is possible that several more agents, all with different mechanisms of action, will become available over the next several years. Keywords: alemtuzumab, daclizumab, dimethyl fumarate, disease modifying treatment, fingolimod, glatiramer acetate, interferon beta, laquinimod, MCDONALD Criteria, multiple sclerosis, natalizumab, teriflunomide ultiple sclerosis (MS) is a chronic disease of the disease from onset, known as primary progres- of the central nervous system (CNS) path- sive MS (Lublin & Reingold, 1996). Mologically characterized by CNS inflam- The etiology of MS is unknown; however, it is mation, demyelination, and axonal loss (Compston thought to be because of a complex interplay of fac- & Coles, 2008). Clinically, the disease is most often tors including genetic risk for autoimmunity, immune characterized by early relapses and remissions of system dysregulation, and environmental factors (i.e., neurological symptoms referable to the CNS, a clin- viral exposure, particularly Epstein Barr, vitamin D ical course known as relapsing-remitting MS (RRMS). deficiency, and smoking; Ascherio & Munger, 2007; After early relapses with characteristic inflammation Giovannoni & Ebers, 2007; Shirani & Tremlett, 2010). and demyelination, there is some functional reorga- Immunologically, the inflammatory process is thought nization and remyelination that occurs early in the to be mediated by T-cell and B-cell responses to CNS disease and helps to restore function. Over time, RRMS autoantigens. The inflammation that occurs within the often transitions to a disease course characterized by a CNS is also responsible, at least in part, for degen- progressive decline in function. Although relapses may erative changes, including axonal loss and damage to still occur, they occur less often; this course of MS is oligodendrocytes that lead to irreversible damage in known as secondary progressive MS. In individuals the brain and spinal cord. with secondary progressive MS, early repair mecha- Symptoms of MS vary widely in type and severity. nisms fail and more axonal loss occurs (Hagemeier, Common symptoms include generalized and fre- Bruck, & Kuhlmann, 2012). Approximately 10%Y15% quently overwhelming fatigue; depression; unilateral of all patients with MS will have a progressive course visual blurring or loss; diplopia; sensory symptoms, such as numbness, tingling, or pain; incoordination; spasticity; weakness; ataxia; and elimination dysfunction, Questions or comments about this article may be directed to such as urgency, frequency, and incontinence of bladder Kathleen Costello, MS RN ANP-BC MSCN MSCS, at kcostel5@ or bowel. Cognitive impairment, such as short-term jhmi.edu. She is a Nurse Practitioner at Johns Hopkins Multiple Sclerosis Center, Baltimore, MD. memory loss and slowed processing, is also possible. Conflicts of interest and source of funding: Kathleen Costello has served on Scientific Advisory Boards for Teva Neuroscience, Diagnostics Genzyme, Sanofi, Aventis, BiogenIDEC, EMDSerono, Questcor, Making the diagnosis of MS can be quite chal- and Novartis Pharmaceuticals. lenging because there is no specific diagnostic test. Copyright B 2013 American Association of Neuroscience Nurses Traditionally, the diagnosis is made if there are at Copyright © 2013 American Association of Neuroscience Nurses. Unauthorized reproduction of this article is prohibited. Supplement to: Volume 45 & Number 6S & December 2013 S15 least two neurological events referable to the CNS, separated or disseminated in space (different areas In the past 10-plus years, the of the CNS) and time (events occur at different points in time), with objective evidence of CNS involvement diagnostic ‘‘standard’’ known as the and all other possible causes of the symptoms are excluded. The diagnosis is mostly based on history of McDonald criteria has been neurological symptoms and neurological examination revised twice to reflect the findings. More recently, magnetic resonance imaging (MRI) findings and other paraclinical testing, such increased evidence of MRI changes as spinal fluid analysis, have been used to establish consistent with MS. 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 MRI and/or cerebrospinal fluid abnormalities to es- diagnostic criteria developed by MS experts that have tablish dissemination in space and/or time when only helped with the diagnosis of MS. In 2001, an inter- a single clinical event has occurred. Imaging criteria national panel of MS experts convened and developed for the 2010 McDonald criteria revision were based criteria that utilized both clinical and MRI findings, on recent publications from the MAGNIMS research including the criteria of dissemination in space and group (Montalban et al., 2010; Rovira et al., 2009; time (McDonald et al., 2001). Since 2001, these cri- Swanton et al., 2007). Fluid-attenuated inversion recov- teria, known as the McDonald criteria, have been ery and T2-weighted sequences are the MRI tech- revised, both in 2005 (Polman et al., 2005) and in 2010 niques that are currently of greatest clinical interest in (Polman et al., 2011). In each of the revisions, the MS, along with postcontrast T1-weighted scans. These MRI criteria have been modified to reflect increased sequences provide information about active inflamma- evidence of MRI changes consistent with MS. tory and subclinical MS activity. Subclinical activity One of the goals of these criteria is to expedite the occurs much more frequently than do clinical symp- diagnosis of MS. Therefore, the McDonald diagnostic toms (Filippi et al., 2011). criteria have traditionally been applied to those indi- On the basis of the McDonald criteria, the criterion viduals who present with a clinically isolated syn- for dissemination in space can be met by the presence drome (CIS). The CIS is a term that describes the first of an MRI lesion in at least two of four areas of the onset of neurological symptoms in an individual, which CNS, which include juxtacortical, periventricular, in- usually involve the optic nerve, brainstem, or spinal fratentorial, or spinal cord (Figure 1). The criterion of cord and are characteristic of MS (Miller et al., 2008). dissemination in time can be met with an additional Symptoms should last a minimum of 24 hours in the T2 lesion and/or gadolinium (Gd)-enhancing lesion absence of infection. Individuals who have symptoms on a subsequent MRI, performed at any time after the and an MRI suggestive of inflammation and demye- initial MRI, or the simultaneous presence of asymp- lination or spinal fluid with findings consistent with tomatic Gd-enhancing lesions and nonenhancing le- MS are considered at high risk to develop additional sions in an individual with CIS (Polman et al., 2011). symptoms and would then be considered to have MS. If the criteria for dissemination in space and time are The diagnostic criteria utilize paraclinical evidence of met in the absence of additional clinical symptoms FIGURE 1 MRI in Multiple Sclerosis Copyright © 2013 American Association of Neuroscience Nurses. Unauthorized reproduction of this article is prohibited. S16 Journal of Neuroscience Nursing and other causes of the symptoms have been com- the interaction of free water protons and bound protons pletely excluded, the diagnosis of MS can be made and provides information about areas of MS damage (Polman et al., 2011). Other possible causes of neu- as well as normal-appearing white matter (Filippi & rological symptoms that must be excluded include Rocca, 2007). MR spectroscopy provides quantifica- other inflammatory conditions, CNS infections, met- tion of chemical changes found in lesions and normal- abolic conditions, vascular conditions, and inherited appearing white matter. Considered a marker of axonal conditions. Table 1 lists some of the diagnostic mimics integrity, N-acetyl aspartate can be measured using of MS. MR spectroscopy and provides evidence of the ex- Although not part of the MRI diagnostic criteria tent of axonal damage (Poloni, Minagar, Haacke, & nor part of the conventional imaging of clinical prac- Zivadinov, 2011). tice, nonconventional imaging techniques have been Optical coherence tomography (OCT), a non-MRI utilized to identify additional CNS pathology in MS. imaging tool, is a noninvasive method to observe and These techniques have added
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