A Review on Glaucoma: A Contribution to the 2021 World Glaucoma Week

Introduction

Glaucoma, one of the leading causes of blindness in the world, is irreversible. This disease is more common than one can imagine. It is hard to diagnose in the early stages and when caught late leads to irreversible blindness. The symptoms include patchy blind spots on the peripheral vision, severe headache in some cases, blurred vision, eye pain, eye redness. Even with treatment, 15 percent of the people lose eyesight at least in one eye[1].

Glaucoma is caused by the neuropathies of the optic nerve and is caused because of the degeneration of the retinal ganglion cells[2]. These ganglion cells are the neurons that belong to the central nervous system whose cell bodies are present in the inner retina and the axons are present in the optic nerve. When these nerves degenerate, the cupping phenomenon occurs which is a characteristic appearance of the optic disc and visual loss[3].

There are a lot of studies that are focused on understanding the factors that lead to the progression of degeneration. Genetic and genomic-wide studies such as the genome-wide association studies (GWAS) are also being carried out to identify the genes that contribute to glaucoma[4]. Although treatment for glaucoma is not effective in most cases, there are a lot of treatment methods that have proven effective such as surgery, medication as well as gene therapy.

Types of Glaucoma

There are many variants of Glaucoma based on the type of damage to the functional nerves in the eye, and they are broadly classified as:

1. Open-angle glaucoma
2. Angle-Closure glaucoma

The other variants include the:

1. Congenital glaucoma
2. Secondary glaucoma
3. Pigmentary Glaucoma
4. Pseudoexfoliative Glaucoma
5. Traumatic Glaucoma
6. Neovascular Glaucoma
7. IridoCorneal Endothelial Syndrome (ICE)
8. Uveitic Glaucoma

Open-Angle Glaucoma

Open-angle glaucoma is the most common form of glaucoma and it accounts for at least 90% of all glaucoma cases. This is caused due to the sudden buildup of Intraocular pressure. This sudden rise in the pressure is because of the blockage in the drainage canals in the eye. Aqueous humor is produced continuously in the posterior chamber of the eye by the ciliary bodies (Figure 1). This then drains into the anterior chamber of the eye. Trabecular meshwork and uveoscleral pathway are responsible for the drainage of the aqueous humor. Although the drainage angle between the cornea and the iris remains at an open-angle (the angle at which the iris meets the cornea is at the appropriate angle as it should be[5]), the open-angle glaucoma is characterized by increased resistance to drainage through the trabecular meshwork. Because of the resistance, there is a blockage in the drainage canals which in turn results in the increase in Intraocular pressure, leading to the damage of the optic nerve.

Figure 1: Fluid Pathway in open-angle glaucoma. Source: [5]

Angle-Closure Glaucoma

Unlike Open-angle glaucoma, angle-closure glaucoma, as the name suggests is due to the closure of the angle where the iris meets the cornea. Space becomes constricted (i.e convex) as seen in Figure 2. This is linked to two kinds of mechanisms: Pupillary block and angle crowding.

Pupillary block is the most common cause of angle-closure glaucoma, however, it can sometimes co-exist with angle crowding [7].

Pupillary block

The aqueous humor moves from the posterior to the anterior chamber of the eye passing between the iris and the lens through the pupil opening. The baseline pressure for the normal flow of the aqueous humor is 0.23 mmHg [6]. In many cases, due to narrow smaller eyes, the passage gets constricted and thus the fluid gets blocked in the passage. This is known as the pupil block. This brings the iris so close to the trabecular meshwork that it gets pushed against the meshwork, in turn blocking the outflow of the aqueous humor. Thus, the Intraocular pressure increases leading to the damage of the optic nerve.

Angle crowding

The angle crowding is similar to the pupillary block in building the IOP, however, the only difference is that instead of the iris being pushed against the trabecular meshwork, the peripheral iris gets held forward in the trabecular meshwork by the propping up of the anteriorly positioned ciliary processes. This usually happens in smaller eyes and the phenomenon is called the “plateau iris configuration”. Angle crowding happens in a lot of people, however, it is very hard to diagnose.

Figure 2: Fluid Pathway in Angle-Closure Glaucoma. Source: [5]

Diagnosis

In the early stages, Glaucoma does not show any noticeable symptoms. Thus, early diagnosis is often not possible.

As a first step, the physician would check for any medical history and perform comprehensive eye tests before proceeding to the Surgery.

Table 1: Different diagnostic procedures

Tonometry

Tonometry is a procedure used by ophthalmologists to measure Intraocular pressure (IOP). This is done using a calibrated instrument and it assumes that the eye is a closed globe with pressure distributed uniformly throughout the anterior chamber. The normal IOP range is from 10 to 21 millimeters of mercury[9]. The only modifiable risk factor in Glaucoma is Intraocular pressure and this can be achieved by monitoring it using tonometry[10].

Figure 3: Tonometry. Source: [12]

Dilated eye examination & Imaging

When the eye is dilated using certain eye drops, the pupil dilates and thus renders the entire view of the eye to the doctor. The undilated eye makes it difficult to view the entire portion of the eye showcasing the retina and optic nerve as seen in Figure 3.

This method is performed to view the optic nerve and identify any damage caused due to Glaucoma. After the dilation of the eye, the optic nerve is examined using several established imaging techniques.

Figure 4: Dilated vs Undilated Pupil. Source [11].

Figure 5: Visualization of the optic nerve. Source: [2]

Visual Field Test

The common symptom among Glaucoma patients is the appearance of blind spots in the peripheral vision. The visual field test helps the doctor in studying where the side vision (peripheral) begins and ends as well as how well a person can see in their peripheral vision. It also helps in determining if a person has blind spots(also called scotoma) in their vision[13].

Figure 6: Results from Visual Field Test. Normal (Left) and Vision loss (Right). Source: [14]

Pachymetry

The thickness of the cornea is important in determining the IOP (Intraocular Pressure). The corneal thickness can mask the accurate reading of the eye pressure. Thin cornea shows lower IOP readings; which may make the doctor miss an elevated IOP. Whereas thick cornea shows elevated IOP; which leads to misdiagnosis as Glaucoma.

Pachymetry is a simple procedure that helps the physician to determine the corneal thickness and thereby determine the exact IOP level.

Figure 7: Pachymetry being performed on a patient. Source: [15].

Gonioscopy

Gonioscopy is the gold standard to determine if the type of Glaucoma is “open” or “closed”. The test would measure the angle between the iris and cornea, and the angle should be between 20 and 45 for it to be considered “open” such that the aqueous humor can flow from the posterior to the anterior chamber[8].

When the case is for an Angle-Closure Glaucoma due to angle crowding, the double hump sign (known also as the sigma sign) is seen. This kind of sinuous configuration is not seen when there is a pupillary block.

Figure 8: Representation of Gonioscopy as viewed by the ophthalmologist(Top). The Gonioscopy image of the eye as viewed by the ophthalmologist(bottom). Source: [16]

Epidemiology

Glaucoma is the second most leading cause of irreversible blindness in the world. The risk factors leading to this prevalent disease are age, gender, myopia, genetics, smoking, race, systemic hypotension and hypertension, vasospasm, use of systemic or topical steroids, migraine, obstructive sleep apnea syndrome, and most significantly, increased IOP[17].

As of 2020, an estimated population of 57.5 million people is diagnosed with POAG[18]. The prevalence of PACG is lower than POAG, as it affects only 0.17% of individuals who are below 40 years of age and East Asians in particular[19].

A study predicts an increase in the number of people who have glaucoma in the age group 40–80 years, from 76 million in 2020 to 111.8 million by 2040[20].

Figure 9: Age-specific prevalence of Glaucoma in 2018. Source: [17]

Figure 10: Characteristics of Primary Angle-Closure Glaucoma (PACG)& Primary Open Angle Glaucoma(PAOG). Source: [17]

Existing Treatments

The damage due to Glaucoma is irreversible. However, when it is caught early, the further effects and vision loss could be controlled with proper treatments. There are so many methods of treatment available for different types of Glaucoma. The main intent of the majority of the treatments is to lower the Intraocular Pressure. The treatment options include prescription eye drops, oral medications, laser treatments, surgery, or a combination of all of these.

Eye Drops

The treatment is usually initiated with eye drops. These eye drops lower the IOP either by improving how the fluid drains or reducing the fluid production in the eye.

These include:

Table 2: Different prescription eye drops[23][27–30]

The results of a systematic review [21] on the effectiveness of the different eye drops in reducing the IOP levels suggest that the prostaglandins are the most efficacious among all the other medications.

The mean reductions (95% credible intervals) in IOP in mmHg at 3 months, ordered from the most to least effective drugs were: bimatoprost 5·61 (4·94; 6·29), latanoprost 4·85 (4·24; 5·46), travoprost 4·83 (4·12; 5·54), levobunolol 4·51 (3·85; 5·24), tafluprost 4·37 (2·94; 5·83), timolol 3·7 (3·16; 4·24), brimonidine 3·59 (2·89; 4·29), carteolol 3·44 (2·42; 4·46), levobetaxolol 2·56 (1·52; 3·62), apraclonidine 2·52 (0·94; 4·11), dorzolamide 2·49 (1·85; 3·13), brinzolamide 2·42 (1·62; 3·23), betaxolol 2·24 (1·59; 2·88), and unoprostone 1·91 (1·15; 2·67)[21].

Although several studies have shown that prostaglandins are the effective treatment option, it depends on the individual patient's disease characteristics and the physician would recommend treatment accordingly.

Surgery and other therapies

Surgery and laser therapy are done to improve the flow of the fluid; thereby lowering the IOP.

Table 3: Different Glaucoma surgical methods[24][27–30]

A network meta analysis[22] on the effects of medication, laser surgery, non-laser surgery(NLS), laser+medication, and NLS+medication on change in the intraocular pressure in one year period. A total of 122 eyes (90 patients) were provided 197 treatment regimens (33 medication, 56 laser, 33 NLS, 41 laser + medication, and 34 NLS + medication segments). The results showed that NLS demonstrated a larger 1-year IOP reduction compared to medication and laser groups.

The type of surgery is completely dependent on the type of Glaucoma as well as the patient characteristics.

On-going clinical trials

Currently, there are 191 ongoing Clinical Trials worldwide for glaucoma. Clinical trials are an effective way to acquire treatment for rare and hard-to-treat diseases; Glaucoma being the leading cause of irreversible blindness, new and modern approaches keep evolving for its treatment frequently.

A complete list of all the on-going Clinical Trials as of March 2021 can be viewed here.

Figure 11: Map showing the currently active Glaucoma trials (adapted from https://clinicaltrials.gov/ )

Gene Therapy

The topical medications and the surgical procedures are effective treatment options for Glaucoma, but the success rate is very low and the probability of recurrence of the disease is high[25]. Gene therapy provides a very good alternative and a long-term advantage in treating glaucoma. The use of viral vectors to deliver the gene of interest into humans has been growing at a very fast pace. With innovations like CRISPR, the field of gene therapy has seen a revolution in the treatment of various diseases by editing the exact genes that are responsible for the particular disease.

Worldwide, there are around 2356 gene therapy clinical trials that have been completed[25] out of which only 34 are for Ocular Gene therapy. A recent study[26] has identified 127 genes associated with open-angle glaucoma. This opens up whole new opportunities for gene-editing to find long-term solutions to treat Glaucoma.

World Glaucoma Week

World Glaucoma Week is celebrated to create awareness of Glaucoma among people around the world. It is a global initiative by the World Glaucoma Association(WGA). The goal of this event is to alert everyone to have regular eye checkups to detect Glaucoma as early as possible.

Headed by Fabian Lerner (Argentina), President of the World Glaucoma Association, and Ivan Goldberg (Australia), Co-Founder of the World Glaucoma Week, the year 2021, marks a decade of raising awareness on glaucoma through the World Glaucoma Week campaign. With the tagline “The world is bright, save your sight!” and a hashtag #glaucomaweek , this global initiative continues this year too from March 07 to 13, 2021, intending to diagnose glaucoma as early as possible by creating awareness among people.

An interesting part of this is that anyone could take part in this event and submit their activity to get featured on the World Glaucoma Association website (https://www.worldglaucomaweek.org/).

Adapted from the WGW site. https://www.worldglaucomaweek.org/

Author’s Conclusions

The author believes that this article would provide all the information regarding Glaucoma to people who want to understand its types, symptoms, how it occurs, existing treatments, the on-going trials that the patients can enroll in, and the recent trends in gene therapy. With the World Glaucoma Week being celebrated on March 7 to 13 this year, this article intends to reach as many people as possible and create awareness to the readers about the importance of a regular eye check-up, particularly to people with a genetic history.

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