# Effect of siponimod on retinal thickness, a marker of neurodegeneration, in participants with SPMS: Findings from the EXPAND OCT substudy.

Patrick Vermersch, R. Gold, A. Bar-Or, B. A. C. Cree, R. J. Fox, G.

Giovannoni, F. Paul, S. Wolf, B. Li, M. C. Mousseau, et al.

<figure><img src="image_1.png" /></figure>

## To cite this version:

Patrick Vermersch, R. Gold, A. Bar-Or, B. A. C. Cree, R. J. Fox, et al. Effect of siponimod on retinal thickness, a marker of neurodegeneration, in participants with SPMS: Findings from the EXPAND OCT substudy. Multiple Sclerosis and Related Disorders, 2025, Multiple Sclerosis and Related Disorders, 94, pp.106259. 10.1016/j.msard.2025.106259. hal-04942056

HAL Id: hal-04942056

https://lilloa.hal.science/hal-04942056v1

Submitted on 12 Feb 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

# Effect of siponimod on retinal thickness, a marker of neurodegeneration, in participants with SPMS: Findings from the EXPAND OCT substudy

Patrick Vermersch<sup>a, *, b</sup>, Ralf Gold<sup>b</sup>, Amit Bar-Or<sup>c</sup>, Bruce A.C. Cree<sup>d</sup>, Robert J. Fox<sup>e</sup>,
Gavin Giovannoni<sup>f</sup>, Friedemann Paul<sup>g</sup>, Sebastian Wolf<sup>h</sup>, Bingbing Li<sup>i</sup>,
Marie-Catherine Mousseau<sup>j</sup>, Tina Maio-Twofoot<sup>k</sup>, Xiaofang Shi<sup>l</sup>, Ludwig Kappos<sup>m</sup>

## ARTICLE INFO

**Keywords:**

Optical coherence tomography

Retinal thickness

Macular ganglion cell and inner plexiform layers

Secondary progressive MS

Siponimod

## ABSTRACT

**Background:** People with MS show abnormal thinning of the retinal layers, which is associated with clinical disability and brain atrophy, and is a potential surrogate marker of neurodegeneration and treatment effects.

**Objective:** To evaluate the utility of retinal thickness as a surrogate marker of neurodegeneration and treatment effect in participants with secondary progressive MS (SPMS) from the optical coherence tomography (OCT) substudy of the EXPAND Phase 3 clinical trial (siponimod versus placebo).

**Methods:** In the OCT substudy population (n = 159), treatment effects on change in the average thickness of the retinal layer, peripapillary retinal nerve fiber layer (pRNFL), and combined macular ganglion cell and inner plexiform layers (GCIPL) were analyzed by high-definition spectral domain OCT at months 3, 12, and 24.

**Results:** Thinning from baseline was observed across all retinal layers and time points in the placebo group. Siponimod significantly reduced GCIPL thinning versus placebo at month 24 (adjusted mean [SE] [µm]: -0.47 [0.81] vs. -4.29 [1.23]; *p* = 0.01), and overall retinal thinning at months 12 (+0.66 [0.54] vs. -1.86 [0.75]; *p* = 0.006) and 24 (-0.05 [0.59] vs. -2.30 [0.88]; *p* = 0.033). Although not significant, results for pRNFL consistently followed the same trends.

**Conclusion:** This exploratory substudy supports further investigation of OCT measurement of retinal atrophy as a non-invasive potential biomarker of treatment effects on neurodegeneration in SPMS.

## 1. Introduction

In people with multiple sclerosis (MS), the retinal layers show abnormal thinning over time reflecting neuroaxonal loss (Green et al.,

2010; Khanifar et al., 2010; Kuchling and Paul, 2020; Parisi et al., 1999; Paul et al., 2021; Petzold et al., 2017). Measurements of retinal layer thinning by optical coherence tomography (OCT) are highly reproducible, allowing longitudinal follow-up of retinal structures (Garcia-Martin

<footnote><sup>a</sup> Univ. Lille, INSERM U1172, CHU Lille, FHU Precise, Lille, France</footnote>

<footnote><sup>b</sup> Department of Neurology, St Josef-Hospital/Ruhr-University Bochum, Bochum, Germany</footnote>

<footnote><sup>c</sup> Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA</footnote>

<footnote><sup>d</sup> Department of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA</footnote>

<footnote><sup>e</sup> Mellen Center for Treatment and Research in Multiple Sclerosis, Neurological Institute, Cleveland, OH, USA</footnote>

<footnote><sup>f</sup> Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom</footnote>

<footnote><sup>g</sup> NeuroCure Clinical Research Center, Charité, Department of Neurology, Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité Universitätsmedizin Berlin, Berlin, Germany</footnote>

<footnote><sup>h</sup> University Hospital of Ophthalmology, Bern, Switzerland</footnote>

<footnote><sup>i</sup> Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA</footnote>

<footnote><sup>j</sup> Novartis Ireland Ltd, Dublin, Ireland</footnote>

<footnote><sup>k</sup> Novartis Pharma AG, Basel, Switzerland</footnote>

<footnote><sup>l</sup> China Novartis Institutes for Biomedical Research Co, Ltd., Shanghai, China</footnote>

<footnote><sup>m</sup> Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Departments of Head, Spine and Neuromedicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital and University of Basel, Basel, Switzerland</footnote>

<footnote>* Corresponding author at: Univ. Lille, Inserm U1172 LilNCog, CHU Lille, FHU Precise, Lille, France.</footnote>

<footnote>E-mail address: patrick.vermersch@univ-lille.fr (P. Vermersch).</footnote>
et al., 2011; Paul et al., 2021). Not confounded by myelin, OCT measures have a spatial resolution (~5 µm) approximately 2–3 orders of magnitude greater than magnetic resonance imaging (MRI), making OCT an ideal tool for assessing neuroaxonal degeneration and treatment effects (Alonso et al., 2018; García-Martín et al., 2010; Graves, 2019; Mehmood et al., 2021; Paul et al., 2021; Siger et al., 2008).

Thinning of retinal layers is associated with MS-related disability, brain atrophy, and disability progression (Alonso et al., 2018; Frau et al., 2018; Gordon-Lipkin et al., 2007; Martinez-Lapiscina et al., 2016; Mir-mosayyeb et al., 2023; Oertel et al., 2019; Paul et al., 2021; Saidha et al., 2015; Swinnen et al., 2023; Vidal-Jordana et al., 2020). Retinal layers include the peripapillary retinal nerve fiber layer (pRNFL), which contains primarily unmyelinated axons emerging from retinal ganglion cell neurons, and the combined ganglion cell and inner plexiform layers (GCIPL), where the axons forming pRNFL originate (Petzold et al., 2017). While some evidence suggests that retinal (more specifically GCIPL) and whole brain atrophy are more strongly associated in progressive MS than in relapsing MS (Saidha et al., 2015), other studies questioned this association in the later stage of the disease due to a plateau or ‘floor effect’ wherein pRNFL and GCIPL atrophy can no longer be detected below a certain level of total thickness (Balk et al., 2016; Winges et al., 2019).

EXPAND was the largest Phase 3 study of participants with secondary progressive MS (SPMS) to date (N = 1651) and siponimod was the first disease-modifying therapy approved in this population (Cree et al., 2022; Kappos et al., 2018). The EXPAND OCT substudy was conducted in a subgroup of EXPAND participants. The objective was to explore the utility of the OCT-measured average retinal layer thickness (including average pRNFL and papillo-macular bundle RNFL [pmbRNFL], GCIPL, and overall retinal thickness) and their subfields as potential markers of axonal degeneration and disability progression in SPMS. The treatment effect on thinning of the different retinal layers, as well as correlations of OCT measures with clinical and radiological outcomes, was explored.

## 2. Methods

### 2.1. Study design and participants

The core part of the EXPAND trial (NCT01665144) was an event-driven, randomized, multicenter, double-blind, placebo-controlled, parallel-group study of variable duration (median 21 months [range 0.2–37.0]) in 1651 participants with SPMS from 294 sites randomized (2:1) to receive either siponimod or placebo (Fig. 1). Details of the EXPAND study including inclusion and exclusion criteria were presented in Kappos et al. (Kappos et al., 2018). This OCT substudy included 159 participants at a subset of sites (29), whose participation was based on access to high-definition (HD) spectral domain OCT machines. Because this substudy was purely exploratory, no pre-defined number of participants was required, and no additional inclusion/exclusion criteria had to be fulfilled. A sensitivity analysis was performed in a subgroup of participants within the substudy, in which those with ongoing ophthalmic disease at the time of screening were excluded (restricted analysis set).

### 2.2. Optical coherence tomography (OCT)

OCT assessments were performed for all participants from the substudy at screening; months 3, 12, 24, 36; and end of treatment/end of study using HD spectral domain OCT machines (including Spectralis™ HRA+OCT [Heidelberg Engineering, Germany] and Cirrus HD-OCT™ [Zeiss, Germany]). The number of available observations at month 36 was very low (three participants) and precluded any conclusions to be drawn. The standard procedure for the acquisition and transmission of OCT examination data was provided in an OCT manual to the sites. Either Nsite-software or standard ophthalmology software were used for image acquisition. OCT images were transferred (blinded to participant name and date of birth) to an independent OCT reading center (Bern Photographic Reading Center [BPRC]) for central evaluation. A

<figure><img src="image_5.png" /><figcaption>**Fig. 1.** EXPAND and OCT substudy design. In the core part OCT assessments were performed at screening and months 3, 12, 24 and 36. Open-label started when patient had an “event.” EDSS, Expanded Disability Status Scale; EoCP, end of core phase; OCT, optical coherence tomography; ophtha exam, ophthamologic examination.</figcaption></figure>
qualified reader at BPRC performed the image grading applying standardized measurement algorithms for retinal thickness and sublayer segmentation. The assessments were conducted and described in accordance to the quality control criteria at the BPRC, which contributed to the establishment of the OSCAR-IB and APOSTEL criteria (Cruz-Herranz et al., 2016; Schippling et al., 2015), now standard for reporting OCT study results. No minimum quality level was defined. The detailed OCT scanning protocol is provided as supplementary data. pRNFL thickness was measured either from the optic nerve head scans (on a circular ring around the optic nerve head; Spectralis) or derived from the optic disc cube scan (Cirrus). Besides the main pRNFL thickness on the ring ('average pRNFL thickness'), various segments of the ring were also measured separately. Subfield areas of mean pRNFL thickness were temporal, nasal superior, temporal superior, nasal inferior, and temporal inferior. The papillo-macular bundle (pmb) thickness was also measured and analyzed (measure available for sites using Spectralis only). GCIPL thickness and overall retinal thickness as well as their respective subfields (central area, inner superior, inner temporal, inner inferior, and inner nasal) were derived from macular cube scans (Spectralis or Cirrus). The thickness of each OCT parameter and subfield was calculated as the mean value of all Amplitude scans (A-scans; type of scan that measure distances between layers with different light reflectances) in the related area.

## 2.3. Statistical methodology

Participants of the OCT substudy had a baseline and one or more postbaseline OCT measurements in at least one eye rated as a valid assessment (Fig. 1). The end of treatment/end of study assessments if available were mapped to protocol scheduled visits according to pre-specified visit-windows/time points. Summary statistics were provided for the change from baseline in the OCT variables (average pRNFL thickness, pmb thickness, GCIPL thickness, overall retinal thickness, and

their subfields) by eye (left, right and both), time point and treatment. The between treatment difference in change from baseline in the OCT variables of interest were assessed using a mixed-model repeated measures (MMRM) approach to consider results from all available time points. The model was adjusted for treatment, age, sex, time point, treatment by time point interaction, and respective baseline OCT variables. The result from each time point were nested in eye and participant to allow for inter-eye and intra-participant dependencies. No adjustment for multiplicity was performed; p-value < 0.05 will be interpreted as 'nominally' significant rather than statistically significant.

A post hoc sensitivity analysis was conducted with adjustment for baseline MRI variables and MS duration as additional covariates to address imbalances in disease characteristics between treatment groups. Another post hoc sensitivity analysis assessed the treatment effect on the percentage change from baseline for each of the OCT measures.

Correlations (based on Pearson's coefficient [r]) were explored graphically between the main OCT variables of interest and the following clinical and visual acuity variables: percentage brain volume change from baseline (overall, cortical grey matter, thalamus) and change from baseline in: Expanded Disability Status Scale (EDSS) score; Symbol Digit Modalities Test (SDMT) score; lower contrast visual acuity (LCVA) score; T2 lesion volume (transformed by taking the cube root since this has shown to produce linear relationships when compared to pRNFL thickness); and T1 hypointense lesion volume.

## 2.4. Ethics

The study protocol and all amendments were reviewed by the Independent Ethics Committee or Institutional Review Board for each center. The study was conducted according to the International Council for Harmonization E6 Guideline for Good Clinical Practice that have their origin in the Declaration of Helsinki (World Medical Association, 2024).

<table><caption>**Table 1**
Baseline demographics and disease characteristics.</caption><thead><tr><th rowspan="2"></th><th colspan="2">OCT substudy population<sup>a</sup></th><th>Remaining study population<sup>b</sup></th></tr><tr><th>Placebo, N = 55</th><th>Siponimod, N = 104</th><th>Total, N = 1486</th></tr></thead><tbody><tr><td>Age, years</td><td>48.1 (7.4)</td><td>48.4 (6.9)</td><td>48.0 (8.0)</td></tr><tr><td>Female, n (%)</td><td>35 (63.6)</td><td>58 (55.8)</td><td>894 (60.2)</td></tr><tr><td><strong>Race, n (%)</strong></td><td></td><td></td><td></td></tr><tr><td>White</td><td>51 (92.7)</td><td>102 (98.1)</td><td>1406 (94.6)</td></tr><tr><td>Black or African American</td><td>3 (5.5)</td><td>2 (1.9)</td><td>5 (0.3)</td></tr><tr><td>Asian</td><td>0 (0.0)</td><td>0 (0.0)</td><td>48 (3.2)</td></tr><tr><td>Unknown</td><td>0 (0.0)</td><td>0 (0.0)</td><td>10 (0.7)</td></tr><tr><td>Other</td><td>1 (1.8)</td><td>0 (0.0)</td><td>17 (1.1)</td></tr><tr><td><strong>Ethnicity, n (%)</strong></td><td></td><td></td><td></td></tr><tr><td>Hispanic or Latino</td><td>12 (21.8)</td><td>17 (16.3)</td><td>77 (5.2)</td></tr><tr><td>Not Hispanic or Latino</td><td>30 (54.5)</td><td>52 (50.0)</td><td>1151 (77.5)</td></tr><tr><td>Not reported</td><td>6 (10.9)</td><td>11 (10.6)</td><td>136 (9.2)</td></tr><tr><td>Unknown</td><td>7 (12.7)</td><td>24 (23.1)</td><td>122 (8.2)</td></tr><tr><td>EDSS</td><td>5.4 (1.1)</td><td>5.3 (1.2)</td><td>5.4 (1.1)</td></tr><tr><td>SDMT</td><td>42.2 (12.3)</td><td>39.9 (12.7)</td><td>38.9 (13.9)</td></tr><tr><td>≥1 Gd+ T1 lesion at baseline, n (%)</td><td>7 (12.7)</td><td>19 (18.3)</td><td>324 (21.8)</td></tr><tr><td>Patients with no relapses in the last year prior to screening, n (%)</td><td>44 (80.0)</td><td>81 (77.9)</td><td>1165 (78.4)</td></tr><tr><td>Number of relapses in the last year prior to screening</td><td>0.3 (0.6)</td><td>0.3 (0.6)</td><td>0.3 (0.6)</td></tr><tr><td>Number of relapses in the last 2 years prior to screening</td><td>0.6 (1.4)</td><td>0.6 (1.1)</td><td>0.7 (1.2)</td></tr><tr><td>Volume of T1 lesions, mm<sup>3</sup></td><td>3923.7, (4278.2)</td><td>7006.7, (9205.2)</td><td>6556.6, (8505.4)</td></tr><tr><td>Volume of T2 lesions, mm<sup>3</sup></td><td>10,717.5, (10,666.7)</td><td>15,658.2, (16,825.9)</td><td>15,431.6, (16,091.1)</td></tr><tr><td>Normalized brain volume, cc</td><td>1431.4 (81.5)</td><td>1414.8 (85.0)</td><td>1423.0 (87.1)</td></tr><tr><td>MS duration since diagnosis, years</td><td>10.8 (7.2)</td><td>13.3 (8.2)</td><td>12.6 (7.7)</td></tr><tr><td>MS duration since first symptom, years</td><td>14.1 (7.9)</td><td>17.7 (8.7)</td><td>16.8 (8.3)</td></tr><tr><td>Time since conversion to SPMS, years</td><td>2.7 (1.9)</td><td>3.6 (3.9)</td><td>3.8 (3.5)</td></tr></tbody></table>

Data are expressed as mean (SD) unless specified otherwise.

<footnote><sup>a</sup> OCT substudy FAS, a subset of FAS that includes participants with a baseline and at least one postbaseline OCT measurement in at least one eye rated as a valid assessment.</footnote>

<footnote><sup>b</sup> Includes FAS participants that are not in the OCT FAS. N is the number of participants in the corresponding group. EDSS, Expanded Disability Status Scale; FAS, full analysis set; Gd+, gadolinium-enhancing; MRI, magnetic resonance imaging; OCT, optical coherence tomography; SD, standard deviation; SDMT, Symbol Digit Modalities Test.</footnote>
All participants gave written informed consent before screening. The study information included the evaluation of OCT images obtained during the study as part of ophthalmic examinations.

# 3. Results

## 3.1. Participants

The OCT full analysis set comprised 159 participants (approximately 10 % of the EXPAND population); 104 participants in the siponimod group and 55 participants in the placebo group. Baseline demographic characteristics were generally balanced across the two groups. The mean age was 48.3 years. The majority of participants were female (58.5 %) and White (96.2 %). The proportions in each category were similar to those observed in the remaining EXPAND core part except for the higher proportion of participants of Hispanic and Latino origin in the substudy (Table 1).

Groups generally had similar baseline characteristics in line with the overall study population, except for some imbalance observed for disease duration/time since conversion to SPMS, T2 lesion volume and level of inflammatory activity at baseline, suggesting that MS disease in the placebo group was somewhat less severe/advanced than in the siponimod group and the rest of the study population. (Table 1). A total of 7 participants (6.7 %) in the siponimod group had a history of optic neuritis, compared to 3 participants (5.5 %) in the placebo group. Among these, 4 participants (3.8 %) in the siponimod group and 1 participant (1.8 %) in the placebo group had ongoing optic neuritis at the time of screening. The mean thickness of OCT parameters at baseline was also consistently slightly lower in the siponimod group compared with the placebo group (Table 2). Most (97.5 %) participants were scanned using the same device throughout the study; only four patients had their final visit performed on a different platform.

## 3.2. Longitudinal analysis of OCT parameters

The change of average pRNFL thickness, GCIPL thickness and overall retinal thickness is presented in Fig. 2.

<table><caption>**Table 2**
Baseline ocular related characteristics at eye level.</caption><thead><tr><th rowspan="3">Mean</th><th colspan="4">OCT substudy population<sup>a</sup></th></tr><tr><th colspan="2">Placebo, N = 55</th><th colspan="2">Siponimod, N = 104</th></tr><tr><th>Right eye</th><th>Left eye</th><th>Right eye</th><th>Left eye</th></tr></thead><tbody><tr><td>LCVA, logMAR</td><td>n = 54<br>0.04 (0.12)</td><td>n = 53<br>0.06 (0.22)</td><td>n = 103<br>0.07 (0.17)</td><td>n = 103<br>0.12 (0.25)</td></tr><tr><td>Global RNFL, µm</td><td>n = 53<br>85.0 (13.6)</td><td>n = 52<br>84.0 (13.7)</td><td>n = 98<br>79.1 (13.5)</td><td>n = 96<br>77.7 (14.9)</td></tr><tr><td>GCIPL, µm</td><td>n = 55<br>70.3 (12.7)</td><td>n = 54<br>70.1 (12.4)</td><td>n = 101<br>66.6 (11.8)</td><td>n = 100<br>65.7 (12.1)</td></tr><tr><td>Retinal thickness, µm</td><td>n = 55<br>304.0 (21.9)</td><td>n = 54<br>302.8 (21.7)</td><td>n = 102<br>300.2 (21.6)</td><td>n = 101<br>300.3 (20.6)</td></tr></tbody></table>

Data are expressed as mean (SD) unless specified otherwise.

<sup>a</sup> OCT substudy FAS, a subset of FAS that includes participants with a baseline and at least one postbaseline OCT measurement in at least one eye rated as a valid assessment. GCIPL thickness derived as the average of central area, inner inferior, inner nasal, inner superior and inner temporal GCIPL thickness if at least 4 out of 5 measurements are nonmissing at the respective visit, by right and left eye respectively. Retinal thickness derived as the average of central area inner inferior, inner nasal, inner superior and inner temporal thickness if at least 4 out of 5 measurements are nonmissing at the respective visit, by right and left eye respectively. N is the number of participants in the FAS; n is the number of participants with nonmissing value. FAS, full analysis set; GCIPL, ganglion cell and inner plexiform layers; LCVA, lower contrast visual acuity; OCT, optical coherence tomography; RNFL, retinal nerve fiber layer.

### 3.2.1. Average pRNFL and pmbRNFL thickness

In the model-based analysis, a consistent numerical decrease in average pRNFL thickness from baseline was observed in the placebo group at months 3, 12 and 24; this was not the case for the siponimod group, wherein the average pRNFL thickness remained stable through month 24. The differences between treatment groups were not significant (Fig. 2A). No clear trend in change in mean pmbRNFL thickness over time was observed with either siponimod or placebo and there was no significant difference in the change from baseline in pmbRNFL thickness at any time point between the treatment groups (data not shown).

### 3.2.2. GCIPL thickness

For GCIPL thickness, a decrease over time was observed for placebo at months 12 and 24 (Fig. 2B). A similar decrease was seen in the siponimod group at month 12, but not at month 24, where a nominally significant difference in favor of siponimod was found (adjusted mean [SE]: -0.47 [0.81] µm with siponimod vs -4.29 [1.23] µm with placebo, *p* = 0.01).

### 3.2.3. Overall retinal thickness

A consistent decrease in mean retinal thickness was observed over time for placebo, but not for siponimod (Fig. 2C). This difference favored siponimod from month 12 onwards, with adjusted mean (SE) of siponimod versus placebo of +0.66(0.54) µm versus -1.86(0.75) µm (*p* = 0.006) at month 12 and -0.05(0.59) µm versus -2.30(0.88) µm (*p* = 0.033) at month 24.

## 3.3. Sensitivity analyses

The results of sensitivity analyses after adjusting for baseline MRI variables and duration of MS since first symptom were consistent with the preplanned analyses across all OCT measures. Percentage changes from baseline were in line with absolute changes across all OCT measures (Supplementary Fig. 1). The sensitivity analyses performed on the restricted OCT analysis set excluding participants with ongoing ophthalmic disease produced similar results for all OCT thickness measures and time points.

## 3.4. Subfields areas

At month 24, across all OCT measures, all the subfield areas except for the temporal pRNFL consistently showed numerically less thinning in participants treated with siponimod compared to those treated with placebo (Fig. 3). The treatment effect on thinning was nominally significant for most GCIPL subfields (central, inner superior, inner temporal, inner nasal) (Fig. 3B); however, no significance was reached for most pRNFL and retinal subfields (Fig. 3A and C).

## 3.5. Correlation between OCT variables and MRI and clinical outcomes

For the overall sub-study population, no correlation was apparent between change from baseline in any of the main OCT variables (average pRNFL, pmbRNFL, GCIPL, and overall retinal thickness) and percentage brain volume change, or changes in EDSS, SDMT, LCVA, T2 lesion volume, and T1 hypointense lesion volume from baseline. Low correlations were found at month 24 between change from baseline in pmbRNFL (r = 0.31 and 0.39 for the right and left eye, respectively) or overall retinal thickness (r = 0.47 and 0.22 for the right and left eye, respectively) and change from baseline in cortical grey matter volume. A low correlation was found between the change from baseline in GCIPL thickness and the change from baseline in EDSS at month 24 (r = 0.37 and 0.31 for the right and left eye, respectively). This positive correlation, suggesting that a worsening of EDSS was associated with higher GCIPL thickness, was weak and mostly driven by two data points only.
<figure><img src="image_6.png" /><figcaption>**Fig. 2.** Adjusted means (95 % CI) of change from baseline in retinal layers. A) pRNFL thickness; B) GCIPL thickness; C) retinal thickness. GCIPL thickness was calculated as the average of central area, inner inferior, inner nasal, inner superior and inner temporal GCIPL thickness if at least 4 out of 5 measurements were nonmissing at the respective visit, for the right and left eye, respectively. Retinal thickness was calculated as the average of the central area, inner inferior, inner nasal, inner superior and inner temporal thickness if at least 4 out of 5 measurements were nonmissing at the respective visit, for the right and left eye, respectively. Negative values correspond to a decrease from baseline. CI, confidence interval; GCIPL, ganglion cell and inner plexiform layers; pRNFL, peripapillary retinal nerve fiber layer. N' is the number of participants included in the analysis (i.e., with at least one postbaseline value and nonmissing covariates). Models were adjusted for treatment, age, sex, baseline value and treatment by time point interaction.</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>**Fig. 3.** Adjusted means (95 % CI) of change from baseline in retinal subfields. A) pRNFL subfields; B) GCIPL subfields; C) retinal subfields. Negative values correspond to a decrease from baseline. CI, confidence interval; GCIPL, ganglion cell and inner plexiform layers; pRNFL, peripapillary retinal nerve fiber layer. N' is the number of participants included in the analysis (i.e., with at least one postbaseline value and nonmissing covariates). The models were adjusted for treatment, age, sex, baseline value and treatment by time point interaction.</figcaption></figure>

## 4. Discussion

This OCT substudy, conducted as part of the core part of the EXPAND study, was designed to evaluate change in the OCT-measured thickness of several retinal layers in participants with SPMS treated with siponimod versus placebo and followed for 2 years (variable duration up to 3 years). The objective was to explore the utility of retinal layer thickness (e.g. average pRNFL, pmbRNFL, GCIPL, and overall retinal thickness) as markers of treatment effects on neuroaxonal degeneration and disability progression in SPMS. Treatment with siponimod significantly reduced GCIPL thinning at month 24, and overall retinal thinning at months 12 and 24. Although the treatment effects for the other time points and other thickness parameters, including pRNFL and pmbRNFL, were not statistically significant, most of the numerical differences consistently favored siponimod versus placebo. The change in subfield thickness also consistently showed similar trends, reaching nominal significance ($p \le 0.05$) for most GCIPL subfields.

Such consistency in treatment-related changes despite the small sample size supports the rationale of using OCT and retinal thickness measurements as an endpoint in clinical trials of progressive MS disease. This is in line with the approach taken by several such trials including SPRINT-MS, FLUOX-PMS, ACTiMuS, or SMART-MS (Lambe et al., 2020; Oertel et al., 2019). While many of these studies are ongoing, or with results not yet published, a post-hoc analysis of phase 2 SPRINT-MS showed that treatment with ibudilast decreased GCIPL atrophy versus placebo in progressive MS (Ehrhardt et al., 2023). The authors, however, noted that this treatment effect was driven by participants with primary progressive MS (PPMS), rather than those with SPMS. According to the researchers, this observation possibly was consistent with the faster brain atrophy in the PPMS cohort, making treatment effects more likely to be detected in this subtype.

Our finding demonstrating a treatment effect of siponimod on GCIPL
is also in line with previous evidence suggesting that change in thickness of GCIPL is a more clinically meaningful biomarker of CNS atrophy than RNFL (thickness). GCIPL is more strongly correlated with visual dysfunction (Saidha et al., 2011) and its decrease is more severe and can be detected much earlier (Gabilondo et al., 2015; Pietroboni et al., 2020) compared with the RNFL layer. These results support the hypothesis that neurodegeneration in this SPMS population may arise from neuronal cell damage (as measured by GCIPL change), more so than only axonal degeneration (as measured by RNFL), consistent with previous observations in RRMS (Paul et al., 2021; Pietroboni et al., 2020).

The RNFL and macular ganglion cells are affected by MS in parallel to clinical and paraclinical parameters, including physical disability, cognitive disorders as well as cerebral atrophy in MRI (Alonso et al., 2018; Mehmood et al., 2021). In our analysis, low correlations were observed between some OCT measures (pmbRNFL and retinal thinning) and change in cortical grey matter volume after 1 year; however, no meaningful correlation was observed between OCT parameters and the other measured clinical or MRI outcomes (EDSS, SDMT, LCVA, T2 lesion volume, and T1 hypointense lesion volume).

This negative result likely reflects one main limitation of this study, inherent to its exploratory nature, which is the small sample size and insufficient statistical power to consistently detect a treatment effect on OCT parameters and their correlations with disease outcomes. Based on our results on GCIPL changes, the estimated sample size with a power of over 90 % to detect a difference of 3 µm between two treatment groups assuming 1:1 randomization would be at least 300 (i.e. 150 participants in each group). Our effect size (approximatively 40 %) and related sample size calculation is in line with that derived from the SPRINT-MS trial of ibudilast in progressive MS (Ehrhardt et al., 2023). In addition, although baseline demographics were generally balanced, baseline disease activity was lower, and OCT measures were better in the placebo group, potentially biasing the results (since higher baseline thickness allows a larger dynamic range from which the retinal layer can thin). Sensitivity analyses were conducted to address these limitations; adjusting for baseline imbalance in disease characteristics yielded results in line with the unadjusted results, and treatment effects on percentage changes in retinal layers thickness were consistent with effects on absolute changes. Another limitation may be related to the improving performance and sensitivity of OCT imaging techniques and post-acquisition analyses, which may not have been optimal at the time this analysis was conducted. This could partly explain the high variability in OCT measures observed in our study, including steep decrease or apparent increase in some of the retinal thickness measures. Such variability, however, also likely reflects some degree of physiological variation in line with earlier reports (Balk et al., 2014, 2012).

In conclusion, the consistent trend in treatment-related OCT changes across all retinal layers and subfields observed in the EXPAND OCT substudy, despite its exploratory nature, supports the utility of OCT as a potential non-invasive biomarker to evaluate treatment effects on retinal layer atrophy in participants with SPMS; however, more results from ongoing or future trials in larger SPMS populations are needed to confirm these findings and establish OCT as a marker of neurodegeneration and its correlation with clinical and MRI outcomes in SPMS.

## Data sharing

Novartis is committed to sharing with qualified external researchers access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

## CRediT authorship contribution statement

**Patrick Vermersch:** Supervision, Writing – review & editing. **Ralf Gold:** Supervision, Writing – review & editing. **Amit Bar-Or:** Supervision, Writing – review & editing. **Bruce A.C. Cree:** Supervision, Writing – review & editing. **Robert J. Fox:** Supervision, Writing – review & editing. **Gavin Giovannoni:** Supervision, Writing – review & editing. **Friedemann Paul:** Writing – review & editing. **Sebastian Wolf:** Supervision, Writing – review & editing. **Bingbing Li:** Software, Writing – review & editing. **Marie-Catherine Mousseau:** Visualization, Writing – original draft, Writing – review & editing. **Tina Maio-Twofoot:** Writing – review & editing. **Xiaofang Shi:** Project administration, Writing – review & editing. **Ludwig Kappos:** Supervision, Writing – review & editing.

## Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Patrick Vermersch, Ralf Gold, Amit Bar-Or, Bruce A.C. Cree, Robert J. Fox, Gavin Giovannoni, Friedemann Paul, Sebastian Wolf, Bingbing Li, Marie-Catherine Mousseau, Tina Maio-Twofoot, Xiaofang Shi, Ludwig Kappos report financial support was provided by Novartis Pharma AG. Patrick Vermersch reports a relationship with Biogen, Roche, Novartis, Sanofi, Teva, Merck, Celgene, Ad Scientiam, and Imcyse and AB Science that includes: consulting or advisory, funding grants, and travel reimbursement. Ralf Gold reports a relationship with Bayer HealthCare, Biogen Idec, Merck Serono, Kyverna, Novartis, Roche, and Teva Neuroscience that includes: consulting or advisory and speaking and lecture fees. Ralf Gold reports a relationship with Bayer HealthCare, Biogen Idec, Merck Serono, Kyverna, Novartis, and Teva Neuroscience that includes: funding grants. Amit Bar-Or reports a relationship with Accure, Atara Biotherapeutics, Biogen, BMS Celgene Receptos, GlaxoSmithKline, Gossamer, Janssen Actelion, Medimmune, Merck EMD Serono, Novartis, Roche Genentech, and Sanofi-Genzyme that includes: consulting or advisory and funding grants. Bruce A.C. Cree reports a relationship with Alexion, Atara, Autobahn, Avotres, Biogen, Boston Pharma, EMD Serono, Hexal Sandoz, Horizon, Immunic AG, Kyverna, Neuron23, Novartis, Sanofi, Siemens and TG Therapeutics that includes: consulting or advisory. Bruce A.C. Cree reports a relationship with Genentech and Kyverna that includes: funding grants. Robert J. Fox reports a relationship with Actelion, Biogen, Celgene, EMD Serono, Genentech, Immunic, Novartis and Teva that includes: consulting or advisory. Robert J. Fox reports a relationship with Biogen and Novartis that includes: funding grants. Gavin Giovannoni reports a relationship with AbbVie, Biogen, Novartis, Teva, Roche that includes: board membership. Gavin Giovannoni reports a relationship with Merck KGaA, Sanofi Genzyme, and Synthon BV that includes: consulting or advisory and speaking and lecture fees. Friedemann Paul reports a relationship with Novartis, MedImmune Viela Biosteering that includes: board membership. Friedemann Paul reports a relationship with Alexion, Chugai, Biogen, Bayer, Merck Serono, Teva, Genzyme, Novartis, Shire, Roche, Actelion, Celgene, and MedImmune that includes: consulting or advisory and speaking and lecture fees. Sebastian Wolf reports a relationship with Zeiss, Novartis, Bayer, and Roche that includes: consulting or advisory. Ludwig Kappos reports a relationship with Actelion, Bayer HealthCare, Biogen, BMS, Genzyme, Janssen, Merck, Novartis, Roche, Sanofi, Santhera, and TG Therapeutics that includes: board membership and consulting or advisory. Ludwig Kappos reports a relationship with Allergan, Bayer HealthCare, Biogen, CSL Behring, Desitin, Genzyme, Merck, Novartis, Pfizer, Roche, Sanofi, Shire, and Teva that includes: speaking and lecture fees. Ludwig Kappos reports a relationship with Bayer HealthCare, Biogen, European Union, InnoSwiss, Merck, Novartis, Roche, Swiss MS Society, and Swiss National Research Foundation that includes: funding grants. Bingbing Li, Marie-Catherine Mousseau, Tina Maio-Twofoot and Xiaofang Shi report a relationship with Novartis that
includes: employment. Ralf Gold has received honoraria as a Journal Editor from SAGE and Elsevier. Gavin Giovannoni is the Co-Chief Editor of Multiple Sclerosis and Related Disorders (Elsevier). Ludwig Kappos' institution (University Hospital Basel) has license fees for Neurostatus products.

Acknowledgments

The authors thank Daniela Piani-Meier and Goeril Karlsson for their
contribution in study design and data interpretation, and Jeff Maca for
his contribution in initial data analysis (all Novartis at the time of the
study).

Funding

This research was funded by Novartis Pharma AG (Basel, Switzerland). Novartis participated in the study design, interpretation of data, writing of the report and decision to submit the article for publication. In addition, Novartis was responsible for manufacturing the investigational product and matching placebo as well as data collection, monitoring, and data analysis.

**Supplementary materials**

Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.msard.2025.106259.

**References**

Alonso, R., Gonzalez-Moron, D., Garcea, O., 2018. Optical coherence tomography as a biomarker of neurodegeneration in multiple sclerosis: a review. Mult Scler Relat Disord 22, 77-82. https://doi.org/10.1016/j.msard.2018.03.007.

Balk, L.J., Cruz-Herranz, A., Albrecht, P., Arnow, S., Gelfand, J.M., Tewarie, P., Killestein, J., Uitdehaag, B.M., Petzold, A., Green, A.J., 2016. Timing of retinal neuronal and axonal loss in MS: a longitudinal OCT study. J Neurol 263 (7), 1323-1331. https://doi.org/10.1007/s00415-016-8127-9

Balk, L.J., Oberwahrenbrock, T., Uitdehaag, B.M., Petzold, A., 2014. Physiological variation of retinal layer thickness is not caused by hydration: a randomised trial. J Neurol Sci 344 (1-2), 88-93. https://doi.org/10.1016/j.jns.2014.06.031.

Balk, L.J., Sonder, J.M., Strijbis, E.M., Twisk, J.W., Killestein, J., Uitdehaag, B.M., Polman, C.H., Petzold, A., 2012. The physiological variation of the retinal nerve fiber layer thickness and macular volume in humans as assessed by spectral domain-optical coherence tomography. Invest Ophthalmol Vis Sci 53 (3), 1251-1257. https://doi.org/10.1167/iovs.11-8209.

Cree, B.A., Arnold, D.L., Fox, R.J., Gold, R., Vermersch, P., Benedict, R.H., Bar-Or, A., Piani-Meier, D., Rouyrre, N., Ritter, S., Kilaru, A., Karlsson, G., Giovannoni, G., Kappos, L., 2022. Long-term efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis: analysis of EXPAND core and extension data up to >5 years. Mult Scler 28 (10), 1591-1605. https://doi.org/10.1177/13524585221083194.

Cruz-Herranz, A., Balk, L.J., Oberwahrenbrock, T., Saidha, S., Martinez-Lapiscina, E.H., Lagreze, W.A., Schuman, J.S., Villoslada, P., Calabresi, P., Balcer, L., Petzold, A., Green, A.J., Paul, F., Brandt, A.U., Albrecht, P., 2016. The APOSTEL recommendations for reporting quantitative optical coherence tomography studies. Neurology 86 (24), 2303-2309. https://doi.org/10.1212/wnl.1000000000002774.

Ehrhardt, H., Lambe, J., Moussa, H., Vasileiou, E.S., Kalaitzidis, G., Murphy, O.C., Filippatou, A.G., Pellegrini, N., Douglas, M., Davis, S., Nagy, N., Quiroga, A., Hu, C., Zambriczki Lee, A., Duval, A., Fitzgerald, K.C., Prince, J.L., Calabresi, P.A., Sotirchos, E.S., ...Saidha, S., 2023. Effects of Ibudilast on Retinal Atrophy in Progressive Multiple Sclerosis Subtypes: post Hoc Analyses of the SPRINT-MS Trial. Neurology 101 (10), e1014-e1024. https://doi.org/10.1212/wnl.100000000000207551.

Frau, J., Fenu, G., Signori, A., Coghe, G., Lorefice, L., Barracciu, M.A., Sechi, V., Cabras, F., Badas, M., Marrosu, M.G., Cocco, E., 2018. A cross-sectional and longitudinal study evaluating brain volumes, RNFL, and cognitive functions in MS patients and healthy controls. BMC Neurol 18 (1), 67. https://doi.org/10.1186/s12883-018-1065-9

Gabilondo, I., Martínez-Lapiscina, E.H., Fraga-Pumar, E., Ortiz-Perez, S., Torres-Torres, R., Andorra, M., Llufriu, S., Zubizarreta, I., Saiz, A., Sanchez-Dalmau, B., Villoslada, P., 2015. Dynamics of retinal injury after acute optic neuritis. Ann Neurol 77 (3), 517-528. https://doi.org/10.1002/ana.24351.

García-Martin, E., Pinilla, I., Idoipe, M., Fuertes, I., Pueyo, V., 2011. Intra and interoperator reproducibility of retinal nerve fibre and macular thickness measurements using Cirrus Fourier-domain OCT. Acta Ophthalmol 89 (1), e23-e29. https://doi.org/10.1111/j.1755-3768.2010.02045.x

García-Martín, E., Pueyo, V., Fernández, J., Martín, J., Ara, J.R., Almarcegui, C., Dolz, I., 2010. Effect of treatment in loss of retinal nerve fibre layer in multiple sclerosis

patients). Arch Soc Esp Oftalmol 85 (6), 209-214. https://doi.org/10.1016/j.oftal.2010.08.004 (Influencia del tratamiento en la pérdida de fibras nerviosas de la retina en pacientes con esclerosis múltiple.)

Gordon-Lipkin, E., Chodkowski, B., Reich, D.S., Smith, S.A., Pulicken, M., Balcer, L.J., Frohman, E.M., Cutter, G., Calabresi, P.A., 2007. Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis. Neurology 69 (16), 1603-1609. https://doi.org/10.1212/01.wnl.0000295995.46586 ae.

Graves, J.S., 2019. Optical Coherence Tomography in Multiple Sclerosis. Semin Neurol 39 (6), 711-717. https://doi.org/10.1055/s-0039-1700528.

Green, A.J., McQuaid, S., Hauser, S.L., Allen, I.V., Lyness, R., 2010. Ocular pathology in multiple sclerosis: retinal atrophy and inflammation irrespective of disease duration. Brain 133 (6), 1591-1601. https://doi.org/10.1093/brain/awq080. Pt.

Kappos, L., Bar-Or, A., Cree, B.A.C., Fox, R.J., Giovannoni, G., Gold, R., Vermersch, P., Arnold, D.L., Arnould, S., Scherz, T., Wolf, C., Wallström, E., Dahlke, F., 2018. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet 391 (10127), 1263-1273. https://doi.org/10.1016/s0140-6736(18)30475-6.

Khanifar, A.A., Parlitsis, G.J., Ehrlich, J.R., Aaker, G.D., D'Amico, D.J., Gauthier, S.A., Kiss, S., 2010. Retinal nerve fiber layer evaluation in multiple sclerosis with spectral domain optical coherence tomography. Clin Ophthalmol 4, 1007-1013. https://doi.org/10.2147/othp.s13278.

Kuchling, J., Paul, F., 2020. Visualizing the Central Nervous System: imaging Tools for Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders. Front Neurol 11, 450. https://doi.org/10.3389/fneur.2020.00450.

Lambe, J., Saidha, S., Bernel, R.A., 2020. Optical coherence tomography and multiple sclerosis: update on clinical application and role in clinical trials. Mult Scler 26 (6), 624-639. https://doi.org/10.1177/1352458519872751.

Martinez-Lapiscina, E.H., Arnow, S., Wilson, J.A., Saidha, S., Preiningerova, J.L., Oberwahrenbrock, T., Brandt, A.U., Pablo, L.E., Guerrieri, S., Gonzalez, I., Outteryck, O., Mueller, A.K., Albrecht, P., Chan, W., Lukas, S., Balk, L.J., Fraser, C., Frederiksen, J.L., Resto, J., ...Villoslada, P., 2016. Retinal thickness measured with optical coherence tomography and risk of disability worsening in multiple sclerosis: a cohort study. The Lancet Neurol. 15 (6), 574-584. https://doi.org/10.1016/s1474-4422(16)00068-5.

Mehmood, A., Ali, W., Song, S., Din, Z.U., Guo, R.Y., Shah, W., Ilahi, I., Yin, B., Yan, H., Zhang, L., Khan, M., Ali, W., Zeb, L., Safari, H., Li, B., 2021. Optical coherence tomography monitoring and diagnosing retinal changes in multiple sclerosis. Brain Behav 11 (10), e2302. https://doi.org/10.1002/brb3.2302.

Mirmosayyeb, O., Yazdan Panah, M., Mokary, Y., Ghaffary, E.M., Ghoshouni, H., Zivadinov, R., Weinstock-Guttman, B., Jakimovski, D., 2023. Optical coherence tomography (OCT) measurements and disability in multiple sclerosis (MS): a systematic review and meta-analysis. J Neurol Sci 454, 120847. https://doi.org/10.1016/j.jns.2023.120847.

Oertel, F.C., Zimmermann, H.G., Brandt, A.U., Paul, F., 2019. Novel uses of retinal imaging with optical coherence tomography in multiple sclerosis. Expert Rev Neurother 19 (1), 31-43. https://doi.org/10.1080/14737175.2019.1559051.

Parisì, V., Manni, G., Spadaro, M., Colacino, G., Restuccia, R., Marchi, S., Bucci, M.G., Pierelli, F., 1999. Correlation between morphological and functional retinal impairment in multiple sclerosis patients. Invest Ophthalmol Vis Sci 40 (11), 2520-2527. https://iosv.arvojournals.org/article.aspx?articleid=2199757.

Paul, F., Calabresi, P.A., Barkhof, F., Green, A.J., Kardon, R., Sastre-Garriga, J., Schipping, S., Vermersch, P., Saidha, S., Gerendas, B.S., Schmidt-Erfurth, U., Agoropoulou, C., Zhang, Y., Seifer, G., Petzold, A., 2021. Optical coherence tomography in multiple sclerosis: a 3-year prospective multicenter study. Ann Clin Transl Neurol 8 (12), 2235-2251. https://doi.org/10.1002/acn3.51473.

Petzold, A., Balcer, L.J., Calabresi, P.A., Costello, F., Frohman, T.C., Frohman, E.M., Martinez-Lapiscina, E.H., Green, A.J., Kardon, R., Outteryck, O., Paul, F., Schipping, S., Vermersch, P., Villoslada, P., Balk, L.J., 2017. Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis. The Lancet Neurol. 16 (10), 797-812. https://doi.org/10.1016/s1474-4422(17)30278-8.

Pietroboni, A.M., Carandini, T., Dell'Arti, L., Bovis, F., Colombi, A., De Riz, M.A., Casazza, E., Scola, E., Fenoglio, C., Arighi, A., Fumagalli, G.G., Triulzi, F., Galimberti, D., Viola, F., Scarpini, E., 2020. Evidence of retinal anterograde neurodegeneration in the very early stages of multiple sclerosis: a longitudinal OCT study. Neurol Sci 41 (11), 3175-3183. https://doi.org/10.1007/s10072-020-04431-4.

Saidha, S., Al-Louzi, O., Ratchford, J.N., Bhargava, P., Oh, J., Newsome, S.D., Prince, J. L., Pham, D., Roy, S., van Zijl, P., Balcer, L.J., Frohman, E.M., Reich, D.S., Crainiceanu, C., Calabresi, P.A., 2015. Optical coherence tomography reflects brain atrophy in multiple sclerosis: a four-year study. Ann Neurol 78 (5), 801-813. https://doi.org/10.1002/ana.24487.

Saidha, S., Syc, S.B., Durbin, M.K., Eckstein, C., Oakley, J.D., Meyer, S.A., Conger, A., Frohman, T.C., Newsome, S., Ratchford, J.N., Frohman, E.M., Calabresi, P.A., 2011. 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 17 (12), 1449-1463. https://doi.org/10.1177/1352458511418630.

Schipping, S., Balk, L.J., Costello, F., Albrecht, P., Balcer, L., Calabresi, P.A., Frederiksen, J.L., Frohman, E., Green, A.J., Klistorner, A., Outteryck, O., Paul, F., Plant, G.T., Traber, G., Vermersch, P., Villoslada, P., Wolf, S., Petzold, A., 2015. Quality control for retinal OCT in multiple sclerosis: validation of the OSCAR-IB criteria. Mult Scler 21 (2), 163-170. https://doi.org/10.1177/1352458514538110.

Siger, M., Dziegielewski, K., Jasek, L., Bieniek, M., Nicpan, A., Nawrocki, J., Selmaj, K., 2008. Optical coherence tomography in multiple sclerosis: thickness of the retinal nerve fiber layer as a potential measure of axonal loss and brain atrophy. J Neurol 255 (10), 1555-1560. https://doi.org/10.1007/s00415-008-0985-5.
Swinnen, S., De Wit, D., Van Cleemput, L., Cassiman, C., Dubois, B., 2023. Optical coherence tomography as a prognostic tool for disability progression in MS: a systematic review. J Neurol 270 (2), 1178–1186. https://doi.org/10.1007/s00415-022-11474-4.

Vidal-Jordana, A., Pareto, D., Cabello, S., Alberich, M., Rio, J., Tintore, M., Auger, C., Montalban, X., Rovira, A., Sastre-Garriga, J., 2020. Optical coherence tomography measures correlate with brain and spinal cord atrophy and multiple sclerosis disease-related disability. Eur J Neurol 27 (11), 2225–2232. https://doi.org/10.1111/ene.14421.

Winges, K.M., Murchison, C.F., Bourdette, D.N., Spain, R.I., 2019. Longitudinal optical coherence tomography study of optic atrophy in secondary progressive multiple sclerosis: results from a clinical trial cohort. Mult Scler 25 (1), 55–62. https://doi.org/10.1177/1352458517739136.

World Medical Association, 2024. Declaration of Helsinki - Ethical Principles For Medical Research Involving Human Subjects. Ferney-Voltaire: Author. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/. Accessed 06 January 2025.