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 Table of Contents    
EDITORIAL COMMENTARY
Year : 2018  |  Volume : 11  |  Issue : 2  |  Page : 101-102  

The Dark Matter of Vision: In search of a Grand Unifying Theory for Glaucoma


NYU Langone Eye Center, Department of Ophthalmology, NYU School of Medicine, NYU Langone Health, New York University, New York, USA

Date of Web Publication28-May-2018

Correspondence Address:
Muneeb A Faiq
NYU Langone Eye Center, Department of Ophthalmology, NYU School of Medicine, NYU Langone Health, New York University, New York
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ojo.OJO_92_2018

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How to cite this article:
Faiq MA. The Dark Matter of Vision: In search of a Grand Unifying Theory for Glaucoma. Oman J Ophthalmol 2018;11:101-2

How to cite this URL:
Faiq MA. The Dark Matter of Vision: In search of a Grand Unifying Theory for Glaucoma. Oman J Ophthalmol [serial online] 2018 [cited 2018 Dec 10];11:101-2. Available from: http://www.ojoonline.org/text.asp?2018/11/2/101/233323



Although mechanical, vascular, biochemical, genetic, glymphatic, translaminar pressure gradient and insulin signaling theories have been proposed, from management point of view, glaucoma still remains synonymous to 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 towards individual differences in the sensitivity of retinal ganglion cells (RGCs) to IOP and arguably additional factors – an individual-specific sensitivity coefficient for RGC loss.

Glaucoma presents with orderly loss (from peripheral to central) of nerve fibers (NFs)[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.

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. However, 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. Furthermore, if NTG is exclusively neurodegenerative in essence, then ocular hypotensive therapy should be ineffective for it (which is not the case).[2]

The cupping paradigm is also a conundrum as a normal optic disc is difficult to define objectively. All optic nerve heads (ONHs) 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.

Is glaucoma a two-stage condition; Elschnig border (EB) degeneration due to ischemia (caused by elevated IOP) with concomitant 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 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 (though the long term effects of even a small pressure deviation can not be ignored).

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 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 (such as brain-derived neurotrophic factor) 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 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 retinal nerve fiber layer 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]

In the light of above discussion, 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; perhaps glaucoma is one of them.



 
   References Top

1.
Hasnain SS. Scleral edge, not optic disc or retina, is the primary site of injury in chronic glaucoma. Med Hypotheses 2006;67:1320-5.  Back to cited text no. 1
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Anderson DR. Normal-tension glaucoma (Low-tension glaucoma). Indian J Ophthalmol 2011;59 Suppl 59:S97-101.  Back to cited text no. 2
    
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Hasnain SS. Pathogenesis of orderly loss of nerve fibers in glaucoma. Optom Open Access 2016;1:110.  Back to cited text no. 3
    
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Murphy 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.  Back to cited text no. 4
    
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Schwartz B, McCarty G, Rosner B. Increased plasma free cortisol in ocular hypertension and open angle glaucoma. Arch Ophthalmol 1987;105:1060-5.  Back to cited text no. 5
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Faiq 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.  Back to cited text no. 6
    
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Faiq 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.  Back to cited text no. 7
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8.
Sabel 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. [doi: 10.1007/s13167-018-0136-8].  Back to cited text no. 8
    
9.
Dewundara SS, Wiggs JL, Sullivan DA, Pasquale LR. Is estrogen a therapeutic target for glaucoma? Semin Ophthalmol 2016;31:140-6.  Back to cited text no. 9
    
10.
Faiq MA. Vision restoration in glaucoma: Nihilism and optimism at the crossroads. Oman J Ophthalmol 2016;9:123-4.  Back to cited text no. 10
[PUBMED]  [Full text]  




 

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