Oman Journal of Ophthalmology

: 2019  |  Volume : 12  |  Issue : 1  |  Page : 1--3

A Glimpse into the mysteries of glaucoma: From theories to clinics

Muneeb A Faiq1, Rayees A Sofi2,  
1 Department of Ophthalmology, Langone Health Centre, New York University School of Medicine, New York, USA; Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
2 Department of Health, J and K Health Services, Srinagar, Jammu and Kashmir, India., India

Correspondence Address:
Dr. Muneeb A Faiq
Department of Ophthalmology, Langone Health Centre, New York University School of Medicine, New York

How to cite this article:
Faiq MA, Sofi RA. A Glimpse into the mysteries of glaucoma: From theories to clinics.Oman J Ophthalmol 2019;12:1-3

How to cite this URL:
Faiq MA, Sofi RA. A Glimpse into the mysteries of glaucoma: From theories to clinics. Oman J Ophthalmol [serial online] 2019 [cited 2020 Jun 2 ];12:1-3
Available from:

Full Text

Theories of glaucoma include mechanical, vascular, biochemical, genetic, glymphatic, translaminar pressure gradient, insulin signaling, excitotoxic, intracranial pressure, lamina fragility, glymphatic, bioenergetics etc, but the disease management still remains synonymous to the tradition of ocular hypertension. Such a scenario is inevitable because intraocular pressure (IOP) is the only proven modifiable factor till now. IOP management is important but insufficient and misleading as glaucoma is not merely “ocular hypertension.” This is because (1) many cases with elevated IOP, but no glaucoma are seen, (2) many individuals with normal IOP develop glaucoma, and (3) several cases still progress to glaucoma even after controlled IOP. The fallacy is that lowering IOP in normotensive cases slows down the progression of the disease pointing toward individual differences in the sensitivity of retinal ganglion cells (RGCs) to IOP and arguably additional factors – an individual specific sensitivity coefficient for RGC loss.

One of the main underestimated and yet profoundly imperative hallmark of glaucoma is the orderly loss of Nerve Fibers in a centripetally directed apoptotic manner. Such a presentation of orderly loss (from peripheral to central) of nerve fibers (NF)[1] subjecting IOP theory to skepticism. The direct impact of IOP is unlikely to cause NF loss in orderly manner. Systematic loss of NFs is the basis for doing perimetry and analyzing paracentral scotomas and arcuate field defects.[1] Such an argument partly puts into question “the neurodegenerative theory of glaucoma” also where the neuronal loss can be thought to occur randomly.

It is important to understand that RGCs are typical neurons with cell bodies and the long axons. Only the soma/cyton of the RGCs is present in the retina with axons forming the optic nerve to synapse in the superior colliculus and lateral geniculate nuclei. Hence, the axons have to pass through a tough multilayered collagenous membrane, the lamina cribrosa (LC). Elevated IOP can precipitate mechanical strain on LC which may damage RGC axons mechanically at the LC or prelaminar area. Following this injury, RGCs start dying. But why normal IOP also presents with glaucoma and why certain cases progress to vision loss despite controlled IOP; is a query that obfuscates the puzzle. Is it that high-tension glaucoma (HTG) is mechanical and normal tension glaucoma (NTG) neurodegenerative with a common overlap in pathology in neuromechanical arena? This outlook may not be a verity because in both HTG and NTG, NFs die following similar pattern. In addition, if NTG is exclusively neurodegenerative in essence, then ocular hypotensive therapy should be ineffective for it (which is not the case).[2]

A revisit to the existing state of evidence points towards a somewhat radical shift of a paradigm in the near future of glaucoma history. The cupping paradigm is also a conundrum as a normal optic disc is difficult to define objectively. All optic nerve heads (ONH) have cups. It is only the ratio of the cup with the disc which gives an idea about normal and pathological ONH. Cases having excavation of the cup with no disease and glaucoma but no cupping also exist. In certain instances, no-cupping scenario is associated with elevated IOP which makes it problematic to envision a comprehensible relation between optic cupping, ONH pathology, and elevation in IOP.

An idea which is gaining importance is to consider if there are distinct functional, structural and biochemical stages in a disease looking like the partially overlapping sequential boxes of a venn diagram. Is glaucoma, a two-stage condition where Elschnig border (EB) degeneration ensues due to ischemia caused by elevated IOP accompanied with posteriorly sinking of LC. This may expose certain areas of NF on higher risk where the additional strain at LC may sever the RGC axons.[3] If that is the case, what then is the role of cerebrospinal fluid? LC is a perforated meshwork at the crossroads of IOP and ICP both working in opposite directions. A relation between the two may be keeping LC intact while the disturbance of this relation may cause it to be pushed posteriorly. IOP elevation mediated cupping and its relation to ICP may be explained by this. The muddle with this model is that ICP and IOP ranges are about 8–15 mmHg and 10–22 mmHg, respectively. Since LC is a multilayered tough structure, it is also densely packed with 0.7–1.7 million NFs which makes it even tougher. A rise of a few mmHg in IOP or a similar drop in ICP may be unlikely to move LC backward to the extent so as to precipitate a pathological optic cup.

Rheology of glaucoma (which includes not only the eye but also the brain with involvement of ICP, IOP, Subarachinoid space pressure around the optic nerve, central retinal artery pressure, pressure at the vrious other loci, glymphatic dynamics etc.) is a complex conglomeration with participation of all the factors in variable permutations and combinations. Such a scenario in turn depends of various systemic factors leading to a surmise that systemic factors may also be a target for glaucoma therapy. The perfusion pressure in the central retinal artery (CRAP) is around 60 mmHg, indicating that a few degrees rise in IOP (as happens in HTG) is not likely to cause any significant ischemia. Since IOP even in HTG is way lower than CRAP, the retinal circulation remains relatively unaffected, and hence, the retina stays healthy. Ciliary pressure (CP) may explain this phenomenon where a reversal of its relationship with IOP emanates. CP, almost equal to the usual capillary pressure of 25 mmHg, supplies EB. Elevation of IOP may lead to chronic ischemia from this route causing simultaneous cupping and ischemia (thereby setting the stage for glial activation and other inflammatory processes), hence ensuing RGC demise.

Brain damage before vision loss[4] and significant loss of neurotrophins (like BDNF) in glaucoma gives birth to neurodegenerative aspects of the disease and renders IOP hypothesis incomplete. However, none of the two schools of thought explain the orderly loss of RGCs. Elevated cortisol in glaucoma patients[5] brings the stress story to forefront and elevation of IOP by cortisol further strengthens the same. The “Brain Diabetes Theory” (Diabetes type-4) proposing glaucoma to be a brain disease[6] with insulin resistance in brain and retinal tissues seems to explain elevation in IOP, glial activation, tauopathy, oxidative stress, neurodegeneration, isolated RGC death and aging in a single conceptual model.[7] It also explains NTG.

Another theory is related to psychological stress where glaucoma may be thought to be a vascular dysregulation syndrome (a manifestation of Flammer Syndrome) secondary to stress.[8] Stress leads to increase in cortisol which elevates IOP and also leads to vascular dysregulation causing ischemia (presumably through ciliary-EB route) with mechanical component complementing the pathogenesis. In addition, the observation that postmenopausal women have a high risk of developing glaucoma[9] brings endocrine biology into the picture which is yet another story that needs attention.

Given the limited efficacy and documented side effects, stopping IOP lowering treatment leads to continued damage to ONH and RNFL which means that IOP elevation is presently the only working hypothesis. It is, therefore, suggestive to consider other options such as neurorestoration, stress reduction, reducing apoptosis, reducing glial inflammation, stem cells treatment, electrical brain stimulation, modulation of gene expression, antioxidant therapy, and addressing insulin resistance.[10]

Putting all the pieces of he puzzle together, a coherent concept emerges that glaucoma may, as of now, be defined as the idiopathic RGC death often associated with elevated IOP beyond a certain individual specific sensitivity coefficient. That makes one conclude by saying that certain maladies are under no obligation to make any sense to the doctor; glaucoma is one of them. We have come a long way in understanding the etiopathogenesis of glaucoma yet we have not been able to devise a clinically proven method of managing glaucoma beyond IOP. To this effect, there is a whole lot of territory which is waiting to be explored.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1Hasnain SS. Scleral edge, not optic disc or retina, is the primary site of injury in chronic glaucoma. Med Hypotheses 2006;67:1320-5.
2Anderson DR. Normal-tension glaucoma (Low-tension glaucoma). Indian J Ophthalmol 2011;59 Suppl:S97-101. doi: 10.4103/0301-4738.73695.
3Hasnain SS. Pathogenesis of orderly loss of nerve fibers in glaucoma. Optom Open Access 2016;1:110.
4Murphy MC, Conner IP, Teng CY, Lawrence JD, Safiullah Z, Wang B, et al. Retinal structures and visual cortex activity are impaired prior to clinical vision loss in glaucoma. Sci Rep 2016;6:31464.
5Schwartz B, McCarty G, Rosner B. Increased plasma free cortisol in ocular hypertension and open angle glaucoma. Arch Ophthalmol 1987;105:1060-5.
6Faiq MA, Dada R, Saluja D, Dada T. Glaucoma – Diabetes of the brain: A radical hypothesis about its nature and pathogenesis. Med Hypotheses 2014;82:535-46.
7Faiq MA, Dada T. Diabetes type 4: A paradigm shift in the understanding of glaucoma, the brain specific diabetes and the candidature of insulin as a therapeutic agent. Curr Mol Med 2017;17:46-59.
8Sabel BA, Wang J, Cárdenas-Morales L, Faiq M, Heim C. Mental stress as consequence and cause of vision loss: The dawn of psychosomatic ophthalmology for preventive and personalized medicine. EPMA J 2018;9(2):133-160. doi: 10.1007/s13167-018-0136-8. eCollection 2018 Jun.
9Dewundara SS, Wiggs JL, Sullivan DA, Pasquale LR. Is estrogen a therapeutic target for glaucoma? Semin Ophthalmol 2016;31:140-6.
10Faiq MA. Vision restoration in glaucoma: Nihilism and optimism at the crossroads. Oman J Ophthalmol 2016;9:123-4.