Progressive Multiple Sclerosis Is Associated with Faster and Specific Retinal Layer Atrophy

Abstract

Objective: Therapeutic development in progressive multiple sclerosis (PMS) has been hampered by a lack of reliable biomarkers to monitor neurodegeneration. Optical coherence tomography (OCT)-derived retinal measures have been proposed as promising biomarkers to fulfill this role. However, it is unclear whether retinal atrophy persists in PMS, exceeds normal aging, or can be distinguished from relapsing-remitting multiple sclerosis (RRMS). Methods: 178 RRMS, 186 PMS, and 66 control participants were followed with serial OCT for a median follow-up of 3.7 years. Results: The estimated proportion of peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell + inner plexiform layer (GCIPL) thinning in multiple sclerosis (MS) attributable to normal aging increased from 42.7% and 16.7% respectively at age 25 years, to 83.7% and 81.1% at age 65 years. However, independent of age, PMS was associated with faster pRNFL (−0.34 AE 0.09%/yr, p < 0.001) and GCIPL (−0.27 AE 0.07%/yr, p < 0.001) thinning, as compared to RRMS. In both MS and controls, higher baseline age was associated with faster inner nuclear layer (INL) and outer nuclear layer (ONL) thinning. INL and ONL thinning were independently faster in PMS, as compared to controls (INL:−0.09 AE 0.04%/yr, p = 0.03; ONL:−0.12 AE 0.06%/yr, p = 0.04), and RRMS (INL:−0.10 AE 0.04%/yr, p = 0.01; ONL: −0.13 AE 0.05%/yr, p = 0.01), whereas they were similar in RRMS and controls. Unlike RRMS, disease-modifying therapies (DMTs) did not impact rates of retinal layer atrophy in PMS. Interpretation: PMS is associated with faster retinal atrophy independent of age. INL and ONL measures may be novel biomarkers of neurodegeneration in PMS that appear to be unaffected by conventional DMTs. The effects of aging on rates of retinal layer atrophy should be considered in clinical trials incorporating OCT outcomes.

Retinal Thickness Analysis in Progressive Multiple Sclerosis Patients Treated With Epigallocatechin Gallate: Optical Coherence Tomography Results From the SUPREMES Study

“…First, the low sample size of our cohort. A previous study estimated that the sample size for a progressive MS trial on neuroprotective agents should be at least n = 173 for pRNFL and n = 125 for GCIP per trial arm for a 3-year study (power 80%, effect size 50%), numbers way larger than achieved in this exploratory outcome analysis ( 47 ).…”

“…Response to DMT is reflected by decreased rates of GCIP thinning ( 45 ) and thinning of INL in RRMS patients ( 46 ). A recent study has shown faster retinal thinning—also compared to RRMS patients and no effect of DMT on thinning rates in progressive MS ( 47 ). The study has been discussed controversially ( 48 ).…”

Interferon-β Is Less Effective Than Other Drugs in Controlling the Rate of Retinal Ganglion Cell Loss in MS

“…Concordant with the premise that earlier, aggressive use of immunotherapy can ameliorate longer-term neurodegeneration, we found that the use of higher efficacy therapies was associated with improved RGC preservation in patients with MS. Although it is generally accepted that modern oral and infusion therapies have better clinical efficacy compared with platform therapies 10 and can help reduce the rate of retinal atrophy in relapsing-remitting MS, 11 few studies have directly compared the effects of 2 platform therapies. Our data suggest that glatiramer acetate has a greater neuroprotective effect, at least on RGCs, than interferon-β, which may have implications for DMT selection in early, relapsing disease.…”

Identifying Progression in Multiple Sclerosis: New Perspectives

“…[57][58][59] In PMS, retinal thinning exceeds that of normal aging and RRMS. 60 OCT has been proposed as an endpoint in clinical trials that include PMS; however, a minimum trial duration of 2 years would be needed to detect meaningful changes, and standardized data acquisitions and rigorous quality control are also necessary. 61,62 Retrogeniculate lesions in the visual pathway can confound OCT measures, 63,64 and depending on the baseline measures, further deterioration in severely thinned retinae might be undetectable over the course of a clinical trial.…”