The plot thickens with Optic Neuritis

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Optic neuritis (i.e. inflammation of the optic nerve at the back of the eye) is one of the most frequent presentations in MS. It can result in either semi-permanent or permanent visual loss. Attempts to aid visual recovery have been partially successful with the use of sodium channel blockers, but not with remyelination therapies, such as anti-LINGO.

This paper on retinal oxygen supply may be the answer to why a remyelination strategies may not work. Whilst sodium channel blockade strategies that protect neurones via the mechanism of reducing nitric oxide (NO) induced mitochondrial compromise may just work.

See the source image
Picture of retinal oxygenation (Yi, Ji & Liu, Wenzhong & Chen, Siyu & Backman, Vadim & Sheibani, Nader & Sorenson, Christine & Fawzi, Amani & Linsenmeier, Robert & Zhang, Hao. (2015). Visible light optical coherence tomography measures retinal oxygen metabolic response to systemic oxygenation. Light: Science & Applications. 4. e334. 10.1038/lsa.2015.107.)

Here Kallab et al. demonstrate that there is reduced retinal (the area where the nerve fibre layer that processes visual information sits) oxygen extraction paralleled by a decrease in blood flow in the ON eye compared to the normal eye (see Figure below). Mitochondrial dysfunction that frequently occurs in ON is probably what leads to the reduction in oxygen extraction in the affected retina.

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Figure: Total retinal blood flow (A) and retinal oxygen extraction (B) in eyes with history of acute optic neuritis (MS+ON), in contralateral eyes with no history of ON (MS-ON) and healthy control eyes are significantly different between the study groups upon ANOVA analysis. MS+ON eyes showed significantly reduced total retinal blood flow and oxygen extraction as compared to MS-ON and healthy eyes.

With these changes there is also a reduction in the density of blood vessels in the ON eye:

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Figure: Capillary density (A) and large vessel density (B) in eyes with history of acute optic neuritis (MS+ON), in contralateral eyes with no history of ON (MS-ON) and healthy control eyes are significantly different between the study groups upon ANOVA analysis. MS+ON eyes showed a significantly reduced capillary density as compared to MS-ON and healthy eyes while large vessel density was significantly different between healthy and MS+ON eyes, only

These eventual structural changes will make it difficult to deliver products to the area most needed without the accompanying blood supply. To make effective changes in the process, any treatment that is being tried as a treatment for ON will need to take place before this pruning of blood vessels starts. The alternative and my crazy suggestion is to use VEGF (vascular endothelial growth factor) – which is periodically given as an injection into the eye for a condition called macular degeneration to promote the growth of blood vessels; here to improve microvascular pruning before commencing a therapeutic trial for the ON.

Abstract

Front Neurosci. 2021 Oct 12;15:761654. doi: 10.3389/fnins.2021.761654. eCollection 2021.

Retinal Oxygen Metabolism and Haemodynamics in Patients With Multiple Sclerosis and History of Optic Neuritis

Martin Kallab Nikolaus Hommer Andreas Schlatter Gabriel Bsteh Patrick Altmann Alina Popa-Cherecheanu Martin Pfister René M Werkmeister Doreen Schmidl Leopold Schmetterer Gerhard Garhöfer 

Vascular changes and alterations of oxygen metabolism are suggested to be implicated in multiple sclerosis (MS) pathogenesis and progression. Recently developed in vivo retinal fundus imaging technologies provide now an opportunity to non-invasively assess metabolic changes in the neural retina. This study was performed to assess retinal oxygen metabolism, peripapillary capillary density (CD), large vessel density (LVD), retinal nerve fiber layer thickness (RNFLT) and ganglion cell inner plexiform layer thickness (GCIPLT) in patients with diagnosed relapsing multiple sclerosis (RMS) and history of unilateral optic neuritis (ON). 16 RMS patients and 18 healthy controls (HC) were included in this study. Retinal oxygen extraction was modeled using O2 saturations and Doppler optical coherence tomography (DOCT) derived retinal blood flow (RBF) data. CD and LVD were assessed using optical coherence tomography (OCT) angiography. RNFLT and GCIPLT were measured using structural OCT. Measurements were performed in eyes with (MS+ON) and without (MS-ON) history for ON in RMS patients and in one eye in HC. Total oxygen extraction was lowest in MS+ON (1.8 ± 0.2 μl O2/min), higher in MS-ON (2.1 ± 0.5 μl O2/min, p = 0.019 vs. MS+ON) and highest in HC eyes (2.3 ± 0.6 μl O2/min, p = 0.002 vs. MS, ANOVA p = 0.031). RBF was lower in MS+ON (33.2 ± 6.0 μl/min) compared to MS-ON (38.3 ± 4.6 μl/min, p = 0.005 vs. MS+ON) and HC eyes (37.2 ± 4.7 μl/min, p = 0.014 vs. MS+ON, ANOVA p = 0.010). CD, LVD, RNFLT and GCIPL were significantly lower in MS+ON eyes. The present data suggest that structural alterations in the retina of RMS patients are accompanied by changes in oxygen metabolism, which are more pronounced in MS+ON than in MS-ON eyes. Whether these alterations promote MS onset and progression or occur as consequence of disease warrants further investigation. 

About the author

Neuro Doc Gnanapavan

11 comments

  • I am an RRMS patient, so (skim!) reading this as a total non-expert.. but reading your second sentence “It can result in either semi-permanent or permanent visual loss” alarmed me greatly. I presented with optic neuritis 4 years ago , which, unbeknown to me at the time, was the beginning of my MS diagnosis. It was incredibly scary. But every doctor I saw – and I saw several before anyone knew what it was – told me that it was “most likely” to heal itself over a few weeks. They said there was no guarantee, but I was given the impression my sight had a good chance of recovering very well . But here you’ve given readers the impression it’s *most* likely to cause some kind of permanent visual loss. It doesn’t seem like a very clear or nuanced way of writing about it. I don’t know what the data shows about how many PwNS recover well from ON , but maybe you should add that in for context?

    • Most people recover vision but you can tolerate substantial amounts of nerve loss without vision loss and as a result of optic neuritis there will be some nerve loss many people wont notice it but some do.

    • Sarah – It depends on how one defines “heal”……I like to use the term “resolve” when describing MS issues and symptoms. A good example is lesions…..a DMT may help scars “heal” but the damage is already done to the neurological pathway.

      My ON resolved itself, but only after my brain and right eye learned how to compensation for the damage to the left, and I started with an aggressive DMT to treat my MS. I still have some blurred vision in my left eye and issues with low light, particularly on the days my MS “reserve” is low. I also understand if I have another relapse and it involves my ON, I could loose my vision in my left eye.

      Honestly, for me the scariest part of NDG post…..“periodically given as an injection into the eye”……Ouch!! And I thought the LP was the worst MS related procedure I would ever have to endure.

      • Regarding injections into the eye, with local anaesthetic applied, you don’t even notice its been done. Not remotely comparable to LP!

        • Only my first LP was horrible. After that it’s the mindset that helped me trough.

          Just another thing that needs to be done, it’s all over in 15 min. And prey that the headache is not that bad.

      • I had a tiny seed stuck in my eye. After administering eye drops my head was clamped still. I could see the instruments coming towards my eye, but then the doctor put them down and sat back. I asked what was wrong, he replied ‘Nothing I’ve done it’. I felt absolutely nothing and didn’t realise it was happening. 🙂

    • I would be curious myself. I had the opposite experience: I’ve had one bout of ON and unfortunately have permanently blurred vision in my left eye because of it. I’d feel better knowing that another bout of ON isn’t necessarily going to result in more permanent damage!

  • Do you think this indicates that hyperbaric oxygen therapy in the acute phase of an ON episode might aid recovery? (We can’t go into a pharmacy and buy phenytoin, but we can pay for HBOT).

    • Uncertain on whether hyperbaric oxygen may help, as we still don’t know exactly what the drivers for this are. But, I am hypothesising that this is secondary to mitochondrial dysfunction and then maybe supporting the respiratory cycle with HBOT may help.

  • Here I’m gonna go again back on my soap box…a little. Me too; one of my earliest MS experiences was ON. I had it three times, once in each eye at different times (totally blind, 4-6 weeks overall duration) and a partial recurrence in one of them that lasted up to year I believe it was. 30 years later, my vision functions normal as far as I can “see” (there is a bit of nystagmus which is something else).

    My recollection now is that at the time (mid 90’s) I was told, and read, it would seem scary but in almost all situations, it went away. I have read various blogs, research, sites etc. forever and ever, and I seldom read that vision becomes an issue, other than the scare and alarm as Sarah describes (and if I am wrong and this is not true for you, please forgive).

    I understand because I was told by Mouse Doctor here, that the optic nerve is BIG and can withstand a lot “knocking around”, unlike other nerve pathways (my words). But my observation and intrigue still continues: ON occurs early, not later, in MS, and most people recover and do so well, like me. I was not on any “heavy duty” DMT in 1995, and I may have had one or two bouts of ON before even going on Interferon. So I still believe there is something else to learn about ON that can help with the understanding of MS progression. Why does someone like me (a sizeable number of the MS population) stop having attacks or deterioration of the optic nerve, versus other nerves? Nothing has changed visually for 30 years and I’m going to predict that nothing else will. So Sarah, in my humble opinion, do everything you ought do (and then some) to treat your MS, but I’m going to console with a non-medical opinion, that vision is one of the last things you’ll need to worry about. (And I like Sarah’s idea about adding or acquiring data about the lasting effects of or further progression of ON in the MS population.)

  • I know this is off-topic. To add recent support to my observation noted above, and support Sarah’s dismay and wish for further data, I note the following: i just completed the semi-annual NARCOMS MS survey update. It is a nationwide (US) accumulation of data done 2x yearly with people with MS. I have been contributing data for a long time (+10 yrs?). I think there is a comparable entity in Britain.

    The only query into vision difficulties was 1) indicating if you have “blurry or double vision” issues, and 2) indicating if you have seen an optometrist (among about 30+ specialties). There are hundreds of questions in the survey. One may say, OK, you see, but not as well. I respond, they certainly do “drill down” when it comes to walking- how it affects this, that and the other in your life, how it makes you feel, on and on. “Sight” just does not get the same considerations, in the survey, at least.

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