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====== PRESENTATION SLIDES ======

[[https://drive.google.com/file/d/1NWfKJQ6TYacU8YgolaIZZJpsyg_WWzYe/view?usp=sharing|External Link]]
====== INTRODUCTION ======

Glaucoma is a common cause of blindness around the world (Harada //et al//., 2019). It results from the buildup of aqueous humour fluid in the anterior chamber of the eye. Aqueous humor is produced by the ciliary body and it flows from the posterior chamber through the pupil into the anterior chamber of the eye (Civan & Macknight, 2004). Normally, this fluid then flows out through a spongy tissue at the front of the eye called the trabecular meshwork and into a drainage canal called Schlemm’s canal (Civan & Macknight, 2004). The aqueous humour plays an essential role in the health of your eye. As well as nourishing the cornea and the lens by supplying nutrients such as amino acids and glucose, the aqueous humour plays an important role in maintaining intraocular pressure (Civan & Macknight, 2004). Individuals with glaucoma are unable to drain out the aqueous humour fluid through the trabecular meshwork because it gets blocked, leading to an increase in intraocular pressure. This buildup of pressure in the eyes can eventually begin leading to irreversible damage to the optic nerve which can impair your vision. Many forms of glaucoma have no warning signs. The effect is so gradual that you may not notice a change in vision until the condition is at an advanced stage. Early treatment of the condition can, however, prevent the condition from leading to blindness. Treatment typically involves prescription eye drops, oral medications, laser treatment, surgery or a combination of any of these. 

<box 33% round | > {{ :3-1.png?300 |}} </box| Figure 1: Anatomy of the eye. (Retrieved from: Bollinger et al., 2012)>

====== HISTORY ======

The term glaucoma dates back to millennia and was first used by Hippocrates in Greece in 400 BC to describe a dimming of vision (Realini, 2011). However, the actual origin of the word is unclear. Even though glaucoma was known about, treatment for glaucoma was hugely delayed for thousands of years because there was not much of an understanding as to what the disease was (Realini, 2011). In fact, there was a misconception that glaucoma is caused by the opacification of the vitreous in the eye. It was not until 1622, when the ophthalmologist Richard Bannister linked glaucoma to intraocular pressure (Realini, 2011). Not much came of this until the mathematician Charles Babbage and Hermann von Hemholtz assembled the first ophthalmoscope in 1851, which is an instrument used to view the interior of the eye. After this invention, Albrecht von Graefe, a German, began a series of clinical tests that solidified the phenotype associated with glaucoma (Realini, 2011).

====== EPIDEMIOLOGY ======

It is estimated that there are 60 million people with glaucoma and 8.4 million people who are blind due to glaucoma in 2012 (Cook & Foster, 2012). Specifically, it is estimated that 4.5 million people are blind due to open-angle glaucoma and 3.9 million are blind due to angle-closure glaucoma. By 2020, it is estimated that 80 million people will be affected by glaucoma, with 5.9 million and 5.4 million people blind due to open-angle and angle-closure glaucoma, respectively (Quigley & Broman, 2006).

Prevalence of glaucoma also varies with racial group. Asians are the largest group affected, comprising 47% of the total affected, with all types of glaucoma, and 87% of primary angle-closure glaucoma (Cook & Foster, 2012). On the other hand, Africans in Africa have the highest prevalence of primary open-angle glaucoma. Prevalence of primary open-angle glaucoma is similar between white Europeans, Americans, and Australians. Additionally, women are more affected than men, making up 59% of all glaucoma (Cook & Foster, 2012).

There are also risk factors associated with primary open-angle glaucoma. African people have a prevalence up to 5 times higher than other ethnic groups to develop glaucoma (Cook & Foster, 2012). There is an exponential increased risk to glaucoma with increased age, with Hispanics having a more pronounced increase with age (Cook & Foster, 2012). Additionally, having thin central corneal thickness and/or a large optic disc diameter has an increased risk to glaucoma. Other factors associated with higher risk is low physical activity, having cardiovascular disease, and hypertension (Cook & Foster, 2012).

<box 25% round | > {{ :wiki:omd_apr_3801.jpg?250  |}} </box| Figure 2: Projected estimates of people affected by glaucoma. (Retrieved from:)>


====== SYMPTOMS ======

<box 50% round | > {{ :wiki:life_sci_4m03_-_presentation_3_glaucoma_5.jpg?500 |}} </box| Figure 3: General symptoms of glaucoma.>

====== CAUSES ======

One of the main causes of Glaucoma is the failure of the eye to maintain balance between aqueous production inside the eye and aqueous drainage out of the eye through the trabecular meshwork (Weinreb & Khaw, 2004). The Fluid is usually able to flow out of the eye through different channels but if the drainage angle is blocked, it leads to buildup. This imbalance can affect the intraocular pressure of the eye. The normal intraocular pressure is 10-21mm Hg but in the case of glaucoma the intraocular pressure could increase up to 70mm Hg (Weinreb & Khaw, 2004). The Deuteriation of the optic nerve fibers lead to blind spots eventually leading to symptoms of Glaucoma.  Some of the lesser common causes include chemical injury to the eye, blocked blood vessels inside the eye and inflammatory conditions
There are also some risk factors associated with glaucoma that could likely increase the chance of an individual developing the disease. Family history is a well- established risk factor. Mutations in the MYOC gene is primarily responsible for open angle Glaucoma, this gene provides information to code a protein called Myocilin (Leske, 2007). Myocilin is found in the trabeculae meshwork and in ciliary body that regulate intraocular pressure. While mutations in the CYP1B1 gene is detected in people with primary congenital Glaucoma. This gene codes for a cytochrome P40 protein which like Myocilin is found in trabeculae meshwork and ciliary body and regulate intraocular pressure (Leske, 2007). Diabetes and high blood pressure can also be risk factors for Glaucoma

<box 30% round | > {{ :wiki:4333.png?300 |}} </box| Figure 4: Prevalence of Glaucoma according to Age and Race (Quigley, 1993).>

====== DIAGNOSIS ======

Early diagnosis of Glaucoma would include examination of optic discs, retinal nerve fibre layer, and visual field (Weinreb & Khaw, 2004). New Imaging and psychological tests can not only detect the disease but also can monitor the progression of the disease (Weinreb & Khaw, 2004). There are five main factors that have to be examined to make a diagnosis using different methods

<box 50% round | > {{ :life_sci_4m03_-_presentation_3_glaucoma_.jpg?500 |}} </box| Figure 5: The various tests used for diagnosing glaucoma.>

===== Tonometry  =====

Tonometry measures the pressure within your eye suing a device called the Tonometer. Eyedrops are used on the patient prior to the test (Eddy //et al//., 1983). The device applies a small amount of pressure to the eye by the puff of air. The range for normal pressure is between 10-20 mm Hg, cases exceeding 20 mm Hg are diagnosed with Glaucoma (Singh //et al//., 2001).

===== Ophthalmoscopy =====

This procedure is used to examine the optic nerve to check for glaucoma damage (Wolf //et al//., 1993). Eyedrops are used to dilate pupil so it is easier for the physician to examine the shape and color of the optic nerve (Wolf //et al//., 1993). A small device with the light on the end is then used to light and magnify the optic nerve. Irregularities in the intraocular pressure and the optic nerve may lead to further glaucoma tests (Wolf //et al//., 1993).

=====  Perimetry  =====


Perimetry is a visual field test that produces a map of your complete field of vision (Johnson & Samuels, 1997). This helps determine if your vision has been affected by glaucoma. Procedure for this test includes looking straight ahead and indicating a moving light on your peripheral side vision (Bengtsson & Heijl, 2000). This test might be repeated multiple times to make sure the results are accurate. Visual test can be done once or twice a year once glaucoma is diagnosed to test the progression of the disease (Bengtsson & Heijl, 2000).

===== Pachymetry ====

Pachymetry measures the thickness of the cornea. Central corneal thickness is an important parameter to diagnose glaucoma (Realini //et al//., 2003). A probe called a pachymeter is placed on the front of the eye to measure its thickness (Brandt, 2004). Corneal thickness can affect eye pressure readings, a thicker than average cornea can lead to a pressure reading that is higher than the actual pressure and a thinner cornea can lead to a pressure reading lower than the actual pressure (Ehlers & Hansen, 1974)

===== Gonioscopy =====

This procedure help dictates whether the angle where the iris meets the cornea is open and wide or narrow and closed. It can help determine the type of glaucoma the patient has (Barken, 1955). Eye drops are provided to the patient to numb the eye, then a handheld contact is placed on the eye (Hsai et al.,2000). The contact lens has a mirror that shows the doctor is the angle between the iris is closed a blocked which is a possible sign of angle- closure or acute glaucoma and wide and open which can be a sign of open angle and chronic glaucoma (Hsai et al.,2000).

====== PATHOPHYSIOLOGY======

The pathophysiology of the heterogeneous group of diseases known as glaucoma, is multifactorial. The death of retinal ganglion cells is influenced by a plethora of factors, which directly affect retinal cell bodies or retinal axons. The primary factors of concern in relation to the development of glaucomatous symptoms are increased intraocular pressure and vascular dysregulation. These two factors are involved in early stages of cell atrophy observed in the development of glaucoma and act by impeding axoplasmic flow in the retinal ganglion cell axons located predominantly at the lamina cribrosa. These factors are also involved in changes to the microcirculation of the optic nerve. Additionally, secondary influencing factors are primarily focused around excitotoxic damage caused by the amino acids glutamate and glycine, which are excreted by damaged neurons affected by persistent oxidative damage. The oxidative damage stems from the excessive production of the compound nitric acid as well as other excitotoxic damage inducing compounds. The net impact of these primary and secondary factors is retinal ganglion cell death resulting in permanent loss of vision. The progression of glaucomatous symptoms associated with cell death is divided into two phases. The initial stages feature cell loss exclusively linked to apoptosis, whereas the second stage is impacted more heavily by toxic effects of cells lost during the initial stage as well as long-term exposure to intraocular pressure (Agarwal //et al//., 2009). 


===== Apoptosis Induced Atrophy =====

During the development of glaucoma, the head of the optic nerve undergoes a transformation near the optic disk. The optic disc is the point of exit for ganglion cell axons leaving the eye. This transformation leads to the cupping of the optic disk, a site known for the loss of ganglion cell axons. The death of both ganglion cell bodies and axon terminals located in the retina and lateral geniculate body respectively, are both involved in the aforementioned loss of cell axons at the site of cupping. All of the cell loss experienced during the development of glaucoma, specifically the death of retinal ganglion cells, occurs via a mechanism known as apoptosis. The mechanism of apoptosis, or otherwise known as programmed cell death, is a process by which a cell induces its own destruction. The characteristic features of this process include chromosome clumping, cell shrinkage, DNA fragmentation, and membrane blebs. Once the nucleus has induced the aforementioned features, the succeeding step is the division of the cell into smaller vesicles. These small membrane bound vesicles are then taken into surrounding cells via a mechanism known as phagocytosis. Apoptosis is the predominant process of retinal cell death during the initial stages of glaucoma development but is complimented by the addition of necrotic cell death during later stages of glaucoma development (Agarwal //et al//., 2009). 
The process of apoptosis is regulated by a family of proteases known as caspases. These caspases are better classified as cysteine aspartyl-specific proteases and are integral to the regulation of programmed cell death. Initially existing in an inactive zymogenic state, the caspases are activated during glaucoma development and are involved in cell death. The caspases cause a cascade of proteolytic events in the cytosol of retinal ganglion cells, eventually leading to cell death. Ligand influenced extrinsic activation of these caspases occurs via binding of proapoptotic receptors located on the surface of the cells. On the other hand, the intrinsic regulation of these caspases occurs via mitochondrial release of proapoptotic substances. One study observed that 34% of retinal ganglion cells survived inevitable apoptosis linked to the inhibition of caspases (Agarwal //et al//., 2009). 


<box 50% round | > {{ :wiki:life_sci_4m03_-_presentation_3_glaucoma_2.jpg?500 |}} </box|Figure 6: Comparison between a healthy eye and a glaucomatous eye with elevated intraocular pressure. (Retrieved from “Glaucoma,” n.d.)>

===== Elevated Intraocular Pressure =====

Increase in intraocular pressure stems from an obstruction in the drainage of aqueous humour. Specifically, the trabecular meshwork undergoes changes which impedes the drainage of aqueous humour. The changes observed in the trabecular meshwork includes altered extracellular matrix and cellularity. There is a strong positive correlation associated with a gradual increase in intraocular pressure being linked to retinal ganglion cell death. Several researchers have observed this correlation through studies conducted on rats, which measured the elevation in intraocular pressure, retinal ganglion cell death, and overall progression of glaucoma. The loss of retinal ganglion cells in association to an elevation in intraocular pressure is divided into two stages. The primary stage features an accelerated loss of retinal ganglion cells at approximately 12% per week. This stage is succeeded by a slower stage of cell death (Agarwal et al., 2009). 


====== TREATMENTS ======

There is currently no cure for glaucoma. Treatment focuses on lowering the intraocular pressure to a level that is less likely to cause further optic nerve damage. Depending on your situation, your options may include prescription eye drops, oral medications, laser treatment, surgery or a combination of any of these.


===== Eye drops/Oral Medications =====

In the early stages of its development, glaucoma can be treated with eye drops that decrease eye pressure by either increasing aqueous humour outflow of reducing the production of the fluid. One or more prescription eye drop medication can be prescribed to an individual with the condition (Sleath //et al//., 2011). In addition, these drugs are typically taken once a day, or sometimes twice per day for life (Sleath //et al//., 2011). Examples of the types of drugs that may be prescribed to an individual include prostaglandins, beta blockers (also available in pill form), alpha-adrenergic agonists, carbonic anhydrase inhibitors (also available in pill form), rho kinase inhibitors, and cholinergic agents (Mayo Clinic, n.d.). If eye drops alone are insufficient in lowering eye pressure, individuals may also be prescribed oral medications (pills), yet these are less often used (Mayo Clinic, n.d.).  

<box 15% round | > {{ :wiki:4.png?150|}} </box| Figure 7: Betaxolol eye drop. This a selective beta receptor blocker used in the treatment of glaucoma. (Retrieved from: MD Supplies)>

===== Laser/Intrusive Treatments =====

Treatment may also involve laser therapy or surgery to improve fluid drainage within the eye as a means of lowering eye pressure. The most common forms include:

  * Unordered List ItemSele ctive Laser Trabeculoplasty (SLT): Involves using a laser beam to open clogged channels in the trabecular meshwork (Latina & Tumbocon, 2012).
  * Laser Peripheral Iridotomy: Involves a laser being used to create an opening in the iris so that fluid can leave the angle of the eye more easily (He //et al//., 2007).
  * Unordered List ItemTrabeculectomy: Involves creating a small channel is to drain fluid from the eye into a reservoir located underneath the eye’s natural lining, the conjunctiva. This reservoir, known as a bleb, may appear like a blister-like bump on the white of the eye. Regarded as the “gold standard” in glaucoma surgery (Brandão & Grieshaber, 2013; Skuta & Parrish, 1987).
  * Tube-Shunt Surgery (Seton glaucoma surgery): Involves small tubes being inserted into the eye to drain away excess fluid and lower eye pressure (Eid & Augsburger, 1997).

<box 30% round | > {{ :wiki:5.png?300 |}} </box|Figure X. Tube shunt (arrow) as seen inside the eye in front of the brown iris (Retrieved from: John Hopkins Medicine)>

===== Future Treatment: Gene Therapy =====
 
There has been a lot of recent research on the use of gene therapy as a means of treating glaucoma. The idea behind gene therapy is to introduce an exogenous gene into a cell in order to modify its activity. Gene therapy is not used to fix defective genes, but to introduce a new gene which down or up-regulates a function of the receiving cell. This is accomplished through the use of inactivated (i.e., they do not express any other activity except the one of the gene of interest and its promoter) vectors (typically, viruses) that are unable to replicate (Fogagnolo & Rossetti, 2011).

In a study conducted by Borrás and colleagues (2001), they investigated the effects on treating the eyes of monkeys with a protein,adenoviral vector expressing rat non-muscle caldesmon fused to green fluorescent protein. After 24-48 hours, trabecular meshwork cells had a change in activity and GFP-caldesmon was hyper-expressed. As a result aqueous humour outflow was increased by 50%. In another study by Borrás and colleagues (2010), they evaluated the effects of an adenoviral vector carrying the gene of metalloproteinase 1 when injected on living sheep before and after the induction of corticosteroids intraocular pressure. Sheep were chosen because they have a high corticosteroid response on intraocular pressure. In sheep with high eye pressure, the injection achieved pressure reductions up to 70% in 24 hours. In eyes with normal pressure, pre-injection protected against the increase in IOP which was induced by the continuous application of the corticosteroid for 5 days.
While the research on gene therapy treatment for glaucoma is growing, and has been investigated with animal models, many important issues such as the long term efficacy and safety of using need to be considered before beginning //in vivo// human studies. 

====== REFERENCES ======

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Bollinger, K. E., Crabb, J. S., Yuan, X., Putliwala, T., Clark, A. F., & Crabb, J. W. (2012). Proteomic similarities in steroid responsiveness in normal and glaucomatous trabecular meshwork cells. //Molecular Vision//, 18, 2001.

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