Evolution of Visual Outcomes in Clinical Trials for Multiple Sclerosis Disease-Modifying Therapies

BACKGROUND The visual pathways are increasingly recognized as an ideal model to study neurodegeneration in multiple sclerosis (MS). Low-contrast letter acuity (LCLA) and optical coherence tomography (OCT) are validated measures of function and structure in MS. In fact, LCLA was the topic of a recent review by the Multiple Sclerosis Outcome Assessments Consortium (MSOAC) to qualify this visual measure as a primary or secondary clinical trial endpoint with the Food and Drug Administration (FDA) and other regulatory agencies. This review focuses on the use of LCLA and OCT measures as outcomes in clinical trials to date of MS disease-modifying therapies. A Pubmed search using the specific key words "optical coherence tomography," "low-contrast letter acuity," "multiple sclerosis," and "clinical trials" was performed. An additional search of the clinicaltrials.gov website with the same key words was used to find registered clinical trials of MS therapies that included these visual outcome measures. As demonstrated by multiple clinical trials, LCLA and OCT measures are sensitive to treatment effects in MS. LCLA has been used in many clinical trials to date, and findings suggest that 7 letters of LCLA at the 2.5% contrast level are meaningful change. Few clinical trials using the benefits of OCT have been performed, although results of observational studies have solidified the ability of OCT to assess change in retinal structure. Continued accrual of clinical trial and observational data is needed to validate the use of OCT in clinical trials, but preliminary work suggests that an intereye difference in retinal nerve fiber layer thickness of 5-6 μm is a clinically meaningful threshold that identifies an optic nerve lesion in MS. Visual impairment represents a significant component of overall disability in MS. LCLA and OCT enhance the detection of visual pathway injury and can be used as measures of axonal and neuronal integrity. Continued investigation is ongoing to further incorporate these vision-based assessments into clinical trials of MS therapies.

Disease of the Year: Multiple Sclerosis Section Editor: Fiona Costello, MD, FRCP(C) From the Section Editor: In March 2018, the Journal of Neuro-Ophthalmology (JNO) launched its inaugural "Disease of the Year" section, featuring multiple sclerosis (MS). Beginning from a "Bench" perspective, Meltzner and colleagues presented an elegant overview of the pathogenic mechanisms believed to underpin central nervous system (CNS) injury in MS. To complement these efforts, Backner and Levin highlighted how the afferent visual pathway, as a putative model of CNS inflammation, can be interrogated with measures of structure and function to capture clinical and sub-clinical evidence disease activity in MS patients. Building on these concepts in this issue of the JNO, Nolan et al summarize how visual outcomes have been employed as outcome measures in MS clinical trials. In addition, Burton and Freedman advance us closer to the "Bedside" arena of clinical care, by surveying the rapidly changing therapeutic landscape, and providing a framework for escalating treatments in MS patients. In the Bench-to-Bedside section of this issue of the JNO, Cree provides a historical account of the how treatment paradigms have evolved over the years, to the modern era in which immunosuppressive agents have taken center stage. Specific emphasis is given to ocrelizumab, which targets CD2O B lymphocytes, as promising new treatment for relapsing remitting and progressive MS patients. Probstel and Hauser broaden the discussion around ocrelizumab by reviewing the role of B-cell depleting agents in the treatment of MS. In their review, they also discuss the development of related biomarkers that may be used to monitor treatment response, as our understanding of MS care continues to advance. Evolution of Visual Outcomes in Clinical Trials for Multiple Sclerosis Disease-Modifying Therapies Rachel C. Nolan, BA, Omar Akhand, BS, John-Ross Rizzo, MD, MSCI, Steven L. Galetta, MD, Laura J. Balcer, MD, MSCE Background: The visual pathways are increasingly recognized as an ideal model to study neurodegeneration in multiple sclerosis (MS). Low-contrast letter acuity (LCLA) and optical coherence tomography (OCT) are validated measures of function and structure in MS. In fact, LCLA was the topic of a recent review by the Multiple Sclerosis Outcome Assessments Consortium (MSOAC) to qualify this visual measure as a primary or secondary clinical trial endpoint with the Food and Drug Administration (FDA) and other regulatory agencies. This review focuses on the use of LCLA and OCT measures as outcomes in clinical trials to date of MS disease-modifying therapies. Methods: A Pubmed search using the specific key words "optical coherence tomography," "low-contrast letter acuity," "multiple sclerosis," and "clinical trials" was performed. An additional search on the clinicaltrials.gov website with the same key words was used to find registered Departments of Neurology (RCN, OA, JRR, SLG, LJB), Population Health (LJB), Ophthalmology (SLG, LJB), and Physical Medicine and Rehabilitation (JRR), New York University School of Medicine, New York, New York. L. J. Balcer has received investigator-initiated research grant funding from Biogen. The remaining authors report no conflicts of interest. Address correspondence to Laura J. Balcer, MD, MSCE, Department of Neurology, NYU School of Medicine, 240 East 38th Street, 20th Floor, New York, NY 10016; E-mail: [e-mail] 202 clinical trials of MS therapies that included these visual outcome measures. Results: As demonstrated by multiple clinical trials, LCLA and OCT measures are sensitive to treatment effects in MS. LCLA has been used in many clinical trials to date, and findings suggest that 7 letters of LCLA at the 2.5% contrast level are meaningful change. Few clinical trials using the benefits of OCT have been performed, although results of observational studies have solidified the ability of OCT to assess change in retinal structure. Continued accrual of clinical trial and observational data is needed to validate the use of OCT in clinical trials, but preliminary work suggests that an intereye difference in retinal nerve fiber layer thickness of 5-6 mm is a clinically meaningful threshold that identifies an optic nerve lesion in MS. Conclusions: Visual impairment represents a significant component of overall disability in MS. LCLA and OCT enhance the detection of visual pathway injury and can be used as measures of axonal and neuronal integrity. Continued investigation is ongoing to further incorporate these vision-based assessments into clinical trials of MS therapies. Journal of Neuro-Ophthalmology 2018;38:202-209 doi: 10.1097/WNO.0000000000000662 © 2018 by North American Neuro-Ophthalmology Society Nolan et al: J Neuro-Ophthalmol 2018; 38: 202-209 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis LOW-CONTRAST LETTER ACUITY AS AN OUTCOME MEASURE IN CLINICAL TRIALS T he afferent visual system has been established as an ideal model to study pathogenesis of multiple sclerosis (MS) and to evaluate neuroprotection and other aspects of novel therapeutic agents. Optic nerve disease is nearly ubiquitous in MS (1,2). Before the use of low-contrast letter acuity (LCLA) as an outcome measure for research and clinical trials in MS, an informative measure of visual dysfunction in patients with MS was lacking. In the 1990s, the National MS Society Clinical Outcomes Assessment Task Force searched for a sensitive visual outcome measure that could be added to the multiple sclerosis functional composite (MSFC). The MSFC was developed and included a timed 25-foot walk (ambulation), 9-hole peg test (arm function), and Paced Auditory Serial Addition Task (PASAT, cognition). Visual outcomes were not initially included because high-contrast visual acuity (HCVA), particularly as included in the Expanded Disability Status Scale (EDSS) score, did not show adequate sensitivity to change over time or demonstrate treatment effects in data sets used to develop the MSFC (3,4). While the Pelli-Robson contrast sensitivity charts used in the Optic Neuritis Treatment Trial (ONTT) were temporarily out of print at the time of consideration of visual outcome measures for the MSFC, the ONTT had established the groundwork for use of low-contrast visual measures in MS clinical trials. The results of ONTT suggested that contrast sensitivity could capture sustained visual dysfunction, or lack of complete recovery, after acute optic neuritis to a degree that was not possible for HCVA. For consideration of inclusion in the MSFC for MS clinical trials, a low-contrast (gray letters on white background) version of the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity charts (standard HCVA charts used in ophthalmology clinical trials) was identified that incorporated Sloan letters. As such, the charts were scored letterby-letter (number of letters identified correctly). These LCLA charts enabled the measurement of acuity at various contrast levels, thus potentially capturing loss of contrast vision at smaller letter size characteristic of neurological disease ("notch" loss of contrast) (4,5). Such was not the case for Pelli-Robson contrast sensitivity charts, which used a single large letter size (20/680 Snellen equivalent at 1 m) at varying contrast levels. The Sloan LCLA charts were first used as an exploratory outcome measure in the International MS Progressive Avonex Clinical Trial (IMPACT) study, a randomized clinical trial of interferon beta-1a vs placebo in patients with secondary progressive MS (SPMS). In parallel, an observational study (forerunner of the MS Collaborative Vision Study) demonstrated that, although both LCLA and PelliRobson contrast sensitivity outperformed HCVA in terms of distinguishing patients with MS from disease-free Nolan et al: J Neuro-Ophthalmol 2018; 38: 202-209 controls, LCLA was better than Pelli-Robson at identifying MS-related visual dysfunction (3,6,7). Patients with MS were found to have significantly lower LCLA scores compared with disease-free controls, especially at the lowest contrast levels (2.5% and 1.25%). Meanwhile, the IMPACT trial vision substudy showed the decline in LCLA scores from baseline measurements during the first year; this decline in visual function was predictive of reductions in EDSS scores for neurologic impairment during year 2 of the IMPACT trial. This finding was robust even when accounting for baseline MSFC composite scores (8). Collectively, the results of IMPACT and observational studies of visual outcomes not only introduced and popularized measures of low-contrast vision in MS research and clinical trials but also established the Sloan LCLA as a now standard method for capturing visual impairment. The performance of LCLA in MS clinical trials was further evaluated in AFFIRM, a Phase 3 randomized trial of natalizumab vs placebo in relapsing-remitting multiple sclerosis (RRMS). Before the design of AFFIRM, 10-letter (2-line) change in score was considered clinically meaningful for HCVA testing based on data regarding test-retest reliability (6). The AFFIRM trial analyses (9-11), a sustained decrease in LCLA defined as 10-letter decrement for 12 weeks was reduced in the natalizumab group by 47% in comparison with placebo at the 2.5% contrast level and by 35% at the 1.25% contrast level (proportions of 10% vs 18% with sustained visual loss) (9,10). Similarly, in the SENTINEL trial, an active-arm comparison with interferon beta-1a as an add-on, the cumulative proportions of patients with similarly defined sustained visual loss for the natalizumab + interferon beta-1a group were 10% vs 12% for the placebo + interferon beta-1a group (11). Observational studies performed in parallel with AFFIRM and SENTINEL showed that a 7-letter reduction in LCLA was associated with clinically meaningful worsening of vision-specific quality of life (4 points or greater on the 25-item National Eye Institute Visual Functioning Questionnaire [NEI-VFQ-25]). Thinning of the retinal nerve fiber layer (RNFL) by OCT was also greatest among patients who had 7-letter reductions in LCLA (7,12). Thus, although a 10-letter reduction in LCLA score was initially used in AFFIRM for analyses of sustained visual loss (11), a 7-letter threshold was later determined to be optimal and used for analyses of visual improvement in AFFIRM (9). It was at this point that MS clinical trials and research studies using LCLA as an endpoint incorporated the 7-letter cutoff as a threshold for clinically meaningful change. The Phase 3 CARE-MS trial of alemtuzumab vs interferon beta-1a in RRMS further reinforced the use of LCLA as a measure monitoring treatment effects on vision. The number of patients demonstrating improvement in LCLA at the 12-month follow-up was significantly increased in the alemtuzumab group; this group also 203 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis showed significant improvement in LCLA scores between the 12- and 18-month follow-up points (13). In a pooled analysis of the OPERA I and II trials, 45% of patients had visual system involvement at baseline (determined by presence of optic atrophy on the EDSS). Ocrelizumab-treated patients had greater improvements in LCLA scores at 2.5% contrast from baseline to week 96 (31.7%) compared with interferon beta-1a-treated subjects (26.6%). This was particularly true among those with visual involvement at baseline (36.6% vs 25.5%). These results suggest a potential benefit of ocrelizumab on visual outcomes when compared with interferon beta-1a, and, importantly, further confirm the capacity of LCLA scores to demonstrate treatment effects in MS clinical trials (14). A trial of 4-aminopyridine (4-AP) vs placebo demonstrated significantly higher rates of responders in the active treatment group when applying the 7-letter threshold for LCLA at 2.5% contrast (15). Improvement of at least 7 letters in LCLA was seen in 7 of 28 eyes for patients receiving 4-AP, compared with clinically significant improvement in 1 of 28 eyes in the placebo group (15). across all MS subtypes (18-25). Patients with "benign" MS and clinically isolated syndromes (first demyelinating events) are similarly affected by RNFL and GCIPL thinning by OCT, suggesting a ubiquity and previous underestimation of visual pathway involvement. Losses of RNFL and GCIPL thickness are associated with reduced scores for LCLA, vision-specific quality of life (NEI-VFQ-25 and 10-item Neuro-Ophthalmic Supplement to the NEI-VFQ-25), global MS disability (EDSS), cognitive function, brain atrophy, and radiological disease activity by MRI (7,8,18,26-40). Longitudinal OCT studies have shown higher rates of RNFL and GCIPL thinning in patients with MS compared with healthy controls; thinner RNFL and GCIPL measures were predictive of worse disability over time in these studies (18,32). OCT has higher resolution and may be a more sensitive measure of neurodegeneration than MRI volumetric measures, requiring smaller sample sizes to detect significant differences. OPTICAL COHERENCE TOMOGRAPHY AS AN OUTCOME MEASURE IN CLINICAL TRIALS SD-OCT measures are sensitive to treatment effects. A recent retrospective analysis of the effect of glatiramer acetate (GA, n = 48), natalizumab (n = 46), and interferon beta-1a administered subcutaneously (IFNsc, n = 35) and intramuscularly (IFNIM, n = 28) on SD-OCT measures showed that both the IFNsc and GA groups had faster rates of GCIPL thinning compared with natalizumab (IFNsc 0.37 mm/yr faster, P , 0.001; GA 0.14 mm/yr faster, P = 0.035) (41). These findings suggest that immunomodulatory therapies such as natalizumab may have a greater effect on preserving retinal thickness; these results also mirror the comparative effects of this group of therapies on brain atrophy in large-scale studies. A prospective open-label study of alemtuzumab showed a 1.5-mm (95% CI 0.2-2.9; P = 0.032) increase in RNFL thickness from baseline to the 2-year follow-up in 26 patients with RRMS. RNFL thinning was also associated with increases (worsening) in the EDSS score (r = 20.42, P = 0.047) and was also reported (42). Further evaluation of the mechanisms underlying the effects of therapies on RNFL and GCIPL thickness in MS is needed, with continued comparison with MRI measures of global structure, quality of life, and visual function. Fingolimod therapy has been associated with macular edema. As such OCT has been used to evaluate the effect of fingolimod on the macula in the TRANSFORMS and FREEDOMS II treatment trials (efficacy of fingolimod in patients with highly active RRMS, and ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis). OCT scanning is now recommended as a safety measure for baseline evaluation and at 3 months after treatment initiation for patients on fingolimod therapy. MRI estimates of MS demyelinating lesion burden and brain atrophy are commonly used in clinical trials. Current disease-modifying therapies reduce the risk of inflammation and neurodegeneration by modulating or suppressing the immune system. Although MRI remains the standard for measuring structure of central nervous system components in MS, both logistical aspects (time and expense) and physiologic factors (age, hydration status, and diseasemodifying therapy) have the need to find additional, nonMRI techniques to assess neurodegeneration in MS in vivo. An article comparing outcomes from the RIVITaLISe and IPPoMS trials in progressive MS found MRI to have poor signal to noise ratios, with limited correlation with clinical measures (16). OCT is a noninvasive and reliable technique that uses near-infrared light in a manner similar to ultrasound to image and to measure thickness for retinal tissues (17). Spectral domain OCT (SD-OCT) has improved on the initial time domain OCT during the last decade, allowing 2-3 mm of resolution for thickness measurement. With the advent of SD-OCT, the RNFL containing unmyelinated axons can be measured along with the layer containing retinal ganglion cell neurons (usually combined with the ganglion cell-inner plexiform layer [GCIPL]). RNFL and GCIPL thinning occur after acute optic neuritis and also throughout the course of MS even in the absence of acute optic neuritis episodes (18). Observational studies and clinical trials in MS have shown reduced RNFL and GCIPL thickness to be associated with MS both in cross-sectional and longitudinal studies and 204 Clinical Trials Using Optical Coherence Tomography in Multiple Sclerosis Nolan et al: J Neuro-Ophthalmol 2018; 38: 202-209 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis The Mesenchymal Stem Cells in Multiple Sclerosis (MSCiMS) trial tested the safety and feasibility of treatment with a candidate cell-based therapy in 10 patients with SPMS involving the visual pathways. The trial used OCT and LCLA measures as secondary outcomes. Baseline OCT measurements confirmed that eyes with a previous history of optic neuritis or symptoms of Uhthoff's phenomenon had reduced RNFL thickness by 15.3% compared with unaffected MS eyes (P = 0.0399). There was also a 28.7% reduction in RNFL thickness among MS eyes compared with healthy control eyes (P = 0.0093) at baseline (43). After mesenchymal stem cells were administered in 10 patients, no significant effects on RNFL or macular volumes were identified, although an improvement in LCLA was found (P = 0.011). The authors of the study suggest that the lack of change in OCT measures supports the idea that structural change for unmyelinated axons, as are contained within the RNFL, was not a significant effect of this treatment (44). Another study of mesenchymal stem cells in MS was conducted using OCT as a secondary outcome measure. This randomized, double-blind, crossover placebo-controlled trial of 9 patients also did not show differences in OCT measurements between treatment groups over the 12-month follow-up period (45). Further clinical testing is needed to assess the role of mesenchymal stem cells for treatment in MS. In a prospective, single-site, 2-year, Phase II, doubleblind, randomized, placebo-controlled trial of lipoic acid in MS (n = 51), OCT was performed at baseline and at Months 12 and 24. No significant differences in annualized rates of change between the placebo and the treatment group were found (RNFL thinning 0.279 vs 0.286 mm, P = 0.99). A post hoc analysis of 47 participants showed annualized thinning rates of 0.31 mm/yr for RNFL and 0.29 mm/yr for GCIPL; these rates did not differ between eyes with a history of optic neuritis vs. those without an optic neuritis history. Eyes with baseline RNFL thickness greater than 75 mm had more annualized RNFL thinning (0.85 mm/yr). Although rates of RNFL and GCIPL thinning were comparable with those found in other longitudinal studies in progressive MS (46,47), rates of decline in RNFL and GCIPL did not mirror MRI measures of brain atrophy in this cohort (48). This could be evidence of a plateau or a floor effect of retinal atrophy in patients with progressive MS or could point to a differential effect of lipoic acid in the brain compared with the retina. Forty-one patients with baseline and 24-month followup OCT and LCLA measures were analyzed as a subset in the STRIVE study, a Phase 4, multicenter, observational, open-label study of natalizumab in anti-JC virus antibodynegative early patients with RRMS. Natalizumab treatment was associated with only mild loss of LCLA (sustained visual loss in 12% of subjects at 2.5% contrast level and 22% of subjects at 1.25% contrast level) and with relative TABLE 1. MS clinical trials and their inclusion of LCLA and OCT measures NCT Number Name of Trial NCT00027300 NCT00030966 AFFIRM SENTINEL NCT00211887 COMBIRX NCT00340834 NCT00355134 NCT00395200 NCT01228266 NCT00530348 NCT00548405 NCT01188811 NCT01247324 NCT01412333 NCT01485003 NCT01815632 TRANSFORMS FREEDOMS II MSCiMS CMM-EM CARE-MS 1 CARE-MS2 Lipoic acid for secondary progressive multiple sclerosis OPERA I OPERA II STRIVE ACTiMuS NCT01982942 NCT02419378 N/A* N/A* SPRINT-MS ALAIN01 IMPACT 4-AP Agent N Natalizumab Natalizumab + interferon beta-1a Interferon and glatiramer acetate Fingolimod Fingolimod Mesenchymal stem cells Mesenchymal stem cells Alemtuzumab Alemtuzumab Lipoic acid 939 1,196 RRMS RRMS X X 1,008 RRMS X 92 1,083 10 9 563 798 54 RRMS RRMS SPMS RRMS RRMS RRMS SPMS X X X 821 821 41 80 RRMS RRMS RRMS Progressive X X X 331 15 434 22 Progressive RRMS SPMS RRMS/progressive Ocrelizumab Ocrelizumab Natalizumab Bone marrow-derived cellular therapy Ibudilast Alemtuzumab Interferon beta-1a 4-aminopyridine MS Subtype LCLA OCT X X X X X X X X X X X X X X X X NCT number is the clinicaltrials.gov identifier. *Study does not have a clinicaltrials.gov number identified in publications. LCLA, low-contrast letter acuity; MS, multiple sclerosis; N/A, not applicable; OCT, optical coherence tomography; RRMS, relapsingremitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis. Nolan et al: J Neuro-Ophthalmol 2018; 38: 202-209 205 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis preservation RNFL thickness (thinning by 1.365 mm, 95% CI 0.404-2.326). In a convenience sample of healthy nonMS subjects for comparison (n = 35), the magnitude of RNFL thinning was 0.2 mm during the same period (49). The first randomized, placebo-controlled trial of nonmyeloablative autologous bone marrow-derived stem cell therapy in MS (ACTiMuS) is being conducted to assess the possibility of neurorepair in progressive patients with MS. This study will use OCT as a secondary outcome, measuring RNFL and macular volume to assess for improvement in the visual pathway (50). Another ongoing trial, a randomized, placebo-controlled, Phase II trial of ibudilast in progressive patients with MS (SPRINT-MS), is using OCT analysis of RNFL, GCIPL, and macular volume thickness as secondary outcome measures. OCT images from eligible subjects (n = 331 enrolled) will be performed every 24 weeks over a 100week trial period to assess the capacity of ibudilast to act as a neuroprotective agent and to evaluate the utility of OCT as an imaging marker in patients with progressive MS (51). In an ongoing study to better understand the mechanisms of action of alemtuzumab in MS (ALAIN01), OCT measures are being used as secondary outcomes. This singlecenter, single-arm, explorative Phase 4 study of 15 patients with RRMS over 3 years will collect various immunological assays to evaluate the potential neuroprotective properties of alemtuzumab, including those pertaining to the retina (52). LOGISTICS AND LIMITATIONS Table 1 lists clinical trials for MS that have used LCLA and OCT as outcomes. Several additional completed and ongoing studies targeting acute optic neuritis before MS diagnosis using LCLA and OCT include those for clemastine, phenytoin, and Lingo-1 (RENEW) (53-55). Unfamiliarity of OCT to many neurologists has limited its utility in MS clinical trials and clinical use. Proper training in scanning techniques and quality control measures for evaluating the scans are essential for use of OCT in MS both clinically and in research studies (56,57). Operator and reader interpretation variability can affect the results of a study. Studies of interrater reliability using semiautomatic retinal layer segmentation have shown good agreement between raters in the inner retinal layers, including RNFL and GCIPL (58,59). Multiple technologies for OCT exist, including the initial time domain and the current spectral domain platforms, which can lead to difficulty interpreting results across various OCT spectrums. Within SD-OCT, various platforms exist; most commonly Spectralis or Cirrus OCT are used. A recent study comparing time domain Stratus OCT with spectral domain Spectralis and Cirrus OCT showed that while on an individual level, the devices demonstrate differences in measurements, relatively small 206 disparities in mean RNFL and GCIPL thickness between Cirrus and Spectralis indicate that data from these devices could be pooled together in clinical trials, as long as participants are scanned on the same machine consistently during the trial (60). CONCLUSIONS Visual impairment represents a significant component of overall disability in MS. Such visual loss was not captured by neurologic disability scales or composite performance measures such as the MSFC before the introduction of LCLA. LCLA is a standardized test of low-contrast acuity that captures visual dysfunction not previously captured by HCVA. LCLA decrements among patients with MS are most appreciable at the 1.25% and 2.5% contrast levels, and 7-letter reductions in scores have been shown to be clinically meaningful. Importantly, LCLA scores have the capacity to identify both sustained worsening and improvement of visual function, and capture treatment effects of therapy. Treatment response markers improving patient selection and therapy guidance remain an unmet need for health care providers. There have been ample findings in support of the utility of OCT measures in assessing neurodegeneration and neuroprotection, including recent meta-analyses (61). The use of OCT in MS clinical trials is increasing. Several studies of both relapsing and progressive MS that use OCT are active and are recruiting patients (listed on www. clinicaltrials.gov). OCT reading centers in these studies help standardize the evaluation of scan quality, grading, and data management. Importantly, ongoing international collaborative studies of OCT measures will soon establish OCTbased criteria for identifying both occult and clinically evident optic nerve lesions based on intereye differences in RNFL and GCIPL thickness (62,63). Preliminary studies suggest that 5-6 mm of intereye RNFL difference and 3-4 mm of intereye GCIPL differenceis a meaningful change (62,63). Such studies will be critical for establishing the optic nerve as a lesion site for an additional imaging-based MS diagnostic criterion (64). REFERENCES 1. Ikuta F, Zimmerman HM. Distribution of plaques in seventy autopsy cases of multiple sclerosis in the United States. Neurology. 1976;26:26-28. 2. Toussaint D, Perier O, Verstappen A, Bervoets S. Clinicopathological study of the visual pathways, eyes, and cerebral hemispheres in 32 cases of disseminated sclerosis. J Clin Neuroophthalmol. 1983;3:211-220. 3. Balcer LJ, Baier ML, Cohen JA, Kooijmans MF, Sandrock AW, Nano-Schiavi ML, Pfohl DC, Mills M, Bowen J, Ford C, Heidenreich FR, Jacobs DA, Markowitz CE, Stuart WH, Ying GS, Galetta SL, Maguire MG, Cutter GR. Contrast letter acuity as a visual component for the multiple sclerosis functional composite. Neurology. 2003;61:1367-1373. 4. Balcer LJ, Raynowska J, Nolan R, Galetta SL, Kapoor R, Benedict R, Phillips G, LaRocca N, Hudson L, Rudick R; Multiple Sclerosis Outcome Assessments Consortium. Validity Nolan et al: J Neuro-Ophthalmol 2018; 38: 202-209 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. of low-contrast letter acuity as a visual performance outcome measure for multiple sclerosis. Mult Scler. 2017;23:734-747. Richman J, Spaeth GL, Wirostko B. Contrast sensitivity basics and a critique of currently available tests. J Cataract Refract Surg. 2013;39:1100-1106. Balcer LJ, Baier ML, Pelak VS, Fox RJ, Shuwairi S, Galetta SL, Cutter GR, Maguire MG. New low-contrast vision charts: reliability and test characteristics in patients with multiple sclerosis. Mult Scler J. 2000;6:163-171. Fisher JB, Jacobs DA, Markowitz CE, Galetta SL, Volpe NJ, Nano-Schiavi ML, Baier ML, Frohman EM, Winslow H, Frohman TC. Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthalmology. 2006;113:324-332. Baier ML, Cutter GR, Rudick RA, Miller D, Cohen JA, WeinstockGuttman B, Mass M, Balcer LJ. Low-contrast letter acuity testing captures visual dysfunction in patients with multiple sclerosis. Neurology. 2005;64:992-995. Balcer LJ, Galetta SL, Polman CH, Eggenberger E, Calabresi PA, Zhang A, Scanlon JV, Hyde R. Low-contrast acuity measures visual improvement in phase 3 trial of natalizumab in relapsing MS. J Neurol Sci. 2012;318:119-124. Chahin S, Balcer LJ, Miller DM, Zhang A, Galetta SL. Vision in a phase 3 trial of natalizumab for multiple sclerosis: relation to disability and quality of life. J Neuroophthalmol. 2015;35:6- 11. Balcer LJ, Galetta SL, Calabresi PA, Confavreux C, Giovannoni G, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Miller DH, O'Connor PW, Phillips JT, Polman CH, Radue EW, Rudick RA, Stuart WH, Wajgt A, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA. Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Neurology. 2007;68:1299-1304. Schinzel J, Zimmermann H, Paul F, Ruprecht K, Hahn K, Brandt AU, Dorr J. Relations of low contrast visual acuity, quality of life and multiple sclerosis functional composite: a cross-sectional analysis. BMC Neurol. 2014;14:31. Balcer LJ, Arnold DL, Cohen JA, Coles AJ, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Brinar V, Giovannoni G, Stojanovic M, Cnar A, Margolin DH, Panzara M, Compston DAS. Alemtuzumab improves visual outcomes in treatment-naïve patients with relapsing-/INS; remitting multiple sclerosis (RRMS): analysis from the phase 3 CARE-MS I study. J Neurol Sci. 2013;333:e375. Balcer LJ, Hauser SL, Kappos L, Leocani L, Saidha S, Julian L, Han J, Comi G. Effect of ocrelizumab vs that of interferon on visual outcomes in patients with relapsing multiple sclerosis in the OPERA studies. Mult Scler J. 2017;23:56. Horton L, Conger A, Conger D, Remington G, Frohman T, Frohman E, Greenberg B. Effect of 4-aminopyridine on vision in multiple sclerosis patients with optic neuropathy. Neurology. 2013;80:1862-1866. Kosa P, Ghazali D, Tanigawa M, Barbour C, Cortese I, Kelley W, Snyder B, Ohayon J, Fenton K, Lehky T, Wu T, Greenwood M, Nair G, Bielekova B. Development of a sensitive outcome for economical drug screening for progressive multiple sclerosis treatment. Front Neurol. 2016;7:131. Syc SB, Warner CV, Hiremath GS, Farrell SK, Ratchford JN, Conger A, Frohman T, Cutter G, Balcer LJ, Frohman EM. Reproducibility of high-resolution optical coherence tomography in multiple sclerosis. Mult Scler. 2010;16:829- 839. Talman LS, Bisker ER, Sackel DJ, Long DA, Galetta KM, Ratchford JN, Lile DJ, Farrell SK, Loguidice MJ, Remington G. Longitudinal study of vision and retinal nerve fiber layer thickness in multiple sclerosis. Ann Neurol. 2010;67:749- 760. Costello F, Hodge W, Pan YI, Eggenberger E, Freedman MS. Using retinal architecture to help characterize multiple sclerosis patients. Can J Ophthalmol. 2010;45:520-526. Costello F, Hodge W, Pan YI, Freedman M, DeMeulemeester C. Differences in retinal nerve fiber layer atrophy between multiple sclerosis subtypes. J Neurol Sci. 2009;281:74-79. Nolan et al: J Neuro-Ophthalmol 2018; 38: 202-209 21. Gelfand JM, Goodin DS, Boscardin WJ, Nolan R, Cuneo A, Green AJ. Retinal axonal loss begins early in the course of multiple sclerosis and is similar between progressive phenotypes. PLoS One. 2012;7:e36847. 22. Lange AP, Zhu F, Sayao AL, Sadjadi R, Alkabie S, Traboulsee AL, Costello F, Tremlett H. Retinal nerve fiber layer thickness in benign multiple sclerosis. Mult Scler J. 2013;19:1275-1281. 23. Oberwahrenbrock T, Ringelstein M, Jentschke S, Deuschle K, Klumbies K, Bellmann-Strobl J, Harmel J, Ruprecht K, Schippling S, Hartung HP, Aktas O, Brandt AU, Paul F. Retinal ganglion cell and inner plexiform layer thinning in clinically isolated syndrome. Mult Scler. 2013;19:1887-1895. 24. Oberwahrenbrock T, Schippling S, Ringelstein M, Kaufhold F, Zimmermann H, Keser N, Young KL, Harmel J, Hartung HP, Martin R. Retinal damage in multiple sclerosis disease subtypes measured by high-resolution optical coherence tomography. Mult Scler Int. 2012;2012:530305. 25. Pulicken M, Gordon-Lipkin E, Balcer LJ, Frohman E, Cutter G, Calabresi PA. Optical coherence tomography and disease subtype in multiple sclerosis. Neurology. 2007;69:2085- 2092. 26. Behbehani R, Al-Hassan AA, Al-Khars A, Sriraman D, Alroughani R. Retinal nerve fiber layer thickness and neurologic disability in relapsing-remitting multiple sclerosis. J Neurol Sci. 2015;359:305-308. 27. Costello F, Coupland S, Hodge W, Lorello GR, Koroluk J, Pan YI, Freedman MS, Zackon DH, Kardon RH. Quantifying axonal loss after optic neuritis with optical coherence tomography. Ann Neurol. 2006;59:963-969. 28. El Ayoubi NK, Ghassan S, Said M, Allam J, Darwish H, Khoury SJ. Retinal measures correlate with cognitive and physical disability in early multiple sclerosis. J Neurol. 2016;263:2287-2295. 29. Garcia-Martin E, Rodriguez-Mena D, Herrero R, Almarcegui C, Dolz I, Martin J, Ara JR, Larrosa JM, Polo V, Fernandez J, Pablo LE. Neuro-ophthalmologic evaluation, quality of life, and functional disability in patients with MS. Neurology. 2013;81:76-83. 30. Gordon-Lipkin E, Chodkowski B, Reich DS, Smith SA, Pulicken M, Balcer LJ, Frohman EM, Cutter G, Calabresi PA. Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis. Neurology. 2007;69:1603-1609. 31. Ma SL, Shea JA, Galetta SL, Jacobs DA, Markowitz CE, Maguire MG, Balcer LJ. Self-reported visual dysfunction in multiple sclerosis: new data from the VFQ-25 and development of an MS-specific vision questionnaire. Am J Ophthalmol. 2002;133:686-692. 32. Martinez-Lapiscina EH, Arnow S, Wilson JA, Saidha S, Preiningerova JL, Oberwahrenbrock T, Brandt AU, Pablo LE, Guerrieri S, Gonzalez I, Outteryck O, Mueller AK, Albrecht P, Chan W, Lukas S, Balk LJ, Fraser C, Frederiksen JL, Resto J, Frohman T, Cordano C, Zubizarreta I, Andorra M, SanchezDalmau B, Saiz A, Bermel R, Klistorner A, Petzold A, Schippling S, Costello F, Aktas O, Vermersch P, Oreja-Guevara C, Comi G, Leocani L, Garcia-Martin E, Paul F, Havrdova E, Frohman E, Balcer LJ, Green AJ, Calabresi PA, Villoslada P. Retinal thickness measured with optical coherence tomography and risk of disability worsening in multiple sclerosis: a cohort study. Lancet Neurol. 2016;15:574-584. 33. Mowry EM, Loguidice MJ, Daniels AB, Jacobs DA, Markowitz CE, Galetta SL, Nano-Schiavi ML, Cutter GR, Maguire MG, Balcer LJ. Vision related quality of life in multiple sclerosis: correlation with new measures of low and high contrast letter acuity. J Neurol Neurosurg Psychiatry. 2009;80:767-772. 34. Raphael BA, Galetta KM, Jacobs DA, Markowitz CE, Liu GT, Nano-Schiavi ML, Galetta SL, Maguire MG, Mangione CM, Globe DR. Validation and test characteristics of a 10-item neuro-ophthalmic supplement to the NEI-VFQ-25. Am J Ophthalmol. 2006;142:1026-1035. e1022. 35. Sabadia SB, Nolan RC, Galetta KM, Narayana KM, Wilson JA, Calabresi PA, Frohman EM, Galetta SL, Balcer LJ. 20/40 or better visual acuity after optic neuritis: not as good as we once thought? J Neuroophthalmol. 2016;36:369-376. 207 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis 36. Saidha S, Syc SB, Durbin MK, Eckstein C, Oakley JD, Meyer SA, Conger A, Frohman TC, Newsome S, Ratchford JN. Visual dysfunction in multiple sclerosis correlates better with optical coherence tomography derived estimates of macular ganglion cell layer thickness than peripapillary retinal nerve fiber layer thickness. Mult Scler J. 2011;17:1449-1463. 37. Sakai RE, Feller DJ, Galetta KM, Galetta SL, Balcer LJ. Vision in multiple sclerosis: the story, structure-function correlations, and models for neuroprotection. J Neuroophthalmol. 2011;31:362-373. 38. Sepulcre J, Murie-Fernandez M, Salinas-Alaman A, GarciaLayana A, Bejarano B, Villoslada P. Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS. Neurology. 2007;68:1488-1494. 39. Toledo J, Sepulcre J, Salinas-Alaman A, Garcia-Layana A, Murie-Fernandez M, Bejarano B, Villoslada P. Retinal nerve fiber layer atrophy is associated with physical and cognitive disability in multiple sclerosis. Mult Scler. 2008;14:906-912. 40. Walter SD, Ishikawa H, Galetta KM, Sakai RE, Feller DJ, Henderson SB, Wilson JA, Maguire MG, Galetta SL, Frohman E. Ganglion cell loss in relation to visual disability in multiple sclerosis. Ophthalmology. 2012;119:1250-1257. 41. Button J, Al-Louzi O, Lang A, Bhargava P, Newsome SD, Frohman T, Balcer LJ, Frohman EM, Prince J, Calabresi PA, Saidha S. Disease-modifying therapies modulate retinal atrophy in multiple sclerosis: a retrospective study. Neurology. 2017;88:525-532. 42. Brandt AU, Martinez-Lapiscina EH, Nolan R, Saidha S. Monitoring the course of MS with optical coherence tomography. Curr Treat Options Neurol. 2017;19:15. 43. Connick P, Kolappan M, Patani R, Scott MA, Crawley C, He XL, Richardson K, Barber K, Webber DJ, Wheeler-Kingshott CA, Tozer DJ, Samson RS, Thomas DL, Du MQ, Luan SL, Michell AW, Altmann DR, Thompson AJ, Miller DH, Compston A, Chandran S. The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments. Trials. 2011;12:62. 44. Connick P, Kolappan M, Crawley C, Webber DJ, Patani R, Michell AW, Du MQ, Luan SL, Altmann DR, Thompson AJ, Compston A, Scott MA, Miller DH, Chandran S. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proofof-concept study. Lancet Neurol. 2012;11:150-156. 45. Llufriu S, Sepúlveda M, Blanco Y, Marín P, Moreno B, Berenguer J, Gabilondo I, Martínez-Heras E, Sola-Valls N, Arnaiz JA, Andreu EJ, Fernández B, Bullich S, Sánchez-Dalmau B, Graus F, Villoslada P, Saiz A. Randomized placebocontrolled phase II trial of autologous mesenchymal stem cells in multiple sclerosis. PLoS One. 2014;9:e113936. 46. Balk LJ, Cruz-Herranz A, Albrecht P, Arnow S, Gelfand JM, Tewarie P, Killestein J, Uitdehaag BM, Petzold A, Green AJ. Timing of retinal neuronal and axonal loss in MS: a longitudinal OCT study. J Neurol. 2016;263:1323-1331. 47. Saidha S, Al-Louzi O, Ratchford JN, Bhargava P, Oh J, Newsome SD, Prince JL, Pham D, Roy S, van Zijl P, Balcer LJ, Frohman EM, Reich DS, Crainiceanu C, Calabresi PA. Optical coherence tomography reflects brain atrophy in multiple sclerosis: a fouryear study. Ann Neurol. 2015;78:801-813. 48. Winges KM, Murchison CF, Bourdette DN, Spain RI. Longitudinal optical coherence tomography study of optic atrophy in secondary progressive multiple sclerosis: results from a clinical trial cohort. Mult Scler. [published online ahead of print November 1, 2017] doi: 10.1177/1352458517739136. 49. Balcer LJ, Galetta S, Perumal J, Balabanov R, Fox RJ, Dong Q, Makh S, Hotermans C, Walsh JS, Campagnolo D, Lee L. Natalizumab in anti-JCV antibody-negative patients with early relapsing-remitting multiple sclerosis: prespecified analysis of optical coherence tomography and visual acuity data. Int J MS Care. 2017;19:27. 50. Rice CM, Marks DI, Ben-Shlomo Y, Evangelou N, Morgan PS, Metcalfe C, Walsh P, Kane NM, Guttridge MG, Miflin G, Blackmore S, Sarkar P, Redondo J, Owen D, Cottrell DA, 208 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. Wilkins A, Scolding NJ. Assessment of bone marrow-derived cellular therapy in progressive multiple sclerosis (ACTiMuS): study protocol for a randomised controlled trial. Trials. 2015;16:463. Fox RJ, Coffey CS, Cudkowicz ME, Gleason T, Goodman A, Klawiter EC, Matsuda K, McGovern M, Conwit R, Naismith R, Ashokkumar A, Bermel R, Ecklund D, Koepp M, Long J, Natarajan S, Ramachandran S, Skaramagas T, Thornell B, Yankey J, Agius M, Bashir K, Cohen B, Coyle P, Delgado S, Dewitt D, Flores A, Giesser B, Goldman M, Jubelt B, Lava N, Lynch S, Miravalle A, Moses H, Ontaneda D, Perumal J, Racke M, Repovic P, Riley C, Severson C, Shinnar S, Suski V. Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis. Contemp Clin Trials. 2016;50:166-177. Ruck T, Afzali AM, Lukat KF, Eveslage M, Gross CC, Pfeuffer S, Bittner S, Klotz L, Melzer N, Wiendl H, Meuth SG. ALAIN01- Alemtuzumab in autoimmune inflammatory neurodegeneration: mechanisms of action and neuroprotective potential. BMC Neurol. 2016;16:34. Green AJ, Gelfand JM, Cree BA, Bevan C, Boscardin WJ, Mei F, Inman J, Arnow S, Devereux M, Abounasr A, Nobuta H, Zhu A, Friessen M, Gerona R, von Budingen HC, Henry RG, Hauser SL, Chan JR. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017;390:2481-2489. Raftopoulos R, Hickman SJ, Toosy A, Sharrack B, Makil S, Paling D, Altmann DR, Yiannakas MC, Malladi P, Sheridan R, Sarrigiannis PG, Hoggard N, Koltzenburg M, Gandini WheelerKingshott CA, Schmierer K, Giovannoni G, Miller DH, Kapoor R. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controllled, phase 2 trial. Lancet Neurol. 2016;15:259-269. Cadavid D, Balcer L, Galetta S, Aktas O, Ziemssen T, Vanopdenbosch L, Frederiksen J, Skeen M, Jaffe GJ, Butzkueven H, Ziemssen F, Massacesi L, Chai Y, Xu L, Freeman S, Investigators RS. Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2017;16:189-199. Tewarie P, Balk L, Costello F, Green A, Martin R, Schippling S, Petzold A. The OSCAR-IB consensus criteria for retinal OCT quality assessment. PLoS One. 2012;7:e34823. Cruz-Herranz A, Balk LJ, Oberwahrenbrock T, Saidha S, Martinez-Lapiscina EH, Lagreze WA, Schuman JS, Villoslada P, Calabresi P, Balcer L, Petzold A, Green AJ, Paul F, Brandt AU, Albrecht P; IMSVISUAL consortium. The APOSTEL recommendations for reporting quantitative optical coherence tomography studies. Neurology. 2016;86:2303-2309. Bhargava P, Lang A, Al-Louzi O, Carass A, Prince J, Calabresi PA, Saidha S. Applying an open-source segmentation algorithm to different OCT devices in multiple sclerosis patients and healthy controls: implications for clinical trials. Mult Scler Int. 2015;2015:136295. Oberwahrenbrock T, Traber GL, Lukas S, Gabilondo I, Nolan R, Songster C, Balk L, Petzold A, Paul F, Villoslada P, Brandt AU, Green A, Schippling S. Multicenter reliability of semiautomatic retinal layer segmentation using OCT. Neurol Neuroimmunol Neuroinflamm. 2018;5:e449. Warner CV, Syc SB, Stankiewicz AM, Hiremath G, Farrell SK, Crainiceanu CM, Conger A, Frohman TC, Bisker ER, Balcer LJ, Frohman EM, Calabresi PA, Saidha S. The impact of utilizing different optical coherence tomography devices for clinical purposes and in multiple sclerosis trials. PLoS One. 2011;6: e22947. Petzold A, Balcer LJ, Calabresi PA, Costello F, Frohman TC, Frohman EM, Martinez-Lapiscina EH, Green AJ, Kardon R, Outteryck O, Schippling S, Vermersch P, Villoslada P, Balk LJ; ERN-EYE IMSVISUAL. Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis. Lancet Neurol. 2017;16:797-812. Nolan RC, Galetta SL, Frohman TC, Frohman EM, Calabresi PA, Castrillo-Viguera C, Cadavid D, Balcer LJ. Optimal intereye Nolan et al: J Neuro-Ophthalmol 2018; 38: 202-209 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis difference thresholds in retinal nerve fiber layer thickness for predicting a unilateral optic nerve lesion in multiple sclerosis. J Neuroophthalmol. [published ahead of print January 29, 2018] doi: 10.1097/WNO.0000000000000629. 63. Nolan RC, Akhand O, Calabresi PA, Paul F, Martinez de Lapiscina EH, Petzold A, Brandt A, Saidha S, Villoslada P, AlHassan AA, Behbehani R, Frohman EM, Frohman TC, Havla J, Hemmer B, Jiang H, Knier B, Korn T, Leocani L, Papadopoulou A, Pisa M, Zimmerman H, Galetta SL, Balcer LJ. Optimal intereye difference thresholds in retinal nerve fiber layer and ganglion cell layer thickness for predicting a unilateral optic nerve lesion in multiple sclerosis: an international Nolan et al: J Neuro-Ophthalmol 2018; 38: 202-209 collaborative study. Presented at NANOS 2018 Annual Meeting, March 3, 2018; Waikoala Village, Hawaii. 64. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, Correale J, Fazekas F, Fillippi M, Freedman MS, Fujihara K, Galetta SL, Hartung HP, Kappos L, Lublin FD, Marrie RA, Miller AE, Miller DH, Montalban X, Mowry EM, Sorensen PS, Tintore M, Traboulsee AL, Trojano M, Uitdehaag BMJ, Vukusic S, Waubant E, Weinshenker BG, Reingold SC, Cohen JA. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17:162-173. 209 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.