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Show Vision in Multiple Sclerosis: The Story, Structure- Function Correlations, and Models for Neuroprotection Reiko E. Sakai, BA, Daniel J. Feller, Kristin M. Galetta, MS, Steven L. Galetta, MD, Laura J. Balcer, MD, MSCE Abstract: Visual dysfunction is one of the most common clinical manifestations of multiple sclerosis (MS). Just over a decade ago, MS clincial trials did not include visual outcomes, but experts recognized the need for more sensitive measures of visual function. Low-contrast letter acuity emerged as the leading candidate to measure visual disability in MS, and subsequent studies found low-contrast acuity testing to correlate well with brain MRI lesion burden, visual-evoked potentials, quality of life (QOL), and retinal nerve fiber layer (RNFL) loss, as measured by optical coherence tomography (OCT). OCT in MS has allowed for assessment of structure-function correlations that make the anterior visual pathway and acute optic neuritis (ON) ideal models for testing novel agents for neuroprotection and repair. New therapies that reduce axonal loss by neuro-protective or myelin repair mechanisms can now be assessed noninvasively by OCT and coupled with visual function data. Based on OCT studies in MS, RNFL thickness is reduced significantly among patients (92 mm) vs controls (105 mm) and is particularly reduced in MS eyes with a his-tory of ON (85 mm). Worsening of visual function by a clini-cally significant $7 letters or approximately 1.5 lines for low-contrast acuity is associated with approximately 4.5 mm reductions in RNFL thickness in MS eyes. Longitudinal studies of OCT have also shown RNFL axonal loss over time that occurs even in the absence of acute ON and that cor-relates with clinically meaningful worsening of vision and QOL, even in patients with benign MS. The latest OCT inves-tigations involve high-resolution spectral-domain (SD) OCT with segmentation and measurement of specific retinal layers using computerized algorithms. These methods allow quantitation of ganglion cell (neuronal) layer loss and axonal degeneration in MS in vivo. In this review, we examine the data from these studies and ongoing trials that highlight the entity of ON as a model to investigate neuroprotection and neurorepair. In doing so, we also present representative group data from studies that have examined visual function, OCT measures, and QOL scales in patients with MS and ON and disease-free controls. These data, and those from recent meta-analyses, may be used to provide reference values for the development of clinical trial protocols. Journal of Neuro-Ophthalmology 2011;31:362-373 doi: 10.1097/WNO.0b013e318238937f © 2011 by North American Neuro-Ophthalmology Society Visual loss has been recognized for decades as one of the most common and disabling clinical manifestations of multiple sclerosis (MS). It was not until a decade ago, how-ever, that MS clinical trials began to include sensitive meas-ures of visual function. Inspired by the effective use of contrast sensitivity (Pelli-Robson charts) to demonstrate visual abnormalities in the Optic Neuritis Treatment Trial (ONTT) (1-6), low-contrast letter acuity was introduced into MS trials as an exploratory outcome to better capture the often subtle visual symptoms experienced by patients with acute optic neuritis (ON) (7-10). Visual symptoms can result from a variety of patholog-ical processes, including inflammation, demyelination, and axonal degeneration in the afferent visual pathway (retina, optic nerves, chiasm, and tracts) (11-15). During the past decade, the contributions of axonal and neuronal loss to disability in MS have been increasingly recognized (12,16-19). Developed initially as a noninvasive tool to monitor retinal disease and glaucoma, optical coherence tomography (OCT) was first applied to cohorts of patients with MS and ON over a decade ago to provide validation of clinical visual outcomes and to capture anterior visual path-way axonal loss (15,20-25). As a result of these early studies Departments of Neurology (RES, DJF, KMG, SLG, LJB); Ophthal-mology (SLG, LJB); and Epidemiology (LJB), University of Pennsyl-vania School of Medicine, Philadelphia, PA. Supported by the National MS Society grants PP1115, RG 3208-A-1, and RG 3428-A/2; National MS Society Translational Research Part-nership TR 3760-A-3; National Institutes of Health/National Eye Institute grants K24 EY 014136 and R01 EY 019473 (L.J.B.); McNeill Foundation; and DADs Foundation. Dr S. L. Galetta has received speaking and consulting honoraria from Biogen-Idec, Novartis, and Teva. Dr L. J. Balcer has received speaking and consulting honoraria from Biogen-Idec, Bayer, and Novartis. Address correspondence to Laura J. Balcer, MD, MSCE, Department of Neurology, University of Pennsylvania School of Medicine, 3 East Gates Building, 3400 Spruce Street, Philadelphia, PA 19104; E-mail: lbalcer@mail.med.upenn.edu 362 Sakai et al: J Neuro-Ophthalmol 2011; 31: 362-373 State-of-the-Art Review Section Editors: Grant T. Liu, MD Randy H. Kardon, MD, PhD Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. and .100 subsequent published investigations of OCT in MS and ON (26), the visual pathway is now recognized as a model for structure-function correlation in MS for study-ing the pathophysiology of disease and for testing both novel and standard therapies that involve neuroprotection and repair. OCT can be used noninvasively to capture reductions in axonal loss that may be associated with neuro-protective or myelin repair therapies; this information can be correlated with visual function and quality of life (QOL) data to further establish the clinical relevance of these struc-tural outcomes. OCT enables investigators to rapidly and reproducibly evaluate the structural composition of the retina. Ulti-mately, OCT could substantially increase our understand-ing of the mechanisms of tissue injury in MS, ON, and other optic neuropathies. A decade after publication of the first studies of low-contrast acuity in MS, this test and OCT measures are commonly used in MS clinical trials. They have formed the foundation for new trials that use acute ON as a model for identifying novel compounds for neurorepair (27-32). This review describes a number of advancements in the development of visual function outcomes in MS and OCT as a novel technology that enables objective analysis of the processes of neurodegeneration. In addition, we present representative group data from studies that have examined visual function, OCT measures, and QOL scales in patients with MS and ON and disease-free controls (Table 1). These data may be used to provide initial reference values and should be viewed in the context of 1) the continually evolv-ing field of vision in MS, 2) the potential challenge inherent in applying group data to individual patients, and 3) the perspective that even the small observed differences in mean OCT values have been shown to correlate with clinically meaningful changes in visual function and QOL in MS patients. VISION IN MS: THE STORY In the late 1990s, the National Multiple Sclerosis Society Clinical Outcomes Assessment Task Force developed the Multiple Sclerosis Functional Composite (MSFC) in response to the need for more sensitive neurologic out-come scale (33,34). Designed to be a battery of performance measures complementary to the Expanded Disability Sta-tus Scale (EDSS), the MSFC includes the 25-Foot Timed Walk, the 9-Hole Peg Test, and Paced Auditory Serial Addition Test (35-38). While multidimensional, the MSFC did not include a measure of visual function. In the evalu-ation of candidate MSFC visual components from MS clinical trial data used to develop the MSFC, Snellen high-contrast visual acuity (VA) did not change over time or demonstrate concurrent changes with EDSS scores (33). Contrast sensitivity, as tested by line gratings and letter charts in MS and by Pelli-Robson charts in the ONTT, had been shown to be a sensitive measure of afferent visu-al function, even among patient with Snellen acuities of 20/20 or better (1-6,39-43). Importantly, measures of low-contrast vision are predictive of "real-world" visual tasks, such as reading rate, facial recognition, and driving (44). Low-Contrast Letter Acuity While used successfully in the ONTT to demonstrate persistent visual abnormalities beyond recovery of high-contrast VA, Pelli-Robson contrast sensitivity charts were not available for purchase in 1998, when the first MS clinical trial to incorporate a low-contrast visual measure as an exploratory outcome was begun. This trial, International MS Progressive Avonex Clinical Trial (IMPACT), incor-porated low-contrast Sloan letter charts (7,8,45,46). These charts are the low-contrast (gray letters on white) "cousin" of the Early Treatment Diabetic Retinopathy Study (ETDRS) high-contrast VA charts used in ophthalmology clinical trials (Fig. 1). Sloan charts have a standardized for-mat based on the ETDRS VA charts. Three contrast levels have been used in MS trials and research studies, including 100% (high-contrast, used to measure VA as a descriptor of the study cohorts), 2.5%, and 1.25% (lightest contrast level). Charts are scored letter by letter, and numbers of letters identified correctly constitute the score for each chart (Table 1). Most recently, visual improvement and loss by the low-contrast acuity chart has been defined as a 7-letter change in score, while 5-letter changes in high-contrast VA are now considered clinically significant for patients with good VA (47). This threshold represents a change that exceeds that which would be expected from repeated testing when there was no real change (45,48) and to correlate with retinal nerve fiber layer (RNFL) axonal loss in patients with MS (47). As shown in Table 1, differences in mean letter scores for MS vs disease-free control groups are consistently $5 letters for VA and $7 letters for low-contrast acuity. Since the 5- and 7-letter criteria are meant to be applied to individual eye or patient differences, differences in mean scores of such magnitude are therefore likely to be clinically meaningful. Furthermore, these 5- and 7-letter mean changes have been shown to correlate significantly with vision-specific and overall QOL, as well as structural measures of OCT RNFL thickness. These associations of OCT and QOL measures with clinically meaningful changes in visual function provide perspective for the data in Table 1, despite the seemingly small magnitudes of differences in means for OCT values. In the IMPACT trial and in heterogeneous MS cohorts (7,8,45), low-contrast letter acuity was shown to be a highly reliable (high intraclass correlations of 0.86-0.95) and prac-tical method that was superior in identifying MS-related visual loss compared to other available tests (Fig. 2). Corre-lations of Sloan chart scores with MSFC and EDSS in these studies were significant and moderate in magnitude (rs = 0.56 vs MSFC; rs = −0.43 vs EDSS, P , 0.0001). These studies Sakai et al: J Neuro-Ophthalmol 2011; 31: 362-373 363 State-of-the-Art Review 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 MS Disease-Free Controls All MS MS, No History of ON MS, History of ON References for Data* 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) 103* (22,47,56,81,84) Binocular testing 66 ± 5 (n = 324 pts) 62 ± 8 (n = 1,007 pts) 63 ± 7 (n = 544 pts) 61 ± 10 (n = 463 pts) 56* (7-10,51) 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) 103* (22,47,56) Binocular testing 43 ± 6 (n = 324 pts) 36 ± 10 (n = 1,007 pts) 38 ± 9 (n = 544 pts) 35 ± 11 (n = 463 pts) 56* (7-10,51) 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) 103* (22,47,56,81,84) Binocular testing 34 ± 8 (n = 324 pts) 24 ± 11 (n = 1,007 pts) 26 ± 11 (n = 544 pts) 22 ± 12 (n = 463 pts) 56* (7-10,51) 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) 103* (49-51,56) 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) 103* (49-51,56) 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) 81* (20-22,47,70-84) 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) 81* (20-22,70-84) 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) 103* (96,105) 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) 103* (96,105) 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) 103* (96,105) *Reference with asterisk is source of data presented in table; references that contain similar data are in parentheses. pts, patients; SD, spectral-domain (Cirrus platform); TD, time-domain (OCT-3 platform). 364 Sakai et al: J Neuro-Ophthalmol 2011; 31: 362-373 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. provided the first ever data demonstrating that low-contrast acuity scores capture unique aspects of dysfunction not cap-tured by standard neurologic scales of EDSS or the MSFC and suggested that adding a visual component to the MSFC would increase the applicability of this measure. In the AFFIRM trial of natalizumab vs placebo for relapsing-remitting MS, low-contrast letter acuity was able to demonstrate treatment effects and changes over time both with respect to reduction of the cumulative probability of sustained visual loss (by 47%, P , 0.001 for 2.5% contrast level) and sustained clinically meaningful visual improvement (by 57%, P = 0.01) in the treatment group (9,10). Similar to previous studies and to MS trial datasets used originally to develop the MSFC, high-contrast VA did not show treatment differences or detect sustained visual loss or improvement over time. The analyses of visual loss in AFFIRM used initially a 2-line (10-letter) criterion for clinically significant change; subsequent ophthalmologic studies for VA, however, suggested use of a 1-line (5-letter cut-off). Examination of interrater and test-retest reliability data for low-contrast acuity revealed 7 letters to represent 2 SDs on the interrater differences; this 7-letter criterion was subsequently incorporated into the AFFIRM analyses of visual improvement and subsequent longitudinal studies of OCT. Vision-Specific QOL Measures The relevance of low-contrast letter acuity measurements to patient functioning has been underscored by studies linking these scores to vision-specific QOL. Scores for the 25-Item National Eye Institute Visual Functioning Ques-tionnaire (NEI-VFQ-25) are reduced among patients with MS (Table 1) (49-51). A 10-Item Neuro-Ophthalmic Sup-plement to the NEI-VFQ-25 has also been designed using MS cohorts to capture symptoms relevant to neurologic dis-ease. In a recent study of 167 patients with MS, 2-line differ-ences in visual function by low-contrast acuity are associated, on average, with .4-point worsening (6.7 - 10.9 points, P , 0.001 accounting for age) in NEI-VFQ-25 composite (overall) score, reductions that are considered to be clinically meaningful based on ophthalmic epidemiologic studies (52-55). In Table 1, the differences in mean scores between MS patients and disease-free controls were $4 points; such differences may be considered clinically significant for both individual changes and group data. Binocular scores for low-contrast acuity also correlated significantly with score for the 10-Item Neuro-Ophthalmic Supplement (P , 0.001), the Impact of Visual Impairment Scale (P , 0.001), and the FIG. 1. Low-contrast letter acuity chart (low-contrast Sloan letter chart; Precision Vision, LaSalle, IL). These charts have a standardized format based on ETDRS VA charts, the standard used in ophthalmology clinical trials, and have several advantages over standard Snellen charts or near vision testing cards as traditionally used in MS trials: 1) letters (Sloan letters) are designed to be equally detectable for normal observers; 2) each line has an equal number of letters (5 per line); 3) spacing between letters and lines is proportional to the letter size; 4) change in VA from one line to another occurs in equal logarithmic steps (change of 3 lines constitutes a doubling of the visual angle); 5) VA (for high-contrast [black letters on white] chart) may be specified by Snellen notation for descriptive purposes (i.e., 20/20), by the number of letters identified correctly. This figure shows the 25% contrast level for purposes of illustrating format; the actual contrast levels used in these trials, 2.5% and 1.25%, have substantially lighter gray letters. The charts measure 14 · 14 inches for easy use and portability in the MS clinical trial setting; charts may also be mounted on a retro-illuminated cabinet, thus eliminating the need for standardi-zation of room lighting levels. Reprinted with permission from Balcer et al (9) (copyright © 2007 AAN Enterprises, Inc.). FIG. 2. Logistic regression analyses demonstrating capac-ity for each visual function test to predict MS vs disease-free control status in a heterogeneous MS cohort, accounting simultaneously for age. Odds ratios in favor of participants with worse vision scores being MS patients (vs disease-free controls) were greatest for low-contrast letter acuity (Sloan charts) and contrast sensitivity (Pelli-Robson chart). These measures thus best distinguish MS patients from disease-free control subjects, even after accounting for age differences between the 2 groups. VF, visual field. Reprinted with permission from Balcer et al (7) (copyright © 2003 AAN Enterprises, Inc.). Sakai et al: J Neuro-Ophthalmol 2011; 31: 362-373 365 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. SF-36 Physical Component Summary (P , 0.001) in this MS cohort. Collectively, these data demonstrated that low-contrast acuity testing provides information on patient-reported aspects of vision. This is a key feature for clinical measures and a prerequisite for their use as primary out-comes in clinical trials. Binocular Summation of Acuity While the earliest studies of low-contrast acuity and QOL examined binocular vision scores (vision testing with both eyes together), monocular measurements (with each eye separately) have more recently been introduced into MS trials and vision research with the inclusion of OCT scanning as a structural correlate to vision (Table 1). Given the importance of both of these types of acuity to measure-ments of function, analyses of MS cohort data, including both binocular and monocular scores, were performed to examine the relation between the two and to determine the potential roles for binocular summation and inhibi-tion (56). Binocular summation of acuity occurs when vision is improved under binocular viewing conditions (binocular score is greater than the scores for either eye alone) (57). In contrast, patients with binocular inhibition have worse binocular vision compared to the better eye alone. Among 1,007 patients with MS and 324 disease-free controls, binocular summation was substantial (5- to 7-letter increases over better eye acuity, 28%-52% with .7 letters, P , 0.001) for low-contrast acuity at the 2.5% and 1.25% levels. For high-contrast VA, only 3.0%-3.4% of patients showed similar degrees of summation. Increasing age (P , 0.0001), greater interocular differences in acuity (P , 0.0001), and history of ON (P = 0.015) were associ-ated with lower magnitudes of binocular summation; in fact, some of these patients had binocular inhibition. Importantly, greater degrees of binocular summation were predictive of better QOL by the NEI-VFQ-25 (P = 0.02) and 10-Item Supplement (P = 0.03), indicating that the capacity to use both eyes together is an important factor in determining how well patients with MS can perform daily activities (56). Relation of Vision to MRI and Visual-Evoked Potentials Correlation with biological markers and electrophysiological measures of disease is one of the most important factors in the evaluation of clinical outcome measures such as low-contrast letter acuity. The first such study determined the relation of binocular low-contrast scores to brain MRI measures of T2 lesion burden (58). This study of 45 patients with MS found that those with worse low-contrast acuity scores had greater T2 lesion volumes in whole brain (3 mm3 increase for every 1-line worsening, P = 0.002- 0.004, accounting for age and disease duration). Area 17 and optic radiation white matter lesion burden specifically correlated with visual function, but non-vision-related white matter did not show associations. These findings were important in providing a structural correlate to low-contrast acuity scores and also in emphasizing a potential postgeni-culate pathway component to binocular low-contrast vision. Standard brain MRI techniques have provided informa-tion regarding disease burden in MS. However, the capacity for these techniques to precisely quantify axonal and neuronal loss, particularly in the anterior visual pathway, has been limited. Electrophysiologic markers such as the visual-evoked potential (VEP) can provide additional infor-mation on anterior visual pathway integrity. Recent studies have combined assessments of vision loss with VEP. Con-ventional VEPs measure the cortical response to monocular stimulation in the central 30° of the visual field. In MS, the latency characteristically is delayed with normal ampli-tude. Axonal loss, however, can reduce this amplitude (59). Abnormal VEPs in unaffected eyes provided evidence for clinically silent lesions in the optic nerve that might help identify dissemination in space and help establish the diagnosis of MS (60). Various studies have shown that contrast sensitivity can be measured by VEP (43), and in MS, low-contrast stimuli VEPs show increased latencies or absent waveforms when compared with high-contrast stim-uli VEPs. Low-contrast VEP may prove to be helpful in identifying demyelination (61). Other studies have con-cluded that multifocal VEP provides higher sensitivity and specificity in detecting abnormalities in visual function in MS and in ON (62). Naismith et al (63) systematically evaluated the utility of OCT and VEPs to detect the presence of clinical and subclinical ON and examined the relation of these meas-ures to visual function. This retrospective cross-sectional study evaluated 65 subjects (n = 96 eyes) with MS (n = 40), clinically isolated syndrome (CIS, n = 1), neu-romyelitis optica (n = 20), and idiopathic demyelination (n = 4). Patients had at least one episode of ON $6 months prior to enrollment. VEPs detected ON in 81% of patients (32% of subclinical ON in unaffected eyes and 75% of all subclinical ON). In contrast, using their criteria, they found that OCT identified 60% of eyes with ON and less than 20% of subclinically affected eyes. The authors concluded that OCT is less sensitive than VEPs in ON. On the other hand, to the extent that this study focused on patients with relatively poor vision, there were likely floor effects with regard to OCT RNFL thickness. STRUCTURE-FUNCTION CORRELATIONS: OCT Although acute ON and demyelination are important contributors to visual dysfunction, irreversible axonal and neuronal degeneration are also final common pathways to permanent visual loss (12-14,24,64). While the relation-ship between visual loss and brain MRI lesion burden discussed above is a relatively new finding, the extremely 366 Sakai et al: J Neuro-Ophthalmol 2011; 31: 362-373 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. high predilection for MS to involve the optic nerves is well-documented and was initially observed long before the advent of advanced optical and neuroimaging. Autopsy studies have shown that up to 94%-99% of MS patients have detectable optic nerve lesions (65,66). Subclinical changes related to visual loss may involve the optic nerves or chiasm, or postchiasmal regions of the optic tract (13,67- 69). Features and Advantages of OCT Imaging OCT provides a noninvasive technique to measure axo-nal and neuronal loss in the anterior visual pathways (24,28-32). As the optical analog of ultrasound B-mode imaging, OCT allows us to image the RNFL (15,20- 32,47,59,70-82). Since, within the retina, these axons are nonmyelinated, the RNFL is an ideal structure to visualize the processes of neurodegeneration, neuroprotection, and potentially even neurorepair. In contrast to the peripapillary RNFL, which contains axons, the macula contains a large proportion of retinal ganglion cell neurons (about 34% of total macular volume) (81). The development of Fourier-domain (or spectral-domain [SD]) detection has in partic-ular enhanced ophthalmic OCT technology. While many of the studies cited in this review utilized time-domain (TD) OCT, some have incorporated the newer SD-OCT technologies. Table 1 presents some representative group data for OCT measures in patients with MS, ON, and disease-free controls. Since OCT measures have been shown to correlate with clinically meaningful changes in visual function and QOL (see above), the differences in mean values between groups shown in Table 1 are likely to have clinical significance. Larger studies and additional meta-analyses will allow us to further refine the precision of these representative average values. OCT Investigations in MS and ON The earliest application of OCT technology to the study of MS was reported by Parisi et al in 1999 (15). In this study, which utilized first-generation OCT technology, 14 patients with MS who had completely recovered from a previous event of acute ON were analyzed. The thickness of the RNFL was shown to be reduced by 46% in the affected eyes of the patients with MS vs the control eyes (P , 0.01) and by 28% when affected eyes were compared with the "unaffected" eyes of the same patient (P , 0.01). Even in the clinically unaffected eyes of patients, however, there was a 26% reduction in RNFL thickness when compared with control eyes (P , 0.01). In 2005, Trip et al (21) reported their observations with OCT in 11 patients with MS and 14 patients with CIS, all of which individuals had a history of a single epi-sode of ON. The study was a cross-sectional analysis with follow-up ranging from 1 to 9 years after the ON event. Corroborating the previous findings by Parisi et al (15), the investigators found a 33% reduction in RNFL thickness in the eyes of the patients when compared with the eyes of matched controls and a 27% reduction when the affected and unaffected eyes of the same patient were compared (P , 0.001). Trip et al (21) extended the utility of OCT by also showing that the macular volume (a reflection of retinal ganglion cell neuronal integrity) was reduced by 11% in the eyes of patients with a history of ON when compared with control eyes (P , 0.001) and by 9% in the affected vs the unaffected eye of the same patient (P , 0.001). In 2006, Costello et al (20) reported that the majority of patients with MS who have ON (approximately 75%) will sustain 10-40 mm of RNFL loss within a period of approx-imately 3-6 months. This finding is striking given that the RNFL is only about 110-120 mm thick by the age of 15 years and that most individuals (without a history of glau-coma or macular degeneration) will lose only about 0.017% per year in retinal thickness, which equates to approximately 10-20 mm over 60 years (25,83). Costello et al (20) also provided compelling evidence identifying an injury thresh-old within the RNFL of about 75 mm; thinning of the RNFL below this level led to a corresponding decline in visual function, as measured by automated perimetry. Using low-contrast letter acuity in MS eyes with a history of acute ON, we have found a similar threshold for abnormal visual function and axonal loss at 80 mm (Fig. 3). The trajectory and time course of RNFL axonal loss following an episode of acute ON are important for determining the "window of opportunity" within which a neuroprotective or repair agent should be adminis-tered in a treatment trial. Sample size calculations for a FIG. 3. Scatter plots showing relation of low-contrast letter acuity to RNFL thickness (in micrometers) for eyes from a heterogeneous MS cohort (n = 82) with a history of acute ON. The left panel shows eyes with abnormal low-contrast acuity scores, defined as 7 letters below the mean of a disease-free control group. Eyes in the right panel have normal low-contrast acuity at 2.5% contrast. Among eyes with abnormal low-contrast acuity, worse scores were sig-nificantly associated with lower (thinner) peripapillary RNFL, accounting for age and adjusting for within-patient intereye correlations. Sakai et al: J Neuro-Ophthalmol 2011; 31: 362-373 367 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. proposed ON trial are also likely to be based on such data. Henderson et al (84) recently addressed both of these questions in a study of 23 patients with acute clinically isolated unilateral ON. Patients underwent TD-OCT assess-ment of RNFL thickness and total macular volume; visual function testing with high-contrast VA, low-contrast acuity (Sloan charts at 1.25%), Farnsworth-Munsell 100 color test-ing, and automated visual fields; and pattern VEP testing. The mean time to 90% loss from the initial RNFL thickness values for affected eyes (initial median 116.5 mm-likely reflecting slight edema) was 2.38 months (95% confidence interval [CI], 1.95-2.77; P , 0.05). Ninety-nine percent of the loss from the initial value to the asymptotic value (lowest point where loss leveled off) occurred by a mean of 4.75 months (95% CI, 3.90-5.54; P , 0.05). The time of first detectable RNFL atrophy compared to the baseline fellow eye value was 1.64 months (95% CI, 0.96-2.32; P , 0.05). Eyes with poor recovery (n = 5), defined as logarithm of the minimum angle of resolution VA . 0.1, had a signifi-cantly greater decline of RNFL from baseline to 3 months (P = 0.002). Macular volumes also declined significantly to the time of last follow-up. Sample size estimates using their models showed that, assuming 80% power, approxi-mately 100-150 patients would be needed to detect a 30% decrease in RNFL loss between the treatment and placebo groups at a 3- to 6-month endpoint. These findings are critical in setting the stage for use of acute ON as a model for neuroprotection and repair trials (84). One of the most important findings that has resulted from the use of OCT MS studies is the correlation between RNFL thinning and visual loss, as measured by low-contrast letter acuity. In 2006, Fisher et al (22) conducted a cross-sectional study that compared RNFL thickness among MS eyes with a history of ON (MS ON eyes), MS eyes without a history of ON (MS non-ON eyes), and disease-free con-trols. In addition to OCT measurement of OCT, they conducted low-contrast visual assessments with low-contrast letter acuity, contrast sensitivity (Pelli-Robson charts), and high-contrast VA (ETDRS charts). The authors found that RNFL thickness was reduced significantly among MS patients (92 mm) vs controls (105 mm, P , 0.001) and particularly reduced in MS ON eyes (85 mm, P , 0.001). Furthermore, lower visual function scores were associated with reduced average overall RNFL thickness in MS eyes; for every 1 line decrease in low-contrast letter acuity or con-trast sensitivity score, the mean RNFL thickness decreased by 4 mm. These findings not only supported the validity of low-contrast visual assessment as a secondary clinical outcome measure in MS trials, they also suggested a poten-tial role for OCT in trials that examine neuroprotective and other disease-modifying therapies. Several other inves-tigations have demonstrated correlations between RNFL thinning and visual loss (21,25,77,85-87). While the above studies used cross-sectional studies to examine relationships between biomarkers measured with OCT and visual function, the first longitudinal study to study the relationship between RNFL thickness and visual loss was carried out by Talman et al in 2010 (47). These investigators used OCT to measure RNFL thickness at baseline and at 6-month intervals during a mean follow-up of 18 months at 3 centers. Low-contrast letter acuity (2.5% and 1.25%) and high-contrast VA were tested. The results indicated that among 299 patients (593 eyes) with at least 6 month follow-up, eyes with visual loss showed greater RNFL thinning compared to eyes with stable vision (low-contrast acuity, 2.5%: P , 0.001; VA: P = 0.005). RNFL thinning increased over time, with average losses of 2.9 mm at 2-3 years and 6.1 mm at 3-4.5 years (P , 0.001 vs 0.5-1 year follow-up). The authors concluded that progressive RNFL thinning occurs as a function of time in some patients with MS, even in the absence of ON (47). Studies such as this draw the important connection between structure (RNFL thickness and macular volume, as measured by OCT) and function (visual performance as measured by low-contrast acuity) and are likely to be instrumental in improving our understanding of the MS disease process. Recently, OCT has also been used to show the capacity of RNFL thinning to distinguish MS disease subtypes. Costello et al (85) found that RNFL comparisons involving eyes with-out ON yielded greater differences between MS subtypes than ON-affected eyes. Overall RNFL values in nonaffected eyes were reduced in patients with secondary progressive multiple sclerosis (SPMS) (83.4 mm), relative to ON as a CIS (101.2 mm) (P = 0.0009), and patients with relapsing-remitting multiple sclerosis (RRMS) (103.7 mm) (P = 0.001); and temporal RNFL atrophy was greater in RRMS (64.4 mm) eyes as compared to CIS eyes (73.2 mm, P = 0.02). In ON-affected eyes, RNFL atrophy was greater in patients with SPMS (39.5 mm) than those with CIS (58.1 mm, P = 0.03) and in patients with RRMS (48.2 mm) relative to those with CIS (P = 0.05). These authors concluded that RNFL thickness might represent an important MS structural mark-er because RNFL thinning reflects disease progression. While RNFL thinning is most marked in patients with SPMS, those with benign MS, traditionally defined as EDSS #3 and $15 years of disease duration, are thought to follow a milder course (88). We recently conducted an analysis of a longitudinal MS cohort to determine the extent of visual pathway axonal loss by OCT RNFL thickness. At 3 academic centers, a subset of patients with EDSS scores, visual function, OCT, and QOL assessments was analyzed. Low- and high-contrast letter acuities were performed to assess visual function. RNFL thickness was determined using OCT-3. QOL scales included the NEI-VFQ-25 and SF-36. Among 68 patients (135 eyes) studied longitu-dinally, 13 (26 eyes) had benign MS using criteria of EDSS #3 and $15 years of disease duration. Benign MS eyes had as much RNFL thinning (−3.6 mm, P = 0.0008 vs baseline, paired t test) as typical MS eyes (−3.3 mm, P , 0.0001). 368 Sakai et al: J Neuro-Ophthalmol 2011; 31: 362-373 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Both groups had significant low-contrast acuity loss over time. History of ON was more frequent in benign MS (69% vs 33% of eyes). History of ON distinguished benign vs typical MS (P = 0.002) and correlated with RNFL thick-ness at baseline (P = 0.002) and disease duration (P = 0.03) but not EDSS (P = 0.32, logistic regression). NEI-VFQ-25 scores were also worse for benign MS, accounting for age (75 ± 21 vs 88 ± 11, P = 0.005). These findings dem-onstrated that patients with benign MS have RNFL axonal loss that is as marked as that of typical MS and have reduced vision and QOL. While overall neurologic impair-ment is mild, visual dysfunction, not well-captured by the EDSS, accounts for a substantial degree of disability in benign MS. The Future of OCT in MS: Retinal Segmentation In addition to axonal degeneration, neuronal loss is increasingly recognized as a correlate of disability in MS (16-19,89-91). While investigations of TD-OCT have shown reductions in total macular volume as a potential marker for neuronal loss in MS eyes, more specific mea-surement of the retinal ganglion cell layer (GCL) and other layers by segmentation has only recently emerged fol-lowing the introduction of high-resolution and high-speed-domain (SD) OCT techniques to study MS (Table 1) (25-27,82,92-100). Earlier studies of total macular volume using TD-OCT suggested that retinal ganglion cell neuro-nal loss occurs in MS eyes and that this correlates with visual function (81). These observations were necessarily based on the structural assumption that approximately 34% of the total macular volume is comprised of ganglion cells. Using SD-OCT, some of the first observations of specific retinal GCL loss in MS eyes were generated by a study that involved manual delineation of the GCL on a Spectralis OCT platform (Fig. 4) (97). In this pilot investigation, eyes of patients with MS (n = 16) had signif-icantly lower GCL volumes than control eyes (P , 0.001, accounting for age and within-patient intereye correlations). Lower volumes were noted among MS eyes with a history of ON (n = 4) compared with MS non-ON eyes (P , 0.001). Reduced GCL volumes were not associated with worse high-contrast VA (P = 0.14), but did predict visual loss by low-contrast acuity (P = 0.003). While manual OCT retinal segmentation demonstrated important findings in these studies, the labor-intensive nature of this technique (approximately 2 hours per eye) limits its large scale use in MS cohorts. Computerized segmentation algorithms have been used successfully in studies of glaucoma (99,100) and have provided the basis for 2 recent investigations in MS cohorts. Saidha et al (96) used a segmentation method developed commercially to study patients with a macular thinning predominant (MTP) MS phenotype. These patients have peripapillary RNFL thickness that is within the normal ranges but exhibit severe ,5th percentile thinning of the macular region on SD-OCT. This group of patient eyes demon-strated thinning of the outer retinal layers (P , 0.001 for inner and outer nuclear layers in MTP vs MS eyes), with relative sparing of the GCL. Patients with the MTP phe-notype also had relatively greater degrees of overall neuro-logic disability, suggesting that these individuals may have a distinct or primary process underlying their neuronal loss. Recent pathologic studies of postmortem eyes from heterogeneous MS cohorts (n = 82) demonstrated that the GCL is a site of neuronal dropout in 79% of eyes (101). Retinal ganglion cell loss has also been shown to occur in vivo in mouse models of relapsing-remitting experimental autoimmune encephalomyelitis with optic nerve involve-ment and to be reduced by neuroprotective therapies, such as resveratrol, in these models (102). To examine GCL loss in MS in vivo in patients with MS, our collaborative MS vision research group has used a novel computerized FIG. 4. Single frame of a macular SD-OCT image with retinal layers labeled and the GCL outlined in red, as segmented manually for the GCL volume analysis. From Davies et al (97). Labeling adapted from Werner et al (105). Sakai et al: J Neuro-Ophthalmol 2011; 31: 362-373 369 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. segmentation algorithm developed at the University of Pittsburgh (103). In this study, patients with MS (n = 122 subjects, 239 eyes) and disease-free controls (n = 31 subjects, 61 eyes) underwent Cirrus SD-OCT (Carl Zeiss- Meditec, Dublin, CA). Images were captured using Macular Cube (200 · 200 or 512 · 128) and ONH Cube 200 · 200 scanning protocols. Retinal layer segmentation was performed using algorithms originally designed for studies of glaucoma. Thicknesses of the GCL/inner plexiform layer (GCL+IPL), RNFL, outer plexiform/inner nuclear layer, and outer nuclear/photoreceptor layer were measured and compared in MS vs control eyes as well as MS ON vs non- ON eyes. Since the IPL is a thin layer that is currently inseparable from the GCL using OCT, the combination GCL+IPL is used to estimate GCL thickness. Macular RNFL and GCL+IPL were significantly decreased in MS subjects vs controls (P , 0.001, P = 0.001) and in MS ON eyes vs non-ON eyes (P , 0.001 for both measures). Peri-papillary RNFL, macular RNFL, and GCL+IPL were all significantly correlated with VA (P # 0.001), 2.5% low-contrast acuity (P , 0.001), and 1.25% low-contrast acuity (P # 0.001). Among OCT measurements, reductions in GCL+IPL (P , 0.001) and macular RNFL (P = 0.006) were the most strongly associated with lower (worse) NEI-VFQ-25 and 10-Item Supplement composite scores for QOL; GCL+IPL thinning was significant even account-ing simultaneously for macular RNFL thickness (P = 0.03 for GCL+IPL and P = 0.39 for macular RNFL). These data demonstrate that GCL+IPL thinning is most significantly correlated with both visual function and vision-specific QOL in MS. GCL thickness is likely to emerge as a useful structural marker of disease. These findings parallel those of MRI studies that show gray matter disease as a marker of neurologic disability in MS. Vision and OCT in MS 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 (104). The authors evaluated 19,961 OCT scans 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. How-ever, in Trial 2, technicians were certified and submitted data prospectively according to the study protocol. OCT scans in Trial 2 had higher signal strengths, fewer errors, and more usable data compared to Trial 1 scans. This study showed that certified technicians and prompt transmission of data for ongoing quality control monitoring 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 represents a unique opportunity for studying disease mechanisms and for testing new therapies that involve neuroprotection and repair. The advent of ocular imaging with OCT has allowed investigators to examine in vivo the morphological changes that accompany visual loss. Sensitive visual function tests, including low-contrast letter acuity, have been shown to correlate with OCT measures of axonal and neuronal loss as well as with patient-reported assessments of QOL. 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