I. Biomechanical Theory:
According to this theory, IOP above the tolerable threshold of the optic nerve head resistance results in deformation of the lamina cribrosa and the glial support framework of the anterior part of the optic nerve. Astrocytes and lamina cribrosa cells can sense strain through integrin receptors that tie their cytoskeletons directly to the adjacent fibrillar extracellular matrix.
Elevated IOP causes backward bowing, stretching and compression of laminar plates within the lamina cribrosa, resulting in misalignment of the fenestrations within the lamina cribrosa (elongation of pores), compression of the nerve fibers resulting in stasis of axoplasmic flow in the axons of the RGCs, and eventually RGC death and GON. Remodelling of the lamina cribrosa may predispose to localized compartment syndrome–like events when perfusion pressure drops.
These changes are associated with disk hemorrhages and visual field damage. And could be interpreted as a limited AION‐like event with venous congestion in an optic nerve structurally altered with narrowed pores in the lamina cribrosa.2
With the advancement in clinical imaging techniques, lamina cribrosa changes are detectable with optical coherence tomography (OCT).
Another concept suggests that compression of the anterior optic nerve is also influenced by intracranial pressure (ICP) that may vary according to or independently of IOP fluctuations. Lamina Cribrosa forms a pressure barrier between the high-pressure compartment of the intraocular space and the low-pressure compartment of the retrobulbar cerebrospinal fluid (CSF) space. The difference between the posteriorly directed IOP and anteriorly directed ICP across the lamina cribrosa is known as the trans-lamina cribrosa pressure difference (TLCPD).3 The retinal and choroidal venous blood drains through the CSF space, therefore elevated CSF pressure may be associated with dilated retinal veins, increased incidence of retinal vein occlusions and thicker choroid.4
Recent clinical studies have shown that patients with normal tension glaucoma (NTG) had significantly lower CSF pressure and a higher trans-lamina cribrosa pressure difference vis-a-vis normal subjects. Therefore, it is plausible that a low CSF pressure may be associated with NTG. A low systemic blood pressure, particularly at night, could physiologically be associated with a low CSF pressure, which leads to an abnormally high TLCPD and as such to a similar situation as if the CSF pressure is normal and the IOP is elevated. This model could explain why patients with NTG tend to have a low systemic blood pressure, and why eyes with NTG and eyes with high tension glaucoma (HTG ), in contrast to eyes with a direct vascular optic neuropathy, show profound similarities in the appearance of the optic nerve head.
Studies have shown that chronic elevation of IOP in animals with experimentally induced ocular hypertension (OHTN) results in RGC death. Recent studies have reported that ICP is higher in patients with OHTN compared with controls.5This elevated ICP may provide a protective effect for the ONH by decreasing the TLCPD, thus explaining why despite elevated IOP most OHTN do not develp POAG.
A recent study has shown that the lamina cribrosa is more deeply located in HTG than in NTG eyes, and in NTG eyes than in healthy controls based on Enhanced depth imaging on Spectral domain OCT measurements. The authors concluded that the lamina cribrosa depth can be a helpful parameter to differentiate HTG from normal eyes, but it does not reach a good level of diagnostic accuracy for detecting NTG.6
II. Vascular theory:
Apart from mechanical stress elevated IOP also triggers initial neuronal damage in glaucoma through ischaemic injury. The vascular theory focuses on the development of intraneural ischaemia resulting from decreased ONH perfusion.
Healthy vascular perfusion of the ONH depends on three factors ; systemic blood pressure, IOP and the autoregulatory mechanism. Intraneural capillary perfusion pressure in the ONH is equal to the systemic blood pressure minus the IOP. Thus decreased blood pressure or increased IOP leading to drop in the perfusion pressure of the ONH vasculature.7
Additionally, IOP fluctuation results in vascular dysregulation which in turn causes reduced blood circulation and this is more damaging than reduced circulation due to a stable elevated IOP or arteriosclerosis. Instability of ocular blood flow leads to reperfusion injury which although is mild but because of being repeateitive, is more detrimental.
In NTG, Endothelin-1 (ET-1) may have both a local and systemic component of vascular dysregulation, while in HTG, effect of ET-1 may be primarily localized to ocular tissue. Thus, ET-1 antagonism may be developed as a possible new approach for the treatment of both NTG and HTG.8
III. Neurochemical theory:
Since mechanical and vascular theories failed to explain glaucomatous optic neuropathy in all cases of glaucoma, the possible role of neurochemical mechanisms leading to glaucomatous neurodegeneration has been researched. These biochemical mechanisms include the role of excitatory amino acids, caspases, protein kinases, reactive oxygen species(ROS), nitric oxide, tumor necrosis factor-alpha, neurotrophins, and metalloproteins.9
An insufficient autoregulation and unstable ocular perfusion with an associated unstable oxygen supply leads to oxidative stress within the axons of the ONH due to an increase in ROS.10 ROS also stimulate apoptosis and inflammatory pathways on the level of the trabecular meshwork, thus explaining the increased resistance.
As glaucoma progresses, RGC mitochondrial dysfunction leads to an imbalance in ROS production and detoxification. Müller cell functions are enhanced to maintain the level of chemicals released from activated microglia and astrocytes to levels that are non-toxic for the weakened RGCs. With further progression of disease, Müller cell functions become overwhelmed and they are unable to manage the neurochemicals accumulating in the extracellular space to levels that can excessively stimulate receptors associated with RGCs. Individual RGCs with defined receptor profiles, are stimulated at different times by these chemicals to an extent that causes influx of calcium which ultimately results in a collapse of mitochondria function and death. 11
The eye is an immune-privileged site so that its delicate structures are protected from dangerous immune reactions and pathogens. However, disease or injury may interfere with the eye’s immune privilege because of the breakdown of the blood-retina barrier or changes in cytokine production.
ROS and NO induced damage has also been implicated as a major force causing antigen-specific immune activation in retina.12 These insults act through common final pathways that eventually activate cellular proteases and neuronal programmed cell death. So, these retinal proteins may be related to the development of glaucomatous optic neuropathy.
Recently,a new hypothesis for RGC death in glaucoma involving chronic Amyloid β neurotoxicity, which causes apoptosis by binding to neurotrophin receptor p75NTR or through the accumulation of protein aggregates mimicking Alzeihmer’s disease at the molecular level.
However, there is an opposing view that immune responses in glaucoma may be neuroprotective or neural destructive. 13For example, T-cell mediated immune responses may initially be beneficial to limit neurodegeneration. Although an initial immune response may be beneficial and necessary to limit neurodegeneration, expansion and secondary recruitment of circulating T cells through an antigen-mediated process are known to shift the protective immunity into chronic autoimmune neurodegeneration. This is usually associated with a failure to control aberrant and stress-induced immune response.
IV. Glymphatic theory:
Evidence from recent studies supports the hypothesis that a “glymphatic system” exists in the eye and optic nerve, analogous to the described “glymphatic system” in the brain. 14,15
The retina is an extension of the CNS, sharing embryological, anatomical, and physiological similarities to the brain therefore, it seems plausible that the branches of the central retinal vessels in the retina are also surrounded by paravascular spaces with the same properties as the paravascular spaces in the brain.
Hu and colleagues have provided evidence for a glymphatic system in human, non-human primate, rat and mouse retina, using multimarker immunohistochemistry. 16They found that an AQP4+ glial network ensheathing the entire retinal vascular system, including between blood vessels. Löffler and colleagues provided support for lymphatic structures in AD mice retinas similar to the glymphatic system in the brain. 17
In glaucomatous eyes, alterations in the lamina cribrosa framework may mechanically interfere with glymphatic flow through it by decreasing the elimination of neurotoxic substances, such as Amyloid β, and subsequent GON.
This paravascular flow restriction may be in proportion to the amount of the trans-lamina cribrosa pressure gradient.
Wostyn and coworkers have hypothesised that restriction of normal glymphatic flow at the level of the lamina cribrosa may lead to progression of glaucoma in patients with nocturnal hypotension and older patients with systemic hypertension. 15 Though nothing conclusive can yet be said, the initial reports suggesting a paravascular transport system in the optic nerve are promising.
Ample research has been done to ascertain the precise pathogenesis of glaucoma, but the results have not yet managed to halt or reveres the disease progression of glaucoma or to cure it.
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