New Approaches to the Diagnosis, Clinical Course, and Goals of Therapy in Multiple Sclerosis and Related Disorders

  • Comprehensive MS Care

Why is this important to me?

Over the past decade, many views of MS have changed, leading to a shift towards personalized, data-driven, proactive diagnosis and treatment of the disease. MS remains unpredictable and is different in each person.


How will I benefit from reading this article?

This article reviews the current approaches to how MS is diagnosed, followed, and treated and will be beneficial to everyone with MS.


What is the objective of this study?

The author reviewed several views of MS that have changed in the last decade and how those changes impact patient care. Topics covered include:

  • Pathology
  • Diagnosis
  • Disease course
  • Therapies


MS used to be thought of as a disease of the white matter (regions of the brain that contain the nerve fibers that convey information from one part of the brain to another). Researchers now understand that MS also affects the gray matter (regions of the brain that include the other parts of the nerve cells such as the nucleus, etc.). Lesions in the gray matter predict the MS disease course better than lesions in the white matter.

MS has long been known as a disease that is mediated by the immune system. MS was long thought to be mediated primarily by a subset of immune cells called T cells. Although T cells are certainly involved, another type of immune cell called B cells have recently been shown to also be important. This is important because therapies can be directed at controlling the function of these cells.


The criteria for diagnosing MS, called the McDonald criteria, were updated most recently in 2010. This revision allows MS to be diagnosed at the time of the first clinical attack if certain imaging criteria are also met. Thus, patients who were previously diagnosed with a type of pre-MS condition called clinically isolated syndrome can sometimes be diagnosed with definite MS. Patients with another diagnosis called radiologically isolated syndrome, in which MS-like lesions are seen with imaging in the absence of clinical symptoms, are now watched more closely for development of MS. Taken together, these new criteria for diagnosing MS result in patients being treated sooner, which produces a better overall outcome.

Disease course

In 2014, the definitions of the clinical course of MS were revised. Although MS is still categorized into relapsing-remitting, secondary progressive, and primary progressive subtypes, additional characteristics are considered. Both relapsing and progressive forms of MS are categorized as showing or not showing evidence of inflammation, which is indicative of new, active relapses. This is in contrast to chronic, long-term lesions. Patients with progressive forms of MS are also characterized as having or not having progression. The absence of inflammation and the absence of disease progression indicate a state called “stable disease” in which the patient’s condition does not worsen. Although MS cannot currently be cured or reversed, achieving stable disease is a potential goal of therapy.

Another model of MS progression involves a continuum of disease activity and progression rather than discrete subtypes that are sometimes difficult for physicians to discern. In this model, five factors are considered important for prognosis: where in the brain lesions are located, relapse frequency, relapse severity, recovery from relapses, and the rate of progression. In this line of thinking, MS is a gradual, permanent, series of repeated symptoms that are determined by where the lesions are located. This model is important because it allows a more personalized description of the disease course, a more personalized approach to monitoring disease, and a potentially more precise approach to treatment.

Another important new consideration is that cognitive problems are now understood to be common and to occur early in the disease course, resulting in earlier intervention.


Since 2010, six new or improved therapies have been approved:

  • Fingolimod
  • Teriflunomide
  • Dimethyl fumarate
  • Glatiramer acetate (three times per week)
  • Pegylated interferon beta-1a (two times per month)
  • Alemtuzumab

These disease-modifying therapies work in a variety of ways. The current approach to therapy for MS is proactive, and therapy should generally be used without interruption. This wide selection of agents and a personalized approach to selection of therapy may allow stable disease to be a viable goal of treatment. Selection of a therapy requires consideration of:

  • Effectiveness
  • Safety, side effects, and risk tolerance
  • Route of administration (oral, injected)
  • Other disease(s) the patient may have

These therapies modulate the immune system in various ways, and predicting the consequences of this in individual patients remains challenging.

A lack of understanding of the fundamental process of progressive disease has hindered development of therapeutic options for this disease subtype.

Another important and emerging approach to MS treatment is holistic and emphasizes wellness, symptom management, quality of life, and patient-reported outcomes.

Future studies will be directed at determining if preventing relapses and lesions will have a long-term impact on progression and preventing the accumulation of disability in patients with progressive disease. The next step in MS therapeutics may be restoring myelin, the fat-like substance that wraps around and protects nerve fibers and that is destroyed by the immune system in MS. Combination therapies, biomarkers, and personalized approaches to treatment selection are also currently under investigation.


How did the author study this issue?

The author reviewed recent literature and recommendations.

Original Article

New Approaches to the Diagnosis, Clinical Course, and Goals of Therapy in Multiple Sclerosis and Related Disorders


Stephen C. Krieger, MD

ABSTRACT The diagnosis, categorization, and treatment of multiple sclerosis (MS) and other demyelinating diseases have shifted over the past decade, and many of the fundamental principles of MS pathogenesis and clinical course are being rewritten. Fundamental issues include selecting the right disease-modifying therapy for someone with active disease and how, or even if, patients with purely progressive MS should be treated. This article provides an overview and introduction to the current thinking in MS diagnosis and therapy with an emphasis on the data-driven and proactive approach that has come to define the current state of the art. Continuum (Minneap Minn) 2016;22(3):723–729.



I fondly recall poring over the 2004 issue of Continuum on multiple sclerosis (MS) as I joined the field, and it is a great honor to serve as guest editor for this issue of Continuum on Multiple Sclerosis and Other Demyelinating Diseases a dozen years later. The past decade has marked several fundamental shifts in how demyelinating disease in general and MS in particular are diagnosed, categorized, and treated. This is a moment of incredible dynamism in the field, where many of the fundamental principles of MS pathogenesis and clinical course are being rewritten. This article provides an overview and introduction to the current thinking in MS diagnosis and therapy with an emphasis on the data-driven and proactive approach that has come to define the current state of the art, the specifics of which will be discussed in greater detail in the articles that follow within this issue of Continuum.

The current understanding of MS obliterates many previously relied upon distinctions. MS is no longer considered intrinsically a “white matter disease,” as it is now recognized to be a disease affecting gray matter as pervasively as white.1 Indeed, gray matter involvement is likely a better predictor of clinical course and disability2 than the white matter lesions that have long been considered the imaging hallmark of this disease. MS is no longer thought to be a purely T-cellYdriven disease, as both pathologic and clinical trial data implicate B-cell involvement in MS pathogenesis3 and as an apt therapeutic target. And MS is now understood to be a disease affecting cognition often and early in the course, rather than rarely and as a late consequence of disease. MS has been a treatable disease since the regulatory approval of disease-modifying therapies in the 1990s, but the explosion of therapeutics in the past 10 years is unprecedented and has brought with it both great opportunities and great challenges for optimal patient outcomes.4

In general, the field has evolved toward a more data-driven, comprehensive, and proactive approach to MS and related central nervous system (CNS) demyelinating disorders. However, perhaps more than ever before, a lack of consensus and great heterogeneity exist in the ways that many pervasive clinical scenarios in demyelinating disease are addressed. These include such fundamental issues as the approach to selecting the right disease-modifying therapy for someone with active disease and how, or even if, patients with purely progressive MS should be treated. This introductory article discusses recent changes to the way demyelinating disease is diagnosed, categorized, and treated, with an emphasis on the current approach to these and other contemporary issues in the management of patients with demyelinating disease.



The current diagnostic criteria for MS, the 2010 revisions of the McDonald criteria,5 are notable in two ways: these criteria simplified the MRI findings needed to establish a diagnosis of MS, and they allowed for MS to be diagnosed decisively at the time of the first clinical attack if sufficient MRI requirements are met. The category of the clinically isolated syndrome has thus shrunk at the margin, as many of these patients can now be definitively diagnosed with MS. While the paradigm of treating patients with clinically isolated syndrome with disease-modifying therapies has been in place for the past decade, the ability to officially diagnose MS at the time of the first attack fosters the rationale for early treatment and streamlines the treatment initiation conversation with patients.

Although the central feature of the McDonald criteria remains the clinical presentation, incidentally observed findings suggestive of demyelinating disease are an increasingly common scenario facing the practicing neurologist. The growing recognition that the radiologically isolated syndrome6 is often a harbinger of clinically apparent MS7 has implications for ensuring an astute reading of such MRI findings and necessitates a fluency with the McDonald radiographic criteria on the part of both neurologists and neuroradiologists. The knowledge that one-third of patients fulfilling imaging criteria for radiologically isolated syndrome will develop MS within 5 years allows clinicians an opportunity to perform close clinical and imaging surveillance and, in certain circumstances, to intervene therapeutically at the earliest detectable stage of disease.



In 2014, Lublin and colleagues revised the clinical course definitions8 that have been foundational for clinical trial design, regulatory approval of therapeutic agents, and treatment decisions for the past 2 decades. These revised clinical course phenotypes, while still organized into relapsingremitting MS, secondary progressive MS, and primary progressive MS phenotypes, now take into account studies that have demonstrated that MRI findings are key indicators of disease activity.9 Crucially, both relapsing and progressive forms of the disease are denoted as either demonstrating or not demonstrating inflammatory activity (new relapses or MRI lesions). In the case of progressive MS, as with the 1996 definitions, secondary progressive MS is still defined as progression that follows an initially relapsing course, while primary progressive MS denotes progression beginning at disease onset. It is important to note that progressive disease is further characterized as having the presence or absence of inflammatory activity as described earlier and the presence or absence of ongoing progression. The absence of both progression and activity yields what is now designated “stable disease.” This new approach to defining disease course has implications for clinical practice in that vigilance for disease activity is warranted both in traditional relapsing-remitting MS as well as in progressive forms and that stable disease is a potential clinical outcome and thus a potential therapeutic goal.

A subsequent clinical course model that builds upon the described categories to propose a unified depiction of the clinical course of MS is the topographical model of MS.10 Rather than dividing MS into clinical course subtypes that may not always be discrete in clinical practice,11 this model proposes that the clinical course of MS can be depicted across a continuum of disease activity and progression. The model visually depicts MS disease course as an interplay of five factors that have been shown to have prognostic significance: the topographical distribution/localization of lesions and the relapses they cause, relapse frequency, relapse severity, relapse recovery, and progression rate. The extent to which a given patient has relapsing or progressive manifestations of the disease is determined by modulating those principal factors.

The topographical model posits that relapses and progression have a specific relationship that underlies MS disease course: like the symptom recrudescence that occurs transiently in Uhthoff phenomenon and pseudoexacerbations, progression in MS manifests as a permanent incremental recapitulation of symptoms referable to the localization of accumulated lesions and the relapses they have caused (a patient’s “disease topography”). This new clinical manifestation framework has the potential to change how neurologists classify their patients with MS as it allows for a more personalized depiction of disease course. Furthermore, it builds on the revised clinical phenotypes in that it encourages vigilance for progression in patients with relapsing MS and vigilance for inflammatory activity in those with progressive disease.



New approaches to MS therapy and goals of care have been driven by the rapidly expanding treatment armamentarium. Six new or revised disease-modifying therapies have been approved just since 2010 (fingolimod, teriflunomide, dimethyl fumarate, glatiramer acetate 3 times a week, pegylated interferon beta-1a 2 times a month, and alemtuzumab), covering an extraordinary range of efficacy, routes of administration, and dosing frequencies. The availability of diverse therapies has outstripped the development of evidence-based guidelines for their optimal selection and utilization. A multivariate decision on the basis of efficacy, safety, route of administration, side effect profile, patient comorbidities, and MS disease history must be undertaken with each therapeutic decision. Furthermore, the risk tolerance of both the clinician and the patient must be taken into account and aligned. Such numerous and personal variables, in the absence of biomarkers to predict efficacy in the individual patient, have been obstacles to the development of broadly applicable treatment algorithms. Indeed, the 2014 position statement issued by the American Academy of Neurology12 and a consensus article issued by the Multiple Sclerosis Coalition13 both advocate for broad availability of the disease-modifying therapies, without interruption, for patients with MS requiring treatment.

What has become abundantly clear is the extent to which investigational and approved therapies have emphasized relapsing forms of MS, leaving a persistent dearth of options for progressive disease. This disparity is apparent every day in clinical practice, where a plethora of therapies exist to discuss with patients experiencing disease activity and a humbling lack thereof for patients whose disability has accumulated insidiously. This unmet need is finally being addressed in late-stage clinical trials, although the failure in 2015 of fingolimod to prevent disability in a large phase 3 trial in primary progressive MS14 was both a major disappointment and a pointed reminder that fundamentals of the pathogenesis of progression remain poorly understood.15

Additionally, the modern therapeutic era in MS has yielded evolving challenges inherent in modulating the immune system, with downstream consequences that are difficult to predict on an individual patient basis. A refined approach to stratifying progressive multifocal leukoencephalopathy (PML) risk with natalizumab has been achieved using the JC virus antibody as a powerful biomarker of risk,16 but a far less well-characterized emerging risk of PML exists with numerous MS therapies. Cases of PML have been observed with both dimethyl fumarate and fingolimod, and the possibility of this risk also merits vigilance in patients treated with alemtuzumab and B-cellYdepleting therapies. More generally, the mandate for clinicians treating MS to be familiar with a broad range of immunologic mechanisms of action has grown with the variability in approach offered by manifold treatment options. Undoubtedly, most neurologists would struggle to recall learning about sphingosine receptors during their training. However, an understanding of the mechanism of action of fingolimod is indeed essential to monitor for the risks and potential adverse events associated with this agent. Alemtuzumab is a powerful and long-lasting therapeutic agent with both a complex set of potential side effects and a multipart risk mitigation program to address them, warranting familiarity with a broad range of potential infectious and inflammatory consequences affecting multiple organ systems. The approval of alemtuzumab as a highly effective therapy for breakthrough relapsing disease in the United States and as a first-line agent in suitable patients in Europe marks another milestone in the changing approach to the risk-benefit ratio of MS treatment.

With the broader array of agents has come an evolving approach to goals of therapy, particularly in relapsing disease. The field has moved beyond the first-line/second-line paradigm toward an attempt to personalize MS therapeutic decisions. Goals of therapy in MS have begun to shift toward “treating to target”Va goal of disease quiescenceVrather than simply relapse rate reduction. Although “no evidence of disease activity” (NEDA)17 cannot be achieved in the majority of patients with the currently approved therapies, it is evident that therapeutic complacency in relapsing MS is insupportable. While devastatingly severe relapsing MS remains relatively unusual, the proactive approach to MS therapy is the hallmark of the current treatment era.

An important aspect of the modern treatment approach to MS is the renewed emphasis on comprehensive care and wellness. While disease modifying therapy decisions are informed by copious data from well-controlled clinical trials, symptom management is typically addressed in a more ad hoc experience-based manner. This too is evolving, with increasing data on many facets of MS symptom management with a growing emphasis on quality of life and patient-reported outcomes in both clinical research and practice. Notably, of the 11 measures included in the AAN 2015 Multiple Sclerosis Quality Measurement Set,18 fully eight pertain to quantified assessments of symptom management, wellness, and quality of life.



Changes in the field have not been limited to MS, with advancements in the diagnosis, clinical course, and therapeutic approach in other demyelinating disorders of the CNS. What was once Devic disease and then neuromyelitis optica (NMO) has been reclassified into distinct clinical entities within the NMO spectrum disorders.19 This new diagnostic approach has redefined this illness along nuanced clinical grounds on the basis of localization, again breaking down distinctions of the former era. Initially described as a demyelinating disease with an absence of clinical or MRI evidence of brain lesions, core clinical features of NMO spectrum disorders now include acute brainstem syndromes, hiccups or vomiting referable to the area postrema, and cerebral syndromes with extensive infiltrative appearing lesions now recognized as a manifestation of this disease spectrum. Given the potentially devastating nature of NMO attacks, definitive preventive treatment in NMO spectrum disorders remains a major unmet need, although mounting data exist to guide therapeutic decisions even as the completion of controlled clinical trials is awaited.



The approach to the patient with demyelinating disease has never been as diagnostically and therapeutically plentiful as in the present day. Although the past decade has witnessed numerous successful clinical trials yielding the approval of new agents and the diagnostic criteria have been honed, MS remains a disease of great heterogeneity and unpredictability. Updated disease course descriptions and models have delineated disease activity and progression as an interplay of parallel processes to better individuate disease course. In light of enhanced vigilance for disease activity, the approach to relapsing disease has never been more proactive. However, the extent to which success in preventing relapses and the accumulation of lesions will truly stave off progression in the long term for today’s patients with relapsing-remitting MS remains uncertain. Moreover, preventing the accrual of insidious disability for patients with progressive disease has been frustratingly elusive.

Truly achieving NEDA will require the development of agents that directly target mechanisms of disease progression. Furthermore, the next vanguard in MS therapeutics is remyelination, for which strategies have entered clinical trials eagerly awaited by the entire MS community. Such remyelination strategies will likely warrant rationally designed combination therapy approaches to both prevent further disease activity and foster CNS repair. This will indeed increase the complexity of therapeutic options by an order of magnitude. While the JC virus antibody, as a biomarker of PML risk, has improved the ability to optimize the risk-benefit ratio of one MS therapy, more such biomarkers are needed, including those that predict efficacy. A comprehensive panel of MS biomarkers would allow for a more evidence-based and personalized approach to treatment selection in what promises to be an era of vastly expanded options.



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Full Article

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