Interesting question. The morphological differences between glaucoma and multiple sclerosis neuritis are likely related to the different pahogenesis associated with each disease.

Experimental studies have shown that apoptosis is the mechanism of cell death in glaucoma neuropathy. High intraocular pressure and neuronal ischemia-reperfusion related to glaucoma causes axonal transport failure, oxidative stress, neurotrophic factor deprivation, mitocondrial dysfunction, and excitotoxic damage. These events trigger the apoptosis cascade. The morphology associated with apoptosis is typically characterized by nuclear and cytoplasmic condensation, and cellular fragmentation with minimal inflammation. These fragments (apoptotic bodies) are taken up by other cells and degraded within phagosomes.

On the other hand, multiple sclerosis is an autoimmune disease characterized by inflammatory demyelination, and neuron loss. Although the apoptosis may also be triggered in multiple sclerosis, the inflammatory basis of the disease induces activation of glial cells and subsequent fibrillary gliosis. This feature is probably responsible for the morphological aspect seen in multiple sclerosis neuritis.

References

Almasieh M et al. The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res. 2012; 31(2):152-81

Fink SL et al. Apoptosis, Pyroptosis, and Necrosis: Mechanistic Description of Dead and Dying Eukaryotic Cells. Infec Immun. 2005; 73(4):1907-16

van Walderveen MA et al. Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis. Neurology. 1998; 50(5): 1282-8

I fully agree with Dr. Meira-Freitas that two separate pathological mechanisms are taking place in glaucomatous disc and in the non-glaucomatous atrophic disc such as due to multiple sclerosis. Then why are the both diseases classified under optic neuropathy? Actually I wanted to have feedback as to why the end-stage histology of the glaucomatous disc and non-glaucomatous disc are so distinctively different.

Before I discuss and render my hypothesis on this issue, I would like to go back to Dr. Meira-Freitas's statement that glaucoma is due to apoptosis of the RGC’s which is triggered by high IOP or other factors.

I am afraid I am unable to convince myself that glaucoma is due to apoptosis or a neurodegenerative disease based on the fact : In glaucoma the nerve fibers are always being destroyed in a specific sequence. The peripheral fibers are destroyed first followed by the paracentral or arcuate and finally the central fibers. The nerve fibers are never destroyed randomly or haphazardly in glaucoma. If the nerve fibers in glaucoma were being destroyed randomly then of course, the visual fields test in glaucoma would have become useless.

Now question arises: How is it possible that apoptosis in glaucoma would always start first with those RGC’s which serve the peripheral fibers, then the middle and finally the central fibers? Why couldn’t apoptosis occur randomly in glaucoma as it occurs in other neurodegenerative diseases? In order for apoptosis to be genetically controlled it must fulfill two requirements: First our genes have to be smart enough to foresee glaucoma. Then they must initiate apoptosis only with those RGC’s which serve the peripheral fibers and not destroy randomly. I don’t think a neurodegenerative disease can destroy the nerve fibers in a specific and predictable pattern as is occurring in glaucoma. In view of aforementioned, I can’t convince myself that glaucoma is a neurodegenerative disease. If the nerve fibers are being destroyed in an orderly sequence in glaucoma then I should expect the mechanism causing their destruction to be an orderly as well.

Then what may be occurring in glaucoma? I hypothesize that optic disc (Lamina Cribrosa) may be sinking in glaucoma due to mechanical failure. Due to sinking disc the peripheral fibers being close to scleral edge will be stretched and broken(severed ) first, followed by paracentral fibers and ultimately the most central fibers and get also severed against the scleral edge. in an orderly fashion. Therefore the nerve fibers are being severed, not atrophied in glaucoma. Glaucoma may not be an optic disc neuropathy but an optic disc axotomy. Severing of the nerve fibers would result in retrograde death of the RGC’s and wallerian degeneration of the neurons in LGN. Splinter hemorrhages at the disc margin appear to be due to severing of the small vasculature.

End-stage glaucomatous disc may not be a 100 % cupped disc but an empty bean-pot left over after the severance of the nerve fibers. In contrast the non-glaucomatous atrophic disc are flat (non–excavated) since here no severing of the nerve fibers is taking place. Histology of non-glaucomatous atrophic disc still reveals nerve fibers though shrunken. I would welcome any feedback. Thank you.

Dr. Hasnain makes several good points, and I agree that the overwhelming evidence is that the damage tot eh RGC axons occurs at the lamina cribrosa. As such, glaucoma may be viewed as an axonopathy, but the mechanism of that damage is largely unknown, however, and there is no evidence that the axons are severed in glaucoma. They are most certainly under both mechanical and physiologic strain at the level of the lamina, but the mechanism of axonal damage remains unknown. The mechanisms are almost certainly multi-factorial. As an example, the blood supply to the axons in the laminar region is carried by capillaries that are wholly contained within the load-bearing laminar beams themselves, and so blood flow may be impeded by mechanical strain in the laminar beams that in turn reduces the lumen size of the contained capillaries. In this way, the axons may be damaged by prolonged ischemia that is driven my IOP-induced mechanical deformation and strain - a melding of the classic 'mechanical' and 'vascular' hypotheses of glaucomatous axonal damage.

Dear Dr. Downs. Thank you very much for your reply.

I was not asking at this time the causes of severance or atrophy of the nerve fibers in glaucoma. My question was simple: Are the nerve fibers being atrophied or severed in glaucoma? Analogy: does this patient has atrophied or an amputated leg? You have mentioned that that there is no evidence that the nerve fibers are being severed in glaucoma.

My hypothesis of severance of the nerve fibers along with its vasculature can be rejected or accepted in seconds: all one needs is to look again the histology of end-stage glaucoma disc (ESGD) (this time not a cursory look but with scrutiny) and decide yourself: is ESGD really a 100% cupped lamina cribrosa filled with atrophied nerve fibers or a crater left over after the severance of all the nerve fibers including its vasculature? ESGD is an empty crater- no nerve fibers- no vasculature- no lamina either, unless rigid multilayered LC has stretched and ballooned and forming the walls of the huge crater-an unlikely scenario. I believe severance of the nerve fibers is the wild card in the mystery of glaucoma. Once we decide on this issue then we can figure out why nerve fibers are being severed in glaucoma. Glaucoma may not be an optic disc neuropathy but an axotomy.

I have put forward my arguments supporting severance of nerve fibers in my published articles on researchgate forum. And now it is up to my colleagues to accept or not.

I would welcome anyone to reject the severance of nerve fibers in glaucoma so I will abandon my struggle and also sleep well. Thanks

Severance of the nerve fibers has been endorsed by a recent article from Saudi Arabia in a following link

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792954/

There is no contradiction between the two states.

A neuron can be severed, we have an evidence in glaucoma as reducing and normalising IOP results in a functional improvement (better visual vield-smaller scotomas) and the final result of a damage can be deat,h apoptosis and disappearence of the cel,l a non revesable imparement. Both "live" side by side.

There is certainly room for both scenarios, but the data points to more atrophy than acute severance as a mechanism for axon loss. The most compelling anecdotal evidence is that axon damage occurs over many years, although there may be shorter periods of active progression within that timeframe. The cupping of the lamina is certainly not an acute process, and is likely the result of remodeling of the connective tissues over time. See our review for details of the current state of the field on this issue:

Downs JC, Roberts MD, Sigal IA: Glaucomatous cupping of the lamina cribrosa: A review of the evidence for active progressive remodeling as a mechanism. Experimental Eye Research, 93:133-140, 2011. PMCID: PMC3026919

Dear Drs. Downs and Wegner

Thank you for your response. My statements may not be contradictory but one thing appears to be certain that the so called phenomenon of ‘cupping’ may not be occurring based on the arrangement of the nerve fibers in the optic disc/retina and the way visual fields defects are produced in glaucoma. The nerve fibers originating closest to the disc lie most superficial (closest to vitreous) and exit from the most central part of disc whereas the nerve fibers originating from the most peripheral retina lie deepest (closest to sclera) and exit closest to the scleral edge.

If cupping was indeed occurring then the central most fibers should be destroyed first resulting in continuous concentric enlargement of the blind spot. Blindness would have occurred much sooner due to earlier involvement of the macular fibers and the peripheral field loss at the end. But in actuality the reverse is occurring in glaucoma since the peripheral fields are lost first and central vision is retained until the end. For me, this fact alone is enough to discredit the concept of cupping in glaucoma.

Dr. Downs, I don’t believe there is room for both scenarios as you have suggested. I think the nerve fibers are either being atrophied or being severed in glaucoma but not both ways. I have read your good article about cupping of lamina in glaucoma.

I have reviewed the histology of several end-stage glaucomatous discs (ESGD) but none of them appears to me as cupped lamina cribrosa. With my different mind set it is difficult for me to accept that a small multilayered rigid connective tissue lamina would stretch and blown (remodeled) into a large bean pot-ESGD.

My paradigm of sinking disc/severing of the nerve fibers is new and it is not easy to compete with 150 -year old established cupping/atrophy of the nerve fibers paradigm. Nevertheless, I am confident as my paradigm becomes more known with time our colleagues would compare and contrast both paradigms and decide which paradigm is more acceptable and this is the only way science progresses.

Regarding Dr. Wegner’s statement about apoptosis or suicide of RGCs occurring in glaucoma we have to remember one important aspect of glaucoma. The nerve fibers in glaucoma are always being destroyed in an orderly fashion starting with the peripheral fibers and ending with the central and never haphazardly.

Surely, apoptosis may be occurring in glaucoma provided it meets two requirements: first, our RGCs must have the ability to predict impending glaucoma, secondly then RGCs should be smart (or stupid) enough to start committing suicide invariably in an orderly tandem fashion starting with RGCs serving the peripheral vision and ending with those serving the central vision and never commit suicide randomly. I don’t think our RGCs have such an extraordinary wisdom to accomplish this magical feat. I don’t believe RGCs are committing suicide but they are being killed after their axons are severed. I certainly thank you both for feedback.

For details about my hypothesis you may visit my facebook. Thanks.

https://www.facebook.com/pages/Glaucoma-Paradigm-Shift-Project/516804278413418

Dear Syed what you are saying is the central most fibres are the ones which would be affected first.,Indeed these are the fibres that are affected first. They are the arcuate fibres closest to the disc .The central most fibres which comprise the central 10 degree field do not enter the vertical portions of the disc and are part of papillomacular bundle which enter the disc from the temporal side.

Dear Syed Hasnain, loss of orbital fat has no place in his theory?

Dear Puneet, according to the arrangement of nerve fibers in retina and the optic disc (source: Glaucoma; section 10, from AAO) the fibers originating farthest from the optic disc lie deepest (closest to sclera) and exit closest to the scleral edge whereas the fibers originating closest to the optic disc lie most superficial (closest to the vitreous). This applies to all the 360 degrees nerve fibers including arcuate fibers. Arcuate fibers lie in the paracentral area (outer to 10 degrees from the fixation point), therefore the arcuate field defects are noticed in the 10 to 20 degrees away from the fixation point. If the entire arcuate fibers would have been exiting from the central most part of the disc then we should not be having arcuate defects in the paracentral area.

Why are the arcuate field defects produced?

All the 360 degrees nerve fibers are being severed simultaneously. In the temporal part the entire group consisting of macular, superior and inferior arcuate are also being severed simultaneously. However the arcuate fibers being fewer in number compared to the macular fibers are depleted earlier giving rise to the arcuate field defects. The thinning of the ganglion cell complex noticed from the very early stages of glaucoma gives credence to the fact that macular fibers are also being destroyed from day one. I believe the severance of the nerve fibers is the missing card in glaucoma Jigsaw puzzle and should answer all the unanswered questions in glaucoma.