Our eyes are a very promising window into the brain. By looking into the eye with a technique called optical coherence tomography (OCT), we are able to visualise the retina’s ganglion cell layer that consists of naked, unmyelinated neurons. When MS’s inflammatory lightning affects the myelin sheet of the optic nerve (which is the case in 99 % of pwMS), this ultimately leads to dying back of neurons in the retina, and thus by consequence thinning of the ganglion cell layer. We already know from other publications that the thickness of the ganglion cell layer correlates with having higher clinical disability scores in the future. This means that when you have a very thin ganglion cell layer at present, you are much more likely to have difficulties walking in ten years from now: ‘Less is More’, unfortunately.
In a new study, Lambe et al. assess to what extent high potency DMT’s such as rituximab and Tysabri as well as a low-potency drug such as Copaxone can undo the accelerated thinning of the the ganglion cell layer in pwMS over time. Although their data are somewhat flawed by the observational nature of the patient cohort, they do show that rituximab and Tysabri reduce the rate at which ganglion cells in the retina die. However, the effect only becomes apparent after 12 months of treatment. In the first 12 months, the ganglion cell layer continues to lose volume as if no treatment was started. After 12 months of follow-up, the thinning of the retinal nerve layer seems to approach the annual volume loss seen in healthy controls. In people treated with Copaxone, there was no difference in ganglion cell layer thinning between the first 12 months of follow-up and thereafter.
The question that comes to mind after reading this article is: Why do these high-potency treatments have such a delayed effect on OCT measurements? This therapeutic lag when it comes to neuroprotection illustrates a very important principle in MS. Essentially, there are two different ways for a drug to prevent MS-induced brain volume loss:
- By an indirect neuroprotective effect: This means that by preventing inflammation in the brain, drugs can prevent demyelination and consequentially also neuronal loss. When a nerve loses his myelin sheet, it loses namely an important source of trophic support, leading to swelling, disorganisation of the cell’s backbone (‘cytoskeleton’) and ultimately death. Importantly, once a neuron or an axon gets damaged by inflammation, it can take up to 6 – 9 months before it actually fully degenerates.
- By a direct neuroprotective effect: This could be achieved by for example promoting remyelination or preventing neuronal energy failure. One strategy for remyelination could be to stimulate oligodendrocytes in the brain to produce more myelin. One of the drugs that has shown some promise in this department is clemastine. This drug is thought to act on M1 muscarinic receptors located on oligodendrocytes. Lab work showed clemastine encourages immature oligodendrocytes to mature into cells capable of making myelin, offering the potential to reverse damage caused by inflammatory lesions in MS. A direct neuroprotective effect does not require modulation of the immune system. We expect to see direct effects shortly after starting the drug. In the clemastine trial, changes in optic nerve conduction velocity were seen after a follow-up period of 90 days.
The timing of OCT improvement thus allows to make the distinction between a direct or indirect neuroprotective mode of action.
Overall, the findings in this article provide further evidence for the fact that our current DMT’s have a much appreciated neuroprotective effect, albeit indirect. They block the access of inflammatory cells to the brain, prevent inflammation and demyelination and consequentially brain volume loss. This implies there will always be an important therapeutic lag between starting an anti-inflammatory treatment and preventing neuronal death. It also means that when new lesions appear while being treated they can still cause a lot of damage. PwMS need thus other treatments with non-immunologic mode of actions that can help damaged neurons in their struggle to survive, because as MS minimalists say: more ganglion cell layer is less disability!
. 2021 Apr 7;10.1212/WNL.0000000000011933.doi: 10.1212/WNL.0000000000011933. Online ahead of print.
Jeffrey Lambe 1, Hunter Risher 1, Angeliki G Filippatou 1, Olwen C Murphy 1, Elias S Sotirchos 1, Henrik Ehrhardt 1, Esther Ogbuokiri 1, Nicole Pellegrini 1, Brandon Toliver 1, Nicholas J Luciano 1, Simidele Davis 1, Nicholas Fioravante 1, Ohemaa Kwakyi 1, Jerry L Prince 2, Peter A Calabresi 1, Kathryn C Fitzgerald 3, Shiv Saidha 3Affiliations expand
- PMID: 33827962
- DOI: 10.1212/WNL.0000000000011933
Objective: To investigate the effects of rituximab on retinal atrophy in patients with relapsing-remitting multiple sclerosis (RRMS), we performed serial optical coherence tomography (OCT) scans among a cohort of RRMS patients on rituximab, and compared rates of ganglion cell+inner plexiform layer (GCIPL) atrophy to those observed among age- and sex-matched glatiramer acetate (GA)- and natalizumab-treated RRMS patients, and healthy controls (HCs).
Methods: In this observational study, patients with RRMS treated with a single disease-modifying therapy, and HCs, were followed with serial OCT for a median duration of 2.8 years. Participants with uncontrolled hypertension, diabetes mellitus, or glaucoma, and eyes with optic neuritis ≤6 months prior to baseline OCT, or during follow-up, were excluded. Statistical analyses were performed using linear mixed-effects regression.
Results: During the overall follow-up period, rates of GCIPL atrophy were -0.28±0.11µm/yr among rituximab-treated RRMS patients (n=35). This was similar to GA-treated (n=49; -0.33±0.05µm/yr; p=0.69) and natalizumab-treated patients (n=88; -0.17±0.10µm/yr; p=0.13), and faster than HCs (n=78; -0.15±0.03µm/yr; p=0.006). Rituximab-treated patients exhibited 0.55±0.23µm/yr faster rates of GCIPL atrophy during the first 12 months of treatment, relative to afterwards (n=25; p=0.02), during which period GCIPL atrophy rates were -0.14±0.13µm/yr.
Conclusions: Retinal atrophy in RRMS is modulated by rituximab. Greater attenuation of retinal atrophy may occur after 12 months of rituximab treatment, following which time GCIPL atrophy rates are similar to those observed among natalizumab-treated RRMS patients and HCs. Our findings raise the possibility that the neuroprotective therapeutic response with rituximab in RRMS may take up to 12 months, though should be confirmed by larger studies.