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Show Clinical Trials to Clinical Use: Using Vision as a Model for Multiple Sclerosis and Beyond Laura J. Balcer, MD, MSCE Abstract: Optical coherence tomography (OCT) has made possible the structure-function correlations that uniquely characterize the afferent visual pathway as a model for understanding multiple sclerosis (MS) and for developing new treatments. During the past decade, OCT measures of retinal nerve fiber layer (RNFL) and ganglion cell/inner plexiform layer (GCL + IPL) thickness have evolved from being a means to validate visual function tests, such as low-contrast letter acuity, to provide a window on the axonal and neuronal loss that are now widely recognized as con-tributors to permanent visual dysfunction in MS. Although acute optic neuritis (ON) leads to thinning of the RNFL by 20%-40% within 3 months after a single episode, thinning of the RNFL and GCL + IPL occur over time in MS eyes even in the absence of an acute ON history. As such, OCT and its functional and patient-reported correlates of low-contrast acuity and vision-specific quality of life (QOL) have now been incorporated into MS clinical trials. Results of an ongoing, phase 2 trial of a remyelinating agent that uses acute ON as a model for assessing therapeutic efficacy will define even further the important role for OCT in document-ing structural changes as we move forward from clinical trials to clinical use. Journal of Neuro-Ophthalmology 2014;34(Suppl):S18-S23 doi: 10.1097/WNO.0000000000000163 © 2014 by North American Neuro-Ophthalmology Society Just over a decade ago, clinical trials for multiple sclerosis (MS) did not include visual outcomes. Experts recog-nized the need for more sensitive measures of visual func-tion, and low-contrast letter acuity emerged as a leading candidate to measure visual impairment. Although low-contrast acuity was quickly shown to correlate well with MRI lesion burden, visual-evoked potentials (VEPs), and quality of life (QOL) in MS, it was the introduction of optical coherence tomography (OCT) to the field of MS that allowed for the direct assessment of structure-function correlations in the anterior visual pathways. This unique capacity to link axonal and neuronal loss with specific impairment (vision) in MS makes the anterior visual system an ideal model for testing novel agents for neuroprotection and repair. The latest OCT investigations involve high-resolution spectral-domain OCT (SD-OCT) with segmen-tation (measurement) of specific retinal layers using computerized algorithms. These methods allow quantita-tion of both retinal nerve fiber layer (RNFL, axonal) and ganglion cell layer (GCL, neuronal) loss in vivo. New ther-apies that reduce axonal and neuronal loss by neuroprotec-tive or myelin-repair mechanisms can now be assessed noninvasively by OCT and coupled with visual function data. Most MS clinical trials now include both OCT and visual function testing, and new clinical trials that use acute optic neuritis (ON) as a model will examine the capacity for OCT measures in particular to demonstrate structural evi-dence for neuroprotection in patients with MS and other neurologic disorders. This review examines the data from observational studies and ongoing trials, presenting representative group data for visual function, OCT measures, and QOL scales in patients with MS, ON, and disease-free controls. These data, as well as those from meta-analyses within the past 5 years, may be used to provide reference values for the development of clinical trial protocols. BACKGROUND In 1974, Frisen and Hoyt (1) first described thinning of the RNFL in patients with MS. Postmortem studies later con-firmed the suspicion that atrophy occurred in the RNFL in nearly 71% of the patients studied (2). The invention of OCT has allowed for objective measurement of the layers of the retina in vivo (3-5). Although acute demyelination as Departments of Neurology and Population Health, New York Uni-versity School of Medicine, New York, New York. Dr. Balcer has received consulting fees from Biogen-Idec, Genzyme and Vaccinex; and is also on a clinical trial advisory board for Biogen-Idec. Address correspondence to Laura J. Balcer, MD, MSCE, New York University School of Medicine, 240 E. 38th Street, 20th Floor, New York, NY 10016; E-mail: laura.balcer@nyumc.org S18 Balcer: J Neuro-Ophthalmol 2014; 34(Suppl): S18-S23 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. a result of ON is an important contributor to visual loss, axonal and neuronal degeneration in the anterior visual pathways are likely important contributors to visual dys-function in MS, even in patients without an acute ON history (3,6-10). Because thinning of the RNFL and GCL + IPL by OCT are associated with reductions in visual function and QOL, OCT measures of axonal and neuronal loss have a unique ability to capture structure-function correlations in MS. Table 1 shows a mean difference in RNFL thickness of 11.8 m between disease-free control and all MS eyes (with and without a history of ON). The ability of OCT to detect these differences supports its potential role as a structural marker in MS clinical trials. OCT provides a noninvasive, objective measure of visual pathway integrity, and, there-fore, could be used to determine effectiveness of neuropro-tective and other MS therapies. Furthermore, OCT can be used in conjunction with visual function testing to follow disease progression of patients with MS. FEATURES AND ADVANTAGES OF OCT IMAGING Within the retina, retinal ganglion cell axons are unmy-elinated until they pass through the lamia cribosa. There-fore, RNFL imaging has the unique advantage of measuring the thickness of axonal and other retinal structures that can ultimately be used in assessing neurodegeneration and potentially neurorepair. OCT is similar to B-mode ultra-sound, but uses light instead of sound to form images. An optical beam is scanned along the retina and the machine measures echo-time delays to synthesize a picture of retinal structure (11-14). Advances in OCT, including the devel-opment of spectral-(Fourier) domain technology, provide increased sensitivity and capacity for careful analysis of path-ologic changes in the retina in vivo. Representative group data for OCT in patients with MS and disease-free controls are presented in Table 1. Time-domain OCT (TD-OCT) (first generation widely studied in MS) shows substantial differences in RNFL thickness between eyes of patients with MS and disease-free controls (95.5 ± 14.5 mm vs 104.5 ± 10.7 mm). MS eyes with a history of ON have even greater degrees of thinning on average (85.7 ± 19.0 mm). For SD-OCT techniques, there are differences in scaling from TD-OCT, leading to smaller absolute differences in RNFL thickness (92.9 ± 10.0 mm for controls vs 87.6 ± 11.1 mm in MS eyes without a history of ON). Larger studies will further refine the precision of these representative average values. Statistically combined data for studies of TD-OCT as of 2009 are presented in a meta-analysis by Petzold et al (13) with analyzable data from 36 OCT studies in patients with MS. An advantage of OCT is that it demonstrates high degrees of both interrater and test-retest reliability for TD and SD techniques (15). In fact, recent studies of SD-OCT show that this newer technology produces measurements that are more reproducible than TD-OCT (16). A study of 58 patients and 38 controls found that intraclass correlation coefficients (ICCs) ranged from 0.92 to 0.97 for intervisit, 0.83 to 0.99 for intrarater, and 0.94 to 0.99 for interrater reproducibility (15). Given its high degrees of reliability, sensitivity, and ease of use (pupillary dilation not usually needed), OCT is an ideal method for assessing pathologic changes in the visual pathway of patients with MS. OCT INVESTIGATIONS IN MS AND OPTIC NEURITIS During the course of their disease, between 30% and 70% of patients with MS will have acute ON (17,18). Because patients with acute demyelinating ON typically have symp-toms of pain on eye movement, visual acuity loss, color desaturation, and visual field abnormalities, followed by substantial RNFL axonal loss by OCT (20-40 mm on aver-age), ON is an ideal model for studying neuroprotective and neurorepair agents in MS. In 1999, OCT was first used in a study by Parisi et al (19) to investigate a group of patients who had a history of ON with complete recovery of visual acuity. When compared with control eyes, RNFL thickness was reduced by 46% in the eyes affected by acute ON. The affected eyes were also found to have RNFL thickness decreased by 28% when compared with the unaffected eyes of the same patient (P , 0.01). A subsequent investigation by Trip et al (20) substantiated these findings among eyes of patients with a history of ON and incomplete recovery. In this cohort of 25 patients with a history of unilateral ON, the ON eyes had a 33% reduction in RNFL thick-ness of patient eyes compared with disease-free control eyes (P , 0.001) (20). These authors also reported reductions in total macular volume in ON eyes compared with controls (P , 0.001) and also showed differences between affected and unaffected eyes of patients in the study (P , 0.001). A more recent study by Costello et al (21) demonstrated that close to 75% of patients with MS with ON will have RNFL losses between 10 and 40 mm in their affected eyes within 3-6 months after the acute event. Considering that the average RNFL thickness by TD-OCT in disease-free controls is 105 mm (92 mm in MS eyes) and that healthy control eyes lose only 0.017% of total RNFL thickness annually, the RNFL thinning associated with acute ON is substantial and provides a target for reduction of axonal loss in future clinical trial of ON (16). Costello et al (21) also established a threshold value of 75 mm by TD-OCT, below which there was a corresponding decline in visual function as measured by mean deviation with automated perimetry (21). Among eyes in a collaborative heterogeneous cohort of patients with MS, eyes with a history of ON seem to have Balcer: J Neuro-Ophthalmol 2014; 34(Suppl): S18-S23 S19 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. Mean reference values from recent investigations of vision, QOL, and OCT in patients with MS Disease-Free Controls All MS MS, No History of ON MS, History of ON References High-contrast VA, ETDRS, number of letters correct 64 ± 5 (n = 61 eyes) 59 ± 8 (n = 239 eyes) 60 ± 6 (n = 150 eyes) 58 ± 9 (n = 87 eyes) 22,24,25,32,39*,43 Binocular testing 66 ± 5 (n = 324 pts) 62 ± 8 (n = 1,007 pts) 63 ± 7 (n = 544 pts) 61 ± 10 (n = 463 pts) 41,42,43* Low-contrast letter acuity (2.5%), number of letters correct 34 ± 8 (n = 61 eyes) 26 ± 11 (n = 239 eyes) 28 ± 9 (n = 150 eyes) 22 ± 12 (n = 87 eyes) 24,25,39*,43 Binocular testing 43 ± 6 (n = 324 pts) 36 ± 10 (n = 1,007 pts) 38 ± 9 (n = 544 pts) 35 ± 11 (n = 463 pts) 41,42*,43 Low-contrast letter acuity (1.25%), number of letters correct 25 ± 7 (n = 61 eyes) 16 ± 10 (n = 239 eyes) 18 ± 10 (n = 150 eyes) 11 ± 11 (n = 87 eyes) 22,24,25,39*43 Binocular testing 34 ± 8 (n = 324 pts) 24 ± 11 (n = 1,007 pts) 26 ± 11 (n =5 44 pts) 22 ± 12 (n = 463 pts) 41,42*,43 NEI-VFQ-25 composite score, best score = 100 96 ± 4 (n = 31 pts) 88 ± 13 (n = 122 pts) 90 ± 12 (n = 111 pts) 85 ± 14 (n = 51 pts) 39*,43 10-item Neuro-ophthalmic supplement to the NEI-VFQ-25, best score = 100 97 ± 3 (n = 31 pts) 87 ± 13 (n = 122 pts) 88 ± 12 (n = 111 pts) 83 ± 14 (n = 51 pts) 39*,43 TD-OCT Peripapillary RNFL thickness, mm 104.5 ± 10.7 (n = 219 eyes) 92.5 ± 16.7 (n = 1,058 eyes) 95.6 ± 14.5 (n = 730 eyes) 85.7 ± 19.0 (n = 328 eyes) 22,24,25,32* Total macular volume, mm3 6.84 ± 0.36 (n = 219 eyes) 6.54 ± 0.51 (n = 1,058 eyes) 6.63 ± 0.48 (n = 730 eyes) 6.36 ± 0.53 (n = 328 eyes) 32* SD-OCT Peripapillary RNFL thickness, mm 92.9 ± 10.0 (n = 61 eyes) 84.3 ± 12.8 (n = 239 eyes) 87.6 ± 11.1 (n = 150 eyes) 78.4 ± 13.6 (n = 87 eyes) 38,39*,44 GCL + IPL, mm 88.9 ± 6.9 (n = 61 eyes) 84.1 ± 8.4 (n = 239 eyes) 87.0 ± 6.6 (n = 150 eyes) 79.7 ± 9.2 (n = 87 eyes) 38,39*,44 Macular RNFL, mm 29.6 ± 6.0 (n = 61 eyes) 23.5 ± 8.2 (n = 239 eyes) 25.5 ± 7.1 (n = 150 eyes) 20.0 ± 9.0 (n = 87 eyes) 38,39*,44 ETDRS, Early Treatment Diabetic Retinopathy Study; NEI-VFQ-25, 25-Item National Eye Institute Visual Functioning Questionnaire; SD, spectral-domain (Cirrus platform); TD, time-domain (OCT-3 platform); QOL, quality of life; OCT, optical coherence tomography; MS, multiple sclerosis; ON, optic neuritis; pts, patients; RNFL, retinal nerve fiber layer; GCL-IPL, ganglion cell layer-inner plexiform layer. *Reference with asterisk is source of data presented in table and rest of the references contain data. S20 Balcer: J Neuro-Ophthalmol 2014; 34(Suppl): S18-S23 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. a threshold of approximately 80 mm by TD-OCT, below which they show sustained abnormalities by low-contrast letter acuity. Trials of neuroprotective or repair agents for ON will likely establish a "therapeutic window" or time frame within which the agent should ideally be given to maximize the effect of preventing axonal/neuronal loss. A recent study used several tests, including high- and low-contrast visual acuity, Farnsworth-Munsell 100 Hue color testing, auto-mated visual fields, pattern VEP, and RNFL thickness by TD-OCT to investigate when changes occurred in the course of ON (22). This study determined that after a mean of 4.75 months of follow-up, 99% of the total amount of RNFL axonal loss had occurred. After 1.65 months (95% confidence interval, 0.96-2.32; P , 0.05), RNFL thinning could be observed when compared with the unaffected fel-low eye. Worse recovery was associated with more signifi-cant RNFL decline over 3 months of observation (P = 0.002). Significant macular volume loss between initial assessment and follow-up also was established (22,23). ON is a predictable cause of axonal and neuronal degeneration in the eyes of patients with MS. Interestingly, recent reports have shown that regardless of a history of ON, RNFL thinning can be seen in heterogeneous MS cohorts. Low-contrast letter acuity loss also is associated with RNFL thinning in MS eyes without a history of ON (24). In a cross-sectional study of 90 patients and 36 disease-free controls, RNFL thickness was reduced in the eyes of patients without a history of ON (105 mm; P = 0.03). This study also showed that both MS eyes with a history of ON and MS eyes without a history of ON had significant damage as compared with disease-free con-trols (24). There was a loss of 4 mm of RNFL thickness for every 1 line of low-contrast letter acuity loss among eyes of MS patients. RNFL thickness was associated with overall degrees of neurologic impairment, worse Expanded Disability Scale Scores (EDSS) and longer disease duration. Studies have shown that RNFL thickness becomes reduced over time in MS regardless of the history of ON (25). Patients with MS and controls at 3 academic centers underwent OCT imaging and visual testing. In patients without a history of ON, an average RNFL thickness of MS eyes were reduced by 2.9 mm after 2-3 years and by 6.1 mm after 3-4.5 years (P , 0.001). These data would indi-cate a significant need for monitoring the structural changes even in eyes without a history of ON. RESEARCH ON OCT IN MS Using scanning laser polarimetry with a GDx-VCC, Zaveri et al (26) demonstrated that RNFL thinning is related to visual loss. Although OCT RNFL thickness is reflective of structural changes in the ganglion cell axons, measurement of the RNFL by scanning laser polarimetry can demonstrate underlying microtubule integrity based on the property of birefringence. This technique is particularly valuable in the setting of MS because it is able to quantify integrity of the RNFL in the setting of optic disc edema. With the development of SD-OCT, segmentation of the layers of the retina is now possible. This is an important advance because neuronal loss is regarded as a correlate of MS disability (27-31). Studies using TD-OCT had shown decreased total macular volume in patients with MS, and this measure could estimate ganglion cell neuronal loss (32). SD-OCT has provided the first opportunity to more directly estimate thinning of the GCL + IPL through man-ual segmentation. In a pilot study, Davies et al (33) showed that the eyes of patients with MS (n = 16) had significantly lower GCL volume as compared with controls (P , 0.001). There was not a significant association between GCL and high-contrast visual acuity loss, and low-contrast acuity cor-related with GCL volume scores (P = 0.003). Given the amount of time required to segment retinal layers manually (approximately 2 hours), there is a need for computerized algorithms that allow for measurement of the retinal layers on a large scale. Studies of patients with glaucoma have successfully used computerized segmenta-tion algorithms to quantify the layers of the retina, and these methods have now been applied to SD-OCT images of eyes of patients with MS (34,35). OCT measurements of RNFL thickness and other parameters can also differ among MS subtypes. Patients with secondary progressive MS (SPMS) have greater reductions in RNFL thickness (83.4 mm by TD-OCT) compared with patients with clinically isolated syndrome (CIS) (101.2 mm, P = 0.0009) and relapsing remitting MS (RRMS) (103.7 mm, P = 0.001) (36). In eyes with a history of ON, patients with SPMS had greater thinning (39.5 mm at follow-up) than in CIS (58.1 mm, P = 0.03) or RRMS (48.2 mm). Benign MS is another area in which definitions and diagnostic criteria may unintentionally minimize the appar-ent role of visual pathway disease. Patients with benign MS most typically have an EDSS #3 and $15 years disease duration, and are therefore thought to follow a milder course when compared with those with typical RRMS. Galetta et al (37) conducted a longitudinal analysis of EDSS scores, visual function, OCT measurements, and QOL as-sessments in a subset of patients with benign MS. RNFL thickness was measured using TD-OCT and QOL scales, including the NEI-VFQ-25 and SF-36. Using the most common definition of benign MS, 13 patients (26 eyes) met inclusion criteria. Despite the relatively low EDSS score, patients with benign MS had similar if not greater degrees of RNFL thinning from baseline during an average follow-up of 1.6 years (benign MS eyes, 3.6 mm, P = 0.0008 vs baseline, paired t test; typical MS eyes, 23.3 mm, P , 0.0001). Vision-specific QOL scores were likewise worse among patients with benign MS who had similar if not greater degrees of RNFL thinning from Balcer: J Neuro-Ophthalmol 2014; 34(Suppl): S18-S23 S21 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. baseline during an average follow-up of 1.6 years (benign MS eyes, 3.6 mm, P = 0.0008 vs baseline, paired t test; typical MS eyes, 23.3 mm, P , 0.0001). Vision-specific QOL scores were likewise worse among patients with benign MS compared with those with typical RRMS (NEI-VFQ-25 composite scores, 75 ± 21 vs 88 ± 11, P = 0.005, accounting for age) and history ON (P = 0.002). These data provide further evidence that the EDSS does not adequately capture visual pathway axonal loss and visual impairment, both of which are likely contributors to dis-ability in patients with benign MS. Patients with the macular thinning predominant phe-notype of MS are of interest to our understanding of gray matter/neuronal loss as manifested in the retina. Saidha et al (38) examined a cohort of patients with normal peripapil-lary RNFL thickness but thinning of the macular region to the fifth percentile or less using SD-OCT. Although this group had thinning of the outer retinal layers (,0.001 for inner and outer nuclear layers), there was minimal thinning of the GCL layer, suggesting a unique pattern of retinal neuronal cell loss in patients with this phenotype. Patho-logic studies of postmortem eyes of patients with MS (n = 82) have shown GCL loss in 79% (10). Using algorithms originally designed for investigation of GCL + IPL thinning in glaucoma and developed at the University of Pittsburgh, Walter et al (39) investigated in vivo measurement of the GCL + IPL and other retinal layers in MS. In 122 patients (239 eyes) and 31 controls (61 eyes), macular RNFL (P , 0.001) and GCL + IPL (P = 0.001) were significantly thinner in MS eyes (accounting for age and within-patient, intereye correlations). Macular RNFL thickness and GCL + IPL also were found to be significantly thinner in MS eyes with a history of ON (P = 0.006) were the retinal layers that were most strongly associated with reduced vision-specific QOL scores (NEI-VFQ-25 and 10-item supplement composite). Ganglion cell layer neuronal loss in MS is likely to be an important indicator visual pathway disease in MS. OCT IN CLINICAL TRIALS: ROLE FOR READING CENTERS The incorporation of OCT and visual outcome measures into MS clinical trials has benefited from the presence of OCT reading centers. The University of California Davis Reading Center recently published the results of Stratus (TD) OCT quality control in 2 multicenter MS clinical trials (40). The authors evaluated 19,961 OCT from 981 patients with the goal of determining the influence of OCT quality control procedures on error rate. In trial 1 (design and therapeutic agent not specified in publication), there was no ophthalmic technician certification and data were obtained by the Reading Center retrospectively. However, in trial 2, technicians were certified and submitted data prospectively according to the study protocol. OCT in trial 2 had higher signal strengths, fewer errors, and more usable data compared with trial 1 scans. This study showed that certified technicians and prompt transmission of data for ongoing quality control mon-itoring provide higher data quality; these factors and the use of Reading Centers should be considered in the design of clinical trials for MS and other neuro-ophthalmologic disorders. CONCLUSIONS Visual dysfunction is not only an important contributor to impairment and disability in MS, but also represents a unique opportunity for studying disease mechanisms and for testing new therapies that involve neuroprotection and repair. 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