My point of view in presented in the enclosed paper

To me it appears important to define what you call "Neuropathy". And why should glaucoma be neuropathy and not neurodegeneration?

Please give your comments

In my research field (ionizing radiation research), secondary glaucoma following radiation therapy has long been recognized. I do not think that its dose response relationship is well established, but secondary glaucoma appears to occur following fractionated exposures to tens Gy, not at several Gy. On the other hand, the effect of ionizing radiation on other types of glaucoma has much less been characterized. A single paper published in 2013 reported a significantly increased risk for normal tension glaucoma in acutely exposed Japanese atomic bomb survivors (https://www.ncbi.nlm.nih.gov/pubmed/24059679 ), but its impact in other exposed cohorts remain uncharacterized except for a single paper reporting an insignificantly increased risk for self-reported glaucoma in the US radiologic technologists cohort exposed at dose and dose rates lower than atomic bomb survivors. More studies are needed to understand manifestation of radiogenic glaucoma and its underpinning mechanisms.

https://www.researchgate.net/publication/326331886_Occupational_radiation_exposure_and_glaucoma_and_macular_degeneration_in_the_US_radiologic_technologists

Can someone tell the most characteristic feature of chronic glaucoma?

To me, the most important and puzzling mystery of glaucoma is: the NFs are being destroyed in an orderly and predictable fashion from peripheral to central which unfortunately researchers never talk about when they put forward their glaucoma theories and publish their articles. If this was not true then we wouldn't be doing visual fields in glaucoma. There is no known biological mechanism which could lead to the orderly loss of NFs in glaucoma, there has to be some mechanical way. Yet elevated IOP or even normal range IOP is definitively the cause of glaucoma. Let us solve this mystery by taking these two features into account and we will surely solve the mystery of glaucoma.

There are so many theories of glaucoma but not a single one can explain all aspects of this “group” of “diseases”. It’s like there are many cancers but each of them has a different etiology.

I was lately going through the theories of electroneutrality and pseudofacility while working for a research project in glaucoma. A very notable arguement was laid out.

The whole concept of the goldmann equation seemed to be challenged by it. The argument was against the known fact .we all know that the rate of production of aqueous is not constant and it has regulatory mechanism. But if so, why doesnt the increased iop due to steroid incuded ocular hypertension decrease its rate of productiom and by doesnt post trab eyes have increased rate of production to compensate the normal levels for that eye?

I think there the an autonomic dysregulation where the body either resets its basleine values or the whole regulatory mechanisms go haywire. It can be contemplated to systemic hypertension. Dont control it ,you end up with complications related to arteriosclerosis and elastoid changes.in our case, the loss of the neuroretinal rim. Mechanical vascular or mixed are the well.known mechanism but these are governend by autonomic nervous system. This could be one of the reasons by autonmic drugs seem to be cyto snd neuroprotective. Systemic drugs such as ca channel inhibitors are used in other autonomic dysfunctiosn such as raynauds, migraine and that could very well be the reason it is found to be protective in normal tension or low pressure glaucoma. Decreasing the iop is the only known modality but a wider look at the factors that govern them need to be evaluated.

@ syed shoed ahmad - i agree to your debate sir. I think its a retrograde deneration. Something i compare with radiculopathy. A nerve basically being impinged (here by a the effects of iop at its entry ) cauing a functional and evetually anatomical deficit to the area it supplies.

raised IOP still remains the main culprit behind Retinal nerve fibre loss giving rise to characteristic optic neuropathy and it remains so far the only modifiable factor in Glaucoma management.

But what is the mystery about that. The mystery is:

1. Why elevated IOP leads to isolated RGC death and not the demise of photoreceptors?

2. Why do the nerve fibers die in orderly fashion?

3. Why is IOP elevation in certain individuals benign?

4. Why is normal IOP in some individuals causative of glaucoma?

5. What is the mechanical relationship between trabecular meshwork and lamina cribrosa?

6. Why do apoptosis or cell death occur centripetally in glaucoma?

7. Why does lowering pressure in normal IOP patients help ameliorate the disease?

8. How and why are brain lesions found in glaucoma patients?

9. What does it mean to observe brain damage before vision loss in glaucoma?

10. What is the role of systemic blood pressure in glaucoma?

11. Does ICP play a role in glaucoma?

12. Is glaucoma mechanical or neurodegenerative?

13. Is glaucoma neurodegenerative or neuropathic?

There are many such questions. It would be great that we start trying to give comments on each of them substantiated from reason and references and citations.

Is glaucoma a two -stage disease?

The most puzzling mystery of glaucoma: one million or so densely packed nerve fibers are being destroyed in an orderly fashion, from peripheral to central, never randomly, which is the reason we do perimetry in glaucoma. Glaucomatous field defects suggest that NFs are being destroyed gradually over a period of several years in a predictable manner, a feat which could never be accomplished by the direct affect of IOP on NFs.

But, it is also a well established fact that elevated IOP is definitively the cause of glaucoma. So then how is the elevated IOP destroying the NFs in an orderly sequence lasting over decades? There must be a indirect mechanical way. There is no biological scenario in which NFs could be destroyed in an orderly and predictable way. There has to be a mechanical way. This is the mystery of glaucoma.

It is hypothesized that glaucoma is a two -stage disease. First, a biological stage in which there is degeneration of the border tissue of Elschnig (BT) due to chronic ischemia induced by slow compression of the circulation of BT by elevated IOP. The time for degeneration of BT will vary from person to person. This period may be called as preperimetric glaucoma or ocular hypertension. Once the BT degenerates the LC will start sinking in the scleral canal (already proven by OCT). The sinking of LC is start of the second stage or mechanical stage or perimetric glaucoma. Sinking of the LC will lead to stretching and breakage of NFs starting with deepest peripheral NFs (being closest to the scleral edge) and ending with the superficial and central NFs in an orderly sequence lasting over several years. Normal- tension glaucoma has same pathogenesis except that in NTGs the normal range IOP has become higher than the ciliary circulation supplying the BT so IOP acting as an elevated IOP in NTGs. In nutshell, Glaucoma is not an optic neuropathy but an optic axotomy

Basically, the RGC have long axon bodies and to get all the necessary neurotrophic factors for their own survival they need a good axoplasmic flow. A high IOP impedes its axoplasmic flow which make them vulnerable to apoptosis and since they make up the inner most layer, they suffer the impact of high IOP the most. Moreover, the concentration of ganglion cell is high in the central region as compare to periphery , the field defects usually appear first in the peripheral region.

Glaucoma has been considered as a major cause of worldwide irreversible blindness (Nuzzi et al. 2018). About 66.8 million people worldwide are afflicted with glaucoma (Quigley and Broman 2006). Glaucoma is currently recognized to be a multifactorial, progressive neurodegenerative disorder. It is characterized by the acquired death of retina ganglion cells and loss of their axons as well as optic nerve atrophy and loss of neurons in the lateral geniculate nucleus and the visual cortex (Kaushik et al. 2003, Nuzzi et al. 2018). The main risk factor for progression is an elevated intraocular pressure (IOP), which can cause damage to the optic nerve head and then to the visual field.