Neuropathology and Therapeutics Addressing Glaucoma, a Prevalent Retina-Optic Nerve-Brain Disease that Causes Eyesight Impairment and Blindness
Imperial College of Science and Technology, St. Mary's Campus, London, UK
Singapore Eye Research Institute (SERI), Singapore
Duke-National University of Singapore Medical School, Singapore
Department of Pharmacology and Neuroscience, University of North Texas Health Sciences Center, Fort Worth, Texas, USA
Department of Pharmacy Sciences, Creighton University, Omaha, Nebraska, USA
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, USA
Global Alliances and External Research, Ophthalmology Innovation Center, Santen Incorporated, Emeryville, CA, USA
Academic Editor: Bart Ellenbroek
Received: January 24, 2022 | Accepted: March 20, 2022 | Published: March 22, 2022
OBM Neurobiology 2022, Volume 6, Issue 1, doi:10.21926/obm.neurobiol.2201116
Recommended citation: Sharif NA. Neuropathology and Therapeutics Addressing Glaucoma, a Prevalent Retina-Optic Nerve-Brain Disease that Causes Eyesight Impairment and Blindness. OBM Neurobiology 2022; 6(1): 116; doi:10.21926/obm.neurobiol.2201116.
© 2022 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
1. Introduction to the Eye and Visual System
As windows for the brain and providing vision, our eyes have a special place amongst the many organs within our bodies. Of the five senses, loss of sight is perceived as one of the most devastating and sorrowful event in the lives of those who experience such an unfortunate fate. Thus, preservation of vision is an extremely important and noble goal for mankind. The eye is indeed a very special organ with a complex structure composed of diverse cell-types with specific functions in the visual system (Figure 1A). At a gross level, compartmentalized into the anterior chamber (ANC) and posterior chamber (PSC) divided by the lens, the fluids within each segment are also unique with a watery nutritive fluid (aqueous humor; AQH ) bathing the ANC and a gelatinous material (vitreous humor) existing in the PSC. While cells lining the ANC are nourished by the AQH, a retinal blood supply provides nutrients to the retinal cells and which also removes metabolites and other substances from the retina, a very active energy-utilizing tissue. In that respect, the trabecular meshwork (TM) system [2,3,4,5], which is connected to the Schlemm’s canal (SC; [6,7,8]) which empties the AQH into the veinous circulation, is also an active tissue that filters the AQH and digests debris present in the AQH (Figure 1B). This activity helps maintain a homeostatic environment which permits the eyeball to retain a constant shape such that the clarity of the AQH provides light a clear unobstructed path to reach the lens and be focused onto the retina . Obviously, any event or factor that compromises the normal functions of the TM and those of the various retinal cells and the optic nerve poses grave consequences for the visual system. Indeed, TM dysfunction causes chronic ocular hypertension (cOHT; ) and damages ganglion cells (which are of different types depending on their receptive field, dendritic branching and conduction velocities [10,11]) and their axons (that form the optic nerve ) through mechanical stretching and disruption of retinal tissue at the back of the eye which eventually leads to damage of retinal-optic nerve-brain connections resulting in various degrees of visual impairment.
Figure 1 Anatomical location of various ocular tissues of the human eye are shown (A). AQH production and drainage from the anterior chamber of the eye via the conventional outflow pathway (via TM) and the uveoscleral (UVSC) pathway are also depicted (B).
Many specialized cells make up the retina including retinal ganglion cells (RGCs) [10,11], interneurons (e.g. amacrine cells, horizontal cells and bipolar cells), Muller glia, photoreceptors (rods and cones), and retinal pigmented epithelial (RPE) cells (Figure 2A, Figure 2B). At the back of the eye, RPE cells lie adjacent to an outer limiting Bruch’s membrane that separates the capillaries of the choroidal circulation from the RPE cells. At the anterior end of the retinal tissue is the inner limiting membrane that seperates the RGC axons from the vitreous humor (Figure 2B). Bundles of unmyelinated axons of RGCs, that form the retinal nerve fiber layer (RNFL) , gather from both sides of the retina towards the mid-line. The axon bundles make a 90-degree turn towards the back of the eye and make an exit from the eye at a site called the optic nerve head (ONH [13,14]). As these axons traverse the width of the retina they pass through a honey-combed structure, lamina cribosa (LC) (Figure 1A, Figure 2B [15,16,17]), and eventually become parts of the optic nerve. In order to optimally conduct the electrical signals generated by the RGCs, their axons are myelinated when they are bundled together to form the optic nerves as they exit the back of the eyeball. The optic nerves cross over at the optic chiasm to innervate the thalamic, pre-tectal and suprachiasmatic nuclei of the contralateral sides of the brain [18,19]. From there, relay axons project to different layers of the visual cortex  which are responsible for decoding the electrical signals from the RGCs for visual perception of the objects bein seen by the eyes (Figure 3).
Figure 2 The elevated IOP-induced mechanical distortion affects all part of the eye and detrimentally impacts the back of the eye structures (A). In particular, the RGCs are injured through activation of resident and invading microglia (B) which release numerous toxic substances such as cytokines, glutamate, NO and endothelin. Note: these events do not necessarily occur sequentially. Also, since numerous types of RGCs exist with different levels of sensitivity to the toxins, not all RGCs are equally affected. Many types of interneurons in the retina are also subject to injury and damage by the deleterious factors in the extracellular space.
Figure 3 This schematic illustrates as a top-view of the components of the visual system encompassing the eye, retina, optic nerves, thalamic and cortical connections. The various layers of the lateral geniculate nuclei (LGN) composed of the parvocellular and magnocellular cells are depicted in the inset.
2. Retinal and Brain Involvement in Visual Processes and Vision Loss
Retinal photoreceptor initate the process of vision, once light hits the eye by converting light to electrical impulses by a hyperpolarization response. At a high-level, a cascade of neurotransmitters are released amongst the retinal cells and neurons whose interactions with specific pre- and post-synaptic receptors initiate a multitude of biochemical and electrical signals. These are progressively relayed to the RGCs which code the visual information and transmit to the brain via the optic nerve. Signal transmission from the retina to the brain occurs in approximately 0.15 seconds, and information transfer happens at roughly 10 million bits per second and vision occurs. This makes the retina and the brain extremely high energy-consuming tissues. Specificity of the visual signals reside in the different types of RGCs that exist in the retina and to the many different neurons in different layers of the lateral geniculate nuclei (LGN) (Figure 3), superior colliculus (SC), pretectal and suprachiasmatic nuclei (SCN), and of course the many different nuclei within the many layers of the visual cortex [18,19,20]. Cells within the LGN and visual cortical layers have specialized functions that code information according to color, shape, contrast, resolution, movement, etc. Furthermore, these many structures receive and send out signals to other important brain regions such as cerebellum, hippocampus and striatum, thereby permitting further modulatory actions on the visual processes and the ultimate image processing and perception by the person.
Specifically, most optic nerve terminals project to specific neurons within the LGN which sorts retinal signals into parallel streams comprised of color, structure, motion and contrast. The top four parvocellular layers of LGN handle color and resolution, while the bottom two magnocellular layers process contrast and motion (Figure 4). The corresponding primary visual cortex (PVC) is also highly organized to receive LGN inputs from their long axons to maintain fidelity and complexity of the image information. Direct mapping of RGCs is precisely imprinted in the PVC on a point-by-point basis in a columnar pattern of connections alternating between the left and right eyes that places objects perceptually in the horizontal and vertical axes. Rapid comparison of the binocular signal inputs by V1-PVC cells allows perception of depth of vision and hence objects appear in three-dimensions. As V1 cells sharpen the lines and edges of images, the cells of V2 region of PVC refines their coloration. Visual perception encompassing form and color in V3 and V4 regions of PVC, recognition of face and object in the inferior temporal lobe, and motion and spatial awareness covered by the parietal lobe of the cortex completes the overall visual picture of the objects being viewed by the person. This is a highly simplified summary of a very intricate visual system and the processes involved in visual perception, and it is hoped that it is sufficient for the current contextual purpose (Figure 4).
Figure 4 A high-level representation of the RGC-LGN-primary visual cortical layers and the related connections are shown in this diagram. The specificity of the connections covering color, contrast and resolution of images as perceived by the visual cortex neurons is described in more detail in the text.
3. Primary Open-Angle Glaucoma (POAG): Molecular and Cellular Pathology in the Retina-Optic Nerve-Brain Axis
The second leading cause of blindness worldwide is primary open-angle glaucoma (POAG) [21,22,23,24] which is often associated with abnormally and chronically high intraocular pressure (IOP) [21,22,23,24], and spontaneous IOP spikes , which is in turn caused by accumulation of excess AQH in the ANC of the eye [9,21,24]. AQH retention in the ANC primarily follows after deposition of aberrant collagen, fibronectin and extracellular matrix [26,27,28,29,30] in and adjacent to the TM, where TM cells that are susceptible to stress [31,32,33] and which have reduced capacity to phagocytose and digest such debris are killed . Additional reduction and/or loss of autophagic mechanisms of TM cells [3,4,9,34] exacerbate the situation causing further elevation of IOP [21,22,23,24]. This elevated IOP (Figure 2A), coupled with low intracranial fluid pressure (ICFP) [35,36,37,38] leads to constriction of the RGC axons at the LC  which damages the unmyelinated part of the optic nerve at the ONH and LC. Increasing evidence indicates that the LC/ONH regions of the retina which are negatively impacted by the high IOP [13,14,40] and the RGC axons there are assaulted by a range of locally released inflammatory cytokines (e.g. tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6) due to inflammasome activation [41,42,43,44,45,46], and by other cytotoxic substances (e.g. glutamate [47,48,49,50,51], ATP , nitric oxide [53,54,55,56,57], endothelin [58,59,60], amyloid-β (AM-β) [61,62], phosphorylated-Tau [pTau]) and matrix metalloproteinases (MMPs) and other proteases [63,64] that degrade the structural matrix of the ONH and LC (Figure 5, Figure 6) [63,64]. Such damage severely reduces the strength and integrity of the RGC axons and the surrounding ECM holding them in place, and where lipofuscin [15,65] accumulate. Again, dysfunctional autophagic processes [19,66], at the ONH/LC regions allow cellular debris to accumulate resulting in scar formation. which leads to bending and stretching of the overall optic nerves resulting in atrophy and shrinkage of the RGC axons, reduction in axonal flow of mitochondria to the RGCs, and thus reduced energy production [67,68,69,70,71] to maintain cellular functions within the RGC somas], and reduced transport of vital growth factors [72,73,74,75] to the RGC bodies and ultimate RGC senescence. Thus, many potential sites of damage within the brain-optic nerve-retina visual system exist involving multiple deleterious neurotoxic and neuroinflammatory molecules and processes [76,77,78,79,80,81,82], reduced cerebral and retinal blood-flow [83,84], and abnormally diminished cerebral spinal/intracranial pressure [35,36,37,38,39] (Figure 5, Figure 6).
Figure 5 The various loci of damage and the different insults and factors involved in causing cOHT/POAG resulting in GON are indicated in this schematic. Many of the inflammatory, immunologic and degenerative processes probably occur simultaneously but may last over different periods of time.
Figure 6 This cartoon shows the multitude of events and damaging molecules involved in causing injury and death of RGCs, RGC axons and their terminals in the brain structures during the course of chronic OHT / POAG / NTG. Due to the heterogeneity of the RGCs and differential susceptibility and sensitivity to physical pressure and toxic agents, it is likely that not all patients will experience the same degree of visual impairment and their disease progression will also differ.
The cascade of damaging events described above, some happening sequentially and some in parallel, are responsible for the loss of many vulnerable RGCs and their axons [85,86,87,88,89,90]. The net result is reduced transmission of visual signals to the brain. Since the brain structures are reliant on electrical activity from the retina to also remain healthy, death signals from the RGC axons due to POAG/ GON may cause senolytic events in the thalamic and visual cortical tissues due to inducted neuroinflammation . Apoptotic and neurodegenerative processes lead to death of neurons in the LGN, magnocellular and parvocellular layers of the thalamus [92,93,94,95,96], trans-neuronal degeneration and extensive brain network reorganization and disruption [97,98,99,100] culminating in reduction of visual acuity (including reduced contrast sensitivity), visual impairment (loss of peripheral vision), and if left undiagnosed and untreated, loss of central vision followed by total blindness.
What is disturbing to the POAG patient, and also to those patients with relatively normal IOPs (normotensive glaucoma [NTG]) [101,102,103,104,105], is that the disease is imperceptible, painless and continues unabated for multiple decades. Due to neuroplasticity, early defects in the retina-optic nerve-brain system are somewhat compensated and perception of suprathreshold contrast in patient’s vision is maintained despite loss of some visual sensitivity . Patients first become aware of their POAG/NTG when their peripheral vision is reduced, black patches randomly intrude into their line of sight, and when this progresses over many decades to “tunnel vision” . These insidious changes in visual perception indicate that now the tipping point has been reached and in fact 400,000 to 600,000 RGCs have been destroyed from the patient’s retina and an equal number of connections to the brain have been silenced. Hence, early diagnosis through regular eye exams is tantamount to receiving treatment close to the time of disease initiation and perhaps slowing down the demise of RGCs and thus reducing disease progression. Sadly, it is estimated that 53-58 million people will be afflicted with POAG by 2040 with the total glaucoma patient population reaching ~112 million by 2040 [108,109]. Therefore, there is an urgent need to diagnose patients at risk of chronic OHT (cOHT) / POAG earlier and discover and bring to the clinic novel IOP-lowering drugs and treatments that offer greater potency/efficacy and longer duration of action with a reduced side-effects profile to existing therapies. Furthermore, it is now well accepted that IOP reduction alone is insufficient to prevent visual defects in POAG/NTG, such that we need to directly protect the RGCs and their axons through some innovative rescue strategies. In addition to neuroprotection strategies to enhance the survival of RGCs, there is a need to repair RGC axons in order to more fully re-establish retino-thalamic connections. Clearly, GON being a multifactorial optic/brain disease will require a multifaceted treatment approach and these elements will be discussed below.
4. Treatment Options for cOHT / POAG: Drugs, Surgeries and AQH Microshunts
With advancing age and/or due to many other disease-initiating processes including loss of TM cells due to natural or abnormal senescence caused by endoplasmic reticular stress, poor autophagy, reduced phagocytic performance of remaining TM cells, the conventional AQH drainage system gets overwhelmed by the accumulating debris and becomes clogged [3,6]. Since the ciliary bodies continue to produce fresh AQH, the anterior chamber of the eye begins to expand and bulge thereby raising the IOP. This elevated IOP is transmitted through the eye and negatively impacts the weakest part of the visual system, the LC that lies just behind the ONH [13,14,19,45] where the unmyelinated axons of the RGCs gather and exit the back of the eye to form the optic nerve. This then initiates the detrimental cascade of events mentioned in the previous section above leading to visual impairment [91,94,98]. Clearly opening up of the TM outflow pathway and engaging the other non-conventional uveoscleral pathway would relieve some damaging effects of the raised IOP. To this end, numerous pharmaceutical drugs that reduce AQH formation (carbonic anhydrase inhibitors (e.g. dorzolamide; ), alpha-2-adrenergic agonists (e.g. brimonidine; ), beta-blockers (e.g. timolol and betaxolol; )), and those drugs that primarily promote AQH efflux via the conventional TM/SC outflow pathway (muscarinic agonists (e.g. pilocarpine; ); rho kinase inhibitors (e.g. ripasudil, netarsudil; [114,115]), and drugs that primarily stimulate AQH outflow via the uveoscleral pathway (prostaglandin (PG) FP-receptor agonists (e.g. latanoprost, travoprost and tafluprost; [116,117,118]), a novel non-PG EP2-receptor agonist (omidenepag isopropyl; [119,120,121,122,123]), and a conjugate of latanoprost and an nitric oxide releasing molecule (latanoprostene; )) have been discovered, developed and introduced into the clinical management of OHT / POAG (Table 1). The duality of mechanism of action of FP-PG agonists such as travoprost  and that of the non-PG EP2-receptor agonist, omidenepag isopropyl , inducing outflow of AQH via the uveoscleral and TM/SC pathways seems unique. Interestingly, the other unique property pertains to the rho kinase inhibitor, netarsudil, which lower IOP by stimulating AQH outflow via the TM/SC and by lowering episcleral veinous pressure in animals and human OHT/POAG patients [125,126]. Additionally, since netarsudil and omidenepag isopropyl lower IOP well in normotensive and OHT animals, they may have clinical utility in treating NTG. However, this remains to be demonstrated in additional clinical studies.
Combinations of approved IOP-lowering medications, allowing engagement of multiple mechanisms of action to achieve higher efficacy, have also been developed for medical treatment of OHT/POAG [127,128]. Furthermore, the durability of the ocular hypotensive activity of drugs has been extended using polymer-based technology that permits the drug to be released into the ANC over time once the polymer rod is intracamerally injected into the ANC [129,130], or the drug is slowly eluted off from a silicon-ring-device placed around the eyeball and remains in contact with the conjunctiva/cornea , or the therapeutic drug is slowly released from punctal plugs , or via nanoparticles [133,134], polycaprolactones [135,136] or via port delivery systems akin to how antibodies are delivered to the eye . Another recent important advent helping significantly lower and control IOP involves microshunts (e.g. Preserflo®) [138,139,140,141,142] which when placed into the ANC of the eye help drain the excess AQH to efficaciously lower IOP over many years, and improve visual acuity . If needed, the patient can have the microshunt placed to drain the AQH and be treated topical ocularly with ocular hypotensive drugs to achieve the target IOP.
Even though the afore-mentioned therapeutic approaches tackle cOHT fairly well, new drugs with new mechanism(s) of action such as lowering IOP by decreasing episcleral venous pressure are needed. Similarly, lowering IOP through novel receptor or enzyme systems with a greater potency/efficacy and with lower side-effects potential [143,144] than existing drugs are continuing to be found and developed for use in the clinical setting (Table 2). Progression of these novel ocular hypotensives drugs targeting many different receptors, enzymes, and ion-channels at the level of TM/SC and UVSC outflow pathways [145,146,147,148,149,150,151,152,153,154,155][156,157,158,159,160,161,162,163,164,165,166,167,168,169] into formal development processes is eagerly awaited.
5. Treatments Beyond IOP-Lowering:
5.1 Cyto- and Neuro-protective Therapies
In view of the multiplicity of damaging and destructive factors involved in the etiology and progression of cOHT/ POAG / NTG (Figure 5, Figure 6), it seems obvious that a singular preventative regimen is unlikely to be very successful. Rather a combinatorial approach  is necessitated with multiple interventional points [171,172,173,174,175,176] involving IOP reduction coupled with slowing/preventing local inflammation at the ONH/LC. However, as the ANC components strongly influence the pathological events at the back of the eye, it is imperative that some rescue strategies be directed there. Thus, means to stimulate autophagic activity of TM cells thus reduce their stress due to ECM accumulation and delivery of anti-oxidants to the ANC would be helpful [177,178,179,180,181,182]. Likewise, since inflammation is a one of the root causes of RGC death and destruction of their axons and of the associated brain neurons, dampening or eliminating such destructive elements is beneficial [183,184,185,186,187,188,189,190,191]. Preventing complement activation  and up-regulating protective endogenous genes and transcription factors [193,194] at the ONH/LC and thalamic and cortical regions is another useful strategy. Many other drugs and treatments [168,195,196,197,198,199,200,201,202,203,204] including senolytic drugs , glutamate receptor antagonists , delta-opioids , histone deacetylase inhibitors , vascular-specific phosphatase blockers , alpha-2 adrenergic agonists , sigma-receptor agonists , and various neurotrophic factors [202,203]. Furthermore, new conjugate/hybrid drugs with multi-pharmacophoric activities [205,206,207,208,209,210] directed at different intervention points of the RGC soma and axonal demise [170,171,172,173,174,175,176] are showing promise as neuroprotective agents.
5.2 Genetics, Cell Transplantation and Exosome-Based Therapies
Specific gene-therapy technologies are being utilized to curb the cyto-destructive and neurogenerative processes occurring during cOHT/POAG/GON. Some are addressing the reduced capacity of TM and other ANC cells to produce ECM-clearing MMPs  or modulating aquaporins to achieve AQH dynamic homeostasis . Gene knock-out [213,214] or gene insertion [215,216,217] to promote delivery of various trophic factors such as brain-derived neurotrophic factor and ciliary neurotrophic factor to RGCs [218,219] that can rescue and preserve retinal and brain neurons are proving beneficial at least in animal models of POAG/GON. The advent and utility of cell replacement techniques and technologies to preserve retinal-optic nerve-brain connectivity and function involving stem cells for ANC pathologies [220,221,222,223,224], Schwann cells for optic nerve sheath replacement [225,226] and for RGC and Muller transplantation [227,228,229,230,231] are gaining prominence. Additionally, the experimental utility of extracellular vesicles and/or use of stem-cell-derived exosomes and secretomes [232,233,234,235] comprising many different protective proteins and micro-RNAs impart beneficial effects on the many cell-types that are integrally involved in the visual processes. Eventually, structural bio-materials may be needed to physically support the optic nerves to halt and prevent further damage of these vital structures [236,237,238,239].
5.3 Dietary Factors Providing Cellular Protection
It is well known that food-derived nutrients possess a multitude of health-promoting chemicals that positively impact bodily muscles, bones and cells of many organs, including the eye [241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258]. In this respect, a whole host of nutraceuticals possessing antioxidant, anti-inflammatory, anti-excitotoxic, and anti-apoptotic properties protect RGCs and brain neurons, including curcumin, ginkgo bilboba, lipoic acid, coenzyme Q10, saffron, vitamin B3, and urolithin from pomegranates. Although somewhat controversial, recent research appears to link the dietary intake of foods with resident microbes in the alimentary canal and as such the latter influencing the disease pathology and thus potential protective properties of the microbiota . However, whilst giving us hope and encouragement, confirmatory clinical trials of the nicotinamide alone  and in combination with pyruvate , and with the urolithin  are needed.
5.4 Axonal and Cellular Regeneration Therapies
There are many limitations of successfully delivering, uptake, incorporation and functional integration of food-derived nutrients, gene- and cell-therapies for the protection and preservation of eyesight of cOHT/POAG/NTG and GON sufferers. To overcome such hurdles, new ways to activate intrinsic cyto- and neuro-protective factors and systems are being explored. These include gross or cell-directed in vitro and in vivo electrical stimulatory systems and devices. Indeed, some success has already been realized in this arena where low-level electrotherapy has helped regenerate RGC axons, promote Muller cell proliferation/differentiation through release of endogenous neurotrophins and other beneficial substances [260,261,262,263]. Translation of these findings to the human situation appear promising [260,263].
6. Novel Techniques and Technologies to Help Preserve Eyesight
As technologies progress, there is continuing hope that they would be applied to help glaucoma patients. Examples of these include the following: stem-cell-derived exosomal delivery of miRNAs and trophic factors [264,265,266], creation of artificial extracellular vesicles and stem cells with selective packaging of the cargos to be delivered [267,268]. Moreover, use of novel cell repair and regeneration methods [269,270,271,272,273,274,275,276,277,278], use of optic nerve and visual field magnetic resonance imaging and mapping [279,280] coupled with artificial intelligence technologies for earlier diagnosis of glaucoma [281,282], functional retinal oximetry to determine the metabolic status of the retinal cells  and adaptive optics to improve the cellular resolution to detect structural changes at the cell soma and dendrites before and after treatment for glaucoma  will undoubtedly help glaucoma patients in the future. Much progress has also been achieved using optogenetic technologies to restore vision in animals [285,286,287,288,289], and using chemical photoswitches  and retinal and brain implants [285,290]. Use of sonar technology to stimulate specific neuronal pathways to protect and enhance vision also holds great promise [291,292].
The early and accurate detection and diagnosis of cOHT / POAG/ NTG is key to helping patients with visual impairment and as such 24-hr monitoring of IOP is essential. A contact lens-based IOP recording device has been developed to aid in this endeavor . Fluid drainage via the traditional pathways from the eye are damaged during development of cOHT/POAG, and thus the ability to engage lymphatic drainage in the eye and brain may be useful [294,295]. Similarly, development of new diagnostic/ biomarker techniques are critical for starting treatment to preserve and slow down GON, and recent reports are encouraging in this respect [296,297,298,299].
Use of single cell transcriptomics , anti-sense oligonucleotides , antibodies directed at inflammatory mediators , and use of specific micro-RNAs to lower IOP and perhaps provide neuroprotection  by exploiting recently discovered cellular nanotubes  are exciting new developments worthy of further pursuit. Last but not least, novel imaging technologies using 2-photon-excited fluorescence and flood-illumination adaptive optics [303,304], coupled with proteostasis drugs to eliminate excess phosphorylated proteins and misfolded proteins [305,306] from the ANC and from the retina/optic nerve/brain offer new treatment paradigms for cOHT/POAG/NTG/GON, especially if the combinatorial treatments [257,307] are reproduced in other clinical trials across the world.
Apart from causing visual impairment in the early stages of GON development, the disease progression robs patients of their ability to perform daily tasks such as reading, driving, and clearly recognizing objects and faces. These difficulties translate into various disabilities associated with visual field deterioration resulting in POAG patients bumping into objects-, falling down and sustaining injuries, and as the situation worsens can then cause anxiety and depression (Figure 7). Thankfully, as described above, significant progress has been made in the last dozen years towards a better understanding of the factors and pathologies involved in the GON disease processes endured by patients that suffer from cOHT / POAG/ NTG. Advancements in early and more accurate diagnosis of these ocular ailments is still lagging behind expectations although new biomarkers and devices hold great promise. The multifactorial nature of the damaging agents, insults and pathways involved in causing the sight-threatening diseases will certainly require a multicomponent treatment regimen. This will also necessitate varied permutations and combinations of drugs/devices/nutraceuticals/regenerative medicines designed to account for genetic, structural and functional elements impacted and experienced by each patient. Such personalized medicine will come to fruition in due course if we collectively continue to forge ahead discovering and developing new treatment modalities in a multidisciplinary manner to help the POAG/NTG patients preserve and protect their eyesight.
Figure 7 The negative impact of glaucomatous optic neuropathy as a result of cOHT / POAG causing visual field loss and various consequences of death of thalamic, cerebellar, and cortical neurons is highlighted in this schematic. Patients suffering from GON not only lose peripheral vision but also experience a whole host of other neurological disturbances which lowers their quality of life due to many types of disabilities listed in this figure.
The author is solely responsible for conceptualizing, researching and writing this article.
The author declares that there is no competing interest in writing this article. The only intention is to gather, collate and disseminate the high-level information about the pathological aspects of glaucoma and ocular hypertension with the hope that it will enhance multidisciplinary awareness about these sight threatening eye diseases. In time, I hope further research will be stimulated and innovation will lead to new and improved therapies for the patients who live with these ocular disorders.
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