Background: Although the retina represents an unmyelinated central nervous system structure, almost all aspects of multiple sclerosis (MS) related pathology (except demyelination) may be observed in the retina. Moreover, the retina represents an opportune site to study neurodegeneration, since optic nerve affliction is virtually ubiquitous in MS. Optical coherence tomography (OCT) derived measures of retinal neurodegeneration have been shown to strongly reflect the global MS disease process, and may be ideal outcomes for assessing neuroprotection, and/or neurorestoration. Accordingly, OCT outcomes are being increasingly incorporated as primary or secondary outcomes in MS clinical trials.
Goals: To describe the effects of MS disease modifying therapies (DMTs) on OCT derived assessment of retinal atophy.
Methods: Discussion of the emerging role of OCT for monitoring MS, as well as the effects of high-potency (including natalizumab and rituximab), and low-potency (including interferons and glatiramer acetate) MS DMTs on rates of OCT derived measures of composite ganglion cell+inner plexiform layer (GCIPL), inner nuclear layer (INL), and outer nuclear layer (ONL) atrophy. Differences in the effects of DMTs on retinal atrophy according to MS subtype will be reviewed. Finally, the role of the international MS visual system (IMSVISUAL) consortium in large scale MS studies will be discussed.
Results: Congruent with the effects of DMTs on rates of brain atrophy, high potency DMTs are associated with slower rates of retinal atophy in relapsing remitting MS (RRMS), as compared to low potency DMTs. Therepeutic optimization of the effect of rituximab on retinal atrophy in MS may take up to 6-12 months in RRMS. INL and ONL atrophy appear to be relatively speficic to progressive MS (PMS; both primary and secondary PMS), as compared to RRMS, and in PMS, INL and ONL atrophy are accelerated, independent of age. Rates of GCIPL, INL and ONL atrophy do not differ significantly between untreated PMS patients, and PMS patients treated with either low or high potency DMTs. Large scale MS studies utilizing visual system outcomes are facilitated by IMSVISUAL.
Conclusions: Rates of GCIPL atrophy are slower in RRMS patients treated with high potency, as compared to low potency DMTs. INL and ONL atrophy measures appear to be relatively specific to PMS, and may be novel outcomes for assessing neuroprotection and/or neurorestoration in PMS. Current, conventional, and primarily anti-inflammatory DMTs (whether high or low potency) have not been shown to significantly reduce retinal atophy in PMS, unlike RRMS.
Optic neuritis (ON) is a frequent manifestation in aquaporin-4 antibody (AQP4-IgG) seropositive neuromyelitis optica spectrum disorders (NMOSD). Due to limited samples, existing optical coherence tomography (OCT) studies are inconsistent regarding retinal changes in eyes with a history of ON (NMO-ON) and without a history of ON (NMO-NON), and their functional relevance.
The CROCTINO (Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica) project aims to reveal correlates of retinal pathology and to generate hypotheses for prospective OCT studies in NMOSD. The objective of this study was to analyze retinal changes of AQP4-IgG seropositive NMO-ON and NMO-NON eyes in an international cross-sectional OCT dataset.
Of 656 subjects, we enrolled 283 AQP4-IgG seropositive NMOSD patients and 72 healthy controls (HC) from 22 international expert centers. OCT data was acquired with Spectralis SD-OCT, Cirrus HD-OCT and Topcon 3D OCT-1. Mean thickness for the combined ganglion cell and inner plexiform layer (GCIP) and inner nuclear layer (INL) were calculated from macular volume scans. Clinical, functional and laboratory testing were performed at discretion of each center.
We compared NMO-ON eyes (N = 260), NMO-NON eyes (N = 241) and HC eyes (N = 136). GCIP was reduced in NMO-ON (57.4 ± 12.2 µm) compared with NMO-NON (75.9 ± 7.7 µm; p < 0.001) and HC (81.4 ± 5.7 µm; p < 0.001). NMO-NON had thinner GCIP (p < 0.001) compared with HC. INL was thicker in NMO-ON (40.3 ± 3.9 µm) compared with NMO-NON (38.6 ± 3.9µm; p < 0.001), but not HC (39.4 ± 2.6 µm). Microcystic macular edema were visible in 6.6 % of NMOSD eyes.
AQP4-IgG seropositive NMOSD is characterized by a functionally relevant loss of retinal neuroaxonal content and a - probably inflammatory - increase of INL after ON. Our study further supports the existence of attack-independent damage in the visual system of patients with AQP4-IgG seropositive NMOSD.
Neuroglial cells are implicated in the pathobiology of Multiple sclerosis (MS). Müller glia, specialized radial glial cells of the retina responsible for helping maintain retinal neuronal integrity, are postulated to be activated in MS. Müller glia activation is also implicated in epiretinal membrane (ERM) formation, an aberrant healing response to retinal damage.
To examine ERM prevalence in MS, and differences in expanded disability status scale (EDSS) and optical coherence tomography (OCT) measured retinal layer thicknesses, between MS patients with (ERM-MS) and without ERMs (non-ERM-MS).
In this cross-sectional study, 1463 MS patients (2926 eyes) underwent Cirrus spectral-domain OCT (with automated macular layer segmentation). All scans underwent qualitative and quantitative quality control (QC), and ERM presence was recorded. Excluding patients with optic neuritis history, ERM-MS (n=48) were matched 1:1 to non-ERM-MS based on age, body mass index (BMI) and sex. Fellow eye layer thicknesses of ERM-MS were compared to the average binocular layer thicknesses of non-ERM-MS patients, to investigate the possibility of a phenotype effect. Mixed effects linear regression models were used in analyses.
ERM prevalence in this MS cohort was 4.9%. Post-matching mean age and BMI were respectively 60.7 years (SD 6.3) and 28.2 kg/m2 (SD 9.6) in ERM-MS, and 60.4 years (SD 5.7) and 27.5 kg/m2 (SD 8.9) in non-ERM-MS (p=0.7 for both). Both groups had 77.1% females. Median EDSS was 4 (IQR 2.5-6.5) in ERM-MS and 3 (IQR 1.5-6) in non-ERM-MS (difference: 1.1, CI: 0.2 – 1.9, p=0.021). Mean ganglion cell-inner plexiform layer (GCIPL) thickness was 67.1 um (SD 6.5) in ERM-MS and 70.2 um (SD 6.2) in non-ERM-MS (difference: -3.1, CI: -6.3 – -0.1, p=0.049). Moreover, mean retinal pigment epithelium (RPE) thickness was 31.6 um (SD 1.3) in ERM-MS and 32.4 um (SD 0.9) in non-ERM-MS (difference: -0.7 um, CI: -1.3 - -0.1, p=0.017).
Our findings suggest ERM-MS patients phenotypically have higher EDSS scores, and lower GCIPL and RPE thicknesses, as compared to non-ERM-MS patients. Blood-retinal barrier disruption due to retinal inflammation, among other reasons, may activate Müller glia in MS. This may help explain our finding that ERM presence in MS may be associated with disability. Moreover, RPE cells may be recruited in the ERM formation process, similarly explaining our finding of reduced RPE thickness among ERM-MS patients.
The visual pathway has emerged as an elective platform to study the interaction between demyelination and neurodegeneration in multiple sclerosis (MS)
We specifically assessed neural damage at this level in progressive MS (PMS), also exploring the evolution over time of functional (trough visual evoked potentials - VEPs) and structural (trough optical coherence tomography - OCT) parameters, as well as their relations with disease course and clinical disability.
We performed a prospective longitudinal study enrolling 350 PMS patients (228 secondary progressive MS - SPMS, 122 primary progressive MS - PPMS) who underwent a cross-sectional evaluation comprehensive of Expanded Disability Statur Scale (EDSS) assessment, high (HCVA)- and low-contrast (LCLA) visual acuity test, full-field (ff-VEPs) as well as multifocal (mf-VEPs) VEPs, and OCT. We performed a follow-up assessment (mean interval 2.0±0.9 years) in 147 patients (52 PPMS and 95 SPMS); a parallel collection of clinical records (including reports MRI scans, performed as per clinical practice) has been also obtained.
Independently from previous optic neuritis (ON), we found visual conduction to be slower among SPMS compared to PPMS patients, particularly for mf-VEPs: mean latency 168.9 ms (95% CI 166.2-171.1) vs 163.8 ms (95% CI 160.7-166.9) respectively, p=0.019. Retinal Nerve Fiber Layer (RNFL) was also found to be thinner among SPMS in comparison to PPMS patients: mean 83.4 μm (95% CI 81.4-85.4) vs 87.0 μm (95% CI 84.4-89.6), p=0.040, with similar results for Ganglion Cell-Inner Plexiform Layer (GCIPL). Considering the evolution over time of functional and structural parameters, we found no significant differences comparing PPMS and SPMS patients. Reclassifying our cohort according to EDSS status (“stable” vs “worsened”) we found a significant between-groups difference in terms of RNFL evolution: mean annualized percent change -0.163 %/year (95% CI -0.467 - -0.141) vs -0.854 %/year (95% CI -1.188 - -0.521) respectively, p=0.003. Similar findings were obtained for GCIPL change. In both cases, these observations were independent from the evidence of MRI activity during follow-up.
our results suggest the presence of a greater functional and structural involvement of the visual system among SPMS compared to PPMS patients, independently from previous ON history; follow-up data suggest however neurodegeneration accrual over time to be similar between these two clinical subgroups. The longitudinal relation between RNFL - GCIPL thinning and EDSS worsening, even in the absence of overt MRI activity and/or clinical relapses, suggests OCT to represent a useful tool to monitor disease progression and to assess neuroprotection in PMS.