Keep Your Eyes Wide Open: On Visual- and Vision-Related Measurements to Better Understand Multiple Sclerosis Pathophysiology

Multiple sclerosis (MS), a demyelinating disease of the central nervous system, is multifaceted. It manifests as acute episodes as well as an accumulative chronic disability; myelin involvement as well as axonal damage; local as well as global effects; and disease load elements as well as compensatory mechanisms. The visual system, with its clear structural organization and relatively direct reflection of damage, may serve as an appropriate model to study MS. In recent years, we have witnessed a blossoming in the field of visual measures in MS. Because it is impossible to cover all different aspects of these measures, we chose to focus on several hot topics in MS literature and shed light on them through studies conducted in the visual system. We argue that numerous methods can be used to study axonal and demyelinating aspects of the disease. Although optical coherence tomography and static visual functions better reflect the axonal aspects of the disease, conduction velocity as measured by visual-evoked potential latencies and dynamic visual function mirrors myelin levels. We also posit that the classic disease load parameters cannot be the only means by which we assess a patient's condition. Novel imaging methods such as diffusion tensor imaging and functional magnetic resonance imaging can be used to assess the global effects of local damage on neighboring white matter and compensatory abilities of the brain. There have been great advances in therapeutic research in MS. However, the stratification of patients according to their prognosis and predictive outcomes in response to treatment is still in its infancy. The many facets of MS make it difficult to piece all the data together into one cohesive conclusion for the individual patient. The visual system, with our ability to assess both structure and function, offers a promising opportunity to study both pathophysiologic mechanisms and novel therapies.

Disease of the Year: Multiple Sclerosis Keep Your Eyes Wide Open: On Visual- and Vision-Related Measurements to Better Understand Multiple Sclerosis Pathophysiology Yael Backner, MSc, Netta Levin, MD, PhD Background: Multiple sclerosis (MS), a demyelinating disease of the central nervous system, is multifaceted. It manifests as acute episodes as well as an accumulative chronic disability; myelin involvement as well as axonal damage; local as well as global effects; and disease load elements as well as compensatory mechanisms. The visual system, with its clear structural organization and relatively direct reflection of damage, may serve as an appropriate model to study MS. Methods: In recent years, we have witnessed a blossoming in the field of visual measures in MS. Because it is impossible to cover all different aspects of these measures, we chose to focus on several hot topics in MS literature and shed light on them through studies conducted in the visual system. Results: We argue that numerous methods can be used to study axonal and demyelinating aspects of the disease. Although optical coherence tomography and static visual functions better reflect the axonal aspects of the disease, conduction velocity as measured by visualevoked potential latencies and dynamic visual function mirrors myelin levels. We also posit that the classic disease load parameters cannot be the only means by which we assess a patient's condition. Novel imaging methods such as diffusion tensor imaging and functional magnetic resonance imaging can be used to assess the global effects of local damage on neighboring white matter and compensatory abilities of the brain. Conclusions: There have been great advances in therapeutic research in MS. However, the stratification of patients according to their prognosis and predictive outcomes in response to treatment is still in its infancy. The many facets of MS make it difficult to piece all the data together into one cohesive conclusion for the individual patient. The visual system, with our ability to assess both structure and function, offers fMRI Unit, Neurology Department, Hadassah Hebrew University Medical Center, Jerusalem, Israel. Supported by research Grant 5128-A-1 from the National Multiple Sclerosis Society and by the Applebaum Foundation. The authors report no conflicts of interest. Address correspondence to Netta Levin, MD, PhD, fMRI Unit, Neurology Department, Hadassah Hebrew University Medical Center, POB 12,000, Jerusalem 91120, Israel; E-mail: [e-mail] Backner and Levin: J Neuro-Ophthalmol 2018; 38: 85-90 a promising opportunity to study both pathophysiologic mechanisms and novel therapies. Journal of Neuro-Ophthalmology 2018;38:85-90 doi: 10.1097/WNO.0000000000000634 © 2018 by North American Neuro-Ophthalmology Society M ultiple sclerosis (MS), a demyelinating disease of the central nervous system (CNS), is multifaceted. It includes acute episodes as well as accumulative chronic disability; myelin involvement as well as axonal damage; disease load elements as well as compensatory mechanisms; local as well as global effects; and antibody-mediated involvement as well as T-cell response. The shift toward personalized medicine affects MS research, and the heterogeneous and disseminated nature of the disease makes it important to match treatment to patient. Moreover, coincident with the increasing availability of disease-modifying treatments, stratifying patients according to their predictive outcome and response to treatment is crucial. Owing to the many aspects of the disease, an attempt at personalized medicine in MS should keep in mind these factors: demyelination, axonal loss, progression of disability, and also the brain's capability to overcome these deficits. Herein lies the attraction of the visual system as a model for studying MS as well as for outcomes assessment in therapeutic trials. The visual system in MS often is damaged; the damage sustained among the most troublesome from the patient's perspective (1). This can result from an acute episode of optic neuritis (ON), a common presenting symptom of the disease; or, may occur without any previous history of ON, such as the damage incurred because of lesions in the optic radiations (2). A slew of targeted methods make this well-defined system, with its clear structural demarcation, relatively direct reflection of damage in function, and accessibility to investigation from various angles into a fine model for outcome assessment in 85 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis research and clinical practice in MS. These methods include visual behavioral tests, structural markers, electrophysiological measures, and the assessment of the relationships between structure and function in the visual pathways (3,4). Imagine a young woman coming to the emergency department with sudden monocular decrease in vision and pain with eye movements. On neurological examination, a relative afferent pupillary defect (RAPD) is confirmed. It is clear that she suffers from acute ON, a diagnosis that can be further affirmed by use of conventional visual evoked potential (VEP) testing. There is no need for more sensitive tools for this straightforward diagnosis, but how can we tell what treatment would best benefit her? How can we track the evolution of her disease? Can we predict what will happen to her in the course of the next decade? In recent years, we have witnessed a blossoming in the field of visual measures in MS. Thus, it is impossible to cover all different aspects in the current review. Therefore, we chose to focus on several hot topics in the MS literature and to shed light on them through the "eyes" of the visual system. AXONAL LOSS AND MYELIN DAMAGE Pathologic studies in MS implicate myelin damage as the primary disease mechanism. Yet, demyelination alone is not sufficient to explain the range of symptoms seen in patients with MS. Lack of correlation between demyelination levels and disease stage, neurologic deficits, or lesion pathology can be explained by axonal transection and subsequent degeneration that usually follows myelin destruction. While remyelination may prevent demyelinated axons from degenerating, it may be limited as a result of repeated attacks. Understanding the complex etiology of MS and the importance of axon integrity is critical for clinicians who attempt to halt neuroaxonal damage. By the time a patient with newly-diagnosed MS experiences the first neurologic symptom, substantial axonal loss has already occurred in the CNS. Thus, there is a need for early treatment and the use of multiple strategies targeting remyelination and the preservation of axons (5). Axonal loss in the visual system can be reliably tracked using optical coherence tomography (OCT), one of the ground-breaking tools used to predict visual impairment in ON. Its primary measure, peripapillary retinal nerve fiber layer (RNFL) thickness, which is reduced following acute ON, reflects damage sustained by the unmyelinated ganglion cell axons (6). Decreased peripapillary RNFL values correlate with worse measures of visual function after ON, including visual fields deficits (7), low-contrast visual acuity decrements (8,9), color vision losses (10-12), and diminished vision-related quality of life outcomes (13). Associations have been found between RNFL thickness and global brain atrophy (14) and worse Expanded Disability Status Scale (EDSS) scores in MS (15). This emphasizes the visual system's ability to reflect more global aspects of CNS injury in MS. 86 Together with the technological advancements in OCT (increased resolution and better segmentation algorithms [16]), a relationship between the inner retinal layers and the disease's pathophysiology has become evident. Disease-associated changes in the inner nuclear layer have been proposed as a marker of inflammatory activity (17,18). Furthermore, it has been found that there is a quantitative predictive relationship between the inner retinal layers in early disease stages and with visual function at a later stage (19). Demyelination, the other prominent aspect of this disease, also can be evaluated within the confines of the visual system. The gold-standard test routinely used in the diagnosis of ON is the full-field pattern-reversal VEP (ffVEP) (20). VEP amplitudes, believed to reflect the number of functional optic nerve fibers, are typically reduced in the acute phase (21), and correlate with various measures of visual function (20,22-24). Prolonged VEP latencies, on the other hand, are believed to reflect demyelination and may persist many years after the acute episode (25). The ffVEP, however, sums the response of the entire stimulated region and is biased toward the macular region and the inferior visual field (26,27). This is problematic because responses from both abnormal and normal regions of the visual field are summed, possibly distorting the true signal (28). Multifocal VEP (mfVEP), on the other hand, represents separate responses from multiple regions of the visual field, achieved by using separate stimuli across the visual field. It therefore provides more accurate evaluation of the damage sustained (29). The behavioral aspect of prolonged conduction velocities, as reflected in ffVEP latencies was reported in context to "dynamic" visual functions, a term used to differentiate them from "static" functions, which do not involve time constraints, motion, or changes in presentation rates. These tests attempt to address the question of the continued visual difficulties reported by patients with ON even after the static functions have returned to normal (30). These difficulties seem to stem from impaired temporal resolution (31) and delay in visual perception (32). Performance of the object-from-motion (OFM) test (33), in which moving dots generate a camouflaged object that cannot be detected when the dots are stationary, was found to be impaired after ON even a full year after the acute episode (34). Correlation was found between the change in ffVEP measurements taken on consecutive visits and OFM performance scores, suggesting that OFM may be used as a behavioral tool for tracking demyelination and remyelination (30). Another aspect of dynamic function is the critical flicker fusion frequency (CFFF)-the shortest interval required between 2 brief flashes of light to be perceived as separate which may be used as a manner of determining the temporal resolution of vision (35,36). Studies have shown reduced CFFF in both patients with ON and patients with MS, Backner and Levin: J Neuro-Ophthalmol 2018; 38: 85-90 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis even when visual acuity and visual fields were intact (31,35- 39). CFFF also correlates with delayed ffVEP latencies as well as with reduced motion perception, thus emphasizing the notion that demyelination affects temporal aspects of visual perception (40). Returning to our patient with ON, suppose that she is suffering from clinically isolated syndrome. It is important to repair myelin damage to prevent further axonal loss. Recently, with the advent of remyelination treatments in MS, the importance of selecting the right tool for assessing therapeutic trial success is becoming evident (41,42). THE CLINICAL-RADIOLOGICAL PARADOX Magnetic resonance imaging (MRI) is an essential tool when diagnosing MS, required to show dissemination of lesions in space and time (43). The known discrepancy between lesion load, as seen on T2-weighted MR images, and the clinical state of the patient, as reflected in their disability or lack thereof, is designated the "clinical-radiological paradox" (44). In some cases, where the patient experiences great disability but presents a modest MRI lesion load, it suggests that tissue damage in MS exceeds areas of focal inflammation, causing more global effects of the disease (45-49). In other patients, the lesion load may be relatively robust, but the patients may have mild evidence of clinical disability, suggesting that mechanisms other than demyelination, remyelination, and axonal loss play a compensatory part (50). In this section we will address these two sides of the paradox and how they are reflected via the visual system. GLOBAL EFFECTS A clear advantage of the visual system is the relatively direct effect that a lesion in the afferent visual pathways has on visual function. On the one hand, a lesion in the optic nerve will invariably cause acute loss of vision, often accompanied by pain with eye movement, and persistent visual deficits, including color vision impairment and difficulty in perceiving depth and motion. It is a spatially and temporally distinct event, facilitating the tracking of changes over time. On the other hand, the visual pathways, being very well-defined, enable tracking of changes in a very elegant manner. Following the optic nerve, the visual signal continues its journey down the optic tracts, its direct continuation, and from there past the synapse in the lateral geniculate nucleus and through the optic radiation to the primary visual cortex. These white matter structures can be delineated using diffusion tensor imaging (DTI) and fiber tractography and their integrity may be deduced using the diffusion parameters extracted. A prominent issue in regards to local versus global damage in the ON visual system is the subject of transsynaptic degeneration. The process of degeneration of optic Backner and Levin: J Neuro-Ophthalmol 2018; 38: 85-90 nerve axons and their myelin sheaths as caused by a focal lesion is generally acknowledged. Retrograde degeneration was widely reported using OCT (6) and the anterograde aspects were studied via the integrity of the optic tract, a direct continuation of the optic nerve, using diffusion tensor imaging (DTI) (51,52). However, the matter of anterograde trans-synaptic degeneration following ON, caused by loss of input, is the subject of dispute. Some studies, using DTI (52,53) and RNFL thickness (54), report the damage to be independent from the proximal damage. Other studies, utilizing voxel-based morphometry and MR spectroscopy methods (55,56), claim trans-synaptic anterograde degeneration does take place. It is possible that the difference between study conclusions is the result of different methods or time from an acute episode. Global changes may also be observed in the effects of lesions within the optic radiations on the optic nerve, as assessed using RNFL thickness, suggesting retrograde transsynaptic effects (52,55,57). It was suggested that there is a link between optic radiation status and the thinning of the RNFL, with an even higher correlation discovered in patients without prior ON (57). These studies show that even when considering highly localized damage, as seen in ON, neighboring and distant white matter tracts can be affected, leading to a global effect in the CNS. COMPENSATORY MECHANISMS The possibility of cortical plasticity, the brain's ability to adapt to damage, in MS is much debated. Because damage in one CNS location might disrupt function to others, we would expect to find brain mechanisms committed to stabilizing neuronal circuits (58). When considering the adult brain, we would not expect the brain to rewire itself after an insult. However, the reinforcement of existing functional networks or the redistribution of the relative weight of certain regions in the network may play a role in the recovery process. Eyes to the Stars, Feet on the Ground: Top- Down Compensation The hierarchy of the visual system is well-known, the understanding of its organization in humans greatly advanced by functional MRI (fMRI), a specialized imaging technique measuring the hemodynamic response related to neural activity in the brain. The human visual regions are divided into early processing areas (analyzing basic features of the visual stimuli), and to late processing areas (dealing with more complex features, such as objects and motion) (59). After ON, the primary visual cortex receives less input through the afferent pathways and displays reduced levels of activation. Several studies have suggested that higher order visual areas may be involved in the clinical recovery after ON (60-63) as a consequence of the change in the 87 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis distribution of the cerebral response to visual stimulation. These studies suggested that adaptive cortical plasticity involving higher visual areas serves to overcome the visual insult. we assess her condition. The global effect of local damage on neighboring white matter structures and the compensatory abilities of her brain also must also be taken into account and be a part of therapeutic decisions in her specific case (69). Seeing Eye to Eye: Binocular Compensation The task-related fMRI studies described in the previous section have focused on the reduced amount of information arriving at the primary visual cortex. The changes they reported in activity levels of high-order visual regions point to modes of spatial reorganization as the main mechanism of compensation for damage occurred. We have previously raised the possibility of an alternative compensatory mechanism, involving temporal aspects of reorganization, stemming from findings regarding delayed impulse conduction in the fellow eye of patients with ON (64). We suggested that delayed ffVEP latencies in the fellow eyes are part of a compensatory mechanism within the temporal domain designed to synchronize input arriving at the primary visual cortex from the 2 eyes (64,65). This seems to be accompanied by a functional advantage, shown through the ability to better perceive time-constrained depth stimuli, in which spatially disparate images are presented, when the time gap between ffVEP latencies of the affected and fellow eye is smaller (64). This central adaptation after ON emphasizes the view of the afferent visual pathways as a whole when considering recovery from a discrete injury to one of its parts (66). Eyes Are the Mirror to the Soul (and to the Entire Brain): Functional Network Connectivity Another way to look at the visual system in a holistic manner is through the visual functional networks. Functional connectivity is determined by the "common interest" of different brain regions working together (50). This can be assessed using resting-state-MRI, a technique measuring synchronous spontaneous fluctuations of different network components without the use of an explicit task (67). A recent study utilizing this method has reported extrastriate areas of stronger connectivity and reduction in connectivity in other regions in ON patients. They further demonstrated that the reduction in connectivity is associated with a higher number of ON recurrences (68). We have shown that functional connectivity increases in the entire visual network after a single ON episode in comparison with patients with clinically isolated syndromes in other systems. The connectivity changes were detected in both highand low-order regions. It is important to note that, in our patient cohort, the functional changes were seen even in the presence of an intact anatomical network, suggesting functional compensation even in the absence of anatomical global effects. Considering our patient with ON, disease load parameters cannot become the only measurement through which 88 CONCLUSIONS Recent years have brought about much advancement in therapeutic research in MS. The classic disease-modifying treatments are now accompanied by new compounds, which target remyelination and regeneration. However, the stratification of patients according to their prognosis and predictive outcome in response to the treatment is still in its infancy. The many facets of the disease make it difficult to piece together all the data into one cohesive conclusion for each individual, and the clinico-radiological paradox, so problematic in predicting outcomes in MS, necessitates the examination of the brain as a whole. Nonetheless, given that visual impairment is a key manifestation of MS, examining structure-function relationships within the visual system, may inform our understanding in this regard. We hope that in the near future, once our patient is discharged from the ward, using the available variety of visual and vision-related tools we will already be able to tailor the best treatment scheme for her and that we would be able to give her a clear picture of her future, both of her visual outcome and that of her overall prognosis. ACKNOWLEDGMENTS The authors thank Dr. Noa Raz and Prof. Tamir Ben-Hur for their thoughtful insights into this subject. REFERENCES 1. Heesen C, Böhm J, Reich C, Kasper J, Goebel M, Gold S. 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Anatomical wiring and functional networking changes in the visual system following optic neuritis. JAMA Neurol. [published ahead of print January 2, 2018] doi: 10.1001/jamaneurol. 2017.3880. Backner and Levin: J Neuro-Ophthalmol 2018; 38: 85-90 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.