Retinal Layer Thinning in MS Advances With Disease Progression

Nancy A. Melville

March 01, 2019

DALLAS — People with progressive multiple sclerosis (MS) show accelerated atrophy in inner and outer nuclear layers of the retina compared to those without the disease, offering important new pieces of the puzzle in understanding the changes that occur as MS advances, researchers say.

"We have found that progressive MS is associated with accelerated inner and outer retinal layer atrophy, independently of age and clinical characteristics," coauthor Elias S. Sotirchos, MD, a clinical and research fellow with Johns Hopkins University School of Medicine in Baltimore, Maryland, told Medscape Medical News.

"This is a novel finding that has important implications for potential utilization of retinal atrophy measures as outcomes in clinical trials in progressive MS, as well as for monitoring patients in clinical practice," he said.

The findings were presented in the IMSVISUAL Symposium here at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2019.

Thinning of the peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell + inner plexiform layer (GCIP), observed on optical coherence tomography (OCT), are known to be accelerated in MS, even in the absence of optic neuritis, which is common in MS.

Changes in the thickness of the inner and outer nuclear layer of the retina have also been identified in MS; however, the changes can be difficult to interpret — while atrophy is identified in as many as 40% of postmortem eyes, increased thickness of the inner nuclear layer has conversely been associated with inflammatory disease activity in MS.

The differences are likely the result of retinal pathology at various stages of the MS disease course. However, with most OCT studies comparing retinal measures between MS subtypes involving small numbers of progressive MS eyes (and focused largely on the pRNFL), a better understanding is needed, Sotirchos said.

To take a closer look at longitudinal changes in retinal thickness in relation to age and MS disease progression, Sotirchos and his colleagues evaluated OCT data on 364 patients with MS — including 174 with relapsing-remitting MS and 186 with progressive MS — and compared them with 66 healthy controls.

While healthy controls had a mean age of 35.9, age was higher in relapsing-remitting MS (41.4 years), and primary progressive MS (mean age 53.3) and secondary progressive MS (51.0 years).

The corresponding mean Expanded Disability Status Scale (EDSS) scores were 2.0, and 5.5 for both primary and secondary progressive MS.

Patients with acute optic neuritis within 6 months of baseline were excluded, as were those with a history of ocular surgery or trauma, diabetes, uncontrolled hypertension, glaucoma, or other ophthalmologic disorders.

With a mean follow-up of 3.6 years, the results showed that, interestingly, compared to healthy controls, rates of atrophy with increased age was slower in those with MS in terms of retinal nerve fiber layer (pRNFL; P < .001), and while healthy controls had accelerated atrophy of GCIP in older age, there were no changes in those with MS (P = .006).

However, the rates of atrophy in both measures were independently associated with disease progression in MS: Compared to those with relapsing-remitting MS, patients who advanced to progressive MS had accelerated increases in atrophy in pRNFL (P = .002) and GCIP (P = .001).

"The changes correspond to 60% faster pRNFL thinning and 53% faster GCIP thinning at (45 years of age) in a subject in the lowest quartile of disability in nonoptic neuritis eyes," Sotirchos said.

Similarly, faster rates of atrophy of the inner and outer nuclear layers were seen with increased age among those with and without MS.

However, independent of age, compared to healthy controls, those with progressive MS had significantly greater atrophy in the inner nuclear layer (-0.09% annualized percent change; P = .03) and outer nuclear layer (-0.12% annualized percent change; P = .04).

These changes, Sotirchos said, "correspond to 38% faster inner nuclear layer thinning and 80% faster outer nuclear layer thinning in progressive MS compared to healthy controls at the centered age (45)."

In addition, the increased atrophy was also seen in those with relapsing-remitting MS compared with healthy controls (inner nuclear layer: P = .008; outer nuclear layer: P = .01).

There were no differences in retinal thinning rates according to gender in those with or without MS.

"Given that accelerated inner- and outer nuclear layer atrophy was observed only in progressive MS patients compared to healthy controls, inner- and outer nuclear layer atrophy appears to be specific to progressive MS and is likely representative of the insidious neurodegeneration which occurs at this stage of the disease," Sotirchos explained.

The findings of accelerated pRNFL and GCIP atrophy in progressive vs relapsing-remitting MS are also novel, he said. "However, all MS disease subtypes had accelerated atrophy of these layers compared to healthy controls, suggesting that this is a feature that progressive and relapsing-remitting MS have in common, albeit faster in progressive MS," Sotirchos explained.  

In addition to the need to reproduce the findings in larger multicenter cohorts, important next steps in the research include the need to look at how the changes relate to disability outcomes and the effect that disease-modifying therapies may have on the retinal changes, Sotirchos said.

In discussing the research in a separate talk at the meeting, Shiv Saidha, MD, senior investigator on the study and an associate professor of neurology at Johns Hopkins University School of Medicine, Baltimore, Maryland, underscored that damage to the optic nerve eventually occurs in nearly all MS patients, believed to stem from optic nerve inflammation.

"At postmortem, up to 99% of MS patients have demyelination in the optic nerve. What that implies is optic neuropathy is a virtually ubiquitous phenomenon in the MS disease process," he explained.

"The prevailing hypothesis is there is demyelination or axonal transection related to acute inflammation that occurs in the optic nerve, with a retrograde degeneration of constituent axons that results in a thinning of the inner and the ganglion cells."

While previous studies have suggested inner nuclear layer thickness at baseline in MS is predictive of future clinical as well as radiological disease activity and progression, the new findings offer important new insights on that relationship, Saidha said.

"Although the study has a decent-sized cohort, I don’t know if I would pin my hat on saying this is it in terms of a novel retinal biomarker that may have utility specific to progressive MS, but I’m very excited about it, and the goal will be to take a much deeper look at this."

Orhun H. Kantarci, MD, an associate professor of neurology at the Mayo Clinic in Rochester, Minnesota, agreed that the study offers compelling data on the role of the inner and outer nuclear layer.

"If we’re going to prevent things from happening clinically, we want to try to stop them sub-clinically before we get to the clinical problem, so I think in that sense it's an extremely important piece of work,” Kantarci told Medscape Medical News.

"Similar to atrophy that we may see in the spinal cord or thalamus or brain, these are markers of the ongoing insidious process that’s happening in the background of MS progression," explained Kantarci, who was not associated with the current research.

"By the time MS progresses, it's already a little late. In the future, if we have markers to tell us what's happening long before we see things clinically, then hopefully we can develop treatment strategies to prevent them."

Sotirchos and Kantarci have disclosed no relevant financial relationships. Saidha has received consulting fees from Medical Logix for the development of CME programs in neurology and has served on scientific advisory boards for Biogen-Idec, Genzyme, Genentech, EMD Serono and Novartis. He is the PI of investigator-initiated studies funded by Genentech and Biogen Idec, and received support from the Race to Erase MS foundation. He has received equity compensation for consulting from JuneBrain LLC, a retinal imaging device developer, and he is the site investigator of a trial sponsored by MedDay Pharmaceuticals.

Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2019: Abstract P022. Presented February 28, 2019.

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