Glaucoma Essay

8/13/2019 Glaucoma Essay

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The Role of Biomechanics in Glaucoma

The human eye is a remarkable organ with a complex anatomy. It is responsible for detecting,

focussing and subsequently, converting photons into electrochemical signals that are then transmitted

to the brain. The eye is roughly spherical and approximately one inch in diameter. Its outermost layer

is made of two tough connective tissues; the cornea and the sclera. The middle layer consists of theiris, ciliary body and the choroid. The choroid contains blood vessels that nourish the retinal cells, and

facilitate metabolite exchange. The iris is responsible for the changing size of the pupil to ensure that

the right amount of light reaches the retina. Finally, the ciliary body, made up of the ciliary processes

and the ciliary muscle is responsible for the production of aqueous humor and the accommodation of

the lens to adapt to changing focal distances, respectively. The innermost layer of the eye, the retina,

is the sensory layer containing neurons, and photoreceptors neurons known as rods and cones that

convert the incident light into neuron firings that are transmitted to the brain via the optic nerve. The

eyeball is divided into the anterior and posterior chambers, filled with aqueous humor and the vitreous

body, filled with vitreous humor. In the absence of any bony processes, the eyeball maintains its

rigidity by maintaining a small positive pressure with respect to the surroundings. This positivepressure is known as the Intraocular Pressure (IOP). The IOP is transmitted throughout the eye by

the vitreous humor. Therefore, the eye remains spherical and rigid, and a stable distance between the

lens and the retina is always maintained. The normal mean value of IOP for the human eye is 15.5

2.6 mm Hg(Ethier & Simmons, 2007).

Figure 1: Image of the anatomy of the human eye (Bonnick, 2013)

A normal IOP is essential to functioning of the human eye. How is this IOP produced and why?Aqueous humor is responsible for the IOP. In the cornea and the lens, because of the need for optical


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transparency, metabolite exchange with blood via perfusion is not possible. Therefore, clear and

colourless aqueous humor also serves as a medium for nutrient exchange. Secreted by epithelial cells

in the ciliary processes, the aqueous humor perfuses the lens and then moves into the anterior chamber

of the eye. From here, it drains out of the eye through special channels in the angle formed by the iris

and the cornea known as the angle of the anterior chamber. The rate of production of aqueous humor

by the ciliary processes is very slow (2.4 0.6 l/min in the normal human eye). However, the

resistance to outflow of aqueous humor during its drainage is what causes the considerable positive

pressure. The drainage of aqueous humor in the eye occurs through two channels; the conventional

route and the unconventional route. The unconventional route or the uveo-scleral route carries only

10% of the outflow, and does not account as the primary site for flow resistance. Majority of the

aqueous humor drains through the conventional route; a series of specialised tissues: the trabecular

meshwork, the canal of Schlemm, and the collector channels/aqueous veins. These are the main cause

of the outflow resistance to aqueous humor (approximately 3-4mm Hg/l/min). Once aqueous humor

leaves the aqueous veins, it drains back into the right side of the heart after joining the episcleral

veins. At the normal values of outflow resistance, the IOP remains at a value of 15.5 mm Hg, which is

normal.

Ocular hypertensionis a condition where the IOP is elevated beyond its normal value, in the absence

of optic nerve damage or visual field loss. Ocular hypertension is the most important risk factor for

glaucoma and thus, functions as a valuable screening tool for glaucoma. According to Casson et al

(2012) glaucomamay be described as:

..a group of ocular disorders of multifactorial aetiology united by a clinically characteristic optic

neuropathy with potentially progressive, clinically visible changes at the optic nerve head (ONH),

comprising focal or generalized thinning of the neuroretinal rim with excavation and enlargement of

the optic cup, representing neurodegeneration of retinal ganglion cell axons and deformation of the

lamina cribrosa; corresponding diffuse and localized nerve-fibre-bundle pattern visual field loss maynot be detectable in early stages; while visual acuity is initially spared, progression can lead to

complete loss of vision..

Chronically elevated IOPis indicated in the development as well as the progression of glaucoma. A

patients IOP may be considered elevated if it is greater than 97.5 percentile of the population

(Casson et al, 2012). It may affect the pressure sensitive cells and tissues in the eye viz. the trabecular

meshwork (TM), the optic nerve head (ONH) including the lamina cribrosa cells and optic nerve head

astrocytes, the peripapillary sclera around the optic nerve head, retinal ganglion cells (RGC) and RGC

axons in the retinal nerve fibre layer (Clark, 2012). This increase in IOP is caused by an increase in

outflow resistance. In a glaucomatous eye, the resistance to outflow maybe as high as or greater than

triple the normal value. There are also some forms of glaucoma in which this increase in IOP is not

due to the increase in outflow resistance. These are categorized as angle-closure glaucoma, which

occurs due to the iris pivoting forward and blocking the access to the drainage structures in the angle

of the anterior chamber. This may be caused due to an anatomic predisposition.

A few hypotheses have been put forth to explain the resistance to outflow in the conventional route

for drainage:

1) Collapse of Canal of Schlemm - Channel collapse is governed by two factors. Theunderlying elastic TM tends to keep the Canal of Schlemm open. Whereas, the pressure drop

across the TM and the inner wall of the canal tends to make it close. On solving the resultingequations drawn up to conserve mass, pressure drop and deformation it was found that for


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typical values of input parameters, the resistance due to the canal of Schlemm would be

negligible, except at very high pressures such as 50mm Hg where the canal collapses. Even

with a collapsed Canal of Schlemm the outflow resistance is not as high as a glaucomatous

eye. Therefore, channel collapse can be ruled out as a cause of Glaucoma (Ethier & Simmons,

2007).

Figure 2: Scanning Electron Micrograph showing an overview of conventional tissues

for aqueous humor drainage(Ethier & Simmons, 2007)

2) Experimental evidence supports the conclusion that the source of normal and increasedoutflow resistance in glaucoma is attributable to the inner wall endothelium, its basement

membrane, the juxtacanalicular connective tissue (JCT), or some combination of all three of

these (Johnson, 2006). Like other epithelial basement membranes in the body, the basement

membrane in the inner wall of the canal of Schlemm may be responsible for the generation of

outflow resistance. However, due to the discontinuous nature of the membrane in the human

eye, this resistance may not account for a large fraction. The porous nature of the JCT as

evinced by transmission electron microscopy shows large open spaces, which may not cause

significant outflow resistance. However, if these spaces were to contain glycosaminoglycansat physiological concentrations, then the flow resistance due to the JCT would be

considerable. Upon further investigation using quick freeze/deep etch electron microscopy

that may preserve GAGs in the sample, similar pores were still seen. Therefore, it remains

unclear whether GAGs account for the outflow resistance, and if yes, till what extent. In the

inner wall, the endothelial cells form a continuous layer attached to each other using tight

junctions. The unique feature of these cells is the formation of vacuoles that are invaginations

of the endothelium into the lumen of the canal of Schlemm, caused by the pressure drop

across the endothelium. These invaginations may account for the outflow resistance. These

vacuoles also contain membrane lined pores that connect the apical and basal side of the cell.

A study has shown that the pore density in the glaucomatous eye is significantly reduced,


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which may mean that these pores account for the increase in outflow resistance as

experienced in glaucoma (Overby, Stamer & Johnson, 2008).

Figure 3: Scanning Electron Micrograph of the inner wall of Schlemms Canal

(Johnson, 2006)

Apart from the elevated outflow resistance, glaucoma causes extensive and progressive neuropathy.

ONH cupping caused by the death of the neurons in the optic nerve is a clinical feature of glaucoma

(Downs, Roberts & Sigal, 2012). RGC axons converge to form the optic nerve that pierces the sclera

to join the brain. Since this is a weak point of discontinuity in the otherwise continuous sclera, it is

additionally susceptible to concentration of stresses. The lamina cribrosa is the porous connective

tissue that spans the sclera canal and supports the RGC axons as they leave the eye as the optic nerve.

Two theories attempt to explain the damage to the RGCs. The mechanical theory of glaucomatous

optic neuropathypostulates that the increased mechanical stresses acting in lamina cribrosa cause

axonal damage. This damage may be mediated through astrocytes. The astrocytes divide and form a

glial scar and fail to provide nutrition and guidance the neurons, thus leading to neuronal death. The

second theory, vasogenic theory, states that the glaucomatous insult results from inadequate vascular

perfusion in the laminar cribrosa, resulting in insufficient oxygen delivery. The resulting ischemia

triggers neuronal cell death (Ethier & Simmons, 2007).

In conclusion, glaucoma is a progressive eye pathology caused by chronically elevated IOP that leads

to irreversible vision loss and if left untreated, blindness. Since the effects may not be clear till they

have progressed considerably, early screening is a must. Once diagnosed, the treatment for glaucoma

involves reduction of the IOP via medication, or surgical treatment. In addition to IOP and ONHbiomechanics, the biomechanics of the cornea and the corneal thickness may also play a role in the

development of glaucoma, especially the progression of ocular hypertension into full fledged

glaucoma (Brown & Congdon, 2006). Therefore, further research into the biomechanics of glaucoma

will help identify risk, early diagnosis, treatment modalities as well as patient prognosis.


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References

Bonnick (2013) CSEC - The Eye - functions of the various parts. Biologs. Weblog. [Online].

Available fromhttp://thebiologs.blogspot.co.uk/2013/09/csec-eye.html.Accessed 24th October 2013.

Brown, K. E. & Congdon, N. G. (2006) Corneal structure and biomechanics: impact on the diagnosis

and management of glaucoma. Current Opinion in Ophthalmology.17 (4), 338-343.

Casson, R. J., Chidlow, G., Wood, J. P., Crowston, J. G. & Goldberg, I. (2012) Definition of

glaucoma: clinical and experimental concepts. Clinical & Experimental Ophthalmology. 40 (4), 341-

349.

Clark, A. F. (2012) The cell and molecular biology of glaucoma: biomechanical factors in

glaucoma.Investigative Ophthalmology & Visual Science. 53 (5), 2473-2475.

Crawford Downs, J., Roberts, M. D. & Sigal, I. A. (2011) Glaucomatous cupping of the lamina

cribrosa: a review of the evidence for active progressive remodeling as a mechanism.Experimental

Eye Research. 93 (2), 133-140.

Ethier, C. R., Johnson, M. & Ruberti, J. (2004) Ocular biomechanics and biotransport.Annual Review

of Biomedical Engineering. 6, 249-273.

Ethier, C. R. & Simmons, C. A. (2007)Introductory biomechanics: from cells to

organisms. Cambridge texts in biomedical engineering. Cambridge, Cambridge University Press.

Johnson, M. (2006) 'What controls aqueous humour outflow resistance?'.Experimental Eye

Research. 82 (4), 545-557.

Overby, D. R., Stamer, W. D. & Johnson, M. (2009) The changing paradigm of outflow resistancegeneration: towards synergistic models of the JCT and inner wall endothelium.Experimental Eye

Research. 88 (4), 656-670.
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