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Multiple Sclerosis

Eyes on the Future

Costello, Fiona E. MD, FRCPC; Burton, Jodie M. MD, MSc, FRCPC

Journal of Neuro-Ophthalmology: March 2018 - Volume 38 - Issue 1 - p 81–84
doi: 10.1097/WNO.0000000000000631
Disease of the Year: Multiple Sclerosis

Departments of Clinical Neurosciences (FC, JMB), Surgery (FC), and Community Health Sciences (JMB), University of Calgary, Calgary, Alberta, Canada.

Address correspondence to Fiona Costello, MD, FRCPC, Clinical Neurosciences, Foothills Medical Centre, 12th Floor 1403, 29 Street NW, Calgary, AB, Canada T2N 2T9; E-mail:

F. Costello has received consultancy fees from Clene and EMD Serono and participated as a site principal investigator in a study sponsored by Novartis. J. M. Burton has received unrestricted educational support and honoraria from Novartis, Sanofi Genzyme, Biogen Idec, and EMD Serono.

In an inaugural segment for 2018, the Journal of Neuro-Ophthalmology will feature multiple sclerosis (MS) at its “Disease of the Year.” With a series of articles over the course of the year, we will highlight current challenges and pivotal discoveries in the field of MS, which are of particular relevance to clinicians who care for these patients. “Disease of the Year” will include a review of pathogenic mechanisms of central nervous system (CNS) injury and repair that are believed to underpin MS-related disability, and highlight the emerging role of the visual system as a model of CNS injury in this disease. We will provide an overview of the current therapeutic landscape in MS, which has evolved from a limited array of interferon agents and glatiramer acetate, to a contemporary arena in which oral, intravenous, and injectable drugs are available. We will explore novel biomarkers being used to track MS-related disease activity and progression, with specific emphasis on advancements in neurophysiology and ocular imaging techniques spearheaded by vision scientists and neuro-ophthalmologists. Finally, we will cast a glance to the horizon and discuss ongoing efforts to make personalized medicine a reality. In this rapidly evolving framework, patients with MS will be stratified based on clinical, radiological, and immunological parameters and, accordingly, treatments will be tailored to meet increasingly ambitious standards of disease control.

MS traditionally is viewed as an immune-mediated disease of unknown cause, characterized by both inflammatory and neurodegenerative processes within the CNS (1). Affecting 2.5 million individuals worldwide, MS is recognized as a leading cause of nontraumatic neurological disability in young adults (1,2). The toll of MS on affected individuals and, indeed, society as a whole is formidable. The lifetime cost per patient with MS is estimated to be approximately $4,000,000, with prescription drugs and indirect expenditures driving the burden of this disease (2). The relatively hefty “price tag” of MS-related care catapults this condition up the ranks, placing second to congestive heart failure in terms medical costs related to chronic conditions (2). Aside from economic hardship, patients with MS bear additional burdens related to reduced quality of life and psychosocial disenfranchisement, which are amplified as their disease, and in turn disability, progress over time. Most MS therapies target CNS inflammation, yet it is unclear how efficacious current agents are at halting neurodegeneration and, consequently, disability, which may be driven in part by noninflammatory mechanisms. Presently, there is only one FDA-approved medication for progressive MS: ocrelizumab. Even in this progressive MS subgroup, however, treatment-response seems to be driven by progressive patients with evidence of active inflammation (3).

The pathologic “signature” of MS is the sclerotic plaque or “la sclérose en plaques” as originally coined by Charcot in 1868 (4). This finding is believed to represent the cumulative effects of inflammation, demyelination, remyelination, oligodendrocyte depletion, astrocytosis, axonal damage, and neuronal loss affecting white and gray matter CNS structures (1). It comes as no surprise that in a condition characterized by chronic and fulminant forms with a wide-ranging phenotypic expression, several pathogenic mechanisms (and combinations thereof) are believed to govern MS-related disability including CNS inflammation as the main pathogenic event; neurodegeneration as the primary CNS pathological event (with inflammation as a secondary response); CNS inflammation and neurodegeneration occurring in concert; and CNS inflammation triggering an intrinsic neurodegenerative susceptibility in a vulnerable host (1). There is ongoing debate about whether MS is predominantly an inflammatory process caused by the migration of autoreactive T cells crossing the blood–brain barrier from the systemic circulation because of an instigating event perpetrated outside the CNS (outside-in model), or a primarily cytodegenerative process involving the oligodendrocyte–myelin complex, with inflammation occurring as a secondary response (inside-out model) (1,5).

The deleterious impact of subclinical activity is well recognized in MS, yet conventional tools used to follow these patients are often insensitive to this activity. MRI has long been viewed as the “gold standard” for the diagnosis of MS, yet there is a dissociation between clinical disability and radiological disease burden as depicted by standard MRI techniques, referred to as “clinical-radiological paradox” (6). Currently, novel MRI techniques better able to detect brain and thalamic atrophy, and diffusion tensor imaging are not part of conventional patient evaluation. Moreover, the Kurtzke Expanded Disability Status Scale (EDSS), which was designed as a research tool, is commonly used to quantify neurological disability among patients with MS. Yet, the EDSS is heavily biased by pyramidal tract dysfunction and does not capture MS-related deficits that impact day-to-day function including cognitive impairment, sphincter dysfunction, and fatigue. In an effort to overcome the lack of biomarkers sensitive to detecting disease progression, MS specialists have attempted to redefine how treatment efficacy is measured with the “no evident disease activity” (NEDA) approach (7). In practice, NEDA-3 represents a composite of 3 measures of disease activity: no relapses; no disability progression; and no MRI activity (7). Although some studies have shown high rates of NEDA in the first years of disease-modifying therapy, long-term maintenance of NEDA in clinical practice remains a significant challenge (8,9). Even in patients with MS undergoing autologous hematopoietic stem cell transplantation, the pooled proportion of NEDA patients at 2 years was 83% (range 70%–92%) and at 5 years was 67% (range 59%–70%) (10). Recently, the outcome of minimal evident disease activity (MEDA) has been posited as a more realistic goal of treatment (9). It is likely that the definitions of NEDA/MEDA will evolve with technological advancements and in response to the practical realities of patient care. Future iterations and applications of NEDA will need to encompass patient-related outcome measures, focal gray matter disease activity, brain atrophy measures, and novel cerebrospinal fluid biomarkers (7). Currently, the overarching goal is to establish more aggressive targets for monitoring treatment outcomes in MS while keeping in mind the risk-to-benefit ratio in the management of any given patient.

The field of neuro-ophthalmology has contributed to an evolving paradigm of CNS injury, which is modeled on the structure and function of the afferent visual pathway (1) (Fig. 1). Balcer et al (11) have shown that visual performance using low-contrast letter acuity correlates with quality of life measures and captures visual deficits that hinder day-to-day function of patients with MS. Klistorner et al (12) have demonstrated correlations between multifocal visual evoked potential latency delays and optical coherence tomography (OCT)–measured neuroaxonal injury after optic neuritis. Raz et al (13) have demonstrated that spatial visual function tests (high- and low-contrast letter acuity, standard automated perimetry, and color vision) normalize weeks to months after optic neuritis, yet motion perception remains impaired in the postacute phase. They also reported that deficits in motion perception correlate with the extent of visual evoked potential latency delay in patients with optic neuritis (14). Advances in OCT have been used to quantify structural changes within the inner retina, which reflect direct and trans-synaptic degeneration from lesions affecting the optic nerves, chiasm, tracts, and optic radiations. In an evolving body of work, OCT measurements of thinning of the retinal nerve fiber layer and ganglion cell layer in patients with MS have been shown to correlate with reduced quality of life measures, visual outcomes, brain atrophy, and global disability (15). Longitudinal OCT studies have shown that inner retinal thinning may manifest as an early phenomenon in MS, and that, loss of neuraxonal integrity in the afferent visual pathway may occur as a consequence of, but also independent of, clinical episodes of optic neuritis (15). There are data to suggest that MS disease–modifying therapies may influence OCT-determined rates of retinal atrophy, thus supporting a potential role for OCT in monitoring the neuroprotective benefits of established and emerging MS therapies (15).

Fig. 1

Fig. 1

A paradigm shift is underway in the field of MS, both in terms of how the disease is diagnosed and distinguished from other demyelinating disorders and how treatment targets are being defined in a patient-centered model of care. The search for easily accessed prognostic biomarkers continues, with growing evidence to support neurofilament assays (16), as well as novel MRI techniques (17,18). In addition, OCT-measured thinning of the retinal nerve fiber layer and ganglion cell layer continue to show a robust correlation with degenerative changes on MRI and clinical measures of disability in MS (19). A significant discovery in recent years has been the identification of myelin–oligodendrocyte glycoprotein (MOG) antibody-positive and aquaporin-4 antibody–negative demyelinating disease. This discovery is changing the clinical approach to investigating cases of recurrent optic neuritis. Unlike aquaporin-4–seropositive patients with neuromyelitis optica spectrum disorder, MOG antibody-positive patients are typically more steroid sensitive, less likely to relapse, and more gender balanced (20). Yet, patients with MOG are at risk for recurrent disease. Therefore, early treatment with prednisone with consideration of immunosuppression is becoming the mainstay of care (20). Neuro-ophthalmologists are positioned to play an integral role in better distinguishing clinical syndromes such as MS optic neuritis from NMOSD optic neuritis and MOG optic neuritis. Specifically, neuro-ophthalmologists have a unique perspective because they understand the limitations of relying on structural and functional tests of the visual pathway in the absence of a thorough clinical examination.

The diagnosis of MS and the biomarkers that assist in that endeavor continue to improve, with prognosis and treatment options growing more personalized as we better identify the range of molecular targets that impact this disease. As “custodians” of the visual system, neuro-ophthalmologists have an important role to play in the increasingly holistic, multidisciplinary approach to managing MS, and improving the lives of these patients.

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© 2018 by North American Neuro-Ophthalmology Society