Pathophysiology of Glaucoma
Updated: Nov 16, 2022
To understand the pathophysiology of glaucoma, it is important to understand three main principles: 1) aqueous production, 2) aqueous outflow, and 3) intraocular pressure
Glaucoma comes in many forms with a number of underlying aetiologies, however fundamentally what all forms have in common is progressive optic neuropathy associated with visual field loss, where intraocular pressure IOP is an important modifiable factor.
Aqueous humour, which fills the anterior and posterior chamber, is produced by the non-pigmented epithelium of the pars plicata, producing around 2.5 μl of aqueous humour per minute. There are three main processes that contribute to this process:
1) Diffusion (passive): Solutes, especially lipid soluble substances, diffuse from an area of high concentration to low through the lipid portions of the membranes between the capillaries and the posterior chamber.
2) Ultrafiltration (passive): A passive process where water-soluble substances, limited by size and charge flow across fenestrated ciliary capillary endothelia, resulting in ultrafiltrated plasma within the ciliary body’s stroma. This also produces an almost protein-free liquid, resulting in an optically clear medium for vision.
These two passive process allow plasma ultrafitrate to accumulate in the stroma, behind tight junctions of the non-pigmented epithelium, where the aqueous humour is produced.
3) Active secretion (active) This process is the main contributor to aqueous formation, responsible for approximately 80% to 90% of the total aqueous humour. As the Na+/K+ ATPase actively transports Na+ ions into the posterior chamber, the water collected in the stroma of the ciliary body follows.
This process is under control by the sympathetic (adrenergic) nervous system. β2 receptor stimulation increases aqueous secretion, whilst α2 receptor stimulation has the opposite effect and decreases it.
Carbonic anhydrase is found in both the non-pigmented and pigmented epithelia. It’s role is to mediate the transport of bicarbonate across the ciliary epithelium by the reversible hydration of CO2, to form HCO3-and protons, as per the following equation:
CO2 + H2O ⇌ H2CO3 ⇌ HCO3- + H+
Bicarbonate has an important effect on fluid production by affecting Na+ and regulating the pH for optimal active transport.
Aqueous humour flows from the posterior chamber into the anterior chamber via the pupil, and exits the eye from one of three routes:
Trabecular outflow (90%)
This conventional route involves flow through the trabeculum, through the Canal of Schlemm, and then into the episcleral veins.
Uveoscleral drainage (10%)
This involves flow across the ciliary body into the suprachoroidal space, and is drained by the venous circulation in the ciliary body, choroid and emissary canals of the sclera (vortex veins).
Small amounts of aqueous drain via the iris.
An important principle regarding the trabecular outflow pathway is that increasing the IOP will increase outflow, we therefore say this outflow route is ‘pressure sensitive’.
IOP depends on the balance between the rate of aqueous production, and the rate of outflow. The average IOP is around 16mmHg with a normal range of 11-21 mmHg on applanation tonometry.
The IOP is thought to be an important modifiable element in all types of glaucoma, however additional factors such as corneal rigidity, blood flow to the optic nerve and size/shape of the optic head may all influence the IOP reading.
It is also important to notice some patients develop glaucomatous changes with an IOP of less than 21mm Hg (normal tension glaucoma), whilst others do not develop any changes despite having a much higher reading.
Optic Nerve Changes
Glaucomatous changes usually occur in 3 places: 1) optic nerve head, 2) peripapillary area, 3) retinal nerve fibre layer.
Optic Nerve Head
The neuroretinal rim is the tissue between the outer edge of the cup and the optic disc margin, containing retinal neuronal cells.
The rim is normally thickest inferiorly, then superiorly, nasally and finally temporally. This can be remembered by the ‘ISN’T’ rule. Part of the glaucomatous changes involve thinning of this neuroretinal rim.
Cup to disc ratio (C/D ratio)
This is the vertical diameter of the cup, as a fraction of the vertical diameter of the optic disc. The normal C/D ratio is 0.3, however some individuals may have something called physiological cupping. This is where there may be a C/D ratio of 0.6 or 0.7 instead, but with no glaucomatous changes.
Pathological cupping is due to a decrease in the number of nerve fibres, glial cells and blood vessels. Four ‘pure’ glaucomatous disc patterns have been identified:
Focal ischaemic discs
Myopic disc with glaucoma
Concentrically enlarging discs
In reality, most discs we see on fundoscopy cannot easily be classified in this way, but it is still useful as a general overview on glaucomatous damage and may provide clues on the underlying pathology. Some other non-specific signs that are likely to pop up in the exam include:
Barring of circumlinear blood vessels
Loss of nasal NRR
Laminar dot sign
This refers to the area around the optic disc. There are two parts:
Alpha (outer) zone : Changes include superficial retinal pigment changes and enlargement.
Beta (inner) zone: Changes include chorioretinal atrophy and enlargement. The area of changes also seems to predict where the visual field loss occurs.
Retinal nerve fibre layer
Subtle changes in the retinal nerve fibre layer comes before any detectable optic disc and visual changes, and usually show up as disc haemorrhages.
Visual Field Defects
The visual field defect we see in glaucoma depend on the pattern of fibres affected in the optic nerve head damage. This includes:
Small paracentral depressions: An early feature, commonly in normal tension glaucoma
Arcuate defects: Typically between 10 and 20 degrees of fixation, as downward or upward extensions of the blind spot. Elongate circumferentially over time following the arcuate nerve fibre distribution.
Nasal step: This refers to a difference in sensitivity above and below the horizontal midline in the nasal fields. For example, inferior optic disc changes will result in superior nasal step.
Ring scotoma: Occurs when a superior and inferior arcuate defect joins (advanced glaucoma)
Early + late changes: Early changes include slight asymmetry between the two eyes, especially in areas that are likely to develop future defects. End stage changes are simply having a small island of central vision only, sometimes with a temporal island too.
GLAUCOMA SPECIALIST BLOG: ‘THE GLOG’. http://ourgsc.blogspot.com/2019/09/aqueous-humor-formation-guest-author.html. Accessed 16 Nov. 2022.
Barton, Keith, and Roger A. Hitchings. ‘Pathogenesis of Glaucoma’. Medical Management of Glaucoma, edited by Keith Barton et al., Springer Healthcare Ltd., 2013, pp. 33–48. Springer Link, https://doi.org/10.1007/978-1-907673-44-3_2.
Goel, Manik, et al. ‘Aqueous Humor Dynamics: A Review’. The Open Ophthalmology Journal, vol. 4, Sept. 2010, pp. 52–59. PubMed Central, https://doi.org/10.2174/1874364101004010052