Visual Evoked Potentials as a Biomarker in Multiple Sclerosis and Associated Optic Neuritis

Multiple sclerosis (MS) is an inflammatory, degenerative disease of the central nervous system (CNS) characterized by progressive neurological decline over time. The need for better "biomarkers" to more precisely capture and track the effects of demyelination, remyelination, and associated neuroaxonal injury is a well-recognized challenge in the field of MS. To this end, visual evoked potentials (VEPs) have a role in assessing the extent of demyelination along the optic nerve, as a functionally eloquent CNS region. Moreover, VEPs testing can be used to predict the extent of recovery after optic neuritis (ON) and capture disabling effects of clinical and subclinical demyelination events in the afferent visual pathway. In this review, the evolving role of VEPs in the diagnosis of patients with ON and MS and the utility of VEPs testing in determining therapeutic benefits of emerging MS treatments is discussed.

Disease of the Year: Multiple Sclerosis Section Editor: Fiona Costello, MD, FRCP(C) From the Section Editor: The next two installments in the JNO "Disease of the Year: Multiple Sclerosis" series focus on lessons that can be learned form the afferent visual pathway, as a putative model of MS. In their article entitled, "Visual evoked potentials as a biomarker in multiple sclerosis and associated optic neuritis" Leocani and colleagues highlight the role of visual evoked potential (VEP) testing as a means of capturing the effects of demyelination, remyelination, and associated neuroaxonal injury in the central nervous system (CNS). Conjointly, Horton and Bennett discuss the acute management of optic neuritis, which is aptly described as an "evolving paradigm." In their state-of-the art overview of the topic, these authors explore the spectrum of inflammatory optic neuropathies, with emphasis on clinical features, neuroimaging findings, and serological markers that help refine diagnosis, and target appropriate treatment strategies. When considered holistically, these reviews prompt us to consider how VEP and other surrogate endpoints can be used to differentiate subtypes of optic neuritis that may ultimately herald a wide variety of CNS inflammatory disorders. Visual Evoked Potentials as a Biomarker in Multiple Sclerosis and Associated Optic Neuritis Letizia Leocani, MD, Simone Guerrieri, MD, Giancarlo Comi, MD Abstract: Multiple sclerosis (MS) is an inflammatory, degenerative disease of the central nervous system (CNS) characterized by progressive neurological decline over time. The need for better "biomarkers" to more precisely capture and track the effects of demyelination, remyelination, and associated neuroaxonal injury is a well-recognized challenge in the field of MS. To this end, visual evoked potentials (VEPs) have a role in assessing the extent of demyelination along the optic nerve, as a functionally eloquent CNS region. Moreover, VEPs testing can be used to predict the extent of recovery after optic neuritis (ON) and capture disabling effects of clinical and subclinical demyelination events in the afferent visual pathway. In this review, the evolving role of VEPs in the diagnosis of patients with ON and MS and the utility of VEPs testing in determining therapeutic benefits of emerging MS treatments is discussed. Journal of Neuro-Ophthalmology 2018;38:350-357 doi: 10.1097/WNO.0000000000000704 © 2018 by North American Neuro-Ophthalmology Society BACKGROUND M ultiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) and the leading cause of neurologic disability in Department of Neurology, Institute of Experimental Neurology- INSPE, San Raffaele University Hospital, Milan, Italy. The author reports no conflicts of interest. Address correspondence to Letizia Leocani, MD, Experimental Neurophysiology Unit, Università Vita-Salute San Raffaele, Via Olgettina 60 - 20132, Milan, Italy; E-mail: [e-mail] 350 young adults. Acute optic neuritis (ON), reported as the onset manifestation in up to one-third of MS cases, may affect up to 70% of patients with MS during the course of their disease (1-3). In addition, involvement of the retrochiasmatic visual pathway may impair visual function. Full-field visual evoked potentials (ff-VEPs) have been performed in clinical practice since the 1970s to assess conduction along the visual pathways with diagnostic, monitoring and prognostic purpose. Visual evoked potential guidelines were updated in 2010 by the International Federation of Clinical Neurophysiology (4) and in 2016 by the International Society for Clinical Electrophysiology of Vision (ISCEV) (5). In 1994, Baseler et al (6) described the technique of multifocal VEPs (mf-VEPs), which tested discrete portions of the visual field (7). Since then, in addition to glaucoma (8), mf-VEPs have been used to assess other optic neuropathies and neurological conditions including MS. This review examines the current and potential future applications of VEPs as a biomarker in MS and associated ON. EVIDENCE ACQUISITION We searched PubMed database up to April 30, 2018, using the terms "visual evoked potentials AND multiple sclerosis," "visual evoked potentials AND optic neuritis." For clinical trials, the https://clinicaltrials.gov/webpage was searched. Leocani et al: J Neuro-Ophthalmol 2018; 38: 350-357 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis VISUAL EVOKED POTENTIALS IN THE DIAGNOSIS OF MULTIPLE SCLEROSIS AND OPTIC NEURITIS VEPs are used to confirm the presence of visual pathology or to detect subclinical asymptomatic involvement of the visual pathway. The presence of increased latency with preserved waveform morphology has been considered a sign of a demyelinating process (9). Early studies showed a prevalence of increased VEP latency in up to 50%-70% of patients with MS without visual complaints (10-12). More recently, the sensitivity of VEP in patients without a history of ON has been reported to be 20%-50% (13,14). However, this sensitivity is, in part, dependent on the timing of the testing. VEPs have been reported as abnormal in 90% of patients tested within 6 months from onset of ON symptoms, but in about 70% when more than 2 years have elapsed (15). Naismith et al (16) reported a sensitivity of 81% for ff-VEPs in 96 eyes experiencing ON at least 6 months previously with similar findings reported by Di Maggio et al (17). Fredriksen and Petrera (18) reported ff-VEPs to be abnormal in 77% of acute ON eyes at onset and in 89% at one or more follow-up sessions, with progressive normalization in 19% over 1 year. The overall sensitivity in MS has been reported up to 85% (9), with differences according to disease duration and course, reaching 90% in progressive MS (19) and ranging from 25% to 50% in clinically isolated syndrome (CIS), regardless of the initial neurologic signs and symptoms (20-23). Normal ff-VEPs cannot exclude the presence of a lesion involving only a portion of optic nerve fibers, or lesions with short longitudinal extension without a significant latency increase (9), or partial retrochiasmal lesions. VEPs were included in the diagnostic criteria of primary progressive MS in the original McDonald criteria (24) and in the first revision (25), but not in subsequent revisions (26,27). The most recent McDonald criteria include VEPs as a means to detect of a demyelinating process in patients presenting with visual symptoms (26,27). Multifocal VEPs were reported as more sensitive compared with standard ff-VEPs both in symptomatic and asymptomatic eyes of patients with MS (28,29) and with promising results in patients with CIS (30). In 26 individuals with unilateral ON, ff-VEPs abnormalities were found in 73% and mf-VEP in 89% and with superior performance in detecting small or peripheral visual field defects (28). In non-ON eyes of 29 patients with CIS, mf-VEP amplitude was abnormal in 48.3% and latency in 20.7% (30). These features have been confirmed in a cohort of 145 patients with MS with 65% abnormal responses in non-ON eyes and up to 90% in ON eyes (31). Similar results had been previously reported by Fraser et al (32) with a different testing equipment (Accumap; ObjectiVision, Sydney, Australia), with mf-VEPs abnormal in 97.3% of ON eyes (previous or acute), whereas NebbioLeocani et al: J Neuro-Ophthalmol 2018; 38: 350-357 so et al (33) found ff-VEPs more sensitive than mf-VEPs (using the Vision Monitor MonPack 120 by Metrovision) in a cohort of 24 patients with acute ON (90.9% vs 77.2%, respectively). These discrepancies may be related to differences in equipment and techniques used as well as patient selection. VEPs have been used to differentiate MS from other inflammatory CNS diseases such as neuromyelitis optica spectrum disorder (NMOSD). Two studies found that P100 latency was more delayed in MS than in NMOSD, with greater proportion of absent responses and less frequent subclinical alterations in the latter group (34,35). These data were obtained in patients of Afro-Brazilian and Japanese origin. By contrast, a study of white patients found more heterogeneous VEP abnormalities in NMOSD (36). PROGNOSTIC ROLE OF VISUAL EVOKED POTENTIALS IN MULTIPLE SCLEROSIS AND OPTIC NEURITIS The prognostic value of VEPs can be assessed in 3 ways: predicting the degree of optic nerve damage and, thus, the long-term visual outcome; predicting the risk of developing MS in patients with CIS; and predicting future disability in patients who already have a diagnosis of MS. After an ON attack, the final visual outcome is not totally predictable by ff-VEPs recorded in the acute phase. Yet, the presence of preserved cortical responses, despite increased latency, is an indicator of partial demyelinating damage suggesting good visual recovery. However, the absence of cortical responses is not necessarily associated with a poor functional outcome, potentially indicating only transient conduction block (37). The persistence of morphological alterations of ff-VEPs beyond 4 months is predictive of a long-term visual impairment. The reappearance of initially absent waveforms, despite their delay in latency, has favorable prognostic implications (38). Although optic nerve lesions tend to remyelinate at a specific rate, smaller lesions seem to recovery more completely with respect to VEP waveform morphology (39). Brain plasticity also seems to play a major role in the recovery of vision after ON (40), possibly offsetting some of the effects of optic nerve damage and mitigating the functional consequences of optic nerve dysfunction. Several studies over the past 30 years have explored the association between ff-VEPs and subsequent development of MS with variable conclusions. From some studies of the 1980s and early 1990s, a significant association between ff-VEPs alteration in patients with various initial neurological manifestations and MS development emerged, with risk increasing from 2.5- to 9-fold (41-43). A prospective multicenter study on 82 patients with suspected MS found only mild positive and negative predictive values (26% and 62%, respectively) in relation to ff-VEP results and development of MS over a mean follow-up of 2.9 years (20). However, 351 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis the inclusion of a not irrelevant proportion of patients with visual symptoms limited ff-VEP validation as biomarker of dissemination in space (20). A retrospective study of 243 patients with CIS diagnosed between 2000 and 2013 evaluated the prognostic role of multimodal evoked potentials with other multiple biomarkers, including magnetic resonance imaging (MRI) and cerebrospinal fluid data. The frequency of altered ff-VEPs did not differ between patients who did or did not develop MS (48.8% vs 49.1%, respectively) (22). Some investigators also analyzed if specific features of VEP responses in the early phase of ON had any prognostic value. Two studies using mf-VEPs found an increased risk of MS conversion in patients with significant increased latency associated with a reduction in amplitude (44,45), whereas another did not identify a relationship between ff-VEP after ON and development of MS (46). Patients with MRI findings placing them at higher risk for MS showed higher mean latency and lower mean amplitude values than low-risk patients (no demyelinating lesions on MRI) (47). This observation was supported by another study including 87 patients with ON, which demonstrated progressive deterioration over the first 12 months after ON episode of both amplitude and latency in fellow eyes to be highly suggestive of MS (48). The cross-sectional and longitudinal correlation between VEPs and global and visual disability has been explored with conflicting evidence (19,37,45-51), because of differences in disease duration and variation in the definition of impairment, especially when assessing visual function. Mild visual pathway involvement may not alter visual acuity but affects other parameters of visual perception. A study on 21 patients with ON found a correlation between the persistence of conduction slowing (VEP latency) and motion perception abnormalities (52). Concerning global disability, it is important to point out the small impact of visual function has on the EDSS score. In a cohort of 28 patients with MS and mf-VEPs available, median EDSS was found to significantly differ between patients with normal or abnormal mf-VEPS amplitude values (53); in another report, a significant correlation was identified between the signal-to-noise ratio of mf-VEP amplitude and EDSS in 28 patients with clinically definite MS (54). Many of these studies also attempted to assess VEPs to predict disability, finding only moderate correlation between ff-VEPs and subsequent EDSS scores (19,49-51). VISUAL EVOKED POTENTIALS TO MONITOR MULTIPLE SCLEROSIS AND OPTIC NEURITIS Can evoked potentials, including VEPs, be used to monitor the natural history of MS and the potential effect of therapeutic interventions? The answer to this question should be cautiously interpreted because of the physiological variability over time of neurophysiological parameters: 352 P100 waveform of ff-VEPs has a very good reproducibility in the general population, but there is a higher test-retest variability in patients with MS because of the complex interplay between demyelinating, remyelinating, and neurodegenerative processes (55,56). Therefore, the use of robust criteria to define the longitudinal changes of the visual response is crucial. Despite these concerns, there is evidence of overall reproducibility of VEPs in both single and multicenter studies (57,58). In this regard, mf-VEPs were reported as more reproducible than standard ff-VEPs (58), particularly considering waveform amplitude (59) with possible implications for their use as a correlate of neuroaxonal damage, as compared to latency, which is considered a measure of the demyelination extent. Although several studies identified either no or equivocal correlations between the evolution over time of ff-VEPs and global or visual disability (19,55,60), other reports documented good correlations between neurophysiologic measures and clinical status (49,61-63). The explanation for these differing results may lie in the redundancy of the CNS, with neurophysiological alterations not necessarily accompanied by a concomitant clinical abnormality. However, these changes may represent a reduction of the functional reserve of a given pathway and have a negative prognostic connotation. In addition, there is a "ceiling effect" (disappearance of the waveform), particularly evident for ff-VEPs and limiting their usefulness in monitoring patients with advanced disease (19). VEPs have been used as primary or secondary outcome measures in clinical trials, testing the effect of putative remyelinating and neuroprotective agents. The visual pathway has been proposed as a reliable model to uncover the mechanisms of CNS damage (64-66). Full field-VEPs were a secondary outcome measure in a double-blind, randomized, placebo-controlled trial testing the effect of IVIg in 68 patients with acute ON: no effect on ff-VEP latency was found. However, only average latency values were used between in the 2 groups (67). Full field-VEPs were used to test the effect of simvastatin given within 4 weeks from ON onset, with significant advantage of active treatment vs placebo on mean latency and amplitude values; however some differences in terms of VEPs response could be already outlined at baseline (68). The RENEW trial, as well as other previous phase 2 studies on erythropoietin and autologous mesenchymal stem cells, emphasized the importance of interindividual variability and variation over time of ffVEP response, when gauging the therapeutic effect of a medication (69-71). The ReBUILD study documented a potential remyelinating role of clemastine fumarate in MS patients with a reduction in ff-VEP latency as positive primary outcome (72). Phenytoin administered within 2 weeks from ON onset was associated with a significant reduction in retinal nerve fiber layer (RNFL) and macular volume loss over time, without significant effect on ff-VEP parameters (73). The authors of this study concluded that more Leocani et al: J Neuro-Ophthalmol 2018; 38: 350-357 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis sensitive measures of visual conduction such as mf-VEPs should be used in future trials (73). This latter technique has been included in a substudy of the RENEW trial (74) demonstrating anti-LINGO-1 treatment to prevent mfVEP amplitude loss in the fellow eyes of patients with unilateral ON. VISUAL EVOKED POTENTIALS COMPARISON WITH OTHER MEASURES In general, good correlations between ff-VEP and mf-VEP parameters in MS and ON have been reported (28,29). Considering other measures, early studies in the 1970s and 1980s pointed out a limited correlation between ffVEPs (in particular latency) and final visual acuity after an ON episode. However, better correlations do exist with other visual function tests such as visual field examination, color vision, and perception latency (75,76). Similarly, an association between mf-VEPs latency and visual acuity has been described in the acute phase of ON (56) but in the absence of any with visual recovery (45). Other studies identified a correlation in patients with MS between mfVEP parameters and low-contrast visual acuity (77) as well as with contrast sensitivity (77,78). The multifocal technique has been suggested as a possible measure of the visual field (79) with mf-VEPs showing a higher sensitivity than and automated perimetry (mainly Humphrey visual field) (53,77,80,81). Several studies combined VEPs testing with retinal structural measures using optical coherence tomography (OCT), to explore the relationship between demyelination and neuroaxonal degeneration. Good correlations between VEPs amplitude and RNFL thickness have been found for both ff-VEPs (82,83) and mf-VEPs (84,85). The latter technique also showed a high topographic correspondence with RNFL sectorial analysis. Several investigators identified a correlation between RNFL and ganglion cell layer thickness and VEP latency, especially in non-ON eyes (83,86- 89), suggesting chronic subclinical demyelination may lead to progressive axonal loss. The relationship between demyelination and subsequent axonal loss seems instead to be less certain after ON (90-92). Comparative studies have reported a higher sensitivity in detecting abnormalities with ff-VEPs over OCT in patients with ON (16), MS (17), and CIS (93). VEPs have been correlated with MRI findings, of both the optic nerve and the brain. At the optic nerve level, good correlations have been found between diffusion tensor imaging (DTI) and amplitude for ff-VEPs (94) and mfVEPs (95,96). Less certain is the relationship between magnetization transfer imaging and VEP latency (97-102), suggesting magnetization transfer imaging may be not entirely specific for myelin. A more robust correlation has been described between VEPs latency and T2-STIR optic nerve lesion length (103,104). In patients with MS, mf-VEPs Leocani et al: J Neuro-Ophthalmol 2018; 38: 350-357 latency was found to correlate with optic radiation lesion load and DTI measures in eyes without previous ON, indicating the presence of retrochiasmal and, in particular, retrogeniculate lesions (105). Finally, mf-VEPs amplitude, analyzed for separate contralateral visual hemifields after acute ON, correlates with optic radiation DTI measures, suggesting the possibility of anterograde trans-synaptic degeneration (106,107). OTHER VISUAL EVOKED POTENTIAL TECHNIQUES It has been speculated that pattern-reversal VEPs to colored checks may be more useful than traditional black and white checks in differentiating the optic neuropathy of ON from that of glaucoma (108). However, the comparison of VEPs obtained in 30 patients with MS with equiluminant chromatic (red-green and blue-yellow) and achromatic stimuli, although confirming the general vulnerability of coloropponent visual pathways in this pathology, showed no statistically significant difference in terms of sensitivity between the 2 techniques (109). Other testing techniques requiring validation include steady-state VEPs to periodic visual stimuli (110) and low-contrast patterned stimuli, with ff-VEPs and mf-VEPs (83,111,112). Finally, VEPs response can be obtained through flash stimulation. Intersubject variability is higher compared with pattern-reversal stimulation, but the flash technique still finds a role in several patient populations including young children, noncompliant individuals, and those suspected of functional neurological disorders or malingering (5). CONCLUSIONS AND FUTURE PERSPECTIVES ff-VEPs represent an important technique in clinical practice, able to rapidly explore the entire visual pathway and to provide robust information. Full field-VEPs can corroborate an attack of ON, and despite limited prognostic implications especially in the acute phase, if repeated over time can document conduction recovery. Evolution of ffVEP results may guide the clinician to correctly interpret visual relapses, discriminating between ON mimickers (e.g., Uhthoff phenomenon) and new inflammatory events. This has important therapeutic implications. Although neurophysiology has been excluded from the latest version of the McDonald criteria for the diagnosis of MS (27), ff-VEPs should be considered a supportive paraclinical test in the routine assessment of patients with suspected MS. mf-VEPs are a promising technique able to topographically assess conduction along the visual pathway, identifying partial defects, which may not alter standard ff-VEPs, and potentially allow for detailed function-structural analysis. mf-VEPs are primarily confined to the field of research because acquisition is time-consuming compared with ff353 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis VEPs and further standardization is required, particularly in the interpretation of testing results. In addition, the use of different stimuli such as low-contrast stimuli (83,111,112) may increase VEPs diagnostic and prognostic power (54,113-115). 18. 19. 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