In clinical practice, several disorders with CNS involvement can mimic MS both clinically and radiologically. Among them, autoimmune connective tissue diseases such as primary Sjögren’s syndrome may present with white matter lesions, episodes suggestive of demyelination, or even optic neuritis, which can lead to misdiagnosis. In such scenarios, additional biomarkers that reflect neuroaxonal damage and can be obtained in a quick and non-invasive manner are highly desirable. OCT has been proposed as one such tool, because it allows direct visualization and quantification of retinal layers that correspond to unmyelinated axons and neurons of the CNS. On this basis, we aimed to investigate whether OCT parameters could help distinguish MS from PSS and from healthy individuals.
Our study showed RNFL thickness was found to be significantly lower in MS participants than in PSS participants and HCs in all RNFL regions (superior, inferior, temporal) except the nasal region. Whole GCC thickness was significantly lower in MS participants than in PSS participants and HC. Foveal volume was lower in MS participants than in PSS participants and HCs. When MS patients were compared with PSS with CNS involvement; retinal thickness were found to be lower only in the parafoveal region in MS patients. Also foveal volume was found to be lower in MS participants with ON than in PSS participants with CNS involvement (p = 0.017).
OCT findings were similar when MS patients without ON and PSS patients with CNS lesions were compared. In MS patients with ON, retinal thicknesses were found to be lower in the parafoveal and perifoveal area in MS patients compared to PSS patients with CNS lesions. When the retinal thicknesses of all MS patients and PSS patients with CNS lesions were compared, retinal thickness was found to be lower in the parafoveal region in MS patients. It can be interpreted that the parafoveal region is prominent in the differential diagnosis of MS patients from PSS patients with CNS involvement. Parafoveal region seems to be important in differential diagnosis of MS.
Our findings are in line with previous work that evaluated OCT for the differential diagnosis of MS and autoimmune connective tissue diseases with CNS involvement. In the study by Wildner et al., OCT measurements were compared among MS patients, patients with CNS involvement in connective tissue diseases, and healthy controls, and significant group effects were demonstrated for peripapillary RNFL and macular parameters, supporting the concept that retinal structural changes may reflect disease-specific patterns of CNS injury [10]. Similar to that study, we observed that MS patients showed more pronounced RNFL thinning than PSS participants and healthy controls, particularly in the superior, inferior, and temporal quadrants, whereas the nasal quadrant was relatively preserved.
OCT has substantially improved our understanding of the pathophysiological mechanisms in MS. Several studies have shown that thinning of the RNFL and ganglion cell–inner plexiform layer (GCIPL) occurs not only after ON but also in eyes without a history of optic nerve inflammation, indicating that retinal neuroaxonal loss is a diffuse manifestation of CNS pathology rather than a purely local phenomenon. These structural changes correlate with visual dysfunction and, in many reports, with global measures of disability, supporting the use of OCT as a biomarker of neurodegeneration in MS (11). The observation of RNFL and macular thinning in our MS cohort, including eyes without ON, is consistent with this concept.
Recent revisions of the McDonald diagnostic criteria (2024) have now formally incorporated the visual system into the diagnostic framework (12). The optic nerve is recognized as a fifth topographic site for dissemination in space, and abnormal findings on orbital MRI, visual evoked potentials or OCT can all provide paraclinical evidence of optic nerve involvement when no better explanation exists. Within these revisions, OCT-derived inter-eye differences in peripapillary RNFL and macular ganglion cell–inner plexiform layer thickness are specifically recommended as supportive measures to document unilateral optic nerve damage. In this updated context, our results suggest that quantitative retinal structural measurements obtained by OCT not only reflect neuroaxonal damage in MS but may also help to document optic nerve involvement and to distinguish MS from PSS with CNS involvement in diagnostically challenging cases, especially when conventional MRI findings are equivocal (12, 13).
Beyond structural OCT, optical coherence tomography angiography (OCTA) has emerged as a promising technique to assess retinal microvasculature in systemic autoimmune diseases. Several studies have reported reduced vessel density in the superficial and deep capillary plexus in MS and in PSS, even in the absence of overt ocular disease. Recently, Wolf et al. used OCTA to directly compare patients with relapsing–remitting MS and patients with PSS and demonstrated distinct patterns of retinal vascular alteration in the two diseases, suggesting that MS and PSS are associated with different retinal pathologies at the microvascular level (10, 11). Although our study did not include OCTA measurements, the structural thinning of RNFL and macular layers that we observed in MS compared with PSS and healthy controls may represent the neuroaxonal counterpart of these microvascular abnormalities.
This study has some limitations that should be acknowledged. The study population was of moderate size and the subgroup of PSS patients with CNS involvement was relatively small, which may have limited our ability to detect more subtle differences in OCT parameters between the groups. In addition, the single-center, cross-sectional design does not capture longitudinal change and may restrict the generalizability of the results. We also focused exclusively on structural OCT measures and did not include OCT angiography, so possible microvascular alterations could not be directly evaluated in this cohort. Finally, although key demographic and clinical factors were considered, the influence of unmeasured confounders cannot be completely excluded. These considerations may help to guide future research, including larger multicenter cohorts and longitudinal studies that combine structural OCT with OCT angiography to further clarify the diagnostic and prognostic value of retinal imaging in MS and PSS.
Our findings, in concordance with previous reports, indicate that OCT-derived retinal biomarkers may assist in differentiating MS, PSS with CNS involvement, and healthy individuals. Structural OCT yields quantitative measures of neuroaxonal damage, whereas OCTA provides complementary information on retinal microvascular alterations. Future studies that integrate both modalities in larger cohorts with longitudinal follow-up are warranted to clarify the interplay between structural and vascular retinal changes and to determine whether their combined use can enhance the early and accurate diagnosis of MS in patients with overlapping clinical or radiological features.