Glaucoma is a serious eye disease, of which recent studies have highlighted important inflammatory aspects, to which we will devote this in-depth study.
Introduction
The glaucoma is a progressive, multifactorial neurodegenerative disease that is the most frequent cause of irreversible blindness.
It was recently estimated that the number of people suffering from glaucoma worldwide will rise from 76.5 million in 2020 to 111.8 million by 2040, mainly due to an ageing population.
The term glaucoma actually encompasses several conditions. Primary open-angle glaucoma (POAG) is the most common form in Western countries. The aetiology of POAG is generally mechanical, when intraocular pressure leads to compression of axons, or vascular, when blood flow and ocular perfusion pressure are reduced.
Glaucomatous pathology
Glaucoma is a chronic degenerative disease affecting the optic nerve, characterised by damage to its nerve fibres and consequent visual field damage. If left untreated, the progressive reduction of the visual field can lead to blindness.
Glaucoma is a major social problem: it is the second leading cause of blindness in the world, and approximately 50% of glaucoma sufferers are unaware of it.
It is a sneaky disease as one often notices the disease when visual changes are already very advanced, whereas previously one did not experience any symptoms. However, if diagnosed early and properly treated, it can be effectively kept under control, allowing good vision throughout life.
Risk factors
Numerous risk factors correlate with the onset of the disease. Among these, the main ones are:
- elevated intraocular pressure (IOP),
- advanced age,
- familiarity.
Intraocular pressure
Intraocular pressure or IOP is the value determined by a fluid circulating within the eye, the aqueous humour. In a healthy eye, the ratio of aqueous humour produced to aqueous humour excreted is such that a constant intraocular pressure is maintained, usually between 11 and 20 mmHg. In the presence of glaucoma, on the other hand, this ratio is altered due to a reduction in aqueous humour elimination that occurs at the level of the trabecular meshwork, the structure that allows the physiological escape of this fluid from the eye.
Classification
Glaucoma can be classified in several ways:
- Depending on the aetiology, glaucoma can be primary, when it occurs in the absence of other ocular or systemic pathologies, or secondary, when associated with pre-existing pathologies;
- Based on the altered outflow of the aqueous humour, we distinguish between open-angle glaucoma, due to increased resistance to outflow at the level of the trabecular meshwork, and angle-closure glaucoma, where there are anatomical problems that prevent the aqueous humour from reaching the trabecular meshwork;
- Based on the value of the main risk factor, IOP, there is high-pressure glaucoma and normal-pressure glaucoma.
Added to these are congenital or acquired glaucoma, if IOP is elevated from birth, and infantile glaucoma if it occurs during the first years of life.
Symptoms
The increase in intraocular pressure and the resulting damage to the optic nerve are not perceptible and, therefore, the main symptom is a progressive narrowing of the visual field. Unfortunately, in the early stages, it is not possible to realise this limitation without an eye examination.
Diagnosis
There are several tests that can be used to rule out or diagnose the presence of glaucoma:
1. the tonometry, which is used to measure intraocular pressure;
2. l'ophthalmoscopywhich allows an objective examination of the optic nerve;
3. the perimeter (or visual field examination), which allows an assessment of overall visual function;
4. the pachymetrywhich assesses corneal thickness;
5. OCT, which evaluates the retinal nerve fibre layer.
Apart from measuring IOP, some of these tests are necessary to monitor the evolution of the disease.
Treatment
Glaucoma therapy involves two types of approach, pharmacological and surgical.
Pharmacological treatment is the first choice and uses anti-glaucomatous drugs aimed at reducing the main risk factor for glaucoma, intraocular pressure.
These drugs are taken as chronic therapy, i.e. administered regularly and consistently throughout life. Full adherence to therapeutic prescriptions is essential for the treatment to produce its effects.
In the event that drug therapy alone fails to achieve a certain target pressure, parachirurgical therapy (laser treatments) or, alternatively, surgical treatment is possible. The most common surgery is called trabeculectomy and involves the creation of an artificial aqueous humour outflow channel.
The role of inflammation in glaucoma
The onset of glaucoma is related to several risk factors, which include - as mentioned above - advanced age, increased intraocular pressure (IOP) and genetic background. Oxidative stress, mitochondrial dysfunction and cellular senescence tend to be increased in the ageing retina and are considered among the main factors increasing the risk of glaucoma. When the retina ages, in fact, oxidative stress and lipid peroxidation are considered the main causes of tissue stress, which leads to the activation of local parainflammation of varying degrees.
Para-inflammation
Parainflammation is defined as an adaptive tissue response to noxious stimuli, stress or malfunction, and has characteristics that are considered to be intermediate between the normal basal tissue state and the inflammatory state. A physiological level of parainflammation is necessary to maintain tissue homeostasis and restore function, but when tissue is exposed to stress and/or malfunction for a prolonged period, inflammation can play a deleterious role and be implicated in both the onset of glaucoma and its progression. Indeed, excessive parainflammation can produce inflammatory responses with a marked release of cytokines and chemokines, which cause irreparable damage to the neuroretina.
Inflammation can also have a detrimental effect on conjunctival and corneal barrier functions and cause activation of the immune system. Consequently, glaucoma appears as a disease in which inflammatory processes may be present to varying degrees throughout the entire structure of the eye.
Inflammation in retinal and optic nerve head degeneration
Glaucomatous degenerative disease is characterised by a progressive loss of retinal ganglion cells (RGCs), thinning of the retinal nerve fibre layer and cupping of the optic nerve head (ONH). Various stimuli, including chronic mechanical stress induced by elevated IOP, hypoxia/ischemia and oxidative stress, together with deprivation of neurotrophic factors, can cause RGC dysfunction and death. Furthermore, it has been suggested that increased stress over a prolonged period may lead to a failure in the regulation of the local protective immune response mediated by glial cells and the complement system, leading to a process of neuroinflammatory degeneration, which contributes to disease progression.
Neuroinflammatory mechanisms in glaucoma
Some studies have proposed a number of molecular and signalling pathways that are regulators of neuroinflammation in the aetiology of glaucoma. These are complex mechanisms involving a close interaction between glial cells, immune cells, endothelial cells and RGCs via autocrine/paracrine pathways. One pathogenetic hypothesis is based on vascular stress at the level of the ONH and retina, which leads to a persistent inflammatory phenotype, with increased oxidative stress and cellular ageing/senescence, associated with a loss of neuroprotection and remodelling of glial cells, release of apoptotic signals, degeneration of RGCs, disruption of the blood-retinal barrier and tissue damage in the ONH.
Inflammation and trabecular meshwork in glaucoma
Upstream of the degeneration of ONH and the loss of RGC characteristic of neuropathy due to glaucoma, as seen, increased IOP plays an important role. Studies have shown that local parainflammation may play a regulatory role in the outflow of aqueous humour from the trabecular meshwork. Several histological studies, in fact, have shown an over-regulation of inflammation-associated genes in the trabecular meshwork, which may be involved in the onset or progression of glaucoma.
Inflammation of the ocular surface in glaucoma
The most visible manifestations of inflammation in glaucoma are those occurring at the ocular surface. Ocular surface disease (OSD) is therefore very common in these patients, who often complain of a foreign body sensation in the eye, redness, itching, pain and photosensitivity. Superficial changes also include effects that are not clinically visible, such as the infiltration of inflammatory cells, a significant decrease in the number and density of central corneal sub-basal nerve fibres, and a reduction in corneal sensitivity.
Modulation of inflammation in glaucoma: perspectives and future directions
We examined how the balance of inflammatory mechanisms is necessary to maintain healthy ocular structures. In fact, parainflammation can quickly go from being a physiological process to becoming a factor contributing to ocular tissue degeneration.
There is evidence that stimuli causing cellular stress, including increased intraocular pressure or decreased blood flow, associated with chronic oxidative stress, may tip the balance from beneficial parainflammation towards toxic levels, participating in the pathogenesis and progression of glaucoma. To date, various therapeutic approaches have been proposed to prevent or modulate excessive inflammatory reactions in glaucoma, but extensive clinical studies will be needed to investigate their safety and efficacy.
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