Relationship Between Retinal Layer Thickness and Disability Worsening in Relapsing-Remitting and Progressive Multiple Sclerosis

Background: Data regarding the predictive value of optical coherence tomography (OCT)-derived measures are lacking, especially in progressive multiple sclerosis (PMS). Accordingly, we aimed at investigating whether a single OCT assessment can predict a disability risk in both relapsing-remitting MS (RRMS) and PMS. Methods: One hundred one patients with RRMS and 79 patients with PMS underwent Spectral-Domain OCT, including intraretinal layer segmentation. All patients had at least 1 Expanded Disability Status Scale (EDSS) measurement during the subsequent follow-up (FU). Differences in terms of OCT metrics and their association with FU disability were assessed by analysis of covariance and linear regression models, respectively. Results: The median FU was 2 years (range 1-5.5 years). The baseline peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell + inner plexiform layer (GCIPL) were thinner in PMS compared with RRMS (P = 0.02 and P = 0.003, respectively). In the RRMS population, multivariable models showed that the GCIPL significantly correlated with FU disability (0.04 increase in the EDSS for each 1-μm decrease in the baseline GCIPL, 95% confidence interval: 0.006-0.08; P = 0.02). The baseline GCIPL was thinner in patients with RRMS with FU-EDSS >4 compared with those with FU-EDSS ≤4, and individuals in the highest baseline GCIPL tertile had a significantly lower FU-EDSS score than those in the middle and lowest tertile (P = 0.01 and P = 0.001, respectively). These findings were not confirmed in analyses restricted to patients with PMS. Conclusions: Among OCT-derived metrics, GCIPL thickness had the strongest association with short-medium term disability in patients with RRMS. The predictive value of OCT metrics in the longer term will have to be further investigated, especially in PMS.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Relationship Between Retinal Layer Thickness and Disability Worsening in Relapsing-Remitting and Progressive Multiple Sclerosis Maria Cellerino, MD, Luca Priano, MD, Nicolò Bruschi, MD, Giacomo Boffa, MD, Maria Petracca, MD, Giovanni Novi, MD, Caterina Lapucci, MD, Elvira Sbragia, MD, Antonio Uccelli, MD, Matilde Inglese, MD, PhD Background: Data regarding the predictive value of optical coherence tomography (OCT)-derived measures are lacking, especially in progressive multiple sclerosis (PMS). Accordingly, we aimed at investigating whether a single OCT assessment can predict a disability risk in both relapsingremitting MS (RRMS) and PMS. Methods: One hundred one patients with RRMS and 79 patients with PMS underwent Spectral-Domain OCT, including intraretinal layer segmentation. All patients had at least 1 Expanded Disability Status Scale (EDSS) measurement during the subsequent follow-up (FU). Differences in terms of OCT metrics and their association with FU disability were assessed by analysis of covariance and linear regression models, respectively. Results: The median FU was 2 years (range 1–5.5 years). The baseline peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell + inner plexiform layer (GCIPL) were thinner in PMS compared with RRMS (P = 0.02 and P = 0.003, respectively). In the RRMS population, multivariable models showed that the GCIPL significantly correlated with FU disability (0.04 increase in the EDSS for each 1-mm decrease in the baseline GCIPL, 95% confidence interval: 0.006– 0.08; P = 0.02). The baseline GCIPL was thinner in patients with RRMS with FU-EDSS .4 compared with those with FUEDSS #4, and individuals in the highest baseline GCIPL Department of Neuroscience (MC, LP, NB, GB, GN, CL, ES, AU, MI), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy; Departments of Neurology (MP, MI), Icahn School of Medicine at Mount Sinai, New York, New York; and Department of Neurology (AU, MI) Ospedale Policlinico San Martino-IRCCS, Genoa, Italy. Supported in part by the NMSS RG 5120-A-3 to M. Inglese. A. Uccelli received grants and contracts from FISM, Novartis, Fondazione Cariplo, and Italian Ministry of Health; received honoraria or consultation fees from Biogen, Roche, Teva, Merck, Genzyme, and Novartis. M. Inglese received research grants from NIH, DOD, NMSS, FISM, and Teva Neuroscience. The remaining authors report no conflicts of interest. Address correspondence to Matilde Inglese, MD, PhD, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Largo Paolo Daneo 3, 16100 Genova, Italy; E-mail: [e-mail] Cellerino et al: J Neuro-Ophthalmol 2021; 41: 329-334 tertile had a significantly lower FU-EDSS score than those in the middle and lowest tertile (P = 0.01 and P = 0.001, respectively). These findings were not confirmed in analyses restricted to patients with PMS. Conclusions: Among OCT-derived metrics, GCIPL thickness had the strongest association with short-medium term disability in patients with RRMS. The predictive value of OCT metrics in the longer term will have to be further investigated, especially in PMS. Journal of Neuro-Ophthalmology 2021;41:329–334 doi: 10.1097/WNO.0000000000001165 © 2020 by North American Neuro-Ophthalmology Society BACKGROUND M ultiple sclerosis (MS) is characterized by the interaction of inflammatory, demyelinating, and degenerative processes within the central nervous system. Although neuroaxonal degeneration has been recognized as the principal substrate of disability severity and progression, the identification of biomarkers associated with an enhanced risk of disability worsening remains a crucial need in MS (1). Optical coherence tomography (OCT) is a fast, noninvasive, and cost-efficient retinal imaging tool that can provide high-resolution images and measures of the peripapillary retinal nerve fiber layer (pRNFL) and of the different retinal layer volumes. The first OCT devices used time-domain technology (TD-OCT), which could measure the pRNFL thickness and the total macular volume (TMV). With the advent of spectraldomain OCT (SD-OCT) technology, it is possible to assess the different segmented macular layers, including the macular RNFL (mRNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), and outer nuclear layer (ONL). Thinning of pRNFL 329 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution and the combined measure of GCL + IPL (GCIPL) are considered a biomarker of neurodegeneration in MS (2). Previous studies showed that the reduction of pRNFL thickness is predictive of short-term and long-term clinical worsening in terms of the Expanded Disability Status Scale (EDSS) (3,4). With regard to macula-derived measures, TMV has been shown to predict long-term disability (5), whereas the GCIPL thickness has been suggested as an independent risk factor for disability worsening in patients with relapsing-remitting MS (RRMS) (6), as well as a predictor for future disease activity and conversion to MS in patients with clinically isolated syndrome (7). However, data regarding the role of OCT measures in patients with RRMS and progressive MS (PMS) are still sparse, and the predictive value of macula-derived measures has not been extensively studied yet, especially in PMS (1). Accordingly, with this study we aimed at: (1) exploring differences in terms of OCT metrics between a relatively large cohort of RRMS and PMS and (2) investigating whether a single OCT assessment including automated intraretinal layer segmentation may help predict the risk of higher disability at follow-up in the short-medium term in both patients with RRMS and patients with PMS . METHODS Population We conducted an observational, retrospective cohort study based on prospectively acquired clinical data. We enrolled 188 patients with MS from 2 MS centers (166 patients from San Martino-IST Hospital, Genova, Italy, and 22 patients from Icahn School of Medicine Mount Sinai, NY) who underwent SD-OCT between 2014 and 2018. Inclusion criteria were (1) age 18–70 years and (2) MS diagnosis according to the 2010 McDonald criteria (7). If treated, patients needed to be stable on their disease modifying treatment for at least 1 year. Exclusion criteria were (1) substantial ophthalmological pathologies (including iatrogenic optic neuropathy/diabetes/uncontrolled hypertension) (2) refractive errors ±6 diopters (D) and (3) previous bilateral optic neuritis (ON). In patients with previous unilateral ON (n = 44, none occurring during the previous 12 months), only the nonaffected eye was analyzed. In patients without a history of ON, OCT metrics were averaged over the 2 eyes. All patients underwent an EDSS score assessment at baseline and had at least 1 EDSS measurement during the subsequent follow-up. The study was approved by the local ethical committees, and written informed consent was obtained from all participants according to the Declaration of Helsinki. from the center of the optic nerve head; peripapillary measurements were averaged from 100 images and macular estimations from 15 automatic real time. Macular volumetric scans consisting of at least 25 single horizontal axial B-scans were acquired in a rectangular section centered over the macula and segmented automatically into different layers using the Heidelberg Eye Explorer mapping software version 6.0.9.0. Segmented layers were checked and manually corrected, if necessary. Macular RNFL (mRNFL), GCIPL, INL, OPL, and ONL thickness were measured. Scans violating international consensus quality control criteria (8) were excluded (n = 8 patients excluded because of poor OCT quality). Statistics Statistical analyses were performed with SPSS (v22.0). Demographic differences between groups were analyzed using chi-square, Mann–Whitney, and independent samples t tests where appropriate. Differences in terms of baseline OCT metrics between patients with RRMS and patients with PMS were assessed by analysis of covariance (ANCOVA) adjusting for sex; P values of analyses additionally adjusted for age and/or disease duration, treatment, and EDSS are also reported. ANCOVA (accounting for sex, age, disease duration, and treatment) was also used to explore differences in terms of baseline OCT metrics between patients who showed—at the end of follow-up period—a significant disability but were still able to walk without assistance for 500 m (patients with follow-up EDSS #4 vs patients with follow-up EDSS .4) and in terms of follow-up EDSS according to the baseline GCIPL thickness tertile. To investigate the ability of macule-derived measures to predict higher EDSS scores in the follow-up, multivariable linear regression models explored associations between baseline OCT metrics and the most recent available EDSS measures (for this analysis the baseline EDSS was added to the covariates listed above); similar analyses limited to patients with baseline EDSS #4 were additionally performed. In line with the literature (5), we chose to use this approach because analyzing the changes in the EDSS over a specific period of time could be partly influenced by the baseline EDSS score (i.e., more likely for patients with the lower baseline EDSS to experience a sustained change in the EDSS over time). All P values were 2-sided and considered statistically significant when P # 0.05. RESULTS Optical Coherence Tomography The standardized SD-OCT protocols (Spectralis, Heidelberg-Engineering) were performed and processed by a single certified neurologist, in accordance with the APOSTEL recommendations (8). The pRNFL was obtained with a 360° RNFL-B circle scan located at 3.4 cm 330 Population Characteristics Of the 188 patients initially enrolled, 8 patients were excluded because of poor OCT quality. Accordingly, a total of 180 patients (101 RRMS and 79 PMS) entered the final analysis. Demographic, clinical, and OCT data are reported Cellerino et al: J Neuro-Ophthalmol 2021; 41: 329-334 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution in Table 1. Among the progressive population, 77% of subjects were primary PMS (PPMS). Sex composition differed between patients with RRMS and patients with PMS (women: 74% of RRMS and 47% of PMS subjects, P , 0.0001); sex was consequently included as a covariate in all the analyses comparing RRMS and PMS. As expected, progressive patients were older and presented higher disease duration and EDSS scores than relapsing subjects (P , 0.0001, P = 0.002 and P , 0.0001, respectively); a statistically significant lower percentage of progressive patients compared with relapsing patients (40% vs 93%, P , 0.0001) were under treatment. Accordingly, differences in terms of OCT metrics additionally adjusted for all the variables listed above were also explored. Optical Coherence Tomography Metrics Diferrences According to Disease Subtype At baseline, we observed a lower thickness of both pRNFL (25.5 ± 1.6 mm) and GCIPL (24.5 ± 1.2 mm) in patients with PMS compared with patients with RRMS. Such difference reached statistical significance for both pRNFL and GCIPL when analyses were adjusted for sex (P = 0.02 and P = 0.003, respectively). When age was included as a covariate in the model the difference remained significant only with respect to the GCIPL (P = 0.03). ANCOVA additionally corrected for disease duration, baseline EDSS, and treatment to account for different stages of disease severity did not show differences in pRNFL or GCIPL thickness according to MS subtypes. None of the analyses described above showed any difference in terms of other maculaderived measures between patients with RRMS and patients with PMS (Table 1). Relationship Between Baseline Optical Coherence Tomography Metrics and Disability at Follow-Up The median follow-up (FU) period was 2 years (range 1–5.5 years). Considering the global population, multivariable models including all the OCT metrics did not find any association between baseline OCT measures and FU-EDSS scores. However, when analyses were restricted to patients with RRMS, we observed that the GCIPL was the only OCT metric significantly associated with subsequent disability (0.04 increase in the EDSS for each 1-mm decrease in the baseline GCIPL, 95% confidence interval [CI]: 0.006–0.08; P = 0.02). No association between OCT metrics and FUEDSS scores emerged when considering patients with PMS alone. Associations between baseline GCIPL thickness and FU-EDSS score in patients with RRMS and patients with PMS are shown in Figure 1. Analyses restricted to patients with baseline EDSS #4 (N = 120; RRMS N = 92; PMS N = 28) showed similar results; in particular, we observed 0.05 increase in the EDSS for each 1-mm decrease in the baseline GCIPL, 95% CI: 0.008–0.08; P = 0.018 in patients with RRMS with baseline EDSS #4, whereas no associations between baseline OCT metrics and disability at follow-up were observed in the global population and in patients with PMS with baseline EDSS #4. Further subgroup analyses showed that the GCIPL thickness at baseline was lower in patients presenting EDSS .4 (76.1 ± 12.7 mm) compared with those with EDSS #4 (81.2 ± 9.9 mm) at follow-up (P = 0.03). Similar results were observed when considering only patients with RRMS but not patients with PMS (Fig. 2). Other OCT metrics did not differ at baseline according to the EDSS score at follow-up. TABLE 1. Demographics, clinical, and OCT variables of global MS population RRMS (n = 101) Demographics PPMS, n (%) Age, mean (SD), y Female, n (%) Disease duration, mean (SD), y EDSS score at baseline, median (range) EDSS score at follow-up, median (range) OCT metrics pRNFL, mean (SD) mRNFL, mean (SD) GCIPL, mean (SD) INL, mean (SD) OPL, mean (SD) ONL mean (SD) PMS (n = 79) P Value* — 39 (10.3) 75 (74%) 8.4 (6.5) 2 (0–6) 2.5 (0–6) 61 49 37 11.8 5 5.5 (77) (10.7) (47%) (8.1) (1.5–7.5) (1.5–8) — ,0.0001 ,0.0001 0.002 ,0.0001 ,0.0001 96.2 (13.7) 19.3 (1.9) 81.1 (10.4) 37.2 (3.4) 33.3 (5.3) 73.8 (15.2) 90.7 19.8 76.5 37.5 34.1 72.6 (12.1) (3.1) (12.1) (3.6) (4.3) (8.5) 0.02 n.s. 0.003 n.s. n.s. n.s. *P values for the RRMS vs PMS comparison; independent samples t test (age), chi-square (sex, treatment), Mann–Whitney (disease duration, EDSS), ANCOVA adjusted for sex (OCT measures), OCT metrics (thickness) are expressed in micron. EDSS, expanded disability status scale; GCIPL, ganglion cell layer + inner plexiform layer; INL, inner nuclear layer; mRNFL, macular retinal nerve fiber layer; ONL, outer nuclear layer; OPL, outer plexiform layer; PMS, progressive multiple sclerosis; PPMS, primary progressive multiple sclerosis; pRNFL, peripapillary retinal nerve fiber layer; RRMS, relapsing-remitting multiple sclerosis; OCT, optical coherence tomography; y, years. Cellerino et al: J Neuro-Ophthalmol 2021; 41: 329-334 331 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution only between individuals in the lowest and those in the highest tertile (P = 0.006). DISCUSSION FIG. 1. Association between baseline GCIPL thickness and Expanded Disability Status Scale (EDSS) score at the end of follow-up period in patients with RRMS and patients with PMS. GCIPL, ganglion cell layer + inner plexiform layer; PMS, progressive multiple sclerosis; RRMS, relapsingremitting multiple sclerosis. Once GCIPL was identified as the macular layer with the strongest association with short-medium term disability, we explored differences in terms of FU-EDSS scores according to the GCIPL thickness tertile at baseline. As shown in Figure 3, differences across the 3 tertiles were statistically significant when considering the global population and in analysis restricted to RRMS subjects (ANCOVA P values 0.008 and 0.02, respectively) but did not reach significance in the PMS population. A post hoc analysis showed that, in the global population, individuals in the highest GCIPL tertile had a significantly lower EDSS score at the end of the follow-up period compared with those in the middle and the lowest tertile (P = 0.01 and P = 0.001, respectively). Considering only RRMS subjects, we observed a significant difference in terms of FU-EDSS score We conducted an analysis of OCT metrics in patients with MS, including a relatively large number of patients with a progressive disease course. First, we observed that—in line with previous findings (10,11)—both pRNFL and GCIPL were significantly different between RRMS and PMS; however, after adjusting for age, the difference remained significant only for the GCIPL; significance disappeared when disease duration, EDSS, and treatment were included as covariates. Although data regarding macula-derived measures in patients with PMS are limited, our findings seem to confirm those of a previous study (11), where lower GCIPL and RNFL values were observed in secondary PMS (SPMS) compared with RRMS, but after correcting for disease duration, this was only significant with respect to the GCIPL. Regarding the association between OCT metrics and subsequent disability, we observed that among OCTderived metrics GCIPL thickness had the strongest association with EDSS scores in the short-medium term followup; however, such association was statistically significant in RRMS but not in patients with PMS. Although one work (6) already suggested that the GCIPL could be a predictor of disability worsening in RRMS, to the best of our knowledge, its predictive value in patients with PMS had never been investigated. In a large previous study focused on the pRNFL (3), which did not segment retinal layers and thus could not explore the predictive value of GCIPL, MartinezLapiscina et al suggested that a single OCT assessment (including only pRFNL and TMV) could be predictive of disability worsening in MS; however, on par with our findings, they did not detect significant differences in baseline OCT features between patients with PMS whose disability worsened and those who remained stable. The weak correlation between baseline OCT metrics and subsequent FIG. 2. Baseline GCIPL thickness according to follow-up Expanded Disability Status Scale (EDSS) score # or .4 in the whole population, patients with RRMS, and patients with PMS. *P values for ANCOVA adjusted for sex, age, disease duration, and treatment. FU-EDSS, follow-up EDSS; GCIPL, ganglion cell layer + inner plexiform layer; PMS, progressive multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis. 332 Cellerino et al: J Neuro-Ophthalmol 2021; 41: 329-334 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. FU-EDSS scores according to baseline GCIPL thickness in the whole population, patients with RRMS, and patients with PMS. Lowest tertile: #76.3 mm; middle tertile: 76.3–84.9 mm; and highest tertile: .84.9 mm; *P values for ANCOVA adjusted for sex, age, disease duration, and treatment; **P values for post hoc analysis. FU-EDSS, follow-up Expanded Disability Status Scale; GCIPL, ganglion cell layer + inner plexiform layer; PMS, progressive multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis. disability in patients with a progressive disease course might be partly explained by the disproportioned retinal injury resulting from higher age, disease duration, and baseline disability, which characterize patients with PMS. Our findings in PMS might be additionally explained by the fact that most of our patients with PMS were PPMS (77%); indeed, the relative sparing of retinal layers in patients with PPMS compared with SPMS is in accordance with several other studies (12,13). It is well known that the afferent visual pathways are less often affected in PPMS than in other disease phenotypes and that there is limited reflection of spinal cord damage (which largely explains disability in patients with PPMS) in the retinal layers. Furthermore, patients with PMS do not always progress uniformly and may remain relatively stable over periods of time; we cannot exclude that a longer follow-up would bring to light an association between baseline retinal atrophy and future clinical worsening. Regarding our observations in the RRMS group, an important finding of our study (including all the retinal layers) is that GCIPL thickness was associated with subsequent disability (FU-EDSS up to 5 years) even accounting for baseline EDSS, whereas the pRNFL was not. We believe that it could be related to the design of our study, which accounts for baseline disability and includes in the analysis all the retinal layer rather than the pRNFL alone (3,4); in this context the study by Rothman et al (5), which had a similar design, reaches similar conclusions (although regarding TMV instead of GCIPL, as their study used TD-OCT and they could not separately examine the GCIPL). Taken together, our findings point at GCIPLs as the OCT measure that better captures neuroaxonal degeneration in MS, especially in patients with a relapsing disease course. Despite increasing evidence suggesting that relapsing and progressive MS represent a different spectrum of the same disease and that the progressive processes start early in the disease (1), the distinction between patients with RRMS and patients with PMS Cellerino et al: J Neuro-Ophthalmol 2021; 41: 329-334 patients is still widely used in clinical practice and often influences treatment choice (8,14); accordingly, identification of biomarker that can help in predicting a higher risk of disability worsening according to the definition of “relapsing” or “progressive” disease course remains crucial for the management of patients with MS (15). 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