They correlate with each other in most model systems.

There is no connection between RGCs and IOP. We should always remember that the nerve fibers in glaucoma are always and invariably destroyed in a specific and orderly fashion starting from the peripheral fibers and ending with the central and never other way around or haphazardly. How is it possible that raised IOP acting directly would always destroy the nerve fibers or their RGCs in an orderly fashion and not randomly.

Same applies to apoptosis: how is it possible that RGCS would commit suicide ((apoptosis) in an orderly fashion and never randomly. I don't think our RGCs are that smart that they would commit suicide in a tandem. In fact there can't be any direct mechanism: either of raised IOP or ischemia or neurodegeneration or of any thing else which by acting directly would result in an orderly destruction of nerve fibers in glaucoma.

Then why are the nerve fibers being destroyed in an orderly fashion in glaucoma? It has to be due to some indirect mechanism resulting from raised IOP or from something else. I propose that raised IOP atrophies the border tissue so disc starts sinking in the scleral canal. As a result the nerve fibers along with its vasculature are severed in an orderly fashion starting with the peripheral fibers and ending with the central. The peripheral fibers are affected first because of they exit closest to the scleral edge. and due to sinking disc they would the first to be stretched and broken. As the sinking of the disc would continue the next in line central fibers would move towards the periphery to occupy the vacant space and thus also get stretched and severed. The sinking of the disc and severing of the nerve fibers can explain the orderly destruction of nerve fibers in glaucoma. Glaucoma may not be an optic disc neuropathy but an optic disc axotomy, a paradigm shift. There is plenty of proof that the nerve fibers along with its vasculature are being severed in glaucoma. All we need is to look the glaucoma disc in the context of severing and thus excavation in the disc. I would appreciate feedback. Thanks.

Thank you, an interesting proposal. If you theorise that raised IOP initiates atrophy in the border tissues leading to retinal cell death/glaucoma then what is the mechanism responsible for normal tension glaucoma?

Matt, you appear young asking very intelligent questions. You have raised a valid question about NTG: I don’t know how our colleagues would answer your good question because they are saying that raised IOP forces RGCs to commit suicide(apoptosis) then why should normal IOP trigger apoptosis in NTGs. However, I hypothesize that the border tissue of Elschnig (BT) lying between the lamina cribrosa and the scleral edge may be the primary site of pathology, not the various sized holes of the lamina cribrosa. BT acts like an ‘O’ ring seal which keeps the optic disc firmly anchored in the scleral opening. If BT atrophies, the optic disc would start sinking in the scleral canal.

Why should the border tissue atrophy in both HTG and NTG? It is a complex and multifactorial subject. First, the interaction between the blood circulation of the BT and IOP, which are opposing forces. Second, the structural integrity of the BT, inherent or acquired. BT is supplied exclusively by the short posterior ciliary arteries (ciliary circulation), a weaker pressure compared to the central retinal artery, which unfortunately, does not participate in the blood supply of the border tissue. Normally the ciliary pressure of the BT should be higher than the IOP for its good perfusion and healthy maintenance. However, if either the IOP becomes higher than the ciliary pressure due to an ocular disease or the ciliary pressure supplying the border tissue itself becomes lower than IOP, due to some systemic problems like chronic hypotension then the IOP will assume the upper hand and will compress the circulation of the border tissue, resulting in chronic ischemia and its atrophy. In latter scenario, if the ciliary pressure becomes lower than any normal range IOP level, then that particular IOP level (even if it happens to be within normal range) will act as a higher IOP for that particular subject, thus NTG will result. The relationship between the IOP and ciliary circulation is relative in every individual, but it is still the IOP, whether above or within the normal range (10- 21), appears to be the culprit in both HTG and NTG. However, we have to look for systemic causes in NTGs as to why they have resulted in IOP taking the upper hand and this may be another way of treating NTGs.

Moreover, it is not only the IOP level important, but also the oxygen carrying capacity of the blood which may also cause chronic hypoxia and atrophy of the border tissue. This may explain the higher incidence of NTG in cases of long- term smokers and those with sleep apnea. In addition to circulation we may have to consider the structural integrity of the border tissue. If someone is endowed with strong border tissue then that particular subject may tolerate the circulatory imbalance for a longer period compared to someone who has weaker border tissue such as in high myopia or various collagen tissue disorders. Keeping all these factors in view, the pathogenesis of atrophy of the BT becomes multifactorial.

Nutshell of my hypothesis: the optic disc is sinking, and as a result the nerve fibers along with its vasculature are being severed. I would be wrong if this is not happening in glaucoma. We have ample proof for their severance: all we need is to look at the glaucomatous disc differently (gestalt switch). Instead of looking for cupping and cup/disc ratio’s we may have to look for sinking, sloping/kinking of blood vessels, excavation and characteristic whitish pallor/ hemorrhages resulting from the severance of the nerve fibers along with its vasculature. If none of aforementioned is evident then most likely glaucoma would be questionable irrespective of cupping or their ratio’s. You may find it an eye opening experience, revealing new wealth of information which we had never seen before, and also may find so convincing that you may support my hypothesis. For details you may find my articles on this forum. Thanks and always looking for feedback.

Excuse my questions but I am new to this area: When you say the optical disk starts sinking in which direction do you mean? towards or away from the eye ball (just to be explicit) ? Do you propose then that the lamina cribrosa is also sinking? or is that still fixed in the sclerial pore?

Lamina cribrosa (LC), the multilayered sieved connective tissue plate is the main constituent part of the optic disc giving it a hard structure. When I said optic disc is sinking I did mean that LC is detaching and moving outward, away from the vitreous. According to the histology of the normal disc, the LC is not a fixed integral part of scleral shell but separated by connective border tissue(BT).

I don’t believe the force of even very high IOP is enough to dislodge the LC in normal situations, otherwise we would have seen acute sinking of the disc in acute glaucoma’s. I think chronic ischemia is important element in causation of atrophy of the BT and for that we need time as chronic starvation would take time to turn an obese person into emaciated one. Therefore chronic glaucoma is indeed chronic disease.

Whatever the cause may be: the bottom line of my hypothesis is that nerve fibers along with its vasculature are being severed, not atrophied in glaucoma. Analogy: the leg is amputated, not atrophied. It appears by your questions that you are doing glaucoma research. If so, I can share my views on personal email. Many thanks for your feedback.