Minimalism in MS: More is Less!


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!

Twitter: @SmetsIde

. 2021 Apr 7;10.1212/WNL.0000000000011933.doi: 10.1212/WNL.0000000000011933. Online ahead of print.

Modulation of Retinal Atrophy With Rituximab in Multiple Sclerosis

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.

About the author

Ide Smets


  • Does the more intense use of your eyes, for example the use of display screen equipment, phone screens, maybe a lot of reading per day. Have an effect on the retinal layer in any way?

  • Thanks for this. Do you think the next step might be less reliance on MRI’s and more on the use of optical coherence tomography (OCT) – or both together?

    • Yes, I do think this will be true when it comes to measuring neurodegeneration in MS. MRI will remain the mainstay to detect inflammatory T2 lesions. But measurement of brain volume loss with MRI is really difficult in a non-research clinical setting in which people are scanned on different scanners, MRI software upgrades etc. Moreover, when you measure brain volume you not only measure neurons but also myelin, water, blood, etc. And this really confounds the results and interpretation. I’m not saying OCT is perfect, but it’s definitely more accessible from a logistical point of view, cheaper, more specific for neurons and there’s less noise on longitudinal measurements.

  • Does this suggest that all pwMS should be offered appropriate meds. I’m not on DMTs, but I often wonder about brain volume loss. Now I will need to add GCIPL atrophy to be concerned about.
    I have never been offered any treatment in the NHS, though I was offered Rebif in France, but declined as it was within 3 year trial and I thought I’d have a weekly 3 hour journey. We returned to the UK before the trial was concluded, so it would have been ab inconvenience to the research project. I would bite your hand off to be in a trial now!

    • No, it means that the meds we use now when treating MS mainly tackle inflammation but not neurodegeneration on itself. If there is no inflammation left in the brain, the drugs cannot be neuroprotective and the risk/benefit profile of the drugs shifts towards risks. We currently do not have drugs available through the NHS that are purely neuroprotective; so you are not missing out on anything. We also don’t have any trials ongoing in our centre that are testing such drugs. GCPIL atrophy is essentially the same as brain volume loss, just easier to measure. So no extra worries there! That leaves us with neuroprotective lifestyle measures for the time being.

      • Ide,

        Thanks for your post.

        What do you think are the most promising drugs / approaches being trialled to tackle neurodegeneration – simvastatin? remyelination drugs eg metformin? BTK inhibitors? Alpha Lipoic Acid? HAART? The fact that so many different drugs / approaches are being trialled makes me think that the “MS experts” still don’t really have a good understanding of what this disease is about ie what kicks it off and what processes lead to the destruction of brain and spinal cord tissue. I wonder if any research presented at the AAN meeting which starts tomorrow will take us any further forward in understanding what MS is.

        • Hi Sid, I think you are right. ATM, there is not one specific pharmacological strategy that is more promising than others. There are some good data on sodium channel blockers, lipoic acid, dimethyl fumarate, pioglitazone, metformin, diets and exercise. I think we understand moretheless why destruction of neurons takes place. However, the problem is how to undo it and understand which pathway allows for a way in without adverse effects.

        • BTKi just starting to show they are significantly lowering neurofilament light chain levels in the blood. It could be a bit of light at the end of the tunnel in showing us why MS progresses, despite relapses.🤞

          • “We currently do not have drugs available through the NHS that are purely neuroprotective; so you are not missing out on anything”

            What about Alemtuzumab and hsct..? they both get people down to a normal yearly brain loss they are the most neuroprotective agents out there.

          • Alemtuzumab and HSCT are upstream agents, i.e. preventing the damage they are neuroprotective. The evidence that they work in late or advanced MS as neuroprotective is weak. As with all anti-inflammatories the earlier you use them the better.

          • Thank you for your time in replying to me. I’ll do a bit of research on these topics.

  • Somedays I feel so old school, shooting up Copaxone for 7 years then switched to Glatopa. It’s an easy routine for Me, old Nurse. Needles old hat. No 25 mile clinic drive to the infusion clinic for infusions I could give myself at home. Oh, those hand IV’s are So nasty, especially when our Hands are sometimes our greatest asset. Why not infusaports? I started Copaxone in 2005 in the CombiRx study. I was found to be very stable and turned out was only on Copaxone. I thought it acted like a decoy for the little nerve chomping MonSters? I equate it to Bee Stings I saw Charles Mraz be called to administer in the 1980’s in Burlington Vermont. I feel like Copaxone is like a bee sting, tiny proteins robbing the MonSters of Something they need to Thrive. Would I be worse without it? I have no doubt. I was having exacerbations at several year intervals. Not treated until third one. No exacerbations since 2005 (knock on wood). As long as you mention a drug and say “We believe “ it acts a certain way, you aren’t being honest with yourselves. Copaxone needs to be respected as a good drug especially for an older Grandma like myself. Convenient, private, no IV’s, simple, effective.

  • When I scan through articles like this I do wonder why people with advanced MS like myself and offered the opportunity to start these (neuro protective) drugs. But they are only ever offered to RRMS patients. If MS is considered to be the same disease throughout its life, just at varying stages, why are SPMS always excluded?

By Ide Smets



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