Status of the inner retinal layers in patients with multiple sclerosis

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A new Italian study1 reported that relapsing-remitting multiple sclerosis (MS) potentially can involve the morpho-functional of all macular areas and sectors and this can occur even in patients who have no history of optic neuropathy, reported first author Lucilla Barbano, MD, from the Istituto di Ricovero e Cura a Carattere ScientificoIstituto di Ricovero e Cura a Carattere Scientifico–Fondazione Bietti, Rome.

She and her colleagues published their results in the Journal of Clinical Medicine.

A great deal of research has been conducted, and particularly of the macular unmyelinated axons of the retinal ganglion cells (RGCs), to determine the retinal involvement in patients with MS.2-5 “These neuronal elements, in fact, can be considered as the cellular target of the retinal neurodegenerative process due to MS, as a consequence of the frequent inflammatory process of the optic nerve, known as optic neuritis (ON),” the authors commented.2-6 

Optical coherence tomography (OCT) images have shown thinning of the ganglion cell/inner plexiform layer (GCIPL) complex, which is evidence of early inner retinal impairment in patients with MS after ON (MSON eyes).3-5,7-9 

The reduced amplitude of the pattern electroretinogram from the central RGCs and relative fibers is a valuable hallmark of functionally impaired ganglionic retinal elements and their axons in MSON eyes.10-12

However, in eyes with MS but no history of ON (MSnoON eyes), “although previous OCT segmentation analyses of the inner retina have documented reductions in the macular retinal nerve fiber layer (RNFL) and CGPIL thicknesses,2-4,13 few data have been reported on the functional condition of the macula,” Barbano and colleagues commented.

Because of this knowledge gap, the investigators assessed the structure and function of the inner retinal ganglionic elements in selected macular areas based on a topographic evaluation method previously applied to MSON eyes.14

The study included 24 patients with MSnoON (mean age, 45.22 ± 5.57 years; 14 women, 10 men; mean duration of MS: 11.07 ± 5.88 years) and in 30 control patients who were a similar age (mean age, 45.09 ± 5.08 years). The participants underwent a complete ophthalmologic examination, OCT, and measurement of the multifocal photopic negative response (mfPhNR). The ganglion cell layer (GCL) thickness on OCT images and the response amplitude density (RAD) by the mfPhNR were measured from localized macular regions, including the rings and Early Treatment of Diabetic Retinopathy Study sectors, the authors explained.

What was the MS effect on the retina?

The authors reported that their comparison of the MSnoON data from all tested retinal areas with the data obtained from the controls showed that the mean values of the macular GCL thickness and mfPhNR RAD were significantly decreased (P < 0.01 by analysis of variance).

“In the MSonON group, considering both the rings and sectors, the GCL thickness values were significantly and linearly correlated (P < 0.01 by Pearson’s test) with the mfPhNR RAD values,” Barbano and colleagues reported.

They concluded, “… our results suggest that in patients with relapsing–remitting MS in the absence of optic nerve inflammation, a potential primary morpho-functional involvement of the inner macular elements occurs. This impairment involves all macular areas and sectors. Thus, the present study offers scientific bases for the primitive morpho-functional impairment of macular RGCs in eyes with MSnoON and a possibility to compare the results with different populations of MSON eyes,14 in which the retrograde degeneration after an episode of ON could be responsible for the inner retinal damage.”

The hope is that future studies may help to confirm if their conclusions also can be applied to different types of MS disease and to different stages of the disease.

References
  1. Barbano L, Ziccardi L, Dell’Aquila C, et al. Structural and functional assessment of the macular inner retinal layers in multiple sclerosis eyes without history of optic neuropathy. J Clin Med. 2025; 14:5919. https://doi.org/10.3390/jcm14165919
  2. Britze J, Pihl-Jensen, G, Frederiksen JL. Retinal ganglion cell analysis in multiple sclerosis and optic neuritis: A systematic review and meta-analysis. J Neurol. 2017;264:1837–1853.
  3. Petzold A, Balcer LJ, Calabresi PA, et al. Retinal layer segmentation in multiple sclerosis: A systematic review and meta-analysis. Lancet Neurol. 2017;16:797–812.
  4. Al-Nosairy KO, Horbrügger M, Schippling S, et al. Structure-function relationship of retinal ganglion cells in multiple sclerosis. Int J Mol Sci.2021;22:3419.
  5. Zahavi O, Nilsson M, Manouchehrinia A, et al. Macular inner retinal layers in multiple sclerosis. Front Neurol. 2025;16:1549091.
  6. Bsteh G, Berek K, Hegen H, et al. Macular ganglion cell-inner plexiform layer thinning as a biomarker of disability progression in relapsing multiple sclerosis. Mult Scler. 2021;27:684–694.
  7. Del Palomar AP, Cegoñino J, Montolío A, et al. Swept source optical coherence tomography to early detect multiple sclerosis disease. The use of machine learning techniques. PLoS ONE. 2019;14:e0216410.
  8. Ziccardi L, Barbano L, Boffa L, et al. Morphological outer retina findings in multiple sclerosis patients with or without optic neuritis. Front. Neurol. 2020;15:858.
  9. Wicki CA, Hanson JVM, Schippling S. Optical coherence tomography as a means to characterize visual pathway involvement in multiple sclerosis. Curr Opin Neurol.2018;31:662–668.
  10. Janáky M, Jánossy Á, Horváth G, Benedek G, Braunitzer G. VEP and PERG in patients with multiple sclerosis, with and without a history of optic neuritis. Doc Ophthalmol. 2017;134:185–193.
  11. Monsalve P. Decoding PERG: A neuro-ophthalmic retinal ganglion cell function review. Curr Ophthalmol Rep. 2019;7:51–58.
  12. Falsini B, Bardocci A, Porciatti V, Bolzani R, Piccardi M. Macular dysfunction in multiple sclerosis revealed by steady-state flicker and pattern ERGs. Electroencephalogr Clin Neurophysiol. 1992;82:53–59.
  13. Albano V, Dammacco, R, Manni A, et al. Macular ganglion cell-inner plexiform layer defect patterns in multiple sclerosis patients without optic neuritis: A Spectral-Domain-Optical Coherence Tomography Cross-Sectional, Case-Control, Pilot Study. Eur J Ophthalmol. 2023;33:546–555.
  14. Parisi V, Barbano L, Antonelli G, et al. Topographical correlation between structural and functional impairment of the macular inner retinal layers in multiple sclerosis eyes with a history of optic neuropathy. J Clin Med. 2023;12:7175.

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