Once upon a time, there were cyclists as Fausto Coppi. He was the kind of guy that attacked 5 km after the start of the race (Milan San-Remo 1946), and then dropped the rest of the lead group with 14 minutes on the ‘Passo del Turchino’ or ‘who-wins-on-the-Turchino-wins-the-race’. He not only won the Tour de France twice, he did it with a ‘martian’ dominance. In 1949, there was a 14’ difference with his lifelong rival Gino Bartali and in 1952 there was an 28’ difference. No Swiss watch needed. May I remind you that Pogacar only beat Roglic with 59’’ in the TDF of 2020? Once Fausto broke away from the peloton, you never saw him again. This happened five times in both the Giro di Lombardia and Giro d’Italia. It was this legend that claimed “Only your eyes can show the suffering,” and we could not agree more (although calves and eyes would probably be more accurate).

In a new study, Lambe et al. showed that in pwMS the thickness of the ganglion cell layer which is located at the back of your eye corresponded with disability worsening 10 years down the line. If the ganglion cell layer measured less than 70 micron, there was a 4-fold increased risk of a meaningful rise on the EDSS disability scale. The ganglion cell layer is a very specific layer of the retina that contains the naked, unmyelinated cell bodies of neurons. The branches of these neurons, also ‘axons’, form the optic nerve. If the optic nerve becomes inflamed and demyelinated, neurons die and this leads to retrograde thinning of the ganglion cell layer. Importantly, this also happens in pwMS that did not have obvious eye problems which is one of the hallmarks of smouldering MS. Therefore, the thickness of the ganglion cell layer is probably a reflection of your brain reserve, and thus mirrors how much neurons you are left with after MS inflammation attacks your brain. This layer can be measured using ‘OCT’ or ‘optical coherence tomography’’ in which an infrared laser beam is directed at your retina. The reflection of this beam allows to model the 3D-shape of the retina. OCT is essentially very similar to an echography.

These are very important findings as the MS community is literally craving to have a reliable, easy-to-implement biomarker of brain volume loss or ‘end organ damage’. Of note, OCT is more promising than the other techniques that aspire to quantify brain volume loss. 

Brain volume measurements on MRI have been extensively researched, but have the following shortcomings:

• Brain volume is a composite measure. It does not only incorporate axons/neuronal bodies but also a lot of glial cells, myelin/oligodendrocytes and water.
• If pwMS start an MS treatment, the brain volume initially disproportionately reduces because the inflammatory oedematous lesions shrink and thus not because there is ongoing damage to the brain. To avoid this confounder, repeated measurements of brain volume over time are needed. 

Neurofilament light levels are released when neurons die and can be measured in blood and the cerebrospinal fluid. However, there are the following shortcomings:

• Cerebrospinal fluid levels are more reliable to quantify but require a lumbar puncture. Hence, they are not suited for repeat measurements. 
• Blood neurofilament levels are easier to access but levels are so low there is a big overlap with healthy individuals. This means it is very difficult to establish reference ranges that would allow to distinguish healthy ageing from pathological ageing in MS. 

The next line of research should focus on how OCT measurements could be implemented in clinic practice. Imagine we would have a measurement of ganglion cell layer thickness when you first attend our clinic and when we decide on a treatment strategy. If your ganglion cell layer is thinner than average (for example lower than 70 micron), how should we act on this – especially if the person with MS at that point is relatively unaffected? Should this prompt a more aggressive second or even third line treatment strategy (e.g. stem cell transplantation)? Personally, I think the answer is yes. Low levels of ganglion cell layer thickness flag there is not much brain reserve left to deal with the damage caused by potential future relapses. In other words, there is a narrow window for disease modification and it needs to be seized asap. This is the trap and beauty of human biology. As we have so much reserve and parallel circuits in the brain, we only present with clinically meaningful symptoms when already a significant amount of our neurons has died. Moreover, the OCT measurements may also be used to properly counsel patient. If your levels are low already at the outset of your disease, it would be wise to manage expectations personally and professionally. 

When Fausto Coppi rode his first race at age 15, he won first prize: 20 lire and a salami sandwich. This article is the first race of OCT as a clinically useful marker of brain damage in pwMS. We need more data, preferably from clinical trials, to understand how ganglion cell layer thickness evolves over time, which cut-offs can be used, how it reflects for example spinal cord damage, what would be a meaningful reduction in ganglion cell layer thickness and to what extent treatments can modify it. Nonetheless, a glimpse at the back of your eye can lift the veil on a suffering MS brain.

Twitter: @SmetsIde

. 2021 Mar 2;10.1212/WNL.0000000000011788.doi: 10.1212/WNL.0000000000011788. Online ahead of print.

Association of Spectral-Domain OCT With Long-term Disability Worsening in Multiple Sclerosis

Jeffrey Lambe ¹, Kathryn C Fitzgerald ¹, Olwen C Murphy ¹, Angeliki G Filippatou ¹, Elias S Sotirchos ¹, Grigorios Kalaitzidis ¹, Elena Vasileiou ¹, Nicole Pellegrini ¹, Esther Ogbuokiri ¹, Brandon Toliver ¹, Nicholas J Luciano ¹, Simidele Davis ¹, Nicholas Fioravante ¹, Ohemaa Kwakyi ¹, Hunter Risher ¹, Ciprian M Crainiceanu ², Jerry L Prince ³, Scott D Newsome ¹, Ellen M Mowry ¹, Shiv Saidha ¹, Peter A Calabresi ⁴Affiliations expand

• PMID: 33653904
• DOI: 10.1212/WNL.0000000000011788

Abstract

Objective: To evaluate whether a retinal spectral-domain optical coherence tomography (SD-OCT) assessment at baseline is associated with long-term disability worsening in people with multiple sclerosis (PwMS), we performed SD-OCT and Expanded Disability Status Scale (EDSS) assessments among 132 PwMS at baseline and at a median of 10 years later.

Methods: In this prospective, longitudinal study, participants underwent SD-OCT, EDSS, and visual acuity (VA) assessments at baseline and at follow-up. Statistical analyses were performed using generalized linear regression models, adjusted for age, sex, race, MS subtype, and baseline disability. We defined clinically meaningful EDSS worsening as an increase of ≥2.0 if baseline EDSS score was <6.0, or an increase of ≥1.0 if baseline EDSS score was ≥6.0.

Results: 132 PwMS (mean age: 43 years; n=106 patients with relapsing remitting MS) were included in analyses. Median duration of follow-up was 10.4 years. In multivariable models excluding eyes with prior optic neuritis, relative to patients with an average baseline ganglion cell+inner plexiform layer (GCIPL) thickness ≥70µm (the mean GCIPL thickness of all eyes at baseline), an average baseline GCIPL thickness <70µm was associated with a 4-fold increased odds of meaningful EDSS worsening (adjusted odds ratio: 3.97; 95% CI: 1.24-12.70; p=0.02), and an almost 3-fold increased odds of low-contrast VA worsening (adjusted odds ratio: 2.93; 95% CI: 1.40-6.13; p=0.04).

Conclusions: Lower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS. Accordingly, SD-OCT at a single time-point may help to guide therapeutic decision making among individual PwMS.

Classification of evidence: This study provides Class I evidence that lower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS.