Glaucoma

Glaucoma is an umbrella term for a group of serious eye conditions that include open-angle glaucoma and angle-closure glaucoma (closed-angle glaucoma) caused by increased pressure inside your eye (raised intraocular pressure [IOP]) that damages your eye’s optic nerve (cranial nerve number 2 [CN II]), potentially leading to irreversible vision loss and blindness, and early detection and treatment are essential for preserving your eyesight. Note a glaucoma called “normal tension glaucoma” or normal or low-pressure glaucoma can happen even with normal eye pressure ¹, ², ³. Glaucoma can happen at any age, but is more common in older adults over 60 years of age. Glaucoma is the second-leading cause of blindness worldwide with more than 80 million people have glaucoma worldwide and this number is expected to surpass 110 million by 2040 ⁴, ⁵, ⁶, ⁷, ⁸. Your optic nerve (cranial nerve number 2 [CN II]) sends visual information from your retina at the back of the eyes to your brain and is vital for good vision. The main cause is of glaucoma is often due to fluid buildup from blocked drainage. This increased pressure inside your eye called increased intraocular pressure or IOP damages the optic nerve, which often progresses slowly, causing gradual vision loss, typically starting with peripheral (side) vision ⁸. This is why glaucoma is called the “silent thief of sight”. Because early stages of damage to your eye’s optic nerve often have no symptoms, regular eye exams, especially for those over 40 years of age or with a family history of glaucoma, are important for detecting glaucoma and preventing vision loss. Later stages of damage to your eye’s optic nerve can cause blurred vision, halos around lights, and tunnel vision. While vision loss caused by glaucoma is permanent and cannot be reversed, treatment can slow down or halt further damage by reducing your eye pressure. Glaucoma treatment may include eye drops, laser treatments, or surgery to lower your eye pressure and prevent further damage. If glaucoma is not treated then people with glaucoma will slowly lose their peripheral vision. Over time, central vision may decrease and eventually this can lead to blindness. Furthermore, glaucoma is an inherited condition, so be sure to tell your first-degree relatives (your parent, brother and sister and child) that you have glaucoma so they can have their eyes checked for glaucoma.

In its early stages, glaucoma may not cause any symptoms or have no warning signs. That’s why up to half of the people in the United States with glaucoma may not know they have it. And symptoms may not appear until glaucoma causes irreversible eyesight damage.

Some of the more common glaucoma symptoms include:

• Eye pain or pressure
• Headaches
• Red or bloodshot eyes
• Double vision (diplopia)
• Blurred vision
• Gradually developing low vision
• Gradually developing blind spots (scotomas) or visual field defects like tunnel vision

Some types of glaucoma, particularly angle closure glaucoma, can cause sudden, severe symptoms that need immediate medical attention to prevent permanent vision loss. Emergency glaucoma symptoms include:

• Blood gathering in front of your iris (hyphema)
• Bulging or enlarged eyeballs (buphthalmos = “ox eye”)
• Nausea and vomiting that happen with eye pain/pressure
• Rainbow-colored halos around lights
• Sudden appearance or increase in floaters (myodesopsias)
• Sudden vision loss of any kind
• Suddenly seeing flashing lights (photopsias) in your vision.

It’s important to have regular eye exams that include measurements of your eye pressure. If glaucoma is found early, vision loss can be slowed or prevented. If you have glaucoma, you’ll need treatment or monitoring for the rest of your life.

Figure 1. Eye anatomy

Figure 2. Retinal layers showing retinal ganglion cell

Footnotes: Schematic representation of the retina and the retinal cell layers. (A) Blood supply and (B) structure of the retina. The retina is a layered structure lining the back of the eye consisting of a pigmented layer called retinal pigment epithelium (RPE), and a multilayered neuroretina. The retinal pigment epithelium (RPE) is in close contact with the outer segments of the photosensitive rod and cone cells of the neuroretina. The connecting cilium connects the photoreceptor outer segments with the cell bodies, which constitute a layer known as the outer nuclear layer (ONL). The axons of the photoreceptors synapse with the neuronal (bipolar, amacrine, and horizontal) cells of the inner nuclear layer (INL) via the outer plexiform layer (OPL). The axons of the inner nuclear layer (INL) cells in turn synapse with the ganglion cell layer (GCL) via the inner plexiform layer (IPL). The axons of the ganglion cells converge to form the optic nerve. Approximately 1.2 million nerve fibers, or axons, make up each human optic nerve. A retinal ganglion cell (RGC) is a type of neuron located near the inner surface (ganglion cell layer [GCL]) of the retina of the eye. A retinal ganglion cell (RGC) receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and retina amacrine cells. Retina amacrine cells, particularly narrow field cells, are important for creating functional subunits within the ganglion cell layer and making it so that ganglion cells can observe a small dot moving a small distance. Retinal ganglion cells collectively transmit image-forming and non-image forming visual information from the retina in the form of action potential to several regions in the thalamus, hypothalamus, and mesencephalon, or midbrain. Visual images from the retina travel through the optic nerve, optic tract, and eventually to the visual part of the brain (the occipital lobe). There the images are processed and interpreted by the brain. Any disease process which affects the optic nerve could disrupt this input, leading to visual loss.

Abbreviations: ILM: internal limiting membrane, NFL: nerve fiber layer, GCL: ganglion cell layer, IPL: inner plexiform layer, INL: inner nuclear layer, OPL: outer plexiform layer, ONL: outer nuclear layer, ELM: external limiting membrane, OS: photoreceptor outer segment, RPE: retinal pigment epithelium

Can glaucoma be reversed?

Glaucoma eyesight damage is permanent and it cannot be reversed. But medicine and surgery can help to stop further damage. To treat glaucoma, your ophthalmologist may use one or more of the following treatments.

• Medications. Glaucoma medications lower pressure inside your eye in different ways. Some of them cause your pupil to relax more, improving aqueous humor drainage. Others slow the production of aqueous humor.
• Glaucoma surgery. This approach usually aims to improve fluid flow and drainage. Examples of glaucoma surgeries that do this include laser trabeculoplasty, laser iridotomy, trabeculectomy (glaucoma filtration surgery), drainage tubes and minimally invasive glaucoma surgery (MIGS).

Aqueous Humor Production and Physiology

The aqueous humor is a water-like fluid that is produced by the ciliary body that sits directly behind the iris (the colored part of your eye). Aqueous humor is produced at a rate of 2-3 microliters per minute (2-3 μL/minute) ¹⁰, ¹¹. The aqueous humor is composed of organic and inorganic ions, carbon dioxide, amino acids, carbohydrates, glutathione, and water ¹⁰, ¹². The aqueous humor fills the anterior chamber of your eye with continual production, secretion, and reabsorption ¹⁰. The cornea and the lens of your eye have no blood supply. They receive nourishment from nutrients in the aqueous fluid that fills your eye. The aqueous fluid flows between the iris and lens through the pupil and to the drainage angle at the junction of the iris and the cornea. Aqueous fluid exits the eye through a tissue called the trabecular meshwork in the drainage angle. As the aqueous fluid passes through the eye, it supplies the lens and cornea with nutrients and carries away waste products. The production, circulation and reabsorption of aqueous humor are vital processes maintaining homeostasis of the eye. The pressure of the fluid in your eye called the intraocular pressure (IOP) is determined by the amount of aqueous humor fluid entering the eye through the ciliary body and exiting the eye through the trabecular meshwork. In most people, the balance between the aqueous humor fluid coming in and going out of the eye results in an eye pressure between 10 and 21 mm of Hg. In patients with glaucoma, aqueous humor fluid drains from the eye through the trabecular meshwork at a slower rate causing the pressure in your eye to rise or increased intraocular pressure (ocular hypertension) resulting in optic nerve damage and glaucoma.

Aqueous humor functions as a physical component allowing clear optics and filling the anterior chamber of the eye ¹⁰, ¹¹. The aqueous humor is responsible for providing nourishment to the avascular components of the anterior chamber including the cornea and lens ¹⁰, ¹¹. In addition, aqueous humor is responsible for removing waste products, blood, macrophages and other debris from the anterior chamber, including the trabecular meshwork ¹⁰, ¹¹. The structure and function of the trabecular meshwork may become compromised by chronic oxidative stress from reactive oxygen species and insufficient antioxidant defense in the aqueous humor ¹⁰, ¹¹, ¹³, ¹⁴. Decreased levels of antioxidants in aqueous humor are present in glaucomatous eyes versus normal eyes, consistent with the presence of increased oxidative stress and low-grade inflammation ¹³, ¹⁴.

The primary anatomic structures vital to the homeostasis of aqueous humor include the ciliary body as the site of principle production, and the trabecular meshwork and uveoscleral pathway as the sites of primary outflow ¹⁰, ¹⁵. Aqueous humor is produced by the ciliary body via a multistep process closely correlating with systemic vascular blood flow ¹⁰, ¹⁶, ¹⁷. Initially, blood enters the ciliary processes, which propels ultrafiltrate from the blood into the ciliary interstitial space via a pressure gradient ¹⁰, ¹⁶, ¹⁷. Next, the ciliary epithelium transports plasma components from the basal to the apical surface in order to synthesize aqueous humor and transport it into the posterior chamber ¹⁰, ¹⁶, ¹⁷. Passive diffusion and ultrafiltration are key in initial synthesis, and active secretion across a blood-aqueous barrier via aquaporins, Na-K-ATPase and carbonic anhydrase enzymes are necessary for final synthesis ¹⁰, ¹⁶, ¹⁷, ¹⁸. These active transport enzymes necessary for final synthesis are common pharmacologic targets in decreasing aqueous humor production. Although systemic blood flow via the ciliary artery is required for the initial production of ultrafiltrate, the production of aqueous humor is independent from systemic blood pressure due to a fixed rate of 4% filtration of plasma ¹⁷. Therefore, there is minimal association between systemic high blood pressure (hypertension) and elevated intraocular pressure (IOP). The estimated rate of aqueous humor production is approximately 2.4 microliters per minute (2.4 μL/minute), with diurnal variations leading to higher aqueous humor flow in the morning and lower flow in the evening ¹⁰, ¹⁶.

While aqueous humor production is well documented, the mechanism of drainage is still poorly understood.

There are 2 main drainage pathways for aqueous humor ¹⁰, ¹⁹, ¹⁶:

1. The conventional pathway via trabecular meshwork, Schlemm’s canal, collector channels, and the episcleral venous system), and
2. The unconventional pathway via uveoscleral, uveovortex, uveolymphatic.

The conventional pathway drainage pathways for aqueous humor involves passive drainage throughout the trabecular meshwork although the Schlemm’s canal has been documented with paracellular and intracellular pores ¹⁰, ¹⁹, ¹⁶. The trabecular meshwork is a triangular porous structure composed of a layer of connective tissue and endothelium with sympathetic innervation from superior sympathetic ganglion, and parasympathetic innervation from the ciliary ganglion ¹⁰, ¹⁹, ¹⁶. The trabecular meshwork may be divided into the uveal meshwork (iris root, ciliary body, peripheral cornea), corneoscleral meshwork (scleral spur), and juxtacanalicular meshwork (transition into Schlemm’s canal) ¹⁰, ¹⁹, ¹⁶. Schlemm’s canal is a structure with composition similar to venous vasculature, with fenestrated thin endothelium surrounded by connective tissue ¹⁰, ¹⁹, ¹⁶. After drainage through the trabecular meshwork and the Schlemm’s canal, aqueous humor continues through collector channels into the episcleral venous system which deposits into the main venous system ¹⁰, ¹⁹, ¹⁶.

Resistance to outflow through the trabecular meshwork and Schlemm’s canal has been documented although it is poorly understood, yet resistance remains an important factor in regulating intraocular pressure and the pathogenesis of glaucomatous processes. In humans, up to 75% of aqueous outflow resistance is contributed by the trabecular meshwork while the remaining 25% is due to resistance beyond Schlemm’s canal ¹⁰. The rate of outflow is directly influenced by iris and ciliary muscles which contract and relax based on cholinergic innervation and pharmacodynamics ¹⁰, ¹⁹, ¹⁶, ¹⁵, ²⁰. In ciliary contraction, the trabecular meshwork and Schlemm’s canal dilate, decreasing resistance and increasing outflow ¹⁰, ¹⁹, ¹⁶, ¹⁵, ²⁰. The rate of outflow is also influenced by intraocular pressure, with higher intraocular pressure altering the structure of endothelial lining in Schlemm’s canal to increase the number of porous vacuoles allowing increased outflow ¹⁰, ¹⁹, ¹⁶, ¹⁵, ²⁰. However, it is still debated if this finding substantially contributes to increasing outflow in glaucomatous eyes ¹⁰, ¹⁹, ¹⁶, ¹⁵, ²⁰.

The unconventional pathway involves drainage into the orbital vasculature, vortex veins and ciliary lymphatics, contributing up to 25-40% of total aqueous outflow in cynomolgus and vervet monkey models. The uveoscleral pathway involves diffusion into the sclera and episcleral through the orbital vasculature. The uveovortex pathway involves osmotic absorption of fluid through the choroid, passing into the vortex veins ¹⁹. Lastly, the uveolymphatic pathway involves drainage into lymphatic vessels within the ciliary body, although the extent of drainage under normal physiological conditions remains controversial ¹⁹. In addition, the unconventional pathway also includes corneal, iridial and retinal routes, albeit less clinically significant ²¹. Regardless of downflow pathway, all unconventional paths require drainage through the interstitial spaces of the ciliary muscle ¹⁹, ²¹. Resistance also exists within the unconventional pathway likely due to ciliary muscle tone, as seen with changes in outflow in the setting of pilocarpine, increasing ciliary tone and decreasing flow, and atropine, decreasing ciliary tone and increasing flow ¹⁹, ²¹. Therefore, the unconventional pathways are also clinically important in moderating intraocular pressure, and serve as a potential target in glaucoma therapy.

Figure 3. Normal aqueous outflow

Footnotes: The ciliary body is a structure that sits directly behind the iris (the colored part of your eye). One of ciliary body’s jobs is to create an important fluid called aqueous humor, a fluid that nourishes the cornea and lens. Aqueous humor flows through a specific route into the front of the eye (the anterior chamber). This route allows aqueous humor to send important nutrients and oxygen to other parts of the eye, such as the lens and cornea. The aqueous humor is produced behind the iris, flows into the anterior chamber through the pupil, and exits the eye between the iris and cornea via the trabecular meshwork, a specialized eye tissue located at the chamber angle of the eye next to the cornea ²². In a healthy eye, this is a constant process. The ciliary body is always producing aqueous humor, and 80%-90% aqueous humor is always draining through the trabecular meshwork. The trabecular meshwork is a specialized spongy tissue in the anterior chamber of the eye that regulates the outflow of aqueous humor ²². The trabecular meshwork acts as a filter, controlling how quickly aqueous humor drains out of the eye through a structure called Schlemm’s canal, ultimately maintaining intraocular pressure (IOP). The canal of Schlemm, also known as Schlemm’s canal or the scleral venous sinus, is a circular, lymphatic-like vessel in the eye that drains aqueous humor from the anterior chamber into the episcleral blood vessels. The canal of Schlemm and the trabecular meshwork (TM) play a crucial role in maintaining intraocular pressure (IOP) by facilitating the outflow of aqueous humor. Too much aqueous humor production or obstruction of its outflow causes a rise in intraocular pressure (IOP) that can lead to glaucoma.

Glaucoma types

There are many different types of glaucoma. However, most glaucomas can be divided into 2 categories ²⁴:

• Open-angle glaucoma: “Open-angle” means that the drainage angle, where the inside of the sclera (the white of your eye) and the outer edge of your iris meet, is open wide. Aqueous humor flows into the drainage angle so it can drain out of the anterior chamber. But other parts of the drainage system don’t drain properly like a clogged drain. This may lead to a slow, gradual increase in eye pressure that starts to damage the optic nerve. Open-angle glaucoma is the most common form of glaucoma. In the United States, open-angle glaucoma is what most people mean when they talk about glaucoma ²⁵. Open-angle glaucoma is painless and causes no vision changes at first.
• Closed-angle glaucoma, also called angle-closure glaucoma or narrow-angle glaucoma, where the drain of the eye is partially or fully obstructed or “closed” by the bulging iris. The bulging iris partially or completely blocks the drainage angle. You can think of it like a piece of paper sliding over a sink drain. As a result, fluid (aqueous humor) can’t circulate through the eye and pressure increases. Angle-closure glaucoma is a uncommon type of glaucoma and usually affects one eye at a time. Angle-closure glaucoma may happen suddenly or gradually. There are 2 main types of closed-angle glaucoma:
  • Acute closed-angle glaucoma is a medical emergency. No fluid can drain out of your eye, so eye pressure increases suddenly. This causes eye pain, blurry vision, and other symptoms. Without prompt treatment, acute angle-closure glaucoma can cause blindness in a few days.
    • Here are the signs of an acute angle-closure glaucoma attack:
      • Your vision is suddenly blurry
      • You have severe eye pain
      • You have a headache
      • You feel sick to your stomach (nausea)
      • You throw up (vomit)
      • You see rainbow-colored rings or halos around lights
  • Chronic closed-angle glaucoma develops slowly over time. You may not have any symptoms at first. Or you may have symptoms such as eye discomfort, blurry vision, redness, or headaches. The symptoms often get better with sleep. Without treatment, vision loss develops slowly.

Within these categories there are different variants of open angle and angle-closure glaucoma which can be classified according to cause:

• Primary glaucomas: No known cause, occurs in susceptible individuals.
• Secondary glaucomas: Secondary glaucoma is when another condition or problem within the eye increases eye pressure such as eye injury, eye surgery or eye procedures, certain medications especially corticosteroids and cycloplegics or other eye diseases (e.g., pigmentary dispersion syndrome, uveitis) causing the glaucoma. This is when another condition or event increases eye pressure, which leads to glaucoma.
• The two most common types of glaucoma are Primary Open Angle Glaucoma (POAG) and Primary Angle-Closure Glaucoma (PACG).

Childhood glaucoma also known as infantile glaucoma or congenital glaucoma. Childhood glaucoma is a rare glaucoma where high pressure builds up inside the eye during fetal development, potentially causing vision loss and even blindness if left untreated. Childhood glaucoma is typically diagnosed within the first few months of life commonly in children under 2 years of age and is caused by a developmental defect in the eye’s drainage system, preventing fluid from flowing out properly. Childhood glaucoma affects about 1 in 10,000 children under 2 years of age in the United States ²⁶, ²⁷. Childhood glaucoma can be caused by aniridia (a rare genetic eye disorder characterized by the complete or partial absence of the iris, the colored part of the eye), Axenfeld-Rieger syndrome, Marfan syndrome, congenital rubella syndrome and neurofibromatosis type 1. In most cases, childhood glaucoma is diagnosed by the age of six months, with 80% diagnosed in the first year of life.

Eye specialist (ophthalmologist) may also refer to someone as a “glaucoma suspect” if they think the person might be showing early signs of glaucoma but they are not yet sure. Many people suspected of having glaucoma at this stage turn out not to have it at all, but some do develop it in time and it is these people who can benefit the most from timely treatment.

Ocular hypertension is diagnosed in individuals with intraocular pressure (IOP) levels exceeding 21 mmHg without signs of glaucomatous optic neuropathy or functional visual field defects ²⁸. Research indicates that around 20% of people with ocular hypertension may progress to glaucoma, highlighting the importance of regular testing, tonometry, and comprehensive eye examinations to initiate appropriate treatment aimed at reducing intraocular pressure (IOP) in the presence of initial glaucomatous damage ²⁹

Figure 4. Glaucoma types

Glaucoma Suspect

Eye specialist (ophthalmologist) will refer to someone as a “glaucoma suspect” if they think the person might be showing early signs of glaucoma such as higher than normal eye pressure called ocular hypertension but have no signs of optic nerve damage. Glaucoma suspects have no symptoms to suggest eye disease. They are usually identified as glaucoma suspects during routine checks by their optometrist. Many people suspected of having glaucoma at this stage turn out not to have it at all, but some do develop it in time and it is these people who can benefit the most from timely treatment. Their ophthalmologist (eye specialist) may notice something different about their optic nerve. Most “glaucoma suspects” have no symptoms. That is why you need to be carefully monitored by your ophthalmologist if you are a glaucoma suspect. An ophthalmologist can check for any changes over time and begin treatment if needed.

If someone has a very high intraocular pressure (high IOP) or very advanced optic nerve damage then the diagnosis of glaucoma is usually straightforward. However sometimes it is not entirely clear whether someone has glaucoma or not. The early signs of glaucoma can be subtle, and many glaucoma patients have a normal pressure.

There is no single test that is 100% effective in confirming the diagnosis of glaucoma all the time. Sometimes the only way to be sure that someone has glaucoma is to arrange follow up eye examinations every 4-6 months or so to work out whether progressive damage is occurring to the optic nerve in one or both eyes. Features in the examination which might lead to a patient being classified as a ‘glaucoma suspect’ include:

• A high pressure within the eyeball (high IOP) but with no optic nerve damage yet this is also referred to as ocular hypertension.
• A ‘suspicious’ optic disc appearance on examination such as ‘cupping’ of the disc or thinning of the neuro-retinal rim or nerve fiber layers.
• Unusual or defective visual fields.

These are changes that can be seen with glaucoma, but can also be seen in other conditions such as farsightedness (myopia) where it may be a variation of normal.

Other risk factors for glaucoma such as a strong family history of glaucoma but without definite changes to the optic nerve as yet. Generally speaking, “glaucoma suspects” will not show any visual field defects on testing, or may show some field defects which are not yet entirely convincing as evidence of glaucoma. If you are a ‘glaucoma suspect’, the most important treatment is good follow-up care.

It is very important that someone suspected of experiencing the early onset of glaucoma has regular eye checks to make sure there is no continuing damage to the optic nerve. Even though a person is not yet receiving any treatment for glaucoma, she or he may still risk losing their vision if in fact they do turn out to have glaucoma. Thus it is very important to maintain follow-up care. Typically for a low-risk glaucoma suspect, this may require visits every 6 to 12 months. At each follow-up visit your eye doctor will check your vision and eye pressure, and examine the front and back of your eye, paying careful attention to the appearance of your optic nerves.

To examine the structure of the optic nerve, your doctor will perform a careful examination in the office, obtain optic nerve imaging, and obtain a baseline set of optic nerve photographs. To examine the function of the optic nerve, an automated visual field test we be implemented with the help of a technician, who will instruct you on the correct way to perform the test. All of these tests may be repeated at yearly intervals (or more or less frequently, as determined by your eye doctor) to assess if there are changes or “progression” over time. The follow-up visits are crucial to maintaining optimal eye health.

Sometimes eye doctors are on the fence about whether to start treatment, and it is only through repeat follow-up visits that they get a sense of whether or not someone has glaucoma. Usually a person thought to be a “glaucoma suspect” will not be treated for the condition until the diagnosis is confirmed. Typically, glaucoma advances slowly so its progress can be tracked safely without treatment until the diagnosis is confirmed.

If you’re a “glaucoma suspect” and needed treatment, initial treatment options may include topical eye drops or laser treatment of the drainage angle to increase the amount of fluid draining from the eye, both of which can lower the eye pressure. The decision to treat is often not a cut-and-dry one; your ophthalmologist will assess all of your risk factors, your examination findings, and seek your input as to whether to treat or continue to observe your eyes over time. Some patients prefer to “watch and wait” or are worried about the side effects of treatment, while others may be more risk-averse and would rather begin treatment and have peace of mind. There are some glaucoma risk calculators available but most eye doctors would agree that these may aid in diagnosis and assessment, but will not replace your doctor’s clinical judgment.

Normal Tension Glaucoma

Normal tension glaucoma (NTG), also known as normal or low-pressure glaucoma, is a type of primary open-angle glaucoma (POAG) where the optic nerve damage and vision loss characteristic of glaucoma occur despite eye pressure (intraocular pressure [IOP]) remaining within the normal range and an open, normal appearing anterior chamber angle ¹, ³¹, ², ³, ³², ³³. The definitions of normal tension glaucoma (NTG), however, may vary slightly amongst different countries. The European Glaucoma Society Guidelines, published in 2021 ³⁴, state that “normal tension glaucoma is a specific type of POAG characterized by glaucomatous optic nerve head damage and corresponding visual field defects in patients with IOP consistently less than 21 mmHg”. The Preferred Practice Pattern Guidelines published in 2021 by the American Academy of Ophthalmology ³⁵ define the normal tension glaucoma as “a common form of POAG, i.e., a chronic, progressive optic neuropathy that results in a characteristic optic nerve head cupping, retinal nerve fiber layer thinning and functional visual field loss, in which there is no measured elevation of the IOP”. In 2015, the Canadian Ophthalmological Society Guidelines ³⁶ reported normal tension glaucoma as “a subgroup of POAG with characteristic visual field defects and glaucomatous optic nerve head changes in patients having normal IOP levels less than 21 mmHg”. The Asia-Pacific Glaucoma Guidelines, published in 2016 ³⁷, reported that “the normal tension glaucoma is a condition in which the typical glaucomatous progressive optic nerve damage and visual field loss occur although the intraocular pressure remains normal”. The Japanese Glaucoma Society published guidelines in 2023 ³⁸, which defined normal tension glaucoma as “a subtype of POAG in which the IOP always remains within the statistically determined normal range during the developmental process of glaucomatous optic neuropathy (GON)”.

Normal eye pressure is 10 to 21 mmHg and approximately 95% of general population will have an intraocular pressure (IOP) between 11 and 21 mmHg ³⁹. A cut-off of 21 mmHg intraocular pressure (IOP) is often applied to define normal tension glaucoma ¹. One of the main risk factors for the development of glaucoma is the increased intraocular pressure (the pressure within your eyeball is higher than normal). The higher the intraocular pressure (IOP), the more likely glaucoma is to develop. However this is not the only risk factor for glaucoma. It is also widely recognized that in about 1/3rd of cases of glaucoma the characteristic optic nerve changes and visual field loss can develop in an eye with normal pressure – this is termed normal tension glaucoma. Unlike the typical glaucoma, where high intraocular pressure (increased IOP) is the primary cause, normal tension glaucoma is often linked to other factors, such as blood flow issues to the optic nerve. Normal-tension glaucoma can also lead to vision loss and blindness. Drance and colleagues ⁴⁰ described two forms of normal tension glaucoma: 1) a non-progressive form typically associated with a transient episode of vascular compromise, and 2) a progressive form thought to result from a chronic vascular insufficiency at the optic nerve. While some try to delineate normal tension glaucoma and primary open angle glaucoma (POAG) as two completely unique disease processes, it has also been suggested that the diseases exist on a continuum with intraocular pressure (IOP) playing a larger role in primary open angle glaucoma (POAG), and vascular or mechanical factors at the etiologic root in normal tension glaucoma ⁴¹.

The histopathological changes in normal tension glaucoma are the same as those found in primary open angle glaucoma (POAG), namely loss of retinal ganglion cell axons (retinal nerve fiber layer – RNFL) and glial tissue at the optic nerve head, leading to optic disc excavation and cupping ⁴². Typically, retinal nerve fiber layer loss is more common in the supero- and inferotemporal neuroretinal bundles, leading to notches, but loss may also be global and concentric ¹. Classically, the presence of small flame shaped optic disc hemorrhages also known as Drance hemorrhages, has been associated with normal tension glaucoma though this finding can be observed in any form of primary open angle glaucoma (POAG) (see Figure 2). Optic disc hemorrhages or Drance hemorrhages are splinter or flame-shaped hemorrhages oriented perpendicular to the optic disc margin ⁴³, ⁴⁴, ⁴⁵, ⁴⁶. Classically, Drance hemorrhages are located in the prelaminar optic disc, cross the peripapillary zone, and extend into the adjacent superficial retinal nerve fiber layer, although they may not occupy the entire length from disc to retina ⁴³, ⁴⁴, ⁴⁵. Alternately, deeper disc hemorrhages may appear round and blotchy ⁴³. Less commonly, a optic disc hemorrhage may be noted in the peripapillary retinal nerve fiber layer reaching within one disc diameter of the optic disc margin ⁴⁶. Additional research is needed to determine exactly why optic disc hemorrhages or Drance hemorrhages occur and to clarify why only some glaucoma patients develop optic disc hemorrhages ⁴⁷. Drance hemorrhages and temporal retinal nerve fiber layer defects with localized, deep paracentral scotomas, more often in the superior hemifield are more common in normal tension glaucoma than in primary open angle glaucoma (POAG) ⁴⁸, ⁴⁹. Anderson et al ⁵⁰ reported the presence of optic disc hemorrhages at the time of diagnosis of normal tension glaucoma as an unfavorable prognostic marker for likely visual field progression.

A recent cross-sectional study aimed to further describe a potential link between the incidence of normal tension glaucoma in patients with dementia ⁵¹. The study demonstrated an association between normal tension glaucoma status and poor cognition (measured with the Telephone Version of the Montreal Cognitive Assessment, T-MoCA) thereby concluding that there exists a disease association and shared features between normal tension glaucoma and dementia when compared to those with high tension glaucoma (HTG) ⁵¹. Conversely, a recent study demonstrated that persons with normal tension glaucoma had increased risk for developing vascular dementia, with particular increased risk when diagnosed with glaucoma at ages >70 ⁵².

While the exact prevalence of normal tension glaucoma can vary by geographic region, normal tension glaucoma is estimated to comprise a significant proportion of all glaucoma cases, with some studies suggesting it may account for up to 30-40% of all glaucoma patients amongst Caucasians or Africans ⁵³, ³¹. Whereas, for unclear reasons, the proportion of normal tension glaucoma amongst primary open angle glaucoma (POAG) in Asian populations was reported as high as 92.3% in Japan (the Tajimi Study), 84.6% in Singapore (the Singapore Malay Eye Study), 83.58% in northern China (the Handan Eye Study), 82% in south India (the Chennai Glaucoma Study), 79.6% in southern China (the Liwan Eye Study), 77% in South Korea (the Namii Study), yet only 31.7% in the United states of America (the Beaver Dam Eye Study) demonstrating that there is a predilection for those of Asian descent ⁵⁴, ⁵⁵. Current research tackles the disparity demonstrated by the aforementioned data, suggesting that other factors/predispositions within specific ethnic groups may be playing a significant role in the pathogenesis of normal tension glaucoma.

The therapeutic approaches to normal tension glaucoma are still strongly debated. Intraocular pressure (IOP)-lowering treatment management should be tailored specifically to each patient. Treatment may need to be changed as the disease progresses or a patient’s response to medicine changes. Considering that large prospective, multicenter, randomized and controlled clinical trials such as the Collaborative Normal-Tension Glaucoma Study (CNTGS) and the Early Manifest Glaucoma Trial (EMGT) have demonstrated that an intraocular pressure (IOP) reduction of at least 25–30% from baseline values is effective in delaying the progression of the visual field damage in a high percentage of normal tension glaucoma patients ⁵⁶, ⁵⁷. It is thus important to note that despite the fact that individuals with normal tension glaucoma have by definition normal intraocular pressure (IOP) levels, lowering the intraocular pressure (IOP) remains the gold standard in the normal tension glaucoma treatment ⁵⁸, ⁵⁹, ⁶⁰.

Many different ocular hypotensive drugs are available on the market: prostaglandin and prostamide analogs, beta-blockers, alpha agonists and carbonic anhydrase inhibitors are examples of topical glaucoma drugs that are frequently used to reduce intraocular pressure (IOP), taken both as topical single therapy or in combination. Prostaglandins and prostamide analogs are the most safe and effective intraocular pressure (IOP)-lowering medications and represent the first choice in normal tension glaucoma therapy ⁵⁹, ⁶¹, ⁶², ⁶³.

The use of local and systemic beta-blockers and oral calcium channel blockers, especially in the evening, is of particular concern in normal tension glaucoma patients, because they may induce severe nocturnal systemic hypotension, with subsequent ocular perfusion pressure drop ⁶⁴, ⁶¹, ⁶⁵, ⁶⁶, which is considered one of the most important risk factors for normal tension glaucoma onset and progression ⁶⁷, ⁶⁸.

Besides providing an intraocular pressure (IOP)-lowering effect, some ocular hypotensive drugs have also shown the ability to increase the optic nerve head blood flow (latanoprost, bimatoprost, betaxolol, carteolol, levobunolol, carvedilol and nebivolol) or neuroprotective properties (brimonidine, betaxolol, carteolol, carvedilol, latanoprost, bimatoprost and tafluprost) ⁶⁹, ⁷⁰, ⁷¹, ⁷², ⁷³, ⁷⁴, ⁶³. These adjunctive (add-on) properties could be particularly useful in treating normal tension glaucoma patients. Moreover, the confirmation of the ability of the novel beta-blockers, carvedilol and nebivolol, to reduce intraocular pressure (IOP) and increase the ocular blood flow in clinical trials in glaucomatous patients may lead to the development of new glaucoma therapies.

For optimal management of normal tension glaucoma, regular monitoring of intraocular pressure (IOP), visual field and optic nerve head by eye care specialists is important. Moreover, performing diurnal intraocular pressure (IOP) curves and addressing intraocular pressure (IOP) peaks are considered to be the most important therapeutic strategies in normal tension glaucoma patients with normal office intraocular pressure (IOP) values ⁶⁷, ⁵⁹.

Considering that normal tension glaucoma patients have, by definition, a baseline intraocular pressure (IOP) within the statistically normal range, it is often difficult to reduce the intraocular pressure (IOP) values with medications alone, so non-medical options are often used, including laser and surgical treatments ⁵⁹. The Collaborative Normal-Tension Glaucoma Study (CNTGS) ⁵⁶ showed that 57% of the patients achieved a 30% intraocular pressure (IOP) reduction with topical medications, laser trabeculoplasty or both; the remaining 43% required filtering surgery, which remains the most proven option in the treatment of normal tension glaucoma patients when medications or laser treatments are unable to stop the visual field and/or optic nerve head damage progression ⁵⁹, ⁷⁵.

Figure 5. Drance hemorrhage (optic disc hemorrhage)

Footnotes: Optic disc hemorrhage or Drance hemorrhage indicating inadequate intraocular pressure control in a patient with normal tension glaucoma. Disc hemorrhages are more common in normal tension glaucoma than in primary open angle glaucoma (POAG). This patient also has peripapillary atrophy, visible as a pale ring around the optic nerve.

Figure 6. Normal tension glaucoma optic disc photographs

Footnotes: Normal tension glaucoma optic disc photographs. (A) Right and (B) Left eye in a patient with normal tension glaucoma. Note the focal superotemporal thinning and associated dropout of the retinal nerve fiber layer. The corresponding visual field defects are seen in Figure 7 below.

Figure 7. Normal tension glaucoma visual fields

Footnotes: Standard automated perimetry of (A) Left and (B) Right eye in a patient with normal tension glaucoma. Note the dense inferior arcuate scotomas occurring near fixation with minimal involvement of periphery. The corresponding optic disc photographs are seen in Figure 6 above.

Normal tension glaucoma causes

The cause and mechanism for the development of normal tension glaucoma is unknown and remains an area of active research and debate. Several theories have been proposed to explain the onset and progression of normal tension glaucoma (NTG). Whereas intraocular pressure (IOP) is the main driver of progressive visual loss in most patients with primary open angle glaucoma (POAG), normal tension glaucoma (NTG) likely represents a diverse and multifactorial group of causes with a common final pathway of retinal ganglion cell loss ¹. Despite intraocular pressure (IOP) in the normal range of 10 to 21 mmHg, there is evidence that an intraocular pressure (IOP)-dependent mechanism plays a role in the cause in many eyes with normal tension glaucoma ⁷⁷, ⁷⁸. Proposed intraocular pressure (IOP)-independent mechanisms include vascular insufficiency (lower blood pressure or reduced ocular blood flow) at the optic nerve head, impaired cerebrospinal fluid (CSF) circulation resulting in low retrobulbar cerebrospinal fluid pressure causing stagnation and decreased optic nerve protection, failure of the glymphatic system in the optic nerve, metabolic and neurodegenerative disorders, oxidative stress, and structural anomalies including structural weakness of the lamina cribrosa ⁷⁹, ⁸⁰, ⁸¹, ⁸², ⁸³, ⁵⁴. All of these mechanisms need further research to better define the pathophysiology of the disease process ⁴¹.

It has been theorized that the disease process in normal tension glaucoma results from an enhanced sensitivity to what would otherwise be physiologic intraocular pressure (IOP), resulting in glaucomatous damage of the optic nerve. This enhanced sensitivity may be due to impaired optic nerve blood flow, a higher translaminar pressure gradient (intraocular pressure [IOP] minus intracranial pressure [ICP]) due to lower intracranial pressure (ICP), or a structurally abnormal lamina cribrosa, which cannot withstand a normal range of intraocular pressure (IOP) ⁴¹. This theory of enhanced sensitivity is useful, at least conceptually, to rationalize the impact of intraocular pressure (IOP) in a disease process that may have an intraocular pressure (IOP) independent underlying etiology ⁴¹. The evidence for a role of IOP contributing to normal tension glaucoma comes from the Collaborative Normal Tension Glaucoma Study, which showed a slowing of disease progression in patients achieving a 30% or more reduction of already normal intraocular pressure (IOP) ⁷⁷, ⁸⁴. While some try to delineate normal tension glaucoma and primary open angle glaucoma (POAG) as two completely unique disease processes, it has also been suggested that the diseases exist on a continuum with IOP playing a larger role in primary open angle glaucoma (POAG), and vascular or mechanical factors at the etiologic root in normal tension glaucoma ⁴¹.

Specific histological studies of eyes with normal tension glaucoma are scarse but in general mimic those changes seen in primary open angle glaucoma (POAG) ⁴¹. Histopathologic changes of the optic nerve head include disarrangement and posterior bowing of the lamina cribrosa along with loss of nerve fibers ⁸⁵. Non-invasive imaging by OCT and scanning laser modalities have characterized thinning of the peripapillary choroid ⁸⁶, as well as thinning of the ganglion cell layers in normal tension glaucoma patients compared to other primary open angle glaucoma (POAG) and normal patients ⁸⁷. In Asian patients this thinning has been correlated with vascular narrowing in asymmetric normal tension glaucoma when compared to normal fellow eyes and primary open angle glaucoma (POAG) patients with elevated pressures ⁸⁸, ⁸⁹, ⁹⁰.

Genetics is also known to play a role in normal tension glaucoma, because of the strong association with family history with 21% of patients reporting a family history of glaucoma and variation in prevalence in different ethnicities that persists after migration ¹. Four major genes have been implicated in normal tension glaucoma: optineurin (OPTN), TANK binding kinase 1 (TBK1), methyltransferase-like 23 (METTL23), and myocilin (MYOC) ⁸². Optineurin (OPTN) gene mutations, particularly the E50K variant, have been strongly associated with normal tension glaucoma, causing early-onset disease, large cup-to-disc ratios, and retinal ganglion cell death ⁴¹. TANK binding kinase 1 (TBK1) copy number variations have also been linked to normal tension glaucoma, with duplications and triplications contributing to retinal ganglion cell (RGC) loss ⁴¹. Methyltransferase-like 23 (METTL23) gene mutations were recently identified in familial normal tension glaucoma cases, with evidence suggesting that these mutations impact histone arginine methylation, potentially leading to retinal ganglion cell (RGC) degeneration ⁴¹. Myocilin (MYOC) gene commonly associated with primary open angle glaucoma (POAG) has been implicated in some normal tension glaucoma cases, though its role remains less clear ⁴¹. Further genetic research is certainly needed to better understand the role of these genes in normal tension glaucoma ⁸².

Genes associated with normal tension glaucoma ¹, ⁸²:

• Optineurin (OPTN)
• TANK binding kinase (TBK1)
• Methyltransferase-like 23 (METTL23)
• Myocilin (MYOC)

Normal tension glaucoma is typically not considered to be a heritable disease, as approximately 2% of normal tension glaucoma cases are caused primarily by a mutation of a single gene and found to be transmitted by an autosomal dominant inheritance pattern ⁴¹. Nevertheless, individuals who carry one of the many autosomal dominant gene mutations may present with symptoms of normal tension glaucoma as early as 23 years old ⁹¹. Genetic and pedigree studies continue to further identify numerous new genes associated with the development of normal tension glaucoma, but further studies that demonstrate a higher incidence of disease are necessary before a clinical indication for genetic screening and counseling can be recommended ⁴¹.

Though the quantity of axons that compose optic nerves in humans remains a predictable constant between individuals, variability in surface area of optic discs is observed. It is unclear if certain optic nerve head parameters place an eye at increased risk of normal tension glaucoma ⁴¹. Optic nerves with a larger surface area and with thinner inferior/inferotemporal rims have been reported to be at an increased risk for developing normal tension glaucoma ⁹², ⁹³. Other studies evaluating the optic nerve head by scanning laser ophthalmoscopy found no morphologic differences between high-tension and normal tension glaucoma patients ⁹⁴.

Frequently an area of peripapillary atrophy in a crescent or halo configuration is observed in patients with normal tension glaucoma. While this pattern of atrophy can be a finding in eyes without normal tension glaucoma, in glaucomatous eyes, peripapillary atrophy often occurs adjacent to areas of greatest disc thinning and corresponding visual field loss ⁹⁵. While thinning of the optic nerve rim is observed in all primary open angle glaucoma (POAG), focal thinning or ‘notching’ is more commonly observed in normal tension glaucoma ⁹⁶.

Intraocular Pressure (IOP)

Although always residing within the normal range for intraocular pressure (IOP), patients with normal tension glaucoma have been suggested to have higher-normal intraocular pressure (IOP) levels ⁹⁷. By contrast, prospective evaluation of patients in the Low-Pressure Glaucoma Treatment Study found no relation between intraocular pressure (IOP) asymmetry and visual field asymmetry ⁹⁸. Wide diurnal fluctuations in intraocular pressure (IOP) and nocturnal intraocular pressure (IOP) spikes have also been correlated with normal tension glaucoma ⁹⁷.

Systemic vascular disease

Patients with systemic conditions that result in ischemic vascular disease such as diabetes and patients with a history of stroke have been shown to be at increased risk for bilateral normal tension glaucoma compared to unilateral normal tension glaucoma ⁴¹. Patients with normal tension glaucoma may have increased diastolic blood pressure and display larger dips in blood pressure overnight compared to normal ⁴¹. Similarly, it has been suggested that obstructive sleep apnea (OSA) may lead to transient episodes of nocturnal hypoxemia and compromised optic nerve head perfusion ⁴¹. A higher prevalence of obstructive sleep apnea (OSA) among normal tension glaucoma patients has been noted in several studies ⁹⁹, ¹⁰⁰, ¹⁰¹. Moreover, one study demonstrated a correlation between moderate/severe obstructive sleep apnea (OSA) and higher progression of retinal nerve fiber layer (RNFL) loss ¹⁰².

Certain vasospastic conditions such as Raynaud disease (a condition where blood vessels in the fingers and toes narrow in response to cold or stress, causing temporary blood flow restriction) are thought to be associated with normal tension glaucoma, with the most reported associated condition being migraine ¹⁰³. Recently, a disease entity termed primary vascular dysregulation (also known as vasospastic syndrome, refers to a condition where the regulation of blood flow isn’t adapted to the needs of tissues, despite anatomically healthy vessels and the absence of an underlying disease) has been described pointing to retinal and optic nerve vasculature dysregulation as a potential risk factor for normal tension glaucoma ¹⁰⁴. As above, a recent study demonstrated a significantly increased risk of developing vascular dementia in individuals diagnosed with normal tension glaucoma, further supporting a vascular deregulatory element in the pathogenesis of normal tension glaucoma ⁵².

A recent cross-sectional study investigated the prevalence of normal tension glaucoma in patients with Conn’s syndrome also called primary aldosteronism. Of the 212 patients with primary hyperaldosteronism included in the study, the prevalence of normal tension glaucoma in primary hyperaldosteronism patients was 11.8%, significantly higher than in hypertensive patients without primary aldosteronism (5.2%) ¹⁰⁵. The study found a fourfold increase in the odds of developing normal tension glaucoma in primary hyperaldosteronism patients compared to those without primary hyperaldosteronism ¹⁰⁵. These findings suggest that aldosterone dysregulation may contribute to the development of normal tension glaucoma, independent of blood pressure, and highlight the need for further research on the potential neuroprotective effects of mineralocorticoid receptor antagonists in normal tension glaucoma patients with primary hyperaldosteronism ¹⁰⁵.

Another recent study explored potential clinical links between normal tension glaucoma and Alzheimer’s disease, focusing on shared neurodegenerative mechanisms ¹⁰⁶. Both normal tension glaucoma and Alzheimer’s disease are progressive conditions, sharing risk factors such as age, female sex, and vascular dysfunction. Neuroimaging studies reveal that normal tension glaucoma may have cerebral manifestations similar to Alzheimer’s disease, further suggesting common mechanisms ¹⁰⁶. Moreover, biomarkers like amyloid beta (Aβ) and tau proteins, traditionally linked with Alzheimer’s disease, have been implicated in normal tension glaucoma, indicating overlapping pathological processes. While connections between the two diseases remain debated, understanding normal tension glaucoma as part of a broader neurodegenerative spectrum may enhance both diagnostics and treatments for normal tension glaucoma, potentially offering insights into Alzheimer’s disease pathogenesis. Further research is needed to elucidate the exact relationship between normal tension glaucoma and Alzheimer’s disease ¹⁰⁶.

Risk factors for normal tension glaucoma

Risk factors for normal tension glaucoma include ¹, ¹⁰⁷, ², ¹⁰⁸, ¹⁰⁹, ¹¹⁰, ⁷⁸:

• Over 40 years of age
• Family history of glaucoma
• Female gender
• Asian
• High Myopia
• Above-average intraocular pressure (IOP)
• Thin central corneal thickness
• Systemic hypertension
• Nocturnal hypotension
• Migraine
• Raynaud phenomenon
• Primary vascular dysfunction also called Flammer syndrome where the body’s blood vessels react abnormally to stimuli like cold or emotional stress ¹¹¹. It’s associated with a cluster of symptoms and signs that can be present in both healthy individuals and those with various diseases, particularly normal-tension glaucoma.
• Frontotemporal dementia and Alzheimer disease
• Obstructive sleep apnea (OSA).

Normal tension glaucoma prevention

Due to the irreversible loss of vision due to normal tension glaucoma, early detection and treatment is important. Screening for and treatment of risk factors associated with normal tension glaucoma, such as nocturnal hypotension, currently does not have a defined role in primary prevention of normal tension glaucoma, particularly in the United States ⁴¹. A recent study that took place in China aimed to evaluate the effectiveness of a glaucoma screening program in identifying early-stage glaucoma cases ¹¹². They compared 76 patients identified through glaucoma screening program with 272 consecutive outpatient cases from the same hospital. The findings indicate that patients detected through the screening program had significantly lower intraocular pressure (IOP) and were more likely to have normal tension glaucoma ¹¹². These screening-detected patients also had less visual impairment and better visual field test results compared to clinic patients ¹¹². The study suggests that health examination center-based glaucoma screening is effective in detecting early-stage glaucoma, especially those with normal tension glaucoma, and can complement opportunistic glaucoma detection ¹¹². This is important in a country like China, where glaucoma is a significant public health concern. Further studies must take place to further characterize the role of primary prevention/screening for normal tension glaucoma before it potentially develops into standard practice, particularly in the US where the incidence of normal tension glaucoma is significantly less than in China ⁴¹. Nevertheless, the Chinese study demonstrates a potential role for glaucoma screening in patients who are particularly high risk of developing glaucoma.

Normal tension glaucoma signs and symptoms

Most patients with normal tension glaucoma in the early stages have no symptoms of the condition ¹¹³. There is no pain and vision seems normal with suspicion of glaucoma raised only by an optometrist during a routine eye testing or an incidental finding with an ophthalmologist ¹¹³, ¹¹⁴.

Even with moderately advanced disease, patients may be unaware of field defects because of unilateral disease, negative scotoma, and gradual onset ¹. Because the intraocular pressure (IOP) is normal, suspicion is usually roused by optic disc appearance or a visual field defect on automated perimetry ¹. If the presentation is advanced, patients may have symptoms of reduced vision, difficulty with low-contrast situations, and awareness of visual field defects. They may experience glare and difficulty adjusting to extreme lighting conditions ¹. A family history of glaucoma and blindness should be obtained. Past medical history should include assessing risk factors for glaucoma, such as the history of steroid use, ocular trauma or surgery, and contraindications to treatments, including allergies. Medication usage should be reviewed.

A relative afferent pupillary defect is typical, though it may not be present in the early or symmetrical disease ¹. Color vision is usually preserved, except in advanced disease. By definition, the intraocular pressure (IOP) is in the normal range ¹¹⁵. Slit-lamp examination and gonioscopy are essential to determine an open iridocorneal angle status and exclude secondary glaucoma causes. In particular, evidence of angle closure, uveitis, pigment dispersion, and pseudoexfoliation syndrome should be sought, as these are common causes of glaucoma presenting with an intraocular pressure (IOP) in the normal range.

A dilated fundus examination revealed changes in the glaucomatous optic disc. There is a progressive loss of ganglion cell neurons, leading to enlargement of the cup-to-disc ratio. This may be a focal (notch, retinal nerve fiber layer (RNFL) defect) or concentric defect (excavation, senile sclerotic disc) ¹. Disc pallor occurs in advanced disease. Measurement of the optic disc size can help identify hypoplasia, physiological disc cupping, and disc asymmetry ¹. Optic disc hemorrhages are more common in normal tension glaucoma than in primary open angle glaucoma (POAG) ¹⁰⁸. So-called Drance hemorrhages are typically small flame hemorrhages at the disc margin in superior or inferior quadrants. Peripapillary atrophy may be seen but is non-specific. Glaucomatous disc abnormalities typically precede visual field defects in early (preperimetric) disease ¹¹⁶.

Normal tension glaucoma diagnosis

The only sure way to diagnose glaucoma is with a complete eye exam. An eye specialist can diagnose glaucoma using an eye exam, including several tests that are part of routine eye exams. A comprehensive eye exam can detect glaucoma long before you have eye damage and the symptoms that follow. Many of these tests involve pupil dilation (mydriasis), so your eye doctor can get a better look inside your eye. Your eye care specialist examines your eyes using a special magnifying lens. This provides a clear view of important tissues at the back of your eye to check for glaucoma or other eye problems. For a few hours after the exam your vision may be blurry and sensitive to light, so you will need someone to take you home.

Some of the most helpful glaucoma tests include:

• Visual acuity testing. A visual acuity test assesses how clearly someone can see at a distance, typically using a Snellen chart or other standardized chart. The test is performed by an optometrist or ophthalmologist and involves reading progressively smaller letters or identifying shapes, with the results expressed as a fraction like 20/20 or 6/6, indicating the distance at which the person can see the letters or shapes
• Visual field testing also called perimetry. This check of your peripheral (side) vision allows your eye care provider to find out how well you can see objects off to the side of your vision without moving your eyes. This test measures the entire area the forward-looking eye sees to document straight-ahead (central) and side (peripheral) vision. It measures the dimmest light seen at each spot tested. Each time patients perceive a flash of light, they respond by pressing a button.
• Depth perception testing. A depth perception test assesses your ability to see the world in three dimensions (3D) and judge distances accurately. It checks if your eyes work together and if your brain processes the visual information correctly. These tests use 3D images or patterns like the Randot Stereo test to gauge how well your eyes coordinate to perceive depth. Some tests involve holding a finger in front of your eyes and focusing on a distant object, checking for double vision of the finger.
• Tonometry. This measures the pressure inside your eye. Increased eye pressure is the most important risk factor for glaucoma. There are several methods of measuring eye pressure. The most common method is known as applanation, in which a tiny instrument contacts the eye’s surface after it is numbed with an eye drop.
  • Air-puff test. You’ll rest your chin on a machine and your eye specialist will blow a puff of air into your eye. This quick and painless test is used as part of a routine glaucoma screening. If the results show that your eye pressure is high, your eye specialist will do other eye-pressure tests to get a more accurate measurement.
  • Applanation tonometry. Your eye specialist will numb your eyes with drops before measuring your eye pressure using one of these methods:
    • You’ll rest your chin on a special magnifying device called a slit lamp. Your eye care specialist will examine your eye through the slit lamp while gently pressing a special tool on your eye to test the pressure.
    • Your eye care specialist will gently press a handheld device against your eye. The device measures your eye pressure.
• Pachymetry. Pachymetry is a simple, painless test that measures the thickness of the cornea, the clear front part of the eye. The eye doctor uses an ultrasonic wave instrument to help determine the thickness of the cornea and better evaluate eye pressure.
• Ophthalmoscopy. Your eye care specialist will do a dilated eye exam to look for damage to your optic nerve. This exam is part of a routine glaucoma check-up. You’ll be given eye drops that widen (dilate) your pupils (the openings that let light into your eyes). You’ll look straight ahead while your eye care specialist looks into your eye using a device with a light and magnifying lens.
• Slit lamp exam. A slit lamp exam is a common eye test that uses a microscope with a focused beam of light to examine the front of your eye and the back of your eye with the aid of special lenses.
• Gonioscopy. Gonioscopy is a specialized eye examination that allows an ophthalmologist to visualize the anterior chamber drainage angle, the space between the iris and the cornea where fluid drains out of the eye. Gonioscopy is a crucial part of diagnosing and monitoring glaucoma and other eye conditions. Eye doctors regularly examine the drainage angle to see if there is any visible obstruction to fluid leaving the eye through the trabecular meshwork. A special lens (gonioscopy lens) is needed to examine the trabecular meshwork. The gonioscopy lens is gently placed against the surface of the cornea and allows eye doctors to see the trabecular meshwork in the drainage angle.

If your eye specialist has a reason to suspect damage to your retina and/or optic nerve, they may also use additional types of eye imaging. These include:

• Optical coherence tomography (OCT). Optical Coherence Tomography (OCT) measures the reflection of laser light similar to the way that ultrasound measures the reflection of sound. Using this device, a 3D reconstruction of the optic nerve can be created. Optical coherence tomography (OCT) is valuable for monitoring morphological changes in the optic nerve and retinal nerve fiber layer, especially in patients with ocular hypertension and early-to-moderate glaucoma ¹¹⁷. The most recent advances of OCT include OCT-A, or OCT-Angiography, whereby the blood flow to vessels surrounding the optic nerve and in the macula can be measured. This is still an active area of research, but scientists do know that some patients’ optic nerves are very vulnerable to changes in optic nerve blood flow, and this new measurement may be useful in evaluating these patients.
• Heidelberg Retina Tomograph (HRT): Heidelberg Retina Tomograph (HRT) is also a laser that can produce a 3D representation of the optic nerve.
• Nerve Fiber Analyzer (GDx): Nerve Fiber Analyzer (GDx) uses laser light to measure the thickness of the nerve fiber layer.
• Fluorescein angiography. Fluorescein angiography is a diagnostic test used to examine the blood vessels in the retina and choroid of the eye. Fluorescein angiography involves injecting a fluorescent dye into the bloodstream and taking photographs of your retina and its blood vessels as the dye circulates, revealing potential blockages, leaks, or other abnormalities in the blood vessels. Fluorescein angiography is often recommended to find and diagnose eye disease including ¹¹⁸:
  • macular edema (swelling in the retina that distorts vision)
  • diabetic retinopathy (damaged or abnormal blood vessels in the eye caused by diabetes)
  • macular degeneration
  • blockage of veins inside the eye, called branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO)
  • macular pucker (a wrinkle in the retina caused by a buildup of fluid behind it)
  • ocular melanoma (a type of cancer affecting the eye)
  • rack changes in eye disease over time
  • target treatment areas
• Less commonly, ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI).

Normal tension glaucoma clinical diagnosis

Normal tension glaucoma is a diagnosis made based on similar criteria to primary open angle glaucoma (POAG) but with important clinical features that include:

• Progressive excavation or ‘cupping’ of the optic nerve head from retinal nerve fiber layer loss resulting in corresponding visual field deficits.
• Gonioscopic confirmation of open anterior chamber angle and absence of findings consistent with pigment dispersion or pseudoexfoliation syndrome.
• Pre-treatment intraocular pressure (IOP) must always be less than 22 mm Hg. (diurnal measurement of intraocular pressure (IOP) to ensure there is not a circadian elevation in pressure that is missed by single period clinical measurement)

The diagnosis of normal tension glaucoma is only reached once other forms of optic neuropathy have been ruled out (e.g. ischemic, traumatic, toxic inflammatory, infectious, congenital, and compressive).

Careful history taking should be undertaken to elucidate any prior events that can mimic normal tension glaucoma such as:

• Traumatic injuries
• Inflammation
• Severe blood-loss or hypotensive events
• Medications that may precipitate a transient pathologic elevation in intraocular pressure (IOP)

After reasonable exclusion of all other causes, the demonstration of visual field loss on static, or less often kinetic, perimetry in conjunction with characteristic optic nerve central cupping with no elevation in intraocular pressure (IOP) above 21 mm Hg cement the diagnosis of normal tension glaucoma.

Other classically associated examination findings with normal tension glaucoma that can be helpful clues in raising suspicion for pursuing a diagnosis include optic nerve or “Drance” hemorrhages (also called optic disc hemorrhage) and peripapillary atrophy. While these findings are not specific, patients with normal tension glaucoma have a higher propensity for optic nerve hemorrhages compared to patients with primary open angle glaucoma (POAG). Focal defects in the retinal nerve fiber layer may be more commonly observed as well.

Visual field testing

Automated static perimetry is the most common modality used to detect and monitor for progression of the field loss associated with normal tension glaucoma ⁴¹. Visual field defects may include those common to primary open angle glaucoma (POAG) including nasal step and arcuate scotoma. However, defects noted in normal tension glaucoma tend to be more focal and occur closer to fixation early in the disease (Figure 4A and B). Dense paracentral scotomas may characteristically be noted at initial diagnosis.

Optic disc imaging

Visual field testing is useful in early detection but may miss early, pre-perimetric disease, as substantial retinal nerve fiber layer may be lost before functional field defects are noted ⁴¹. Therefore, optic disc imaging is an important and objective structural assessment of the optic nerve health ⁴¹. For several decades, the gold standard for detecting disease and monitoring changes in the optic nerve head has been stereo disc photography (Figure 3 A and B). In recent years, scanning laser ophthalmoscopy and optical coherence tomography (OCT) is gaining popularity as another means of detecting pathologic thinning of neural tissue and monitoring progression ⁴¹. Furthermore, with the introduction of Artificial Intelligence (AI), OCT interpretation continues to become more prevalent when classifying an eye as either a glaucoma suspect or early normal tension glaucoma ⁴¹. This was demonstrated in a recent study where a deep-learning algorithm was developed to discriminate between the normal tension glaucoma by using the parameter of Bruch’s membrane opening — minimum rim width, peripapillary retinal nerve fiber layer (RNFL) thickness and color classification of retinal nerve fiber layer (RNFL) — achieving an area under the curve of 0.966 ¹¹⁹. Ultimately, these advances continue to improve the diagnostic specificity associated with either normal tension glaucoma or primary open angle glaucoma (POAG) ¹¹⁹.

A recent meta-analysis investigated differences in peripapillary choroidal thickness (PPCT) between primary open angle glaucoma (POAG), normal tension glaucoma, and healthy eyes ¹²⁰. A systematic review of 18 studies, including 935 healthy control eyes, 446 normal tension glaucoma eyes, and 934 POAG eyes, was performed ¹²⁰. OCT revealed significant reductions in peripapillary choroidal thickness (PPCT) in both POAG and normal tension glaucoma eyes compared with healthy eyes. POAG eyes demonstrated a mean reduction in peripapillary choroidal thickness (PPCT) of −16.32 µm compared to healthy controls, while normal tension glaucoma eyes showed a larger reduction of −34.96 µm compared to controls ¹²⁰. Additionally, normal tension glaucoma eyes exhibited significantly thinner peripapillary choroidal thickness (PPCT) compared with POAG eyes, with a mean difference of −26.64 µm ¹²⁰. These findings suggest that glaucomatous eyes, especially normal tension glaucoma eyes, have significantly reduced peripapillary choroidal thickness (PPCT), highlighting the potential role of peripapillary choroidal thickness (PPCT) as a diagnostic and monitoring tool in glaucoma management ¹²⁰.

Pachymetry

Assessment of central corneal thickness (CCT) through pachymetry is essential in the work up of normal tension glaucoma ⁴¹. The measured intraocular pressure (IOP) by applanation may be artifactually low in eyes with low central corneal thickness (CCT) ⁴¹. Many patients with a diagnosis of normal tension glaucoma will demonstrate a low central corneal thickness (CCT) ¹²¹, ¹²². In some cases, correction of this under measurement may reveal an actual intraocular pressure (IOP) more consistent with primary open angle glaucoma (POAG) ¹²¹, ¹²².

Neurological Evaluation

At times, the diagnosis of normal tension glaucoma may simulate other neurological conditions. Most concerning to the clinician is an intracranial tumor masquerading as normal tension glaucoma. While these diagnoses are rare, clinicians should maintain a low threshold for neuroimaging with CT or MRI and a full neurological evaluation whenever the following exist ⁴¹:

• Marked asymmetry or unilateral optic nerve involvement
• Unexplained visual acuity loss
• Color vision deficits in the absence of visual field deficits
• Visual field defects not corresponding or out of proportion to optic nerve damage
• Vertically aligned visual field defects
• Atypical neurologic symptoms for glaucoma
• Optic nerve pallor in excess of cupping
• Age less than 50 years

Normal tension glaucoma treatment

Management of normal tension glaucoma mirrors the medical and surgical management of the other forms of glaucoma and hinges on reduction of intraocular pressure (IOP) from baseline ⁴¹. Identification of patients with clinical evidence of progression is important in the decision to initiate treatment for normal tension glaucoma. The natural history of normal tension glaucoma does not always include progression without treatment. As initially described by Drance ⁴⁰, a significant portion of patients with normal tension glaucoma may not demonstrate clinical progression regardless of treatment.These patients typically had a history of systemic vascular compromise resulting in a one-time insult to the optic nerve. Nonetheless, for the majority of patients with normal tension glaucoma, reduction of intraocular pressure (IOP) remains the focus of treatment.

The Collaborative Normal-Tension Glaucoma Study (CNTGS) ⁷⁷, ⁸⁴ demonstrated the benefit of intraocular pressure (IOP) reduction for the treatment of patients with normal tension glaucoma. The Collaborative Normal-Tension Glaucoma Study (CNTGS) concluded that a 30 percent reduction in baseline intraocular pressure (IOP) resulted in a reduced risk of disease progression ⁷⁷, ⁸⁴. Criteria for initiation of treatment of the normal tension glaucoma patients in this study were defined as: documented visual field or optic nerve progression, visual field loss threatening fixation, or presence of disc hemorrhage ⁷⁷, ⁸⁴. The treatment group had a 12% risk of progression at 5 years compared to 35% progressing in the non-treatment group ⁸⁴. The Collaborative Normal-Tension Glaucoma Study (CNTGS) was therefore instrumental in demonstrating the role of IOP in the pathogenesis of normal tension glaucoma and the benefit of treatment to lower it. The Collaborative Normal-Tension Glaucoma Study (CNTGS) also presents a reasonable goal for treatment in 30% intraocular pressure (IOP) reduction from patient’s baseline. Treatment intraocular pressure (IOP) goals may then be modified over the course of treatment to a level that sufficiently prevents or slows progression of disease.

Outside of intraocular pressure (IOP) lowering therapy, other aspects should be considered in the management of normal tension glaucoma patients. This may include cardiovascular problems such as systemic hypotension, nocturnal hypotension, anemia, and cardiac arrhythmias that can compromise optic nerve head perfusion ⁴¹. Consultation with primary care physicians can be helpful in addressing these concerns, but limited evidence is available to confirm a treatment benefit for normal tension glaucoma ⁴¹.

Medications

Topical intraocular pressure (IOP) lowering medications including prostaglandin analogues, alpha-2 agonists, beta-blockers, carbonic anhydrase inhibitors, and more recently Rho-kinase inhibitors are the mainstays of normal tension glaucoma medical therapy ⁴¹. Medications should be chosen on an individual basis to provide treatment that achieves a sufficient intraocular pressure (IOP) reduction with minimal side effects and ease of administration. Medication choice should also be cost-effective for the patient based on their resources.

Particularly with normal tension glaucoma, the effect of medications on systemic blood pressure, heart rate, and optic nerve perfusion should be considered. Furthermore, medications that have neuroprotective or intraocular pressure (IOP) independent effects would be extremely beneficial and remain an ongoing search. The Low-Pressure Glaucoma Study (LoGTS) demonstrated the importance of intraocular pressure (IOP) independent factors when choosing medical therapy for normal tension glaucoma ¹²³. In the Low-Pressure Glaucoma Study (LoGTS), patients with low-tension glaucoma were randomized to treatment with either brimonidine tartrate 0.2% or timolol maleate 0.5% ¹²³. While intraocular pressure (IOP) reduction was similar between the two treatment groups, patients treated with brimonidine were less likely to have visual field progression compared to patients treated with timolol ¹²³. It is unclear whether this difference is due to an additional neuroprotective effect of brimonidine or a detrimental vascular effect from timolol ¹²³. Moreover, Rho-kinase inhibitors are thought to be neuroprotective and increase vascular flow at the optic nerve head via the nitric oxide pathway ¹²⁴, ¹²⁵. The newer class of Rho-kinase inhibitor showed efficacy in both intraocular pressure (IOP) reduction in normal tension glaucoma and as add-on treatment in normal tension glaucoma patients with inadequate baseline intraocular pressure (IOP). The Rho-kinase (ROCK) inhibitor class of medication blocks the contraction of trabecular meshwork cells and increases the outflow of aqueous humor, thereby reducing intraocular pressure (IOP) ¹²⁶, ¹²⁷.

In patients with evidence of vasospasm, calcium channel blockers have been proposed to stabilize vascular tone, particularly in patients with concurrent hypertension, though the benefit has not been evaluated in large clinical trials ⁴¹.

Medical follow up

Once medical treatment is initiated, patients should be followed up 6-8 weeks later to ensure good adherence, minimal side effects, and adequate intraocular pressure (IOP) lowering efficacy ⁴¹. Different medication classes, laser treatment or surgical therapy may be trialed until an appropriate treatment is found ⁴¹. Once treatment goals have been met, periodic measurement of IOP during medical therapy is recommended every 3-4 months to ensure maintenance of goal intraocular pressure (IOP) and absence of progression ⁴¹. New technology has allowed for patients to partake in home tonometry. Patients can frequently report their findings to their supervising ophthalmologists allowing for a more complete representation of intraocular pressure (IOP) mean, peak and range (numerous measurements can be taken throughout the day) and closer follow-up ⁴¹. In addition to intraocular pressure (IOP), patients should be monitored for signs of progression by periodic assessment of the optic nerve head (disc photos, HRT, OCT, etc.) and visual field testing every 6-12 months, with more frequent intervals in advanced or actively progressing disease ⁴¹. If progression is detected despite goal intraocular pressure (IOP), treatment goals should be lowered with advance of therapy to achieve them ⁴¹.

Surgery

Laser and surgical treatment options for normal tension glaucoma mirror those for primary open angle glaucoma (POAG) ⁴¹. These include laser trabeculoplasty, minimally invasive glaucoma surgery (MIGS), trabeculectomy, and glaucoma drainage devices.

Selective Laser trabeculoplasty (SLT) may be a useful moderately invasive treatment with or without medical therapy ⁴¹. There is some literature that supports an IOP lowering, and decreased IOP variability, effect of Selective Laser trabeculoplasty (SLT) in normal tension glaucoma patients ¹²⁸. For patients with IOP targets that are not achievable with medical/laser therapy, filtration surgery with or without a drainage device has traditionally been the mainstay of surgically lowering IOP ⁴¹. However, recent trends and practice patterns according to the American Academy of Ophthalmology Intelligent Research Insight Registry (IRIS) reveal a significant increase in the use of minimally invasive glaucoma surgery (MIGS) procedures from 2013-2018, and normal tension glaucoma is no exception ¹²⁹.

Minimally invasive glaucoma procedures such as goniotomy with Kahook Dual Blade (KDB), the iStent trabecular bypass device, and the XEN gel stent have demonstrated an important although limited role in the surgical management of normal tension glaucoma ⁴¹. In theory, angle-based MIGS procedures can only lower IOP to a level equal to or above episcleral venous pressure of approximately 8-11 mm Hg ⁴¹. Goal IOP for normal tension glaucoma patients may be below this level making it difficult to achieve treatment goals by surgical means alone ⁴¹. However, maintaining a goal IOP with fewer medications is a reasonable indication for minimally invasive glaucoma surgery (MIGS) in normal tension glaucoma. This rationale also applies to laser trabeculoplasty, which augments aqueous outflow to the downstream episcleral venous system as well. According to American Academy of Ophthalmology Intelligent Research Insight Registry (IRIS) data regarding initial surgery for normal tension glaucoma, iStent has been the most common performed surgery and minimally invasive glaucoma surgery (MIGS) procedures in general are performed at a higher rate than filtration surgeries for normal tension glaucoma ¹²⁹.

In the Collaborative Normal-Tension Glaucoma Study (CNTGS), the IOP reduction of 30% was only achieved in 57% of patients by topical medication and/or laser trabeculoplasty, while the remaining 43% required filtering surgery ⁴¹. While IOP lowering with filtration surgery has been shown to be effective in decreasing visual field progression a continued, slowed progression has been reported in postoperative patients followed for up to 6 years ⁴¹.

A lower starting IOP with normal tension glaucoma patients and a 30% reduction target may result in a narrower margin between therapeutic IOP reduction and hypotony in these patients ⁴¹. Increase risk of filtering surgery complications has been reported in this subset of primary open angle glaucoma (POAG) patients ⁴¹.

Selection of anti-metabolite drugs and means of application in filtering surgery is an important consideration and should be guided by specific treatment goals and surgeon specific experience with these agents ⁴¹. Mitomycin C (MMC) has been associated with achievement of lower IOPs post operatively compared to 5-fluorouracil (5-FU) in some studies, though literature also suggests equivalence of efficacy of these two agents in primary trabeculectomy for primary open angle glaucoma (POAG) ⁴¹. Mitomycin C use in normal tension glaucoma glaucoma has an associated increased risk of over-filtration complications that may play a role in the risk of visual field progression. Therefore, meticulous use of mitomycin C (e.g. 0.2-0.4 mg/ml for 1-3 minutes), careful flap suturing, and judicious use of viscoelastic with frequent postoperative follow up have been proposed as methods to mitigate the risks of hypotony early in the post operative phase while achieving target IOP ⁴¹. Early suture lysis may be required to achieve low target IOPs but should be weighed against the risk of resultant over-filtration. Given the context of a higher risk of hypotony following filtering surgery in patients with normal tension glaucoma, the XEN gel stent has recently been deployed to achieve a lower IOP goal while maintaining a lower rate of hypotony ⁴¹. One recent study demonstrated a mean IOP decrease of 5.6 +/- 2.7 mmHg in normal tension glaucoma patients, which represented an IOP reduction of 29% ¹³⁰. Also, the use of the EX-PRESS glaucoma mini shunt has been employed as a means of preventing complications, while still achieving similar IOP goals compared to standard trabeculectomy ⁴¹. In one experience, the smaller, consistent outflow opening of the EX-PRESS shunt allows for earlier suture lysis to achieve low IOP targets with less risk of hypotony ⁴¹. The utility of this device remains an area of debate considering the additional cost of the device and mixed outcomes in the literature ⁴¹.

Cyclodestructive procedures provide the only surgical means of suppressing aqueous production to lower IOP. Due to their potentially vision threatening side effects, these procedures are typically reserved for eyes refractory to treatment or with poor visual potential ⁴¹. Ablation of the ciliary processes may be accomplished by transscleral cyclophotocoagulation (CPC) or by endoscopic cyclophotocoagulation (ECP) ⁴¹. Endoscopic cyclophotocoagulation (ECP) offers the unique advantage of direct visualization of the target tissue allowing a more targeted approach to achieve less inflammation and side effects ⁴¹.

A recent systematic review and meta-analysis evaluated the efficacy of angle-based minimally invasive glaucoma surgery (MIGS) in patients with normal tension glaucoma ¹³¹. The study analyzed outcomes from 15 studies, totaling 367 normal tension glaucoma eyes, with procedures including the iStent, iStent inject, Hydrus Microstent, Kahook Dual Blade, and Trabectome ¹³¹. The review found significant reductions in IOP and glaucoma medication usage postoperatively ¹³¹. Specifically, combined phacoemulsification and angle-based MIGS showed a mean IOP reduction of 2.44 mmHg at 6 months, 2.28 mmHg at 12 months, and sustained reductions up to 36 months ¹³¹. Glaucoma medication usage was also significantly reduced by 1.21 medications at 6 months and 1.18 at 12 months postoperatively. These findings suggest that angle-based MIGS, particularly in combination with cataract surgery, can be effective in reducing IOP and medication burden in normal tension glaucoma patients while maintaining a favorable safety profile ¹³¹.

Normal tension glaucoma prognosis

Like any form of glaucoma, normal tension glaucoma may progress to irreversible blindness, but is dependent on factors that include the disease severity at diagnosis, effectiveness of treatment, individual risk factors, overall ocular health and your general health ¹³², ¹³³, ¹³⁴, ¹³⁵, ¹³⁶, ¹, ⁴¹. Similar to other types of glaucoma, normal tension glaucoma can progress to irreversible unilateral or bilateral blindness in the worst cases, even despite therapy ¹³³. The prognosis for visual preservation is good in patients who undergo adequate treatment through intraocular pressure (IOP) reduction ⁴¹. The main risk factors associated with the normal tension glaucoma disease progression in both treated and untreated patients have been demonstrated to be female gender, greater variation in diurnal IOP and diastolic blood pressure, presence of disk hemorrhage, greater vertical cup/disc ratio and migraine at baseline ³¹. Age, mean IOP and baseline IOP were not shown to be risk factors for progression ³¹. Epidemiology studies have shown that Asians tend to show a slower rate of disease progression ¹³², ¹³⁴, ¹³⁵, ¹³⁶. On average, the visual field damage progression has been reported to be slower in normal tension glaucoma than in primary open angle glaucoma (POAG), but with higher inter-patient variability ¹³⁵.

The cumulative risk to develop legal unilateral blindness in treated normal tension glaucoma patients under standard ophthalmic care has been calculated to be 5.8% and 9.9% at 10 years and 20 years, respectively ³¹. The risk for bilateral blindness at 10 and 20 years was 0.3% and 1.4%, respectively ¹³³. Patients presenting advanced damage at the diagnosis or rapidly progressing visual field loss, the so-called “rapid progressors”, are most likely to become blind due to the disease ³¹. It is fundamental that these patients need to be identified and managed with more aggressive treatment to avoid irreversible visual loss ¹³³.

In the Collaborative Normal-Tension Glaucoma Study (CNTGS), 65% of patients in the control group with normal tension glaucoma did not progress even without treatment ⁸⁴, ⁷⁷. However, an intraocular pressure (IOP) reduction of 30% with treatment further lowered the likelihood of progression to only 12% ⁸⁴, ⁷⁷. The Early Manifest Glaucoma Trial (EMGT), a randomized double-masked clinical trial conducted on 255 open-angle glaucoma patients with early visual field defects, including 53% of normal tension glaucoma cases, showed that a 25% reduction in IOP can reduce the risk of disease progression to 45% in the study group, compared to 62% in the control group, after a 6-year follow-up ⁵⁷. These studies have suggested that, to be significantly effective in decreasing the risk of normal tension glaucoma progression, the reduction in IOP should be at least 30% or more ¹³⁷, ⁵⁶. Moreover, studies with long follow-ups have shown that the amount of IOP reduction seems to be directly related to the reduction in the visual field progression rate in normal tension glaucoma patients ⁵⁹. Additionally, the benefits of the IOP reduction in normal tension glaucoma patients seem to be significantly higher in females with migraine and a family history of glaucoma, without disk hemorrhages, family history of stroke and personal history of cardiovascular disease ¹³⁴.

Patients with normal tension glaucoma that previously suffered an acute vascular compromise have also been shown to not progress over time as well ⁴⁰. Given this relatively high rate of non-progression, some clinicians have suggested a conservative “wait and see” approach to initiating treatment ⁴¹. This recommendation should be cautioned, as it is often difficult to determine which patients will progress, and other studies have shown variable rates of progression in this disease ⁴¹. Risk factors for progression of visual field defects in normal tension glaucoma include migraine, disc hemorrhage, and female gender. Asians have been shown to have a slower rate of progression ¹¹⁰.

Pigmentary glaucoma

Pigmentary glaucoma is a type of secondary open-angle glaucoma where small pigment granules from the back of the iris breaks off and clogs the eye’s drainage system at the angle where the iris and cornea meet, leading to increased intraocular pressure (IOP) and potential optic nerve damage ¹³⁸, ¹³⁹, ¹⁴⁰, ¹⁴¹, ¹⁴², ¹⁴³. Pigment gives your iris its color. Pigment dispersion syndrome (PDS) is characterized by the presence of melanin pigment granules that circulate within the aqueous humor and accumulate on different structures found in the anterior chamber of the eye, including corneal endothelium deposits also known as the Krukenberg spindle, lens surface, zonules, iris, iridocorneal angle, and trabecular meshwork ¹⁴⁴. The pigment granules that accumulate in the angular structures and trabecular meshwork can give rise to reduced aqueous outflow, leading to elevated intraocular pressure (IOP). Pigment dispersion syndrome (PDS) can cause ocular hypertension and can lead to secondary rise in intraocular pressure (IOP) that can damage the optic nerve resulting in pigmentary glaucoma development, which is a secondary type of glaucoma. Pigment dispersion syndrome (PDS) and pigmentary glaucoma in reality reflect different levels of severity on a continuum disease spectrum ¹⁴². Pigment dispersion syndrome (PDS) is used to classify individuals who exhibit these features but who have not progressed to optic nerve damage and/or visual field loss (signifiers of pigmentary glaucoma), even if the intraocular pressure (IOP) is elevated. Pigment dispersion syndrome (PDS) is an important risk factor in the development of ocular hypertension and pigmentary glaucoma ¹⁴³.

Pigmentary glaucoma is a result of pigment dispersion syndrome (PDS), where pigment granules detach from the iris and accumulate in the trabecular meshwork, which is the main drainage channel of the eye. Pigment dispersion syndrome (PDS) happens when the pigment rubs off the back of your iris. The pigment then floats around to other parts of your eye. The tiny bits of pigment can clog your eye’s drainage angle. This pigment can raise eye pressure and lead to pigmentary glaucoma. Features of pigment dispersion syndrome (PDS) include anterior chamber pigment dispersion, spoke-like iris defects on trans-illumination, central corneal endothelial deposits also known as the Krukenberg spindle, and increased pigmentation in the iridocorneal angle ¹⁴². However, not everyone who has pigment dispersion syndrome (PDS) will develop pigmentary glaucoma. Approximately 15% of patients with pigment dispersion syndrome (PDS) will convert to pigmentary glaucoma after 15 years ¹³⁸. Some people with pigment dispersion syndrome (PDS) or pigmentary glaucoma may see halos or have blurry vision after activities like jogging or playing basketball that stir up the pigment granules. See your ophthalmologist if you have these or other symptoms.

The iris of your eye is a flat ring of muscle that contains melanin, the pigment that gives your eyes their color. In front of and behind your iris are spaces filled with a fluid called aqueous humor. Pressure from the aqueous humor helps your eye hold its globe-like shape. When you have pigment dispersion syndrome (PDS), your iris can’t hold its shape and dips back too far ¹⁴⁵, ¹⁴⁶. That makes the back of your iris press against the muscle fibers that control your lens shape. As your iris widens or narrows, the iris rubs against those fibers and pigment granules in the iris wear away, like flakes of paint chipping away from a piece of wood ¹⁴⁵, ¹⁴⁶. Patients with pigment dispersion syndrome or pigmentary glaucoma have a 15-fold higher concentration of aqueous pigment granules in their anterior chamber compared to normal controls ¹⁴⁷.

The release of pigment showers in the anterior chamber is mainly due to the friction and rubbing between the iris pigment epithelium and posterior surface and zonules of the lens, which is favored by the backward posterior bowing of the iris that can be found in moderate myopic eyes that have more space ¹⁴⁸ and by reverse pupillary block mechanisms due to increased iridolenticular touch ¹⁴⁹. Ultrasonographical studies have shown that events leading to increased friction and contact between anterior chamber structures that favor reverse pupillary block include physiological events such as accommodation, blinking, eye movements, head positions, and exercise ¹⁵⁰. The increased contact between the iris and lens structures in eyes at risk of having a deep anterior chamber and/or a large iris can create a ball-valve mechanism in certain conditions in which the aqueous humor moves from the posterior chamber to the anterior chamber in a unidirectional mode, thus creating a high pressure in the anterior chamber that favors further apposition between the iris and lens surface ¹⁵¹. The aqueous humor trapped in the anterior chamber can cause posterior bowing and further friction between the peripheral posterior iris and zonules and lens structures leading to pigment dispersion showers.

Once those pigment granules are loose and floating in the aqueous humor, the flow of fluid carries them to other places inside your eye. The aqueous humor has a drainage system, the trabecular meshwork, and granules can accumulate in that meshwork and damage it ¹⁵², ¹⁴⁷, ¹⁵³. When that happens, aqueous humor fluid can’t drain out of your eye properly, causing high pressure inside your eye (ocular hypertension) and eventually causing glaucoma ¹⁴⁶, ¹⁵⁴. Without treatment, glaucoma causes irreversible, severe vision loss and blindness.

It was originally thought that pigment dispersion syndrome (PDS) and pigmentary glaucoma had a congenital cause or may be inherited (passed from parent to child), due to pigment loss from the iris from congenital mesodermal dysgenesis ¹⁵⁵ or atrophy or degeneration of the iris pigment epithelium (IPE) ¹⁵⁶, ¹⁵⁷. Possible genetic factors have been hypothesized to explain the familial presence of Krukenberg spindle ¹⁵⁸. Although the low incidence of familial pigment dispersion syndrome and pigmentary glaucoma, studies have reported a possible autosomal dominant inheritance for pigment dispersion syndrome ¹⁵⁹ and multifactorial pattern of inheritance ¹⁶⁰, which may play a role in the clinical expression of factors related to iris color, gender, and refractive error. Anderson et al. ¹⁶¹ reported a possible gene responsible for pigment dispersion syndrome located on chromosome 7Q35-q36 based on an autosomal dominant pattern observed in patients from 4 Irish families with pigment dispersion syndrome. Studies have reported several genetic locus associated with pigment dispersion syndrome, which include Glycoprotein nmb (GpnmbR150x), Gene Gpigment dispersion syndrome1 (glaucoma-related pigment dispersion syndrome 1), and (OMIM ID 600510) ¹⁶².

There are other reasons why pigment granules might break free from your iris. When there’s another cause for pigment displacement, that’s called “secondary pigment dispersion syndrome”.

Some causes of secondary pigment dispersion syndrome include:

• Eye injuries
• Tumors or growths inside your eye
• An artificial intraocular lens (IOL) that moves out of position

There are are several possible contributing factors for developing pigmentary glaucoma:

• Genetics. Research connects several DNA mutations with pigment dispersion syndrome and pigmentary glaucoma. That’s why pigment dispersion syndrome and pigmentary glaucoma can run in families but it’s usually in an unpredictable way. Direct examination of a small set of family members of patients with pigment dispersion syndrome showed that the disease was present in 2 out of 19 related individuals (12%) ¹⁶³. In another family, signs of pigment dispersion syndrome were present in 36% of subjects’ parents and 50% of their siblings (but in no children), suggesting a possible autosomal dominant inheritance pattern with incomplete penetrance ¹⁶⁴, ¹⁶⁵, ¹⁶⁶. Pigmentary glaucoma or pigment dispersion syndrome has also been described in families across multiple generations, with roughly 50% of family members described as having either condition, reinforcing the idea of an autosomal dominant inheritance pattern ¹⁶⁷, ¹⁶⁸.
• Male sex. Pigment dispersion syndrome and pigmentary glaucoma disproportionately affects males with case series showing a male to female ratio of between 2:1 and 5:1. Much less of a male predominance is noted for pigment dispersion syndrome, with case series describing male to female ratios between 1:1 and 2:1 ¹⁶⁹, ¹⁶⁵, ¹⁷⁰, ¹⁷¹, ¹⁷².
• Age. Diagnosis of pigment dispersion syndrome generally happens sometime between ages 20 and 50. Male patients with pigmentary glaucoma or pigment dispersion syndrome most often present in their 30s, whereas female patients typically present roughly a decade later in life ¹⁶⁵, ¹⁷⁰, ¹⁷¹, ¹⁷³, ¹⁷⁴. However, cases of pigment dispersion syndrome have been identified in patients as young as 12–15 years of age ¹⁷⁵, ¹⁷⁶, ¹⁷⁷. Pigment dispersion syndrome and pigmentary glaucoma may be most common in middle age once the lens has enlarged and the iris is flexible enough to form a concave position ¹⁴⁵.
• Race. People who are of Black or Asian descent have a lower risk for pigment dispersion syndrome and pigmentary glaucoma, while the risk for white people is higher ¹⁶⁹, ¹⁷⁰.
• Being nearsighted. People with myopia (nearsightedness) have a higher risk of pigment dispersion syndrome and pigmentary glaucoma. The more nearsighted you are (typically in the range of -3 to -4 D), the higher the risk of having pigment dispersion syndrome or having it turn into pigmentary glaucoma.
• Eye structure. Pigment dispersion syndrome and pigmentary glaucoma are more likely to happen when you have a deep anterior chamber. A deeper chamber means it can hold more fluid, which can make the iris “bow” backward toward the lens. Having flatter corneas can also be a contributing factor.
• Concave iris and posterior iris insertion. Concave iris and more posterior iris insertion are more common in patients with pigment dispersion syndrome or pigmentary glaucoma than in the normal population and result in greater iridolenticular contact in these individuals ¹⁷⁸, ¹⁷⁹, ¹⁸⁰.
• Flat corneas. Patients with pigment dispersion syndrome and pigmentary glaucoma have significantly flatter corneas than control subjects of similar age and refractive error ¹⁸¹, ¹⁸². A flat cornea might be more likely to result in burping of aqueous humor from the posterior chamber to the anterior chamber with blinking, resulting in increased irido-zonular contact ¹⁸².
• Excessive activity level. Research links pigment dispersion syndrome and pigmentary glaucoma to excessive exercise or physical activity. If you have pigment dispersion syndrome or pigmentary glaucoma, your eye specialist will likely ask about how physically active you are. If your activity level could contribute to your pigment dispersion syndrome or pigmentary glaucoma — either now or in the future — your eye specialist will likely recommend reducing your activity level.

The treatments for pigment dispersion syndrome and pigmentary glaucoma are very similar to treatments for other forms of glaucoma. The treatments can involve one or more of the following:

• Medications. Glaucoma medications lower pressure inside your eye in different ways. Some of them cause your pupil to relax more, improving aqueous humor drainage. Others slow the production of aqueous humor.
• Glaucoma surgery. This approach usually aims to improve fluid flow and drainage. Examples of glaucoma surgeries that do this include laser trabeculoplasty, and incisional surgery with either trabeculectomy or glaucoma drainage implant.

In many cases, a combination approach may offer the best results for people with pigment dispersion syndrome and pigmentary glaucoma. An example would be combining medications with laser surgery. This works well when medication alone doesn’t lower pressure inside your eye as much as you need.

Your eye specialist is your best source of information about treatment approaches. Your eye specialist can advise you on how treatments are likely to affect you, what your alternatives are and what kinds of side effects you can expect.

Figure 8. Krukenberg spindle

Footnote: Slit lamp photograph showing a Krukenberg spindle visible on the corneal endothelium.

Figure 9. Scheie stripe (pigment deposition along the insertion of the zonular fibers to the lens)

Pigmentary glaucoma causes

The iris of your eye is a flat ring of muscle that contains melanin, the pigment that gives your eyes their color. In front of and behind your iris are spaces filled with a fluid called aqueous humor. Pressure from the aqueous humor helps your eye hold its globe-like shape. When you have pigment dispersion syndrome (PDS), your iris can’t hold its shape and dips back too far ¹⁴⁵, ¹⁴⁶. That makes the back of your iris press against the muscle fibers that control your lens shape. As your iris widens or narrows, the iris rubs against those fibers and pigment granules in the iris wear away, like flakes of paint chipping away from a piece of wood ¹⁴⁵, ¹⁴⁶. Patients with pigment dispersion syndrome or pigmentary glaucoma have a 15-fold higher concentration of aqueous pigment granules in their anterior chamber compared to normal controls ¹⁴⁷.

The release of pigment showers in the anterior chamber is mainly due to the friction and rubbing between the iris pigment epithelium and posterior surface and zonules of the lens, which is favored by the backward posterior bowing of the iris that can be found in moderate myopic eyes that have more space ¹⁴⁸ and by reverse pupillary block mechanisms due to increased iridolenticular touch ¹⁴⁹. Ultrasonographical studies have shown that events leading to increased friction and contact between anterior chamber structures that favor reverse pupillary block include physiological events such as accommodation, blinking, eye movements, head positions, and exercise ¹⁵⁰. The increased contact between the iris and lens structures in eyes at risk of having a deep anterior chamber and/or a large iris can create a ball-valve mechanism in certain conditions in which the aqueous humor moves from the posterior chamber to the anterior chamber in a unidirectional mode, thus creating a high pressure in the anterior chamber that favors further apposition between the iris and lens surface ¹⁵¹. The aqueous humor trapped in the anterior chamber can cause posterior bowing and further friction between the peripheral posterior iris and zonules and lens structures leading to pigment dispersion showers.

Once those pigment granules are loose and floating in the aqueous humor, the flow of fluid carries them to other places inside your eye. The aqueous humor has a drainage system, the trabecular meshwork, and granules can accumulate in that meshwork and damage it ¹⁵², ¹⁴⁷, ¹⁵³. When that happens, aqueous humor fluid can’t drain out of your eye properly, causing high pressure inside your eye (ocular hypertension) and eventually causing glaucoma ¹⁴⁶, ¹⁵⁴. Without treatment, glaucoma causes irreversible, severe vision loss and blindness.

It was originally thought that pigment dispersion syndrome (PDS) and pigmentary glaucoma had a congenital cause or may be inherited (passed from parent to child), due to pigment loss from the iris from congenital mesodermal dysgenesis ¹⁵⁵ or atrophy or degeneration of the iris pigment epithelium (IPE) ¹⁵⁶, ¹⁵⁷. Possible genetic factors have been hypothesized to explain the familial presence of Krukenberg spindle ¹⁵⁸. Although the low incidence of familial pigment dispersion syndrome and pigmentary glaucoma, studies have reported a possible autosomal dominant inheritance for pigment dispersion syndrome ¹⁵⁹ and multifactorial pattern of inheritance ¹⁶⁰, which may play a role in the clinical expression of factors related to iris color, gender, and refractive error. Anderson et al. ¹⁶¹ reported a possible gene responsible for pigment dispersion syndrome located on chromosome 7Q35-q36 based on an autosomal dominant pattern observed in patients from 4 Irish families with pigment dispersion syndrome. Studies have reported several genetic locus associated with pigment dispersion syndrome, which include Glycoprotein nmb (GpnmbR150x), Gene Gpigment dispersion syndrome1 (glaucoma-related pigment dispersion syndrome 1), and (OMIM ID 600510) ¹⁶².

There are other reasons why pigment granules might break free from your iris. When there’s another cause for pigment displacement, that’s called “secondary pigment dispersion syndrome”.

Some causes of secondary pigment dispersion syndrome include:

• Eye injuries
• Tumors or growths inside your eye
• An artificial intraocular lens (IOL) that moves out of position

Risk factors for developing pigmentary glaucoma

There are are several possible contributing factors for developing pigmentary glaucoma:

• Genetics. Research connects several DNA mutations with pigment dispersion syndrome and pigmentary glaucoma. That’s why pigment dispersion syndrome and pigmentary glaucoma can run in families but it’s usually in an unpredictable way. Direct examination of a small set of family members of patients with pigment dispersion syndrome showed that the disease was present in 2 out of 19 related individuals (12%) ¹⁶³. In another family, signs of pigment dispersion syndrome were present in 36% of subjects’ parents and 50% of their siblings (but in no children), suggesting a possible autosomal dominant inheritance pattern with incomplete penetrance ¹⁶⁴, ¹⁶⁵, ¹⁶⁶. Pigmentary glaucoma or pigment dispersion syndrome has also been described in families across multiple generations, with roughly 50% of family members described as having either condition, reinforcing the idea of an autosomal dominant inheritance pattern ¹⁶⁷, ¹⁶⁸.
• Male sex. Pigment dispersion syndrome and pigmentary glaucoma disproportionately affects males with case series showing a male to female ratio of between 2:1 and 5:1. Much less of a male predominance is noted for pigment dispersion syndrome, with case series describing male to female ratios between 1:1 and 2:1 ¹⁶⁹, ¹⁶⁵, ¹⁷⁰, ¹⁷¹, ¹⁷².
• Age. Diagnosis of pigment dispersion syndrome generally happens sometime between ages 20 and 50. Male patients with pigmentary glaucoma or pigment dispersion syndrome most often present in their 30s, whereas female patients typically present roughly a decade later in life ¹⁶⁵, ¹⁷⁰, ¹⁷¹, ¹⁷³, ¹⁷⁴. However, cases of pigment dispersion syndrome have been identified in patients as young as 12–15 years of age ¹⁷⁵, ¹⁷⁶, ¹⁷⁷. Pigment dispersion syndrome and pigmentary glaucoma may be most common in middle age once the lens has enlarged and the iris is flexible enough to form a concave position ¹⁴⁵.
• Race. People who are of Black or Asian descent have a lower risk for pigment dispersion syndrome and pigmentary glaucoma, while the risk for white people is higher ¹⁶⁹, ¹⁷⁰.
• Being nearsighted. People with myopia (nearsightedness) have a higher risk of pigment dispersion syndrome and pigmentary glaucoma. The more nearsighted you are (typically in the range of -3 to -4 D), the higher the risk of having pigment dispersion syndrome or having it turn into pigmentary glaucoma.
• Eye structure. Pigment dispersion syndrome and pigmentary glaucoma are more likely to happen when you have a deep anterior chamber. A deeper chamber means it can hold more fluid, which can make the iris “bow” backward toward the lens. Having flatter corneas can also be a contributing factor.
• Concave iris and posterior iris insertion. Concave iris and more posterior iris insertion are more common in patients with pigment dispersion syndrome or pigmentary glaucoma than in the normal population and result in greater iridolenticular contact in these individuals ¹⁷⁸, ¹⁷⁹, ¹⁸⁰.
• Flat corneas. Patients with pigment dispersion syndrome and pigmentary glaucoma have significantly flatter corneas than control subjects of similar age and refractive error ¹⁸¹, ¹⁸². A flat cornea might be more likely to result in burping of aqueous humor from the posterior chamber to the anterior chamber with blinking, resulting in increased irido-zonular contact ¹⁸².
• Excessive activity level. Research links pigment dispersion syndrome and pigmentary glaucoma to excessive exercise or physical activity. If you have pigment dispersion syndrome or pigmentary glaucoma, your eye specialist will likely ask about how physically active you are. If your activity level could contribute to your pigment dispersion syndrome or pigmentary glaucoma — either now or in the future — your eye specialist will likely recommend reducing your activity level.

Disease Progression

• Intraocular pressure (IOP). A retrospective study from Olmstead County Minnesota found IOP > 21 mm Hg to be the only risk factor for progression from pigment dispersion syndrome to pigmentary glaucoma ¹⁶⁵.
• Degree of iridolenticular contact in patients with asymmetric disease. More iris–lens contact in one eye vs the other may be associated with greater risk of disease progression ¹⁸⁰.
• Greater trabecular meshwork pigmentation. In eyes with bilateral pigment dispersion syndrome, worse disease is typically found in the eye with more severe trabecular meshwork pigmentation.

Pigmentary glaucoma prevention

There’s nothing you can do to prevent pigment dispersion syndrome and pigmentary glaucoma. They happen unpredictably and people often don’t know they have these conditions until an eye specialist sees the changes during a routine eye exam or they start developing symptoms.

Pigmentary glaucoma signs and symptoms

Pigment dispersion syndrome (PDS) often doesn’t cause symptoms, so many people don’t know they have it. When it does, they’re usually similar to the most common glaucoma symptoms. Those include:

• Eye pain
• Eye redness
• Light sensitivity (photophobia)
• Blurred vision
• Seeing a glare or halos around lights after exercise.

In time, as the optic nerve becomes more damaged, you may notice that blank spots begin to appear in your field of vision. You usually won’t notice these blank spots in your day-to-day activities until the optic nerve is significantly damaged and these spots become large. If all of the optic nerve fibers die, blindness results. That is why it is so important to have an eye exam with your eye doctor.

Pigmentary glaucoma diagnosis

The most useful test for detecting pigment dispersion syndrome before it causes symptoms is a routine eye exam.

Some of the changes that pigment dispersion syndrome or pigmentary glaucoma can cause that show up on an eye exam include:

• Krukenberg spindle. This is a faint, vertical line in front of your pupil that’s the same color as your iris (see Figure 4 above). It happens when higher pressure inside your eye pushes fluid forward and keeps loose pigment granules pressed against the inside surface of your cornea.
• Radial iris defects. These are thin lines on your iris with worn-away pigment. They look like the spokes on a bicycle wheel. An eye specialist can see them using special lighting techniques.
• Pigment accumulation near the outer rim of your iris. Your eye specialist can use a technique called gonioscopy to see pigment granules deposited there.

Several glaucoma tests can help with diagnosing pigment dispersion syndrome and pigmentary glaucoma. Some of these are common features of a routine eye exam, while others are a little more specific. Your eye specialist can tell you which tests they think will be the most helpful for diagnosing or ruling out pigment dispersion syndrome and pigmentary glaucoma.

These tests often include one or more of the following:

• Visual acuity testing. A visual acuity test assesses how clearly someone can see at a distance, typically using a Snellen chart or other standardized chart. The test is performed by an optometrist or ophthalmologist and involves reading progressively smaller letters or identifying shapes, with the results expressed as a fraction like 20/20 or 6/6, indicating the distance at which the person can see the letters or shapes
• Visual field testing also called perimetry. This check of your peripheral (side) vision allows your eye care provider to find out how well you can see objects off to the side of your vision without moving your eyes. This test measures the entire area the forward-looking eye sees to document straight-ahead (central) and side (peripheral) vision. It measures the dimmest light seen at each spot tested. Each time patients perceive a flash of light, they respond by pressing a button.
• Depth perception testing. A depth perception test assesses your ability to see the world in three dimensions (3D) and judge distances accurately. It checks if your eyes work together and if your brain processes the visual information correctly. These tests use 3D images or patterns like the Randot Stereo test to gauge how well your eyes coordinate to perceive depth. Some tests involve holding a finger in front of your eyes and focusing on a distant object, checking for double vision of the finger.
• Tonometry. This measures the pressure inside your eye. Increased eye pressure is the most important risk factor for glaucoma. There are several methods of measuring eye pressure. The most common method is known as applanation, in which a tiny instrument contacts the eye’s surface after it is numbed with an eye drop.
  • Air-puff test. You’ll rest your chin on a machine and your eye specialist will blow a puff of air into your eye. This quick and painless test is used as part of a routine glaucoma screening. If the results show that your eye pressure is high, your eye specialist will do other eye-pressure tests to get a more accurate measurement.
  • Applanation tonometry. Your eye specialist will numb your eyes with drops before measuring your eye pressure using one of these methods:
    • You’ll rest your chin on a special magnifying device called a slit lamp. Your eye care specialist will examine your eye through the slit lamp while gently pressing a special tool on your eye to test the pressure.
    • Your eye care specialist will gently press a handheld device against your eye. The device measures your eye pressure.
• Pachymetry. Pachymetry is a simple, painless test that measures the thickness of the cornea, the clear front part of the eye. The eye doctor uses an ultrasonic wave instrument to help determine the thickness of the cornea and better evaluate eye pressure.
• Ophthalmoscopy. Your eye care specialist will do a dilated eye exam to look for damage to your optic nerve. This exam is part of a routine glaucoma check-up. You’ll be given eye drops that widen (dilate) your pupils (the openings that let light into your eyes). You’ll look straight ahead while your eye care specialist looks into your eye using a device with a light and magnifying lens.
• Slit lamp exam. A slit lamp exam is a common eye test that uses a microscope with a focused beam of light to examine the front of your eye and the back of your eye with the aid of special lenses.
• Gonioscopy. Gonioscopy is a specialized eye examination that allows an ophthalmologist to visualize the anterior chamber angle, the space between the iris and the cornea where fluid drains out of the eye. Gonioscopy is a crucial part of diagnosing and monitoring glaucoma and other eye conditions

If your eye specialist has a reason to suspect damage to your retina and/or optic nerve, they may also use additional types of eye imaging. These include:

• Optical coherence tomography (OCT). Optical Coherence Tomography (OCT) measures the reflection of laser light similar to the way that ultrasound measures the reflection of sound. Using this device, a 3D reconstruction of the optic nerve can be created. Optical coherence tomography (OCT) is valuable for monitoring morphological changes in the optic nerve and retinal nerve fiber layer, especially in patients with ocular hypertension and early-to-moderate glaucoma ¹¹⁷. The most recent advances of OCT include OCT-A, or OCT-Angiography, whereby the blood flow to vessels surrounding the optic nerve and in the macula can be measured. This is still an active area of research, but scientists do know that some patients’ optic nerves are very vulnerable to changes in optic nerve blood flow, and this new measurement may be useful in evaluating these patients.
• Heidelberg Retina Tomograph (HRT): Heidelberg Retina Tomograph (HRT) is also a laser that can produce a 3D representation of the optic nerve.
• Nerve Fiber Analyzer (GDx): Nerve Fiber Analyzer (GDx) uses laser light to measure the thickness of the nerve fiber layer.
• Fluorescein angiography. Fluorescein angiography is a diagnostic test used to examine the blood vessels in the retina and choroid of the eye. Fluorescein angiography involves injecting a fluorescent dye into the bloodstream and taking photographs of your retina and its blood vessels as the dye circulates, revealing potential blockages, leaks, or other abnormalities in the blood vessels. Fluorescein angiography is often recommended to find and diagnose eye disease including ¹¹⁸:
  • macular edema (swelling in the retina that distorts vision)
  • diabetic retinopathy (damaged or abnormal blood vessels in the eye caused by diabetes)
  • macular degeneration
  • blockage of veins inside the eye, called branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO)
  • macular pucker (a wrinkle in the retina caused by a buildup of fluid behind it)
  • ocular melanoma (a type of cancer affecting the eye)
  • rack changes in eye disease over time
  • target treatment areas
• Less commonly, ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI).

Pigmentary glaucoma treatment

Pigment dispersion syndrome treatment varies depending on how it is affecting your eye pressure (IOP):

• For pigment dispersion syndrome with normal or only slightly elevated intraocular pressure (IOP), there is a low risk of damage to the optic nerve. No treatment is needed other than seeing your ophthalmologist one time each year. They will monitor your condition by checking your IOP and looking for any changes in your vision.
• For pigment dispersion syndrome with elevated intraocular pressure (IOP), there is a greater risk of damage to the optic nerve. To lower IOP, you may be treated with medicated eye drops or laser therapy.
• When intraocular pressure (IOP) from pigment dispersion syndrome is so high that it damages the optic nerve, this is then called “pigmentary glaucoma”. In this case, treatment is needed and it may be medicated eye drops, laser therapy, or surgery.

Eye drops

Glaucoma treatment often starts with prescription eye drops. Some may decrease eye pressure by improving how fluid drains from your eye. Others decrease the amount of fluid your eye makes. Depending on how low your eye pressure needs to be, more than one eye drop may be prescribed.

Prescription eye drop medicines include:

• Prostaglandins. These increase the outflow of the fluid in your eye, helping to reduce eye pressure (IOP). Medicines in this category include latanoprost (Xalatan), travoprost (Travatan Z), tafluprost (Zioptan), bimatoprost (Lumigan) and latanoprostene bunod (Vyzulta). Possible side effects include mild reddening and stinging of the eyes, darkening of the iris, darkening of the pigment of the eyelashes or eyelid skin, and blurred vision. This class of medicine is prescribed for once-a-day use.
• Beta blockers. These reduce the production of fluid in your eye, helping to lower eye pressure. Examples include timolol (Betimol, Istalol, Timoptic) and betaxolol (Betoptic S). Possible side effects include difficulty breathing, slowed heart rate, lower blood pressure, impotence and fatigue. This class of medicine can be prescribed for once- or twice-daily use depending on your condition.
• Alpha-adrenergic agonists. These reduce the production of the fluid that flows throughout the inside of your eye. They also increase the outflow of fluid in the eye. Examples include apraclonidine (Iopidine) and brimonidine (Alphagan P, Qoliana). Possible side effects include irregular heart rate; high blood pressure; fatigue; red, itchy or swollen eyes; and dry mouth. This class of medicine is usually prescribed for twice-daily use but sometimes can be prescribed for use three times a day.
• Carbonic anhydrase inhibitors. These medicines reduce the production of fluid in your eye. Examples include dorzolamide and brinzolamide (Azopt). Possible side effects include a metallic taste, frequent urination, and tingling in the fingers and toes. This class of medicine is usually prescribed for twice-daily use but sometimes can be prescribed for use three times a day.
• Rho kinase inhibitor. This medicine lowers eye pressure by suppressing the rho kinase enzymes responsible for fluid increase. It is available as netarsudil (Rhopressa) and is prescribed for once-a-day use. Possible side effects include eye redness and eye discomfort.
• Miotic or cholinergic agents. These increase the outflow of fluid from your eye. An example is pilocarpine (Isopto Carpine). Side effects include headache, eye pain, smaller pupils, possible blurred or dim vision, and nearsightedness. This class of medicine is usually prescribed to be used up to four times a day. Because of potential side effects and the need for frequent daily use, these medicines are not prescribed very often anymore.

Combination drugs:

• Timolol/Brinzolamide (Azarga-not available in the US)
• Timolol/Dorzolamide (Cosopt)
• Timolol/Latanoprost (Xalacom-not available in the US)
• Timolol/Bimatoprost (Ganfort-not available in the US)
• Timolol/Brimonidine (Combigan)
• Brinzolamide/Brimonidine (Simbrinza)

Because some of the eye drop medicine is absorbed into the bloodstream, you may experience some systemic side effects unrelated to your eyes. To minimize this absorption, close your eyes for 1 to 2 minutes after putting the drops in. You also may press lightly at the corner of your eyes near your nose to close the tear duct for 1 to 2 minutes. Wipe off any unused drops from your eyelid.

You may be prescribed multiple eye drops or need to use artificial tears. Make sure you wait at least five minutes in between using different drops.

Never change or stop taking your glaucoma medications without talking to your ophthalmologist. If you are about to run out of your medication, ask your ophthalmologist if you should have your prescription refilled.

Oral medicines

Eye drops alone may not bring eye pressure down to the desired level. So an eye doctor also may prescribe oral medicine. This medicine is usually a carbonic anhydrase inhibitor. Possible side effects include frequent urination, tingling in the fingers and toes, depression, stomach upset, and kidney stones.

Surgery, laser and other therapies

Other treatment options include laser therapy and surgery. The following techniques may help to drain fluid within the eye and lower eye pressure:

• Laser trabeculoplasty is an option if eye drops can’t be tolerated. Laser trabeculoplasty also may be used if medicine hasn’t slowed the progression of the glaucoma. An eye doctor also may recommend laser surgery before using eye drops. It’s done in the eye doctor’s office. An eye doctor uses a small laser to improve the drainage of the tissue located at the angle where the iris and cornea meet. It may take a few weeks before the full effect of this procedure becomes apparent.
• Laser iridotomy. Laser iridotomy is for people who have angle-closure glaucoma. The ophthalmologist uses a laser to create a tiny hole in the iris. This hole helps fluid flow to the drainage angle.
• Glaucoma filtration surgery also called a trabeculectomy. The eye doctor (ophthalmologist) creates an opening in the white of your eye, which also is known as the sclera. This is where your eye surgeon creates a tiny flap in the sclera. They will also create a bubble like a pocket in the conjunctiva called a filtration bleb. It is usually hidden under the upper eyelid and cannot be seen. Aqueous humor will be able to drain out of the eye through the flap and into the bleb, lowering eye pressure. In the bleb, the fluid is absorbed by tissue around your eye.
• Drainage tubes. In this procedure, the eye surgeon inserts a small drainage tube in your eye to drain excess fluid to lower eye pressure. The glaucoma drainage implant sends the fluid to a collection area called a reservoir. Your eye surgeon creates this reservoir beneath the conjunctiva. The fluid is then absorbed into nearby blood vessels.
• Minimally invasive glaucoma surgery (MIGS). An eye doctor may suggest a minimally invasive glaucoma surgery (MIGS) procedure to lower eye pressure. This procedure generally require less immediate postoperative care and have less risk than trabeculectomy or using a drainage device. A minimally invasive glaucoma surgery (MIGS) procedure is often combined with cataract surgery. There are a number of minimally invasive glaucoma surgery (MIGS) techniques available.
• Cataract surgery. For some people with narrow angles, removing the eye’s natural lens can lower eye pressure. With narrow angles, the iris and the cornea are too close together. This can cover (block) the eye’s drainage channel. Removing the eye’s lens with cataract surgery creates more space for fluid to leave the eye. This can lower eye pressure.

After your procedure, you’ll need to see your eye doctor for follow-up exams. You can expect to visit your ophthalmologist about every 3 to 6 months. However, this can vary depending on your treatment needs. And you may eventually need to undergo additional procedures if your eye pressure begins to rise or other changes happen in your eye.

Laser iridotomy

Some reports have demonstrated that laser iridotomy can eliminate iris concavity and reduce iridolenticular contact in eyes with pigment dispersion syndrome ¹⁸⁴, ¹⁸⁵, ¹⁸⁶, ¹⁵¹. However, some eyes may retain a concave iris configuration even after laser treatment ¹⁸⁷. In addition, laser iridotomy may not always prevent exercise-induced pigment release and intraocular pressure (IOP) elevation ¹⁸⁸, ¹⁸⁹. There is limited data on whether laser iridotomy is effective in controlling intraocular pressure (IOP) in patients with pigment dispersion syndrome or pigmentary glaucoma. While one small randomized controlled trial of 21 patients demonstrated a lower rate of IOP elevation over 2 years of follow-up in eyes treated with laser iridotomy as compared to eyes that were not ¹⁹⁰, a retrospective study of 60 patients did not suggest any laser iridotomy benefit ¹⁹¹. A 2016 Cochrane review based on 5 randomized controlled trials showed that there was inadequate evidence to use peripheral iridotomy to treat pigmentary glaucoma, and further studies are needed to evaluate the clinical use of this laser treatment in pigment dispersion syndrome and pigmentary glaucoma patients ¹⁹².

Follow-up after laser iridotomy is similar to the follow-up for iridotomy performed for angle closure glaucoma.

Rise in IOP after laser iridotomy is greater in pigment dispersion syndrome and pigmentary glaucoma patients than in patients with occludable angles. Ways to mitigate this concern include the use of lower energy levels for surgery, the administration of alpha-adrenergic agonists before and after the laser treatment, and the use of argon laser instead of YAG laser, as it is less disruptive in terms of pigment liberation and inflammation ¹⁹³.

Pigmentary glaucoma prognosis

Not everyone who has pigment dispersion syndrome will have it lead to pigmentary glaucoma. But the risk of it doing so goes up over time. About 10% of people with pigment dispersion syndrome will develop pigmentary glaucoma within 10 years. That number rises to 15% after 15 years  ¹³⁸. The lifetime risk is between 35% and 50%.

Because pigment dispersion syndrome and pigmentary glaucoma usually start much earlier in life than other forms of glaucoma, it’s important to manage this condition as best you can. Part of that is seeing your eye specialist for regular follow-ups. Those visits can happen every three to six months or yearly, depending on the details of your case. Follow-up visits allow your eye doctor to detect pressure increases and recommend treatment to prevent damage or at least stop it from getting worse.

Ongoing monitoring and managing of your pigment dispersion syndrome or pigmentary glaucoma are key to keeping your eyesight. It’s rare for people who prioritize follow-up visits and manage their condition based on their specialist’s recommendations to have permanent blindness ¹⁹⁴.

In a community-based study of 113 patients with pigment dispersion syndrome or pigmentary glaucoma who were followed for a median of 6 years, 1 patient experienced unilateral blindness and another became bilaterally blind ¹⁶⁵. In the same study, 10% of patients with pigment dispersion syndrome progressed to pigmentary glaucoma at 5 years, while 15% progressed at 10 years; 23% of patients were noted to have pigmentary glaucoma at diagnosis  ¹⁶⁵. Visual fields worsened in 44% of patients with pigmentary glaucoma over a mean follow-up period of 6 years. A group of patients followed from a glaucoma clinic showed higher rates of progression (35% over a median follow-up at 15 years), and roughly 40% of patients with pigmentary glaucoma experienced worsening of optic nerve damage ¹⁷⁴. In some cases, trabecular meshwork pigmentation and iris transillumination defects have been observed to normalize over time, as has elevated IOP, suggesting return of normal trabecular meshwork function ¹⁹⁵, ¹⁷², ¹⁷⁷, ¹⁹⁶. Some older patients with a diagnosis of normal tension glaucoma have been identified with iris transillumination defects and dense trabecular meshwork pigmentation, suggesting they may have had pigmentary glaucoma at some point with subsequent IOP normalization due to cessation of pigment release ¹⁹⁷. In such patients, the presence of “pigment reversal sign” helps to distinguish between different types of glaucoma.

Childhood glaucoma

Childhood glaucoma also known as congenital glaucoma, pediatric glaucoma, infantile glaucoma is a rare childhood eye condition where high pressure builds up inside the eye during fetal development that is either present at birth or develops during very early childhood, potentially causing vision loss and even blindness if left untreated ¹⁹⁸, ¹⁹⁹, ²⁰⁰, ²⁰¹, ²⁰², ²⁰³, ²⁰⁴. Glaucoma can affect one eye or both. Children with childhood glaucoma have ocular hypertension (high pressure inside their eyes). The fluids in their eyes (aqueous humor) fail to drain normally, so they build up, raising the pressure inside. This puts stress on their optic nerves and can eventually cause structural changes to their eyes. Childhood glaucoma is typically diagnosed within the first few months of life commonly in children under 2 years of age caused by a developmental defect in the eye’s drainage system, preventing fluid from flowing out properly and is  often suspected when there is eye enlargement at birth ²⁰¹. Congenital glaucoma affects about 1 in 10,000 children under 2 years of age in the United States ²⁶, ²⁷.

Eye doctors often classify childhood glaucoma by the age when it first appears ²⁰³:

1. Newborn (neonatal) onset (0-1 month)
2. Infantile onset (>1-24 months)
3. Late onset or late-recognized (>24 months)
4. Spontaneously arrested primary congenital glaucoma (very rare), classic findings of eye stretching including Haab striae with normal intraocular pressure (IOP); must follow as glaucoma suspects.

Primary congenital glaucoma commonly presents between the ages of 3-9 months, but the most severe form is the newborn onset ²⁰³. Infantile glaucoma affects individuals between the ages of 1 and 36 months ²⁰⁵, while juvenile glaucoma is used to indicate individuals diagnosed with glaucoma between the ages of 3 and 40 years ²⁰⁶. In most cases, childhood glaucoma is diagnosed by the age of six months, with 80% diagnosed in the first year of life.

The elevated intraocular pressure (IOP) is associated with the classic “triad” of symptoms such as eyes are sensitive to light (photophobia), excessive tearing of the eye (epiphora) and uncontrollable muscle twitching that forces eyes closed (blepharospasm), which occurs due to rapid expansion of the child’s eye causing buphthalmos (“ox-eyed” in Greek), corneal enlargement, horizontal or oblique breaks in Descemet membrane (Haab striae) and subsequent corneal edema and opacification (see Figure 3 and 4 below). If Haab striae and buphthalmos are seen without elevated intraocular pressure (IOP), optic nerve cupping or corneal edema, then the patient has spontaneously arrested primary congenital glaucoma ¹⁹⁹. It’s very important to recognize and treat childhood glaucoma as soon as possible to minimize the damage and vision loss it can cause in your child.

Due to the elasticity of the eye in young children, the 2013 International Classification System for Childhood Glaucoma defined childhood glaucoma as irreversible or reversible damage to the whole eye and not just the optic nerve as glaucoma is defined for adults ¹⁹⁹. Therefore, additional important clinical signs in primary congenital glaucoma, besides elevated intraocular pressure (IOP) and optic nerve cupping, are corneal enlargement and clouding, Haab striae, and buphthalmos. Not all signs are always present, however, and other parts of the eye also stretch with elevated intraocular pressure (IOP). Diagnosis of childhood glaucoma can be delayed if corneas remain clear, despite being enlarged, and bilateral primary congenital glaucoma can be missed if signs and symptoms are mild in one eye. Irreversible vision loss results if elevated intraocular pressure (IOP) is untreated or uncontrolled in primary congenital glaucoma. Optic nerve damage occurs, and focal corneal edema overlying Haab striae, which can be single or multiple, can lead to permanent corneal scarring and opacification. This corneal scarring can obscure the visual axis or cause astigmatism (a common eye condition where the cornea or sometimes the lens doesn’t have a perfectly round spherical shape leading to blurry or distorted vision at all distances, this irregular shape causes light rays to focus at multiple points on the retina instead of a single point, resulting in a fuzzy or wavy image) with or without refractive amblyopia. Amblyopia may also develop due to optic nerve damage, anisometropia (a condition of asymmetric refraction between the two eyes), strabismus or a combination.

There are many causes of childhood glaucoma. It can be hereditary or it can be associated with other eye disorders.

• If childhood glaucoma cannot be attributed to any other cause, other noticeable eye defects or systemic problem, it is classified as primary congenital glaucoma. The cause of primary congenital glaucoma is not completely understood, though there is significant research to suggest that the trabecular meshwork is immature and compressed. Studies suggest that the normal posterior migration of embryonic neural crest cells destined to become the trabecular meshwork is abnormally halted ²⁰⁷. The drainage angle where the inside of the sclera (the white of your eye) and the outer edge of your iris meet of children with primary congenital glaucoma is described as immature, thick, and compressed. High intraocular pressures (IOP) are believed to be a consequence of increased resistance to aqueous outflow in this abnormal trabecular meshwork. Researchers have identified several gene mutations that can lead to primary congenital glaucoma. Mutations in the CYP1B1 (cytochrome P450 family 1 subfamily B member 1) gene are the predominant genetic anomalies linked to primary congenital glaucoma ²⁰⁸.
• If childhood glaucoma is a result of another eye disorder, eye injury, or other disease, it is classified as secondary childhood glaucoma.
  • Associated with eye abnormalities e.g., Axenfeld-Rieger syndrome, aniridia (a rare genetic eye disorder characterized by the complete or partial absence of the iris, the colored part of the eye), iridotrabecular dysgenesis, Peter’s anomaly, sclerocornea (a rare, non-progressive, congenital condition where the cornea, normally transparent, becomes opaque and blends with the sclera, the white part of the eye), microcornea (a congenital condition where the cornea, the transparent front part of the eye, is smaller than normal, with a horizontal diameter of less than 10-11 mm), microphthalmos (a developmental disorder of the eye where one or both eyes are abnormally small and have anatomical malformations), ectopia lentis, persistent fetal vasculature, oculodermal melanocytosis, posterior polymorphous dystrophy,
  • Associated with systemic abnormalities e.g., chromosomal disorders like trisomy 21 (Down syndrome), connective tissue disorders such as Marfan syndrome, Stickler syndrome (a group of genetic disorders that primarily affect connective tissues, particularly in the face, eyes, ears, and joints), phakomatoses (a group of genetic disorders also known as neurocutaneous syndromes or neuro-oculo-cutaneous syndromes characterized by systemic hamartomas, primarily affecting the central nervous system, eyes, and skin) common examples include neurofibromatosis (types 1 and 2), Sturge-Weber syndrome, tuberous sclerosis, Lowe syndrome and von Hippel-Lindau disease
  • Glaucoma secondary to acquired causes e.g., retinopathy of prematurity, eye trauma, intraocular tumors, uveitis, eye inflammation, lens‑induced (with/without pupillary block), steroid-induced, intraocular infections, maternal rubella (congenital rubella syndrome), raised episcleral venous pressure
  • Glaucoma after surgery for congenital cataract.

Childhood glaucoma commonly starts with a defect in the way your child’s eye develops. The most common defect is in the trabecular meshwork, the tissue that the eye fluids (aqueous humor) drain through. When the trabecular meshwork doesn’t develop right, the aqueous humor fluids don’t drain properly. The buildup of fluids (aqueous humor) causes pressure in your child’s eye, which damages their optic nerve. It can also cause their cornea to enlarge, stretch, tear and scar. This process is progressive. How fast it progresses depends on how severe the defect in your child’s eye is, how much fluid (aqueous humor) is building up and how high the pressure is inside the eye (intraocular pressure [IOP]). When glaucoma appears in young infants, it’s because these conditions were already progressing during fetal development. When symptoms appear later, it’s because these conditions were less severe at birth, so they took longer to build up.

To diagnose childhood glaucoma, your child’s eye doctor will ask about your child’s medical history and do a complete eye examination of your child.

Furthermore, your child’s eye doctor may perform diagnostic procedures such as:

• Visual acuity test – the common eye chart test (with letters and images), which measures vision ability at various distances.
• Pupil dilation – the pupil is widened with eyedrops to allow a close-up examination of the eye’s retina and optic nerve.
• Visual field – a test to measure a child’s side (peripheral) vision. Lost peripheral vision may be an indication of glaucoma.
• Tonometry – a standard test to determine the fluid pressure inside the eye.

Younger children may be examined with hand-held instruments, whereas older children are often examined with standard equipment that is used with adults. An eye examination can be difficult for a child. It is important that parents encourage cooperation. At times, the child may have to be examined under anesthesia, especially young children, in order to examine the eye and the fluid drainage system, and to determine the appropriate treatment.

Specific treatment for glaucoma will be determined by your child’s eye doctor based on:

• your child’s age, overall health, and medical history
• extent of the disease
• your child’s tolerance for specific medications, procedures, or therapies
• expectations for the course of the disease
• your opinion or preference

It is important for treatment of childhood glaucoma to start as early as possible. Treatment may include:

• Medications. Some medications cause the eye to produce less fluid, while others lower pressure by helping fluid drain from the eye.
• Surgery. The purpose of surgery is to create a new opening for fluid to leave the eye. Surgical procedures are performed by using microsurgery or lasers.

Both medications and surgery have been successfully used to treat childhood glaucoma. However, surgery is the primary treatment modality for primary congenital glaucoma. In managing secondary childhood glaucoma, medications is the first-line treatment ²⁰⁹.

Surgical procedures used to treat glaucoma in children include the following:

• Trabeculotomy and goniotomy.
  • Trabeculotomy is a surgical procedure, primarily used in the treatment of childhood glaucoma, that creates a new drainage opening in the eye’s trabecular meshwork, improving the outflow of aqueous humor and reducing the intraocular pressure (IOP).
  • Goniotomy is a microinvasive glaucoma surgery (MIGS) technique that improves fluid flow in the eye to lower intraocular pressure (IOP). A goniotomy involves making a small incision within the trabecular meshwork, the eye’s natural drainage system, to create a more efficient pathway for fluid outflow. This procedure can be used to treat conditions like childhood glaucoma.
• Trabeculectomy. Trabeculectomy is a surgical procedure that involves the removal of part of the trabecular meshwork drainage system, allowing the fluid to drain from the eye. Trabeculectomy works by creating a new drainage pathway for the fluid (aqueous humor) within the eye, allowing it to drain into a space beneath the outer layer of the eye (conjunctiva). This new pathway, called a bleb, helps reduce eye pressure and can slow or prevent further vision loss.
• Iridotomy. Iridotomy is a surgical procedure to treat or prevent angle-closure glaucoma, a condition where the iris (colored part of the eye) blocks the drainage angle, leading to increased eye pressure. The eye surgeon may use a laser to create this hole. Laser iridotomy involves using a laser to create a small hole in the iris, allowing fluid to flow freely and preventing or relieving pressure build-up.
• Cyclophotocoagulation. Cyclophotocoagulation is a laser procedure that uses a laser beam to freeze selected areas of the ciliary body – the part of the eye that produces aqueous humor – to reduce the production of fluid and reduce intraocular pressure (IOP). Cyclophotocoagulation is a type of cyclodestruction procedure, meaning it aims to reduce intraocular pressure (IOP) by damaging the ciliary body, a key part of the eye that produces aqueous humor. This type of surgery may be performed with severe cases of childhood glaucoma.

The primary treatment of primary congenital glaucoma is angle surgery, either goniotomy or trabeculotomy, to lower intraocular pressure (IOP) by improving aqueous outflow. If angle surgery is not successful, trabeculectomy enhanced with mitomycin C or glaucoma implant surgery with a Molteno, Baerveldt, or Ahmed implant can be performed. In refractory cases, cycloablation can be performed using an Nd:YAG laser, diode laser, or cryotherapy, with diode laser being the most widely used device. Medications, either topically or orally, is typically used as a temporizing measure prior to surgery and to help decrease corneal clouding to facilitate goniotomy, and to supplement intraocular pressure (IOP) control after surgery.

Figure 10. Congenital glaucoma

Footnote: Primary congenital glaucoma with cloudy corneas.

Figure 11. Buphthalmos in primary congenital glaucoma

Footnotes: Buphthalmos is derived from “ox-eyed” in Greek. Buphthalmos describes the visible enlargement of the eyeball at birth or soon after due to increased intraocular pressure (IOP) ²¹⁰. Buphthalmic eyes typically have corneal diameters exceeding 12 mm in newborns or 13 mm in children older than 1 year ²¹⁰. The corneal diameters sometimes exceed 16 mm, with the globe appearing noticeably enlarged. Normal corneal diameters are 9.5 to 10.5 mm at birth and 11 to 12 mm by age 1 ²¹¹. Primary congenital glaucoma (onset at birth) and primary infantile glaucoma (onset after birth to 3 years) are the most frequent causes of buphthalmos ²¹², ²¹³. Corneal edema, increased corneal diameter, and optic disc cupping are the classical manifestations in patients with buphthalmos ²¹⁴.

Figure 12. Haab striae in primary congenital glaucoma

Footnotes: Haab striae are curvilinear breaks in Descemet’s membrane, resulting acutely from stretching of the cornea in primary congenital glaucoma. Haab striae are typically oriented horizontally or concentric to the limbus in contrast to Descemet’s tears, resulting from birth trauma, that are usually vertical or obliquely oriented.

Childhood Glaucoma types

According to the Childhood Glaucoma Research Network (CGRN) classification, childhood glaucoma is classified into primary glaucoma, secondary glaucoma and glaucoma suspect (Figure 6) ¹⁹⁹.

1. Primary childhood glaucoma encompasses primary congenital glaucoma (PCG) and juvenile open-angle glaucoma (JOAG)
   • Primary congenital glaucoma (PCG) is further classified as:
     • Neonatal onset (0–1 month of age),
     • Infantile onset (1–24 months of age),
     • Late onset or late recognition of disease (>2 years of age),
     • Spontaneously arrested primary congenital glaucoma (PCG). Spontaneously arrested primary congenital glaucoma (PCG) was diagnosed in the presence of buphthalmos and Haab striae, with normal intraocular pressure (IOP), normal-appearing optic discs, and no corneal edema ²¹⁷.
   • Juvenile open-angle glaucoma (JOAG) is defined as a diagnosis of open-angle glaucoma between age 4 to less than 40 years of age, not exhibiting features of primary congenital glaucoma (PCG) (i.e., buphthalmos, Haab striae). Individuals were further reported to have normal-tension glaucoma (NTG, described as maximum recorded IOP ≤ 21 mmHg) or high-tension glaucoma (HTG, maximum recorded IOP > 21 mmHg) in the affected eye/s, where possible.
2. Secondary childhood glaucoma is classified based on the underlying pathology. Secondary childhood glaucoma includes glaucoma associated with nonacquired ocular anomalies (e.g., Axenfeld-Rieger spectrum, iris hypoplasia, aniridia), glaucoma associated with nonacquired systemic disease (e.g., phacomatoses, Juvenile Idiopathic Arthritis [JIA]), and glaucoma associated with acquired conditions (e.g., uveitis, trauma, or intraocular surgery). Glaucoma following cataract surgery is classified separately ²¹⁸.
   • Glaucoma associated with acquired conditions in which glaucoma is secondary to a condition that is not present at birth.
   • Glaucoma associated with nonacquired ocular anomalies in which glaucoma is secondary to a nonacquired condition that is predominantly ocular.
   • Glaucoma associated with nonacquired systemic disease in which glaucoma develops in the presence of a disease that is predominantly systemic, with or without ocular manifestations.
   • Glaucoma following cataract surgery in which cataract surgery precedes glaucoma onset regardless of any coexisting ocular or systemic abnormality.

As per the Childhood Glaucoma Research Network (CGRN) classification, individuals were classified as having glaucoma associated with nonacquired ocular anomalies, even in the presence of systemic disease, if the disorder was predominantly ocular ¹⁹⁹. This includes individuals with Peters’ anomaly or Axenfeld-Rieger spectrum (ARS) ¹⁹⁹. Peters anomaly is a rare congenital disorder characterized by central corneal opacity with a relatively clear peripheral cornea, often with iris and lens adhesions ²¹⁹. Peters anomaly can have associated systemic abnormalities like cleft lip, cleft palate, short stature, abnormal ears, and intellectual disability ²¹⁹. Individuals with only posterior embryotoxon and no systemic features were not considered to have Axenfeld-Rieger spectrum (ARS) as per the 9th Consensus Report of the World Glaucoma Association ¹⁹⁹. When an individual had anterior segment dysgenesis (ASD) that did not fit a specific phenotype, experts used the term “unclassified ASD” as recommended by Idrees et al ²²⁰. Individuals with primary angle-closure glaucoma were classified as having glaucoma associated with nonacquired ocular anomalies because this entity is caused by anatomic disorders of the iris, lens, and retrolenticular structures ²²¹.

Figure 13. Childhood Glaucoma types

Footnotes: Childhood Glaucoma Research Network and World Glaucoma Association algorithm for the classification of childhood glaucoma.

Abbreviations: AL = axial length; C/D = cup-disc; JOAG = juvenile open-angle glaucoma; ROP = retinopathy of prematurity; VF = visual field

Congenital glaucoma causes

There are many causes of childhood glaucoma. It can be hereditary or it can be associated with other eye disorders.

• If childhood glaucoma cannot be attributed to any other cause, other noticeable eye defects or systemic problem, it is classified as primary congenital glaucoma. The cause of primary congenital glaucoma is not completely understood, though there is significant research to suggest that the trabecular meshwork is immature and compressed. Studies suggest that the normal posterior migration of embryonic neural crest cells destined to become the trabecular meshwork is abnormally halted ²⁰⁷. The drainage angle where the inside of the sclera (the white of your eye) and the outer edge of your iris meet of children with primary congenital glaucoma is described as immature, thick, and compressed. High intraocular pressures (IOP) are believed to be a consequence of increased resistance to aqueous outflow in this abnormal trabecular meshwork. Researchers have identified several gene mutations that can lead to primary congenital glaucoma. Mutations in the CYP1B1 (cytochrome P450 family 1 subfamily B member 1) gene are the predominant genetic anomalies linked to primary congenital glaucoma ²⁰⁸.
• If childhood glaucoma is a result of another eye disorder, eye injury, or other disease, it is classified as secondary childhood glaucoma.
  • Associated with eye abnormalities e.g., Axenfeld-Rieger syndrome, aniridia (a rare genetic eye disorder characterized by the complete or partial absence of the iris, the colored part of the eye), iridotrabecular dysgenesis, Peter’s anomaly, sclerocornea (a rare, non-progressive, congenital condition where the cornea, normally transparent, becomes opaque and blends with the sclera, the white part of the eye), microcornea (a congenital condition where the cornea, the transparent front part of the eye, is smaller than normal, with a horizontal diameter of less than 10-11 mm), microphthalmos (a developmental disorder of the eye where one or both eyes are abnormally small and have anatomical malformations), ectopia lentis, persistent fetal vasculature, oculodermal melanocytosis, posterior polymorphous dystrophy,
  • Associated with systemic abnormalities e.g., chromosomal disorders like trisomy 21 (Down syndrome), connective tissue disorders such as Marfan syndrome, Stickler syndrome (a group of genetic disorders that primarily affect connective tissues, particularly in the face, eyes, ears, and joints), phakomatoses (a group of genetic disorders also known as neurocutaneous syndromes or neuro-oculo-cutaneous syndromes characterized by systemic hamartomas, primarily affecting the central nervous system, eyes, and skin) common examples include neurofibromatosis (types 1 and 2), Sturge-Weber syndrome, tuberous sclerosis, Lowe syndrome and von Hippel-Lindau disease
  • Glaucoma secondary to acquired causes e.g., retinopathy of prematurity, eye trauma, intraocular tumors, uveitis, eye inflammation, lens‑induced (with/without pupillary block), steroid-induced, intraocular infections, maternal rubella (congenital rubella syndrome), raised episcleral venous pressure
  • Glaucoma after surgery for congenital cataract.

Childhood glaucoma commonly starts with a defect in the way your child’s eye develops. The most common defect is in the trabecular meshwork, the tissue that the eye fluids (aqueous humor) drain through. When the trabecular meshwork doesn’t develop right, the aqueous humor fluids don’t drain properly. The buildup of fluids (aqueous humor) causes pressure in your child’s eye, which damages their optic nerve. It can also cause their cornea to enlarge, stretch, tear and scar. This process is progressive. How fast it progresses depends on how severe the defect in your child’s eye is, how much fluid (aqueous humor) is building up and how high the pressure is inside the eye (intraocular pressure [IOP]). When glaucoma appears in young infants, it’s because these conditions were already progressing during fetal development. When symptoms appear later, it’s because these conditions were less severe at birth, so they took longer to build up.

Primary congenital glaucoma

Most cases of primary congenital glaucoma are sporadic without a family history of the disease ²⁰¹, ²⁰³, ¹⁹⁸, ²²². The significant risk factors for primary congenital glaucoma are consanguineous marriage also known as cousin marriage (a marriage between two individuals related by blood, typically first or second cousins, or closer), genetic predisposition, and first-degree relatives (including siblings) with glaucoma. Approximately 90% of cases belong to this category. About 10-40% are familial with an autosomal recessive inheritance pattern with incomplete penetrance ranging from 40% to 100% ¹⁹⁹, ²⁰¹. Autosomal dominant inheritance has also been reported ²²³.

Mutations in the CYP1B1 (cytochrome P450 family 1 subfamily B member 1) gene are the predominant genetic anomalies linked to primary congenital glaucoma ²⁰⁸. The CYP1B1 (cytochrome P450 family 1 subfamily B member 1) gene is essential for the formation of the trabecular meshwork and the anterior portion of the eye. The CYP1B1 gene codes for an enzyme that metabolizes compounds vital for the developing eye, such as fatty acids and vitamins ²²⁴, and is expressed in fetal and adult neuroepithelium and ciliary body ¹⁹⁹, ²²⁵. Severe trabecular meshwork atrophy is seen in mouse models deficient of CYP1B1 ²²⁶. In zebrafish, CYP1B1 has been found to indirectly affect neural crest migration to the anterior segment and angle by playing a role in ocular fissure closure ²²⁷. While the exact mechanism by which CYP1B1 mutations causes primary congenital glaucoma is unknown, scientists know that levels of a protein product of this gene are inadequate for appropriate embryogenic ocular development, resulting in goniodysgenesis. A twin study demonstrated that CYP1B1 gene activity may be implicated in a common pathway primary congenital glaucoma, juvenile open-angle glaucoma (JOAG), and primary open angle glaucoma (POAG). Recent studies propose that the CYP1B1 mutation may also interfere with the ability of retinal ganglion cells to respond to the stress generated by high intraocular pressure (IOP) and the resultant increase in reactive oxygen species ²²⁸, ²²⁹. CYP1B1 mutations are associated with 15-20% of primary congenital glaucoma cases in Japan and the United States, 75-100% of cases in Saudi Arabia, and all cases in Slovakia Roma ²³⁰, ²³¹.

Additional implicated genes, including LTBP2 (latent transforming growth factor beta binding protein 2), are located next to the GLC3C locus ²³², ²³³. These genetic mutations cause a dysfunctional trabecular meshwork, obstructing proper drainage of aqueous fluid and increasing intraocular pressure (IOP). Several gene loci have been linked to primary congenital glaucoma, which includes GLC3A, GLC3B, GLC3C, GLC3D, and GLC3E. Locus GLC3A has been linked to the CYP1B1 gene ²³⁴.

Mutations in CYP1B1 (cytochrome P450 family 1 subfamily B member 1) gene are most commonly responsible for autosomal recessively inherited cases ²³⁵. A recent systematic review reported that CYP1B1 was the most common gene mutation reported in the current literature and that the other gene variants related to childhood glaucoma included MYOC (myocilin), LTBP2, FOXC1 (forkhead box C1), PITX2 (paired-like homeodomain transcription factor 2), ANGPT1 (angiopoietin 1) and TEK (or receptor tyrosine kinase) ²³⁶.

Currently, the chance of identifying a genetic cause is 40% when genetic testing is done ²³⁷.

Studies from Western countries have reported primary congenital glaucoma incidences ranging from 1 per 10,000 to 1 per 30,000 live births ²³⁸. The incidence is reportedly as high as 1/2500 in countries like Saudi Arabia. Slovakian Roma have the greatest incidence at 1/1250 ²³⁹. The higher incidence in particular countries and ethnic groups is related to the higher prevalence of consanguineous marriages, particularly in those with frequent cousin-cousin marriages.

Approximately 65% to 80% of cases of primary congenital glaucoma are bilateral ²³⁷. A male-to-female ratio of 3:2 has been reported in studies from the United States and Europe ²⁴⁰ A Japanese study quoted a male-to-female ratio of 6:5 in patients with CYP1BI mutation and 19:2 without the mutation ²⁴¹. Several studies have reported that glaucoma accounted for 7% to 18% of children registered in blind schools ²⁴², ²⁴³. Asia, India, and Saudi Arabia have a mean presentation age of 3 to 4 months compared to 11 months in Western countries ²⁴⁴. primary congenital glaucoma appears earlier in high-incidence ethnicities.

Risk factors for developing primary congenital glaucoma

The only known risk factors are genetic – consanguinity and affected siblings. Parents of primary congenital glaucoma patients should be aware that the chance of a second child with primary congenital glaucoma is a small but real risk that usually is no more than 3%. If two children have the disease, then the risk of subsequent children increases to as high as 25%, with the assumption of autosomal recessive inheritance ²⁴⁰. In 2018, Yu-Wai-Man et al ²³⁷ compiled the clinical utility gene card for primary congenital glaucoma which describes situations for which gene testing may be useful. Carriers of the CYP1B1 gene mutation and double null CYP1B1 alleles are, on average, more likely to have higher intraocular pressure (IOP) and require more surgeries ²²⁴.

Primary congenital glaucoma pathophysiology

The primary pathophysiologic process in primary congenital glaucoma is the defect in the development of the trabecular meshwork and the anterior chamber angle. This hampers the aqueous outflow through the anterior chamber and increases intraocular pressure (IOP). In 1955 and 1966, Barkan ²⁴⁵ and Worst ²⁴⁶ proposed that the presence of an imperforate membrane at the angle of the anterior chamber impeded the aqueous outflow; this was later disproved. The obstruction site is trabecular, as opposed to pretrabecular. The isolated maldevelopment of the trabecular meshwork, known as isolated trabeculodysgenesis, is the fundamental disease ²⁴⁷.

The formation of an immature angle is believed to stem from the developmental arrest of tissues originating from neural crest cells during the third trimester of gestation. The degree of angle abnormalities is contingent upon the point at which angle development is halted ²⁴⁸. The pathophysiology is believed to result from compacted thick trabecular sheets that merge and inhibit the posterior movement of the iris during the development of the anterior portion. The trabecular sheets position the iris more anteriorly, leading to the iris’ characteristic “high” insertion in children with primary congenital glaucoma.

Currently, the most accepted theory of the pathogenesis of primary congenital glaucoma proposed by Anderson states that excessive or premature accumulation of collagenous beams within the trabecular meshwork prevents normal insertion of the ciliary body and iris ²⁴⁹. This results in an anteriorly inserted iris root and ciliary muscle, which can obstruct the trabecular meshwork, and narrow or completely compress the Schlemm canal elevating intraocular pressure (IOP) ²⁵⁰, ²⁴⁹. Increased intraocular pressure (IOP) leads to the typical symptoms of buphthalmos (enlargement of the eye) and Haab striae (breaks in the Descemet membrane). Histopathological and electron microscopic studies of primary congenital glaucoma have demonstrated obstruction through the outflow pathway ²⁵⁰. Frequently, the ciliary muscle is inserted high on the trabecular meshwork. Moreover, a detailed framework analysis has shown an excessive amount of collagen in the trabecular meshwork. Other studies have demonstrated fibrillary collagen fibers, elastin fibers, and ground substances in the intervening trabecular meshwork and the canal of Schlemm ²⁵¹. The microscopic observations explain the clinical manifestation of elevated intraocular pressure (IOP) and optic nerve impairment.

More recently, ultrasound biomicroscopy and anterior segment optical coherence tomography have been used to determine angle abnormalities in primary congenital glaucoma patients ²⁵².

Childhood glaucoma prevention

There is no known way to prevent primary congenital glaucoma. Early detection and treatment are essential to maximize visual potential. A family history of glaucoma and a parental consanguineous marriage are essential elements to consider when considering a diagnosis of primary congenital glaucoma ²⁵³.

In the future, prenatal genetic screening may emerge as a preventative measure. It can be offered to parents in at-risk populations, such as those with family history or in consanguineous relationships in areas with higher primary congenital glaucoma prevalence (Slovakia, Saudi Arabia, China, etc.). Parents with unborn children who test positively for mutations in CYP1B1 on genetic screening can be alerted about the potential need for urgent surgical management soon after birth ²²⁴.

Childhood glaucoma signs and symptoms

Childhood glaucoma symptoms may not be as obvious in children. The following are the most common symptoms of childhood glaucoma. However, each child may experience symptoms differently. Symptoms may include:

• Excessive tearing (epiphora)
• Eye(s) that is sensitive to light (photophobia)
• Closure of one or both eyes in the light
• Cloudy, enlarged cornea (cloudy cornea)
• One eye may be larger than the other (bupthalmos)
• Vision loss

The classic triad of childhood glaucoma symptoms includes:

1. Epiphora (watery eyes, tearing).
2. Photophobia (light sensitivity).
3. Blepharospasm (uncontrollable eyelid twitching).

Other signs of childhood glaucoma may include:

• Buphthalmos (enlarged eyeballs or ox-eye).
• Bluish discoloration of the eyeball.
• Whitening or clouding of the cornea.

You may or may not be able to tell that your child has vision issues, like:

• Blurry vision (astigmatism).
• Nearsightedness (myopia).
• Favoring one eye (anisometropia).

An eye exam might reveal further signs of glaucoma, like:

• Corneal edema (swelling).
• Tears in the cornea.
• Corneal scarring.

Children usually have signs and symptoms in both eyes. But sometimes, they appear only in one.

If the eye pressure increases rapidly, there may be pain and discomfort. Parents may notice that the child becomes irritable, fussy, and develops a poor appetite. Early detection and diagnosis is very important to prevent loss of vision. The symptoms of glaucoma may resemble other eye problems or medical conditions. Always consult your child’s doctor for a diagnosis.

Childhood glaucoma complications

Untreated intraocular pressure (IOP) or delayed treatment in an infant eye may lead to severe complications and significant visual impairment in addition to permanent optic nerve damage and glaucomatous visual field defects. High intraocular pressure (IOP) causes corneal edema and corneal stretching with development of Haab striae. With prolonged corneal edema, both diffuse and focal overlying Haab striae, the cornea can become permanently opacified. Buphthalmos with axial elongation, and Haab striae cause abnormally high refractive errors including myopia and astigmatism, that can impair vision both by blurring vision and causing refractive amblyopia, which can be exacerbated by anisometropia in unilateral cases. In severe buphthalmos, with continued stretching, the lens could dislocate, and risk of retinal complications increases (i.e. lacquer cracks and retinal detachments). Overcoming these complications can be difficult in severe cases. Corneal transplantation for corneal opacification is avoided if possible due to high risk of failure and complications in young children.

Childhood glaucoma diagnosis

The diagnosis of primary congenital glaucoma can often be made clinically via thorough and precise ophthalmologic assessment, even without an accurate measurement of intraocular pressure (IOP). The hallmark of primary congenital glaucoma, however, is an elevated intraocular pressure (IOP) and ocular stretching in the absence of other ocular and systemic conditions that can cause glaucoma, such as Axenfeld-Reiger syndrome, aniridia, or surgical removal of cataract in infancy (i.e. glaucoma following cataract surgery) ²⁵⁴ .

The clinical diagnosis of primary congenital glaucoma can be difficult, especially when a child does not cooperate with intraocular pressure (IOP) measurement. If a reliable intraocular pressure (IOP) measurement is elevated in the setting of other classic signs of ocular stretching, then the diagnosis of glaucoma is made, and if no other ocular or systemic developmental anomalies are seen, then primary congenital glaucoma is the diagnosis. The presence of Haab striae suggests congenital glaucoma, and if seen without ocular developmental anomalies or systemic syndromes, then primary congenital glaucoma is the diagnosis. If intraocular pressure (IOP) is normal with Haab striae, then one may have a case of spontaneously arrested primary congenital glaucoma, which still needs to be followed over time for elevated intraocular pressure (IOP) ²⁰³.

Medical History

Primary congenital glaucoma patients often present to the physician’s office due to abnormal appearance of the eyes such as a cloudiness or a blue tint to the eyes, or patient behavior such as eye rubbing or shying away from light. While there may be tearing, there is no ocular discharge and usually no eye redness. The patients are otherwise healthy. A positive family history is helpful but often is not present since most cases are sporadic.

Physical Examination

The clinical examination must include ²⁵⁵:

• Fixation of light: The patient’s ability to fixate and follow light should be tested with each eye separately. There may be exotropia (where one or both eyes turn outward, away from the nose) due to poor fixation and nystagmus in long-standing cases.
• Sclera: The sclera(e) may appear bluish in color because of high myopia, scleral thinning, and exposure to underlying uveal tissue ²⁵⁶.
• Cornea: Corneal examination might reveal signs of corneal enlargement or buphthalmos. Normal corneal size from birth to 6 months should be between 9.5 to 11.5 mm. A size of greater than 12 mm should raise the suspicion of glaucoma. A corneal diameter of more than 13 mm in any child older than 6 months indicates corneal enlargement. The slit-lamp examination may reveal horizontal or oblique tears and breaks in the Descemet membrane called Haab striae (see Figure 4). Another critical finding is corneal edema. This usually starts as epithelial edema and then gradually involves the deeper layers of the cornea, occasionally causing permanent opacities impairing vision profoundly ²⁵⁷.
• Anterior chamber: The anterior chamber is usually deep.
• Iris: Iridodonesis, ectropion uvea, hypoplasia, or any atrophic patches may be present ²⁵⁸.
• Pupil: The pupil may be oval, dilated, and ischemic.
• Lens: The clinician should evaluate for lenticular opacities or lens subluxation due to excessive stretching of zonules ²⁵⁹.
• Optic disc: This typically demonstrates reversible cupping in the early stages. Later stages may present with an enlarged cup-to-disc ratio or even atrophy ²⁶⁰, ²⁶¹.
• Intraocular pressure (IOP): Intraocular pressure (IOP) is usually elevated at presentation and can be measured using a pneumotonometer in the outpatient setting ²⁵⁴.

Childhood glaucoma signs

The main clinical signs of primary congenital glaucoma include elevated intraocular pressure (IOP) >21 mmHg, corneal edema and/or enlargement of the eye with buphthalmos, and Haab striae. The intraocular pressure (IOP) at presentation is usually between 30-40 mmHg, though it can be outside this range ²⁶². Intraocular pressure (IOP) in the low-20s mmHg is acceptable if the optic nerve is healthy and the patient’s eye growth is within normal limits, but may not be if there are other more severe signs of primary congenital glaucoma.

With intraocular pressure (IOP) in the 30-40s mmHg, the cornea becomes cloudy due to diffuse and/or focal edema. As in adult eyes, the endothelial cell layer cannot pump fluid out of the cornea in an eye with elevated intraocular pressure (IOP). In young children however, there is the additional insult of corneal stretching from the high intraocular pressure (IOP) causing not only enlargement of the cornea, but Descemet breaks, leading to “striae,” which are areas of bare stroma bordered by two separated edges of Descemet membrane that become ridges due to deposition of hyaline ²⁴⁰. These are called Haab striae and are associated with acute overlying focal corneal edema when the intraocular pressure (IOP) is high. They occur in about 25% of primary congenital glaucoma eyes presenting at birth, and more than 60% of primary congenital glaucoma eyes identified at 6 months of age ²⁶³. There may be single or multiple, and are oriented horizontally or obliquely. After normalization of intraocular pressure (IOP), corneal edema may clear; however, Haab striae remain and may be associated with corneal scarring. The poorly controlled cases of primary congenital glaucoma may end up with dense stromal opacification even after intraocular pressure (IOP) is controlled.

A newborn’s cornea is typically 9.5-10.5 mm in diameter and increases to 10.0-11.5 mm by age 1 ²⁶⁴. Any diameter above 12.0 mm before 1 year of age suggests an abnormality, especially if there is asymmetry between the two eyes. If the diameter is greater than 13 mm at any age, glaucoma suspicion should be high. Along with corneal stretching in the setting of elevated IOP, there is stretching of the scleral wall and all tissues within the eye leading to buphthalmos. Corneal enlargement stops around age 3 years, while sclera can continue to stretch up to age 10 years of age ²⁴⁰.

Other signs related to the eye distension include abnormally deep anterior chamber, myopia (mainly due to elongation and enlargement of the eye), astigmatism (from Haab striae and corneal stretching), anisometropia (almost always present in unilateral primary congenital glaucoma), and optic nerve cupping.

The optic nerve cupping in very young children may be seen solely due to optic canal stretching and posterior bowing of the lamina cribrosa without a decrease in the neuroretinal rim ²⁶⁵, ²⁶⁶. When the IOP is normalized, there can be notable reversal of cupping. While cupping may resolve, retinal nerve fiber layer damage, if present, is permanent. In older children and those with advanced glaucoma, cupping occurs due to neuroretinal rim tissue loss, especially at the vertical disk poles ²⁴⁰.

Any asymmetry between eyes in the aforementioned signs should raise suspicion of glaucoma. Lastly, amblyopia, either deprivation or both, may also be present with the other signs mentioned above.

Diagnostic procedures

The main diagnostic test for childhood glaucoma is the measurement of the intraocular pressure (IOP), which should be done prior to instilling dilating drops. In a cooperative infant or young child, this measurement can be obtained in the clinic setting with a Perkins applanation tonometer, Tono-pen (a portable Mackay-Marg-type tonometer) and/or Icare rebound tonometer. In older patients, standard Goldmann applanation tonometry can be performed. A pneumotonometer may be useful to confirm intraocular pressure (IOP) during examination under anesthesia or in clinic if available, and may be less influenced by corneal abnormalities. A Schiötz indentation tonometry is not recommended in these patients due to under- or overestimation of intraocular pressure (IOP) in childhood glaucoma ²⁶⁷, ²⁶⁸. For the uncooperative child, an examination under anesthesia should be performed.

Of note, the Icare rebound tonometer has decreased the need for examinations under anesthesia as it does not require a topical anesthetic ²⁶⁹. Two models available in the United States (Icare TAO1i and Icare ic100) require the patient to be upright, while the newest model, recently approved in the US (Icare ic200), allows measurement in a supine patient. The IOP measured by Icare in cooperative, awake children with known or suspected glauacoma, has been shown to be within 3 mmHg of IOP obtained by Goldmann applanation tonometry in 63% and is higher than measured by Goldmann applanation tonometry in 75% of children ²⁷⁰. By contrast, Icare tonometry may under-measure the IOP compared to Tono-pen readings in the setting of corneal edema ²⁷¹.

Because anesthetic agents variably alter the intraocular pressure (IOP), with most lowering intraocular pressure (IOP), measurements should be obtained as soon as possible after induction of anesthesia and before intubation. If the intraocular pressure (IOP) is actually elevated, it often remains greater than 20 mmHg under anesthesia, which suggests glaucoma. The normal intraocular pressure (IOP) is lower in infants and young children than adults. A newborn has an average intraocular pressure (IOP) of 10-12 mm Hg, increasing to 14 mm Hg by age 7 or 8 years of age. An asymmetric measurement or an elevated intraocular pressure (IOP) measurement in the presence of other clinical signs helps make the diagnosis of glaucoma.

Corneal diameter measurement is another key diagnostic procedure for childhood glaucoma. Some providers check horizontal diameters only, while some check horizontal and vertical diameters. If there is pannus or scarring obscuring the limbus, the measurement may not be accurate. In the office a millimeter ruler can be placed above the eyes and if the child is not cooperative, a close-up digital photograph can be taken with the ruler in place, and a measurement can be made from the photo. This is most amenable to horizontal corneal diameter measurement. While under anesthesia, calipers with the tips placed at the limbus 180 degrees apart are used across the widest diameter, and then measured with a graduated ruler to check the measurement. Ideally, the measurement can be estimated to the nearest 0.25 mm ¹⁹⁹.

Examination for Haab striae is done with an oblique slit beam with a portable slit lamp if the patient is younger or under anesthesia, or on a regular slit lamp in the clinic if the patient is older. Retroillumination can also be used to identify Haab striae. . In older patients with treated primary congenital glaucoma, corneal endothelial protuberances and hyperproliferation of the Descemet membrane/pre-Descemet’s layer complex have been demonstrated with anterior segment OCT (ASOCT). These may demarcate areas in which the edges of the Descemet membrane have re-approximated during the healing process ²⁵⁷.

If a view through the cornea allows it, gonioscopy is done in clinic if tolerated, ideally a Sussman (or similar) indirect gonioscopy lens as it fits easily between a young child’s small palpebral fissure. Using a gonioscopy lens without a handle may be easier as it allows the examiner to hold open the eyelids while placing the lens. More commonly, for initial diagnosis of primary congenital glaucoma, gonioscopy is performed under under anesthesia with a Koeppe or similar direct gonioscopy lens and portable slit lamp. There are different sized Koeppe lenses to fit different corneal diameters. The Koeppe lens is best handled with a glove to avoid fingerprint smudges. The Koeppe lens cup is filled with balanced salt solution and placed quickly on the eye or placed on the eye and tilted with one edge abutting the sclera while filling the space between the lens and eye with solution. Then a binocular microscope such as the portable slit lamp is angled towards the angle of interest and the lens can be shifted slightly toward the angle to optimize the view.

Gonioscopy in these cases helps guide surgical planning in cases of primary congenital glaucoma, and may also identify other angle abnormalities which might identify other secondary glaucoma types, for example Axenfeld-Rieger anomaly (many irido-corneal attachments with anteriorly placed Schwalbe line). Infants with primary congenital glaucoma usually do not have a visible scleral spur because the peripheral iris inserts into the trabecular meshwork (in contrast to normal infants whose peripheral iris and ciliary body have recessed to the scleral spur or posterior to it). There may also be scalloped edges of the peripheral iris and pale peripheral iris stroma in front of the angle causing a “morning mist” appearance. If there are peripheral anterior synechiae, posterior embryotoxon, or other abnormalities, then the diagnosis is unlikely primary congenital glaucoma. Gonioscopy photographs can be taken by instilling the eye with coupling gel and angling the camera lens (i.e. RetCam) obliquely toward the angle of interest and adjusting the focus until the angle comes into clear view.

Axial length is measured with A-scan ultrasonography, ideally using the immersion and not contact method, either in clinic or under anesthesia. It is best done under anesthesia, during baseline examination to determine if the axial length is greater than normal for the patient’s age, and repeated approximately every 3-4 months to assess if the growth rate is greater than average. Of note, measuring axial length itself is not an indication for examination under anesthesia if a patient is otherwise doing well, and can be performed at intervals when examination under anesthesia is needed for clinical management. Sampaolesi and Kiskis provided linear regressions from data of normal children. Sampaolesi used immersion A-scans and found the normal axial length for a one-month-old lies between 17.25 mm (5th percentile) and 20.25 mm (95th percentile). Sampaolesi also recommended that axial length be measured after dilation with cycloplegic drops ²⁷², ¹⁹⁹.

Optic nerve evaluation is performed with either indirect or direct ophthalmoloscopy with attention to the cup-to-disc ratio. In the setting of a small pupil, a magnified view of the nerve can be obtained by using a direct ophthalmoscope through a Koeppe gonioscopy lens on the eye. Fundus photography is also recommended for comparisons between serial examinations. B-scan ultrasonography is recommended if the cornea does not allow fundus examination to rule out posterior disease. Severe optic nerve cupping may sometimes be noted on the posterior B-scan.

Pachymetry is used to measure central corneal thickness. The central cornea may be thicker due to corneal edema, and has also shown to be thinner in primary congenital glaucoma patients without corneal edema, likely due to stretching of their tissues ²⁷³. Other small studies have shown either no significant difference in central corneal thickness between normal eyes and eyes treated for primary congenital glaucoma, or the central corneal thickness was thicker in eyes treated for primary congenital glaucoma than in normal eyes ²⁷⁴, ²⁷⁵. Corneal hysteresis and corneal resistance factor have been found to be lower in eyes with primary congenital glaucoma compared to normal eyes ²⁷⁴, ²⁷⁵.

Perimetry can be attempted starting around age 7-8 years of age if the patient does not have nystagmus, cognitive impairment or severe vision loss. Quicker testing algorithms such as SITA-FAST may allow children to perform more reliably ²⁷⁶. Goldman perimetry can be very helpful in young children.

Standard tabletop optical coherence tomography (OCT) can be considered once a child can be examined at the regular slit lamp to evaluate the retinal nerve fiber layer and ganglion cell layer. It may be helpful especially if the child cannot perform perimetry. While devices currently do not carry normative data for children, studies have collected data on normal children ²⁷⁷, ²⁷⁸, ²⁷⁹, ²⁸⁰. Handheld and mounted spectral-domain OCT devices are emerging technologies that can be used during examination under anesthesia ²⁸¹, ²⁸².

Childhood glaucoma diagnostic criteria

Childhood glaucoma diagnostic criteria per Childhood Glaucoma Research Network definition ¹⁹⁹:

Definition of childhood glaucoma required two or more of the main categories (1‑5)

• Intraocular pressure (IOP) >21 mm Hg (investigator discretion if examination under anaesthesia data alone)
• Optic disc cupping
  • Progressive increase in cup‑disc ratio
  • Cup‑disc asymmetry of ≥0.2 when disc sizes are similar
  • Focal rim thinning
• Corneal findings
  • Haab striae
  • Diameter
    • >11 mm in newborn
    • >12 mm in child <1 year of age
    • >13 mm any age
• Progressive myopia /myopic shift coupled with an increase in ocular dimensions out of keeping with normal growth
• Reproducible visual field defect that is consistent with glaucomatous optic neuropathy with no other observable reason for the visual field defect

Childhood glaucoma differential diagnosis

The differential diagnoses of childhood glaucoma can be remembered by the mnemonic STUMPED, which includes the following conditions:

• S: Sclerocornea, congenital hereditary stromal dystrophy ²⁸³. This uncommon disorder is characterized by corneal opacification and may be mistaken for primary congenital glaucoma. A flattened cornea with no concomitant elevation in IOP or optic nerve impairment defines Sclerocornea.
• T: Trauma, tears in Descemet membrane or endothelial (ie, from forceps).
• U: Ulcer caused by various factors, including viral, fungal, bacterial, neurotrophic, and pythium (a parasitic aquatic oomycete that causes vision-threatening keratitis) ²⁸⁴, ²⁸⁵, ²⁸⁶
• M: Metabolic disorders, eg, mucolipidoses, mucopolysaccharidosis, tyrisinosis
• P: Peters anomaly, an uncommon disorder characterized by central corneal opacity and adherence of the iris to the cornea, may manifest with glaucoma; the principal anomaly is the corneal-lenticular contact ²⁸⁷
• E: Endothelial dystrophy, congenital hereditary endothelial dystrophy, posterior polymorphous dystrophy, Fuchs dystrophy ²⁸⁸
• D: Dermoid ²⁸⁹

Other significant differentials which should be kept in mind include:

• Interstitial keratitis
• High myopia
• Megalocornea
• Corneal abrasion
• Messman dystrophy
• Reis-Buckler dystrophy
• Retinoblastoma
• Retinopathy of prematurity
• Persistent primary hyperplastic vitreous
• Traumatic glaucoma ²⁹⁰
• Congenital rubella syndrome
• Sturge-Weber syndrome
• Aniridia
• Optic disc pit
• Optic atrophy ²⁹¹
• Coloboma

Childhood glaucoma treatment

It is important for treatment of childhood glaucoma to start as early as possible. The management of childhood glaucoma is directed toward lowering and controlling the intraocular pressure (IOP) and treating the secondary complications such as refractive change and amblyopia that develop during the course of the disease.

Childhood glaucoma treatment may include:

• Medications. Some medications cause the eye to produce less fluid, while others lower pressure by helping fluid drain from the eye.
• Surgery. The purpose of surgery is to create a new opening for fluid to leave the eye. Surgical procedures are performed by using microsurgery or lasers.

Both medications and surgery have been successfully used to treat childhood glaucoma. However, surgery is the primary treatment modality for primary congenital glaucoma. In managing secondary childhood glaucoma, medications is the first-line treatment ²⁰⁹.

Surgical procedures used to treat glaucoma in children include the following:

• Trabeculotomy and goniotomy.
  • Trabeculotomy is a surgical procedure, primarily used in the treatment of childhood glaucoma, that creates a new drainage opening in the eye’s trabecular meshwork, improving the outflow of aqueous humor and reducing the intraocular pressure (IOP).
  • Goniotomy is a microinvasive glaucoma surgery (MIGS) technique that improves fluid flow in the eye to lower intraocular pressure (IOP). A goniotomy involves making a small incision within the trabecular meshwork, the eye’s natural drainage system, to create a more efficient pathway for fluid outflow. This procedure can be used to treat conditions like childhood glaucoma.
• Trabeculectomy. Trabeculectomy is a surgical procedure that involves the removal of part of the trabecular meshwork drainage system, allowing the fluid to drain from the eye. Trabeculectomy works by creating a new drainage pathway for the fluid (aqueous humor) within the eye, allowing it to drain into a space beneath the outer layer of the eye (conjunctiva). This new pathway, called a bleb, helps reduce eye pressure and can slow or prevent further vision loss.
• Iridotomy. Iridotomy is a surgical procedure to treat or prevent angle-closure glaucoma, a condition where the iris (colored part of the eye) blocks the drainage angle, leading to increased eye pressure. The eye surgeon may use a laser to create this hole. Laser iridotomy involves using a laser to create a small hole in the iris, allowing fluid to flow freely and preventing or relieving pressure build-up.
• Cyclophotocoagulation. Cyclophotocoagulation is a laser procedure that uses a laser beam to freeze selected areas of the ciliary body – the part of the eye that produces aqueous humor – to reduce the production of fluid and reduce intraocular pressure (IOP). Cyclophotocoagulation is a type of cyclodestruction procedure, meaning it aims to reduce intraocular pressure (IOP) by damaging the ciliary body, a key part of the eye that produces aqueous humor. This type of surgery may be performed with severe cases of childhood glaucoma.

The primary treatment of childhood glaucoma is angle surgery, either goniotomy or trabeculotomy, to lower intraocular pressure (IOP) by improving aqueous outflow. If angle surgery is not successful, trabeculectomy enhanced with mitomycin C or glaucoma implant surgery with a Molteno, Baerveldt, or Ahmed implant can be performed. In refractory cases, cycloablation can be performed using an Nd:YAG laser, diode laser, or cryotherapy, with diode laser being the most widely used device. Medications, either topically or orally, is typically used as a temporizing measure prior to surgery and to help decrease corneal clouding to facilitate goniotomy, and to supplement intraocular pressure (IOP) control after surgery.

Medications

Medications for childhood glaucoma is typically used as an adjunct (add-on) to surgery. Most medications in the United States have not been approved for children, however many studies have been performed that inform doctors on their safety and efficacy in children. Timolol (a non-selective beta blocker) is the first choice in pediatric glaucoma. In cases with insufficient reduction of the intraocular pressure (intraocular pressure (IOP)), the combination of timolol once a day and dorzolamide twice a day brings about a good control of the intraocular pressure (IOP). Both medications are effective and well tolerated. The alpha2-agonists have more and potentially serious adverse effects in children and are contraindicated for children younger than 2 years of age. Latanoprost tends to be less effective in lowering intraocular pressure (IOP) in children than in adults ²⁹².

• Beta-blockers (beta-adrenergic antagonists): Topical beta-blockers play a large role in childhood glaucoma treatment and include timolol (non-selective beta-1 and beta-2 blocker, concentrations of 0.1% available in some countries, 0.25% and 0.5% solutions, and 0.25% and 0.5% gel-forming solution), and betaxolol (selective beta-1-blocker, concentrations of 0.25% and 0.5% solutions). Given potentially high plasma levels of the medication from topical instillation in small children, the lowest concentration available should be initiated first. The solution drops are approved for BID dosing though may be just as effective dosed once in the morning. The gel-forming solutions are approved for once daily dosing. Beta-blockers typically reduce intraocular pressure (IOP) by 20-30%. Side effects are mainly systemic and include respiratory distress, caused by apnea or bronchospasm (which may present as coughing instead of wheezing), and bradycardia. Beta-blockers should be avoided in patients with bradycardia, second- or third-degree atrioventricular block, and active asthma or “reactive airways.” Betaxolol may be less likely to cause pulmonary distress (e.g. asthma attacks) and cardiac side effects ²⁹³.
• Carbonic anhydrase inhibitors: Oral carbonic anhydrase inhibitors include acetazolamide (Diamox, dose 10-20 mg/kg/day divided into 3 or 4 doses) and methazolamide (Neptazane, dose < 2 mg/kg/day, divided into 2 doses) ²⁹⁴, ¹⁹⁹. Acetazolamide can be prepared in a flavored syrup (have the pharmacist crush the tablets and suspend the powder in syrup) with a concentration of 50 mg/ml for ease of use. Children can also take the tablet crushed in applesauce or something similar. It reduces the intraocular pressure (IOP) about 20-35%. Side effects occur in >40% of patients and include lethargy, decreased appetite, weight loss, gastrointestinal discomfort, diarrhea and metabolic acidosis. Topical carbonic anhydrase inhibitors include dorzolamide 2% (Trusopt) and brinzolamide 1% (Azopt) drops twice a day (BID) or three times a day (TID). These medications may produce less reduction in intraocular pressure (IOP) (about 25%) than oral carbonic anhydrase inhibitors, but also appear to have fewer systemic side effects. Rarely, side effects can occur, particularly in premature infants, such as metabolic acidosis ²⁹⁵. Topical carbonic anhydrase inhibitors ideally should be avoided or used as a later option in the setting of compromised corneas, especially of a corneal transplant ¹⁹⁹.
• Combination beta-blocker/carbonic anhydrase inhibitor: Timolol 0.5%-dorzolamide 2% (Cosopt) drop twice a day (BID) has been shown to be effective in reducing intraocular pressure (IOP) in children requiring more than one topical medication. It is approved for twice a day (BID) dosing, but cautious use in young children is warranted due to the higher concentration of timolol.
• Adrenergic agonists (avoid or use with caution in children younger than age 6 years or weight less than 20 kg): Apraclonidine 0.5% (Iopidine) and brimonidine (Alphagan, Alphagan P, 0.1%, 0.15%, 0.2%) are alpha-2 selective agonists and are dosed twice a day (BID) to three times a day (TID). Their effectiveness has not been studied specifically for childhood glaucoma. The side effects in children limit their use. Due to being highly lipophilic, brimonidine passes through the blood-brain barrier potentially causing severe sleepiness, respiratory depression, apnea and coma, especially in neonates and infants, thus it is strictly contraindicated in patients 2 years old or younger. It may also cause bradycardia, hypotension, hypotonia, and hypothermia. Apraclonidine is more hydrophilic which reduces its blood-brain barrier penetration and thus has fewer central nervous system side effects than brimonidine. It must still be used with caution and is best used for short- or intermediate-term intraocular pressure (IOP) lowering. Tachyphylaxis and ocular allergy limit its effectiveness long-term.
• Combination beta-blocker/alpha-2 adrenergic agonists: Timolol 0.5%-brimonidine 0.2% (Combigan) must not be prescribed to children if there is a contraindication to the individual components.
• Prostaglandin analogs: Latanoprost 0.005% (Xalatan), travoprost 0.004% (Travatan), bimatoprost 0.01% (Lumigan), and tafluprost (Zioptan, preservative-free) are dosed nightly. Latanoprost reduces the intraocular pressure (IOP) in primary congenital glaucoma 15-20% ²⁹⁶. While the FDA has not approved prostaglandin analogs in children, Europe has approved latanoprost for children. Side effects mainly include lash growth, conjunctival injection, and less commonly iris pigmentation alteration, allergy, uveitis and periocular hyperpigmentation. Side effects seem more prominent with use of travoprost and bimatoprost and less with latanoprost. Long-term side effects are still unknown in children. Prostaglandin-related periorbitopathy has been described in children ²⁹⁷. This class of medication is relatively contraindicated when active inflammation or uveitis is present.
• Combination beta-blocker/prostaglandin analog: Available in countries outside the United States.
• Miotic agents: These do not play much of a role in childhood glaucoma likely due to their immature angle anatomy and high ciliary muscle insertion. They include echothiophate, phospholine iodide (irreversible cholinesterase and pseudocholinesterase inhibitors) and pilocarpine (direct parasympathomimetic). Miotic are useful perioperatively for angle surgery. Pilocarpine (0.5-6%, most common 1-2%) is dosed once to four times a day, usually 2-3 times a day after angle surgery. Side effects include miosis, decreased heart rate, apnea, sweating, and hypersalivation, and theoretically may induce cataract and retinal detachment.
• Modified prostaglandin analogs and rho-associated protein kinase inhibitors: Latanoprostene bunod (Vyzulta) and netarsudil (Rhopressa) have not been studied in patients younger than 18 years of age.

Doctors can start with a either a carbonic anhydrase inhibitor, beta-blocker or prostaglandin analog, or a combination, and progressively add another medication class, keeping in mind medications are generally a temporizing measure prior to surgery. If prescribed before initial surgery, medications should not be used without fairly frequent follow-up, and ideally surgery performed within 2 weeks of childhood glaucoma diagnosis. Early discussion preparing family and caregivers for surgery is necessary. Medications should be continued until surgery, and may help maximize corneal clearing by reducing the intraocular pressure (IOP). After surgery, medications may still be needed as an adjunct and family and caregivers should be made aware of this. Compliance may be an issue when the medication regimen becomes complex and should be addressed. Childhood glaucoma requires lifelong serial measurements of intraocular pressure (IOP), corneal diameter, axial length, refractive error, and optic nerve cupping. If an adequate assessment is not possible in the outpatient clinic, an examination under anesthesia should be performed.

Surgery

Surgery is the mainstay of treatment for patients with primary congenital glaucoma. The type of surgical procedure depends on the disease severity, cornea clarity, and surgeon’s choice and experience. There are 4 major surgical options for primary congenital glaucoma; however once the diagnosis of primary congenital glaucoma is established, angle surgery is the first procedure of choice to incise/open the trabecular meshwork with the hope of allowing aqueous flow from the anterior chamber directly into Schlemm canal. It is generally agreed that angle surgery is most successful in infantile-onset primary congenital glaucoma, and less so in newborn or late-recognized primary congenital glaucoma. Goniotomy is preferred by some surgeons when the cornea is clear enough to permit visualization of anterior segment structures (although some prefer trabeculotomy regardless of the corneal clarity, see below). An incision is made across the trabecular meshwork under direct gonioscopic visualization using a goniotomy knife (Swan knife, needle-knife, disposable 25-gauge needle on a syringe) and surgical goniotomy lens (i.e. Barkan or other goniotomy lens). Traditionally, it is first performed nasally, however modifications can be made to complete it temporally as well at one surgical session. If a surgeon is comfortable with devices and modified techniques such as using the Kahook dual blade, Trabectome, gonioscopy-assisted transluminal trabeculotomy with suture or lighted microcatheter, or Omni, these devices can be used safely to perform a goniotomy in children, however it is not recommended to use these devices in a pediatric eye prior to extensive experience in an adult eye. There is no data to suggest these modified techniques do better than traditional goniotomy or trabeculotomy. Complications include hyphema, anterior chamber shallowing, peripheral anterior synechiae, and rarely, iridodialysis, cyclodialysis, cataract, scleral perforation, epithelial ingrowth, and retinal detachment ¹⁹⁹, ²⁹⁸.

When the cornea is not clear enough to permit visualization of the angle, or if preferred due to technical factors or surgeon experience or preference, trabeculotomy ab externo (“trabeculotomy”) is the procedure of choice. Access to Schlemm canal is obtained externally via a partial scleral flap to allow cannulation of Schlemm canal. The older technique opened ~90 degrees of Schlemm canal with a curved rigid pronged probe called a trabeculotome, which can then be rotated gently into the anterior chamber to incise through the trabecular meshwork. A trabeculotome curved in the opposite direction can then be used to cannulate another 90 degrees of Schlemm canal and complete 180 degrees of trabeculotomy. Alternatively, and preferred by many angle surgeons at this time, a 6-0 polypropylene (Prolene) suture or an illuminated microcatheter can be threaded into the entire Schlemm canal and pulled across the anterior chamber to complete a 360-degree trabeculotomy. Complications include hyphema, unintentional filtering blebs, choroidal detachment, cyclodialysis, iridodialysis, lens injury, and infection.

Traditional goniotomy and trabeculotomy ab externo (incising 2 quadrants) have success rates ranging for goniotomy 30-65% and for trabeculotomy 40-80%, with success reported as low as 10% to as high as 94% ¹⁹⁹, ²⁹⁹.

Combined trabeculotomy and trabeculectomy (CTT) can be performed if Schlemm canal could not be cannulated or prior trabeculotomy failed, in which a trabeculectomy is added to the trabeculotomy by removing a block of tissue in the scleral flap bed followed by a surgical iridectomy as done in regular trabeculectomy. Mitomycin C may be used with care. Combined trabeculotomy and trabeculectomy (CTT) can be an initial surgical procedure, especially in Indian and Middle Eastern patients ³⁰⁰, ³⁰¹.

Filtering surgery is considered when one or more angle surgeries have failed and includes traditional trabeculectomy with or without mitomycin C and glaucoma drainage device implantation. Trabeculectomy may be best done using techniques of the Moorfields Safer Surgery System, including fornix-based conjunctival flaps, small radial cuts, mitomycin C under the sclera flap and subconjunctival tissue with wider spread to enhance posterior aqueous flow and reduce bleb-related complications. Use of an anterior chamber maintainer in all cases and releasable sutures are also recommended ³⁰², ³⁰³, ³⁰⁴. EX-PRESS mini glaucoma shunts are not used commonly in primary congenital glaucoma as safety and efficacy have not been established long-term in young children. Severe complications of trabeculectomy include vitreous loss, ectasia, scleral collapse, retinal detachment, and phthisis. The child is also at lifelong risk of complications and infection including bleb leak, wound rupture, blebitis, and endophthalmitis.

Reported success rates for trabeculectomy performed for primary congenital glaucoma range between 50-87% ¹⁹⁹. The risk of failure is 5.6 times higher in patients age 1 year or less ³⁰⁵. The higher risk of failure in advanced primary congenital glaucoma young patients is due to buphthalmos, lack of scleral rigidity, and highly active healing and scarring.

When trabeculectomy fails or is not a desirable option, then the other filtering option with glaucoma drainage device (GDD) surgery or cyclodestructive procedures are the next surgical choices. All models of glaucoma drainage devices (Molteno, Baerveldt, and Ahmed valve) can be used in primary congenital glaucoma patients, and glaucoma drainage devices can be implanted safely in neonates with attention to eye and implant parameters. Generally, it is advisable to use a fornix incision with conjunctival and Tenon capsule incision 8 mm posterior to the limbus, and double-layer closure with running 8-0 polyglactin (Vicryl) suture on a vascular needle. The flexible implants (Baerveldt and Ahmed) can be trimmed posteriorly so as to prevent plate-optic nerve touch. The amount to trim can be calculated with the online Freedman-Margeta GDD calculator (https://people.duke.edu/~freed003/GDDCalculator/) ³⁰⁶. Some surgeons place the first tube inferior nasal to preserve conjunctiva superiorly for possible trabeculectomy when the patient is older, however others prefer superior temporal placement of the first tube, for better efficacy, and are able to perform successful trabeculectomy superior nasal at a future time. Complications from glaucoma drainage devices are many and include those of trabeculectomy plus cornea-tube touch, tube erosion through the conjunctiva or cornea, implant migration, and cataract. Infection rates are low ³⁰⁷. The Ahmed valve may additionally fail due to fibrovascular ingrowth into the valve chamber ³⁰⁸.

Success rates vary widely for primary congenital glaucoma and childhood glaucoma. For the Molteno, the range is 56-95%, with slightly higher success with the double-plate implant compared to the one-plate implant ³⁰⁹, ³¹⁰. The Baerveldt success rates range from 80-95% at 12 months, decreasing to < 50% by 60 months ³¹¹, ³¹². The Ahmed glaucoma valve has about a 55% success rate at 5 years ³¹³, ³¹⁴.

Cyclodestructive procedures are useful tools in managing refractory primary congenital glaucoma after all other options have been tried, to reduce aqueous production. Results are unpredictable and complications exist. Laser cyclophotocoagulation (CPC) has largely replaced cyclocryotherapy, and diode laser is preferred to Nd:YAG laser due to decreased adverse events such as sympathetic ophthalmia. Transscleral and endoscopic application of laser are both options, with endoscopic preferred if the eye anatomy allows. Transscleral Micropulse-cyclophotocoagulation may have less severe complications than traditional transscleral cyclophotocoagulation and be as effective in children ³¹⁵, though further research is needed. The limbal anatomy may be distorted and blind application of transscleral cyclophotocoagulation may be better guided with ultrasound biomicroscopy ³¹⁶. A general rule of thumb for all cyclodestructive procedures is to maintain 1-2 clock hours of untouched ciliary processes, even after repeated sessions, thus careful documentation of treated areas is recommended. Rare complications include hypotony, retinal detachment, visual loss, and phthisis.

Success for transscleral cyclophotocoagulation ranges from 30-79% with retreatment in ~70% of patients, and has been comparable to implanting a second glaucoma drainage device (GDD) in children ³¹⁷, ³¹⁸, ³¹⁹, ³²⁰. Endoscopic cyclophotocoagulation (ECP) has been reported to be 64% successful at 1 year, and 16% by 5 years, with sequential endoscopic cyclophotocoagulation (ECP) bringing the rate up to 81% at 1 year, and 34% at 5 years ³²¹, ³²².

Surgical Complications

Surgical complications include:

• Hyphema
• Shallow anterior chamber ³²³
• Peripheral anterior synechiae
• Iridodialysis
• Cyclodialysis (a condition where the longitudinal ciliary muscle fibers separates from the scleral spur, the area where the muscle attaches to the eye’s wall) ³²⁴
• Cataract ³²⁵, ³²⁶
• Epithelial ingrowth
• Choroidal detachment
• Retinal detachment
• Phthisis bulbi

Filtering Procedure-Related Complications:

• Over or under-filtration
• Blebitis
• Vitreous loss
• Scleral collapse
• Scleral flap leak
• Tube lens touch
• Endothelial decompensation from tube cornea touch
• Tube erosion
• Implant migration
• Diplopia from implant-related restrictions
• Endophthalmitis

Cyclodestructive Procedure-Related Complications:

• Hypotony
• Retinal detachment ³²⁷
• Phthisis

Anesthesia-Related Complications:

• Oculocardiac reflex
• Anaphylaxis
• Malignant hyperthermia
• Cardiovascular collapse
• Hepatic porphyria
• Hypoxic brain injury.

Postoperative and Rehabilitation Care

The children undergoing surgery should be started on topical steroids, either prednisolone 1% or dexamethasone 0.1% for 1 week each using an 8/7/6/5/4/3/2/1 tapering dosage. In addition, a topical antibiotic in the form of tobramycin 0.3% or 0.3% moxifloxacin or gatifloxacin 4 times per day for 20 days should be supplemented to prevent secondary infection. These patients will need close follow-ups postsurgery to look for signs of hypotony, inflammation, or infection. Moreover, the IOP needs to be recorded every 3 to 4 months for at least 2 years postsurgery.

Cycloplegic refraction will be needed every 6 months for these patients. Moreover, lifelong regular follow-up every 6 months is needed for intraocular pressure (IOP) monitoring and early detection of any surgery-related complications. Cases of failing angle or filtration surgery should be counseled for the need for glaucoma drainage device (GDD) and the risk of subsequent failure, amblyopia, blindness, and phthisis bulbi (a shrunken, disfigured, and non-functional eye that has undergone significant damage).

Surgical follow up

In the short term, patients require frequent follow up to follow response to treatment and monitor for hypotony, infection, and excessive inflammation. For young patients, or patients with less than 2 years of intraocular pressure (IOP) control, follow-up is recommended at least every 3-4 months. Regular life-long follow-up is needed (at least every 6 months) because even if long-term intraocular pressure (IOP) control from a surgical intervention is achieved, asymptomatic relapse can occur at any time and will need to be managed with medications or further surgery. Additionally, vision-threatening complications may occur at any time, especially after filtering surgeries.

Glaucoma drainage device (GDD) patency can be assessed with B-scan ultrasonography in the clinic ³²⁸.

Childhood glaucoma prognosis

The prognosis for children with primary congenital glaucoma is quite variable, with some achieving good vision, while others go blind ²⁰³. While primary congenital glaucoma accounts for less than 0.01% of all patients with eye diseases, it has been blamed for 5% of childhood blindness worldwide ²³⁷. Vision loss is secondary to corneal scarring or optic nerve damage, and often amblyopia in asymmetric or unilateral cases. Surgical management is the primary treatment modality. If intraocular pressure (IOP) is controlled, vision in the better eye ultimately can be 20/60 or better ³²⁹, ³³⁰.

A study from the United States showed a lack of progression following adequate treatment in 90.3% at 1 year, 83.1% at 5 years, 70.8% at 10 years, and 58.3% at 34 years ³³¹. Thus highlighting the importance of appropriate management and follow-ups for these patients. Another study showed that angle procedures were 90% successful among patients presenting between 2 months and 1 year of age, compared to 50% among those presenting either in infantile or late-onset or late-recognized cases ³³².

Consideration must also be given to the burden on caregivers, whose actions likely will affect the patient’s prognosis. Recent studies have highlighted that one-third of primary congenital glaucoma caregivers could have moderate to severe depression, and quality of life is poorer for the caregiver if the patient is older and has had the disease longer ³³³, ³³⁴.

Open-angle glaucoma

Open-angle glaucoma causes

Scientists aren’t sure what causes glaucoma, but the most common types usually happen when the fluid pressure inside your eye (IOP) slowly rises, damaging the optic nerve. As the optic nerve gradually gets worse, blind spots develop in your vision. Primary open-angle glaucoma (POAG) is the most common type of open-angle glaucoma that is characterized by raised intraocular pressure (IOP) caused by increased resistance to drainage in the trabecular meshwork, despite the drainage angle between the cornea and iris remains open ³³⁷. Due to this blockage in the trabecular meshwork, the pressure in the eye gradually increases, resulting in optic nerve damage and progressive visual loss. Many different abnormalities have been noted on histopathological examination of the drainage angle in patients with primary open-angle glaucoma (POAG). These include narrowed intertrabecular spaces, thickened basement membranes, fused trabecular beams, reduction in trabecular endothelial cells, reduction in actin filaments, narrowing of collector channels, foreign material accumulation, scleral spur thickening, and closure of Schlemm’s canal ³³⁶ .

Secondary open-angle glaucoma can have multiple causes but is far less common than primary open-angle glaucoma (POAG). Secondary glaucoma is when another condition or problem within the eye increases eye pressure such as eye injury, eye surgery or eye procedures, certain medications especially corticosteroids and cycloplegics or other eye diseases (e.g., pigmentary dispersion syndrome, pseudo-exfoliation syndrome, uveitis) causing the glaucoma.

Genetics

• Myocilin (MYOC) gene mutation on chromosome 1q24.3: The MYOC (myocilin) gene provides instructions for producing a protein called myocilin ³⁴⁸. Myocilin is found in certain structures of the eye, called the trabecular meshwork and the ciliary body, that regulate the pressure within the eye (intraocular pressure) ³⁴⁸. Myocilin is a cytoskeletal protein expressed in the trabecular meshwork and is also known as trabecular meshwork glucocorticoid-inducible response protein ²²¹. Myocilin’s function is not well understood, but it may help to control the intraocular pressure through its action in the muscle tissue of the ciliary body. Researchers believe that myocilin functions together with other proteins in the eye as part of the extracellular matrix, which is an intricate lattice that forms in the space between cells and provides structural support ³⁴⁸. Myocilin may interact with a number of other proteins that also function in the extracellular matrix. The MYOC gene is implicated in cases of hereditary juvenile open-angle glaucoma and adult open-angle glaucoma ²²¹.
• WD repeat domain 36 (WDR36) gene mutation on chromosome 5q22.1: The WDR36 (WD repeat domain 36) gene is a gene in humans that encodes a protein containing WD repeat domains that is involved in ribosomal ribonucleic acid (RNA) processing, p53 stress-pathway response, cell cycle progression, signal transduction, apoptosis, and gene regulation ³⁴⁹, ³⁵⁰, ³⁵¹, ³⁵², ³⁵³. WDR36 gene been identified as a causative gene for primary open-angle glaucoma (POAG) ³⁵⁴, ³⁵³, ³⁵⁵, ³⁵⁶, ³⁵⁷, ³⁵⁸. WDR36 protein is expressed in the lens, iris, sclera, ciliary muscles, ciliary body, trabecular meshwork, retina, and optic nerve in the eye ³³⁵. WDR36 protein is also expressed outside the eye in the human heart, placenta, liver, skeletal muscle, kidney, and pancreas. Four mutations in WDR36 at the GLC1G locus (N355S, A449T, R529Q, and D658G) have been identified, with a study implicating the gene in approximately 6% of patients with primary open-angle glaucoma (POAG) ³³⁵. However, results from a recent 2017 Chinese study repudiated this claim by showing that the association between WDR36 and primary open-angle glaucoma (POAG) is inconsistent across populations and calls for more data supporting the WDR36 protein’s role in primary open-angle glaucoma (POAG) ³⁵⁹, ³⁶⁰.
• CAV1/CAV2 genes mutation on chromosome 7q31:
  • The CAV1 (caveolin-1) gene provides instructions for making a protein called caveolin-1. CAV1 (caveolin-1) protein appears to have diverse functions in cells and tissues throughout the body ³⁶¹. Caveolin-1 (CAV1) is the major component of caveolae, which are small pouches in the membrane that surrounds cells. Caveolae have multiple functions, some of which are not well understood. They are known to be involved in the transport of molecules from the cell membrane to the interior of the cell (endocytosis), processing of molecules on their way into the cell, maintaining the cell structure, and regulating chemical signaling pathways. Studies suggest that caveolae are particularly numerous in adipocytes, which are cells that store fats for energy. Adipocytes make up most of the body’s fatty (adipose) tissue. In these cells, caveolae appear to be essential for the normal transport, processing, and storage of fats. Caveolin-1 (CAV1) is also found in many other parts of cells, where it regulates various chemical signaling pathways. Through these pathways, caveolin-1 is involved in regulating cell growth and division (proliferation), the process by which cells mature to perform specific functions (differentiation), cell survival and the self-destruction of cells (apoptosis), and cell movement. The functions of caveolin-1 likely differ depending on the type of cell and the part of the cell where the protein is found.
  • The CAV2 (caveolin-2) gene encodes a protein that is a major component of caveolae, which are invaginations of the plasma membrane. It plays a role in various cellular processes like signal transduction, lipid metabolism, and cell growth. Caveolin-2 (CAV2) is co-expressed with CAV1 (caveolin-1), forming hetero-oligomers within caveolae. It also interacts with G-protein alpha subunits and can regulate their activity, as well as acting as a scaffolding protein.
  • Caveolin-1 (CAV1) and Caveolin-2 (CAV2) are expressed in most human cell types, including tissues such as the scleral spur cells, trabecular meshwork, and retinal ganglion cells. In vitro studies of CAV1 showed consistent upregulation in the trabecular meshwork after one hour of increased intraocular pressure (IOP) ³⁶², ³⁶³.
  • CAV1/CAV2 genes are associated with primary open-angle glaucoma (POAG) susceptibility in populations of European and East Asian ancestry ³³⁵.
• Cyclin dependent kinase inhibitor 2B antisense noncoding RNA (CDKN2B-AS1) gene mutation on chromosome 9p21: CDKN2B-AS1 is a cyclin-dependent kinase inhibitor 2B antisense long non-coding ribonucleic acid (lncRNA) that regulates cyclin-dependent kinase inhibitor 2A and 2B in the cell cycle ³⁶⁴. A United States-based observational case study found that this region modifies optic nerve vulnerability to glaucomatous change. Single nucleotide polymorphism (SNP) in CDKN2B-AS1 gene is thought to be implicated in primary open-angle glaucoma (POAG) by causing retinal ganglion cells (RGCs) to undergo apoptosis during their quiescent post-mitotic state ³⁶⁵, ³⁶⁶.
• Optineurin (OPTN) gene on chromosome 10p13: Optineurin (OPTN) is the coiled-coil protein product implicated in adult-onset primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG) ³³⁵, ¹, ⁸². Optineurin (OPTN) is involved in various cellular functions, including apoptosis, cellular morphogenesis, inflammation, vasoconstriction, membrane protein trafficking, vesicular trafficking, and transcription activation ³⁶⁷.
• Lysyl oxidase-like 1 (LOXL1) gene on chromosome 15q24.1: Lysyl oxidase-like 1 (LOXL1) gene codes for an extracellular copper-dependent amine oxidase enzyme that catalyzes the first step in crosslinking collagen and elastin in the extracellular matrix and is implicated in cases of pseudoexfoliation syndrome. Single nucleotide polymorphism (SNP) in the LOXL1 gene is associated with excessive levels of crosslinked amyloid-like fibrillar glycoproteins that deposit in the anterior segment and are more common in Scandinavian populations ³⁶⁸, ³⁶⁹. Single nucleotide polymorphism (SNP) in the LOXL1 gene can present as exfoliation glaucoma as the first signs of a more systemic severe condition that implicates multiple tissues with the expression of copper-dependent amine oxidase enzyme, including the liver, kidney, and gallbladder ³⁷⁰, ³⁷¹.

Several study results based on whole-exome sequencing using gene-based and single-variant analyses have revealed more than 40 new previously unreported genes associated with glaucoma phenotypes ³⁷². Understanding open-angle glaucoma genetic and molecular mechanisms is crucial to developing new drug targets ³⁷³, ³⁷⁴.

Risk factors for developing open-angle glaucoma

Risk factors for developing open-angle glaucoma include ³³⁵:

• Older age (African American, 40+ years; Caucasians, 65+ years) ³⁷⁵
• Race (African-American, Afro-Caribbean, and West African patients have a 4-fold increased risk of developing open-angle glaucoma) ³⁷⁵
• Family history of glaucoma (eg, the Rotterdam Eye study found a 9.2 times higher risk of developing open-angle glaucoma if first-degree relatives had glaucoma) ³⁷⁶
• Elevated intraocular pressure (IOP) ³⁷⁷
• Myopia or nearsightedness (eg, results from studies have reported an increased risk of glaucoma of up to 20% for each diopter increase in myopia) ³⁷⁸, ³⁴²
• Increased cup-to-disc ratio ³⁷⁹
• Optic disc hemorrhage also called Drance hemorrhage ³⁸⁰
• Thin central corneal thickness ³⁸¹, ³⁴²
• Low ocular perfusion pressure ³⁸²
• Low blood pressure (systolic and diastolic blood pressure) also known as hypotension ³⁸³
• High blood pressure also known as hypertension (systemic arterial hypertension has been associated with but is not a confirmed risk factor for open-angle glaucoma) ³⁸⁴
• Type 2 diabetes ³⁸⁵
• Hypothyroidism (underactive thyroid)
• Obstructive sleep apnea (OSA)
• Steroid use
• High pattern standard deviation on visual fields ³⁸⁶
• Migraine or vasospasm (a condition of sudden constriction of a blood vessel, reducing its diameter and flow rate) ³⁸⁷
• Low intracranial pressure or low cerebral spinal fluid (CSF) pressure ³⁸⁸
• Oral contraceptive pill or hormonal birth control pill ³⁸⁹
• Lifestyle risk factors include smoking, obesity, alcohol, anxiety, stress, and sleep apnea ³⁹⁰.

Intraocular pressure (IOP)

The most important risk factor for developing open-angle glaucoma is an elevated intraocular pressure (IOP) (i.e., ocular hypertension), usually defined as intraocular pressure (IOP) above 21 mm Hg ³⁷⁷. In patients with ocular hypertension (raised IOP but no signs of glaucomatous optic disc or visual field changes), higher intraocular pressure (IOP) is associated with a higher risk of developing open-angle glaucoma ³⁷⁷. Raised intraocular pressure (IOP) in animal models results in glaucomatous optic neuropathy. Population studies have shown increased prevalence of glaucoma with increasing intraocular pressure (IOP). Approximately 10% of patients with an elevated intraocular pressure (IOP) develop glaucoma after five years, and 30% at 20 years ³⁷⁵. Although the risk of glaucoma progression is directly related to the degree of elevation of intraocular pressure (IOP), up to 40% of patients with glaucoma have normal intraocular pressure (IOP) at initial diagnosis, and about 5% of people in the United States have ocular hypertension without glaucoma ³⁴², ³⁵, ³⁹¹. Intraocular pressure (IOP) is also thought to be a risk factor for normal tension glaucoma, despite intraocular pressure (IOP) never being higher than the normal range.

Age

The prevalence of open-angle glaucoma increases with age, even after compensating for the association between age and intraocular pressure (IOP). Age was also found to be an important risk factor for the conversion of ocular hypertension to open-angle glaucoma in both Ocular Hypertension Treatment Study (OHTS) and the European Glaucoma Prevention Study (EGPS).

Race

Several studies have shown primary open-angle glaucoma (POAG) to be more prevalent in people of African-Caribbean descent compared with Caucasians ³³⁶. Not only is open-angle glaucoma more prevalent in black race, its onset is earlier, and disease progression has been shown to be faster and more refractory to treatment. Black patients with ocular hypertension have been found to be more likely to progress to open-angle glaucoma. The prevalence of primary open-angle glaucoma (POAG) in Hispanics is thought to be between that of African-Caribbean and Caucasian populations.

Refractive error

Myopia has been shown to be a risk factor for primary open-angle glaucoma (POAG) in several studies. However, it can be difficult to diagnose true open-angle glaucoma in myopic patients and controversy exists over whether it is real risk factor. Myopic optic discs are notoriously difficult to assess, and myopic patients may have visual field defects unrelated to any glaucomatous process.

Central corneal thickness

A thinner cornea has been shown to be a risk factor for ocular hypertension patients developing primary open-angle glaucoma (POAG). This may be in part due to IOP measurement error (IOP tends to be read lower in patients with thinner corneas), but there are also theories that a thinner cornea may indicate less rigid support structures around the optic nerve head, and a resultant increased propensity to damage ³³⁶.

Family history of glaucoma

A first-degree relative (i.e., parents, brother and sister and children) with primary open-angle glaucoma (POAG) is a risk factor for the development of open-angle glaucoma. This has been reported in several studies with the odds ratio varying from 3 to 13 ³³⁶. The risk is thought to be higher still if the affected relative is a sibling (brother or sister) ³³⁶. Several genes associated with open-angle glaucoma have been identified, though these account for less than 5% of all open-angle glaucoma in the general population ³³⁶. It is therefore thought that the hereditary aspect of open-angle glaucoma is likely to be polygenic and that gene-environment interactions are important ³³⁶.

Other risk factors

A high prevalence of open-angle glaucoma has been found in diabetic patients, and a high prevalence of diabetes has been found in open-angle glaucoma patients. People with diabetes are 2 times more likely to get glaucoma than people without diabetes ³⁷⁵. However, controversy exists as to whether diabetes truly is a risk factor for open-angle glaucoma, as several large population studies have found no association ³³⁶ . The role of blood pressure in the development of open-angle glaucoma is complicated and there is no consensus ³³⁶. High blood pressure (hypertension) may predispose to glaucomatous damage via increased peripheral vascular resistance in small vessels, while a low blood pressure may reduce the perfusion pressure of the optic disc ³³⁶. There is a relative scarcity of data regarding the lifestyle and nutritional epidemiology of open-angle glaucoma ³³⁶. There is a suggestion that exercise and a diet high in green collards and with a high omega 6 to omega 3 fatty acid ratio are protective against open-angle glaucoma ³³⁶.

Open-angle glaucoma signs and symptoms

Most patients with primary open angle glaucoma (POAG) have no symptoms of the condition. There is no pain and vision seems normal. In its early stages, glaucoma may not cause any symptoms or have no warning signs. Most people with open-angle glaucoma do not notice any change in their vision until the damage is quite severe. This is why glaucoma is called the “silent thief of sight” and up to half of the people in the United States with glaucoma may not know they have it. And symptoms may not appear until glaucoma causes irreversible eyesight damage. As the disease progresses, blind spots develop in your peripheral (side) vision. Side vision also is called peripheral vision. In later stages, difficulty seeing things in your central vision.

It’s important to have regular eye exams that include measurements of your eye pressure. If glaucoma is found early, vision loss can be slowed or prevented. If you have glaucoma, you’ll need treatment or monitoring for the rest of your life.

Some of the more common glaucoma symptoms include:

• Eye pain or pressure
• Headaches
• Red or bloodshot eyes
• Double vision (diplopia)
• Blurred vision
• Gradually developing low vision
• Gradually developing blind spots (scotomas) or visual field defects like tunnel vision.

Open-angle glaucoma signs

The International Society for Geographical and Epidemiological Ophthalmology has published a consensus definition for primary open-angle glaucoma (POAG). This definition does not include intraocular pressure (IOP) – i.e. primary open-angle glaucoma (POAG) is diagnosed based on signs of glaucomatous optic neuropathy regardless of the level of intraocular pressure (IOP). Patients can be classified as normal tension glaucoma (NTG) or high tension glaucoma (HTG) based on the intraocular pressure (IOP). Sometimes an intraocular pressure (IOP) spike may be missed in a clinical setting. In these cases, if high tension glaucoma (HTG) is suspected, measurement of intraocular pressure (IOP) at hourly intervals throughout the day, beginning in the early morning, may be indicated. This is termed phasing. If a patient has all the features of primary open-angle glaucoma but consistently normal intraocular pressure (IOP) (less than or equal to 21 mmHg), this is considered normal tension glaucoma (NTG).

Open-angle glaucoma complications

Complications of glaucoma include:

• Blindness: usually painless
• Painful blind eye or absolute glaucoma: Open-angle glaucoma predisposes to central retinal venous occlusion (CRVO), leading to neovascular glaucoma and painful blind eye ³⁹².

Open-angle glaucoma diagnosis

The only sure way to diagnose glaucoma is with a complete eye exam. An eye specialist can diagnose glaucoma using an eye exam, including several tests that are part of routine eye exams. A comprehensive eye exam can detect glaucoma long before you have eye damage and the symptoms that follow. Many of these tests involve pupil dilation (mydriasis), so your eye doctor can get a better look inside your eye. Your eye care specialist examines your eyes using a special magnifying lens. This provides a clear view of important tissues at the back of your eye to check for glaucoma or other eye problems. For a few hours after the exam your vision may be blurry and sensitive to light, so you will need someone to take you home.

Some of the most helpful glaucoma tests include:

• Visual acuity testing. A visual acuity test assesses how clearly someone can see at a distance, typically using a Snellen chart or other standardized chart. The test is performed by an optometrist or ophthalmologist and involves reading progressively smaller letters or identifying shapes, with the results expressed as a fraction like 20/20 or 6/6, indicating the distance at which the person can see the letters or shapes
• Visual field testing also called perimetry. This check of your peripheral (side) vision allows your eye care provider to find out how well you can see objects off to the side of your vision without moving your eyes. This test measures the entire area the forward-looking eye sees to document straight-ahead (central) and side (peripheral) vision. It measures the dimmest light seen at each spot tested. Each time patients perceive a flash of light, they respond by pressing a button.
• Depth perception testing. A depth perception test assesses your ability to see the world in three dimensions (3D) and judge distances accurately. It checks if your eyes work together and if your brain processes the visual information correctly. These tests use 3D images or patterns like the Randot Stereo test to gauge how well your eyes coordinate to perceive depth. Some tests involve holding a finger in front of your eyes and focusing on a distant object, checking for double vision of the finger.
• Tonometry. This measures the pressure inside your eye. Increased eye pressure is the most important risk factor for glaucoma. There are several methods of measuring eye pressure. The most common method is known as applanation, in which a tiny instrument contacts the eye’s surface after it is numbed with an eye drop.
  • Air-puff test. You’ll rest your chin on a machine and your eye specialist will blow a puff of air into your eye. This quick and painless test is used as part of a routine glaucoma screening. If the results show that your eye pressure is high, your eye specialist will do other eye-pressure tests to get a more accurate measurement.
  • Applanation tonometry (Goldmann Applanation Tonometry). Your eye specialist will numb your eyes with drops before measuring your eye pressure using one of these methods:
    • You’ll rest your chin on a special magnifying device called a slit lamp. Your eye care specialist will examine your eye through the slit lamp while gently pressing a special tool on your eye to test the pressure.
    • Your eye care specialist will gently press a handheld device against your eye. The device measures your eye pressure.
• Pachymetry. Pachymetry is a simple, painless test that measures the thickness of the cornea, the clear front part of the eye. The eye doctor uses an ultrasonic wave instrument to help determine the thickness of the cornea and better evaluate eye pressure.
• Ophthalmoscopy. Your eye care specialist will do a dilated eye exam to look for damage to your optic nerve. This exam is part of a routine glaucoma check-up. You’ll be given eye drops that widen (dilate) your pupils (the openings that let light into your eyes). You’ll look straight ahead while your eye care specialist looks into your eye using a device with a light and magnifying lens.
• Slit lamp exam. A slit lamp exam is a common eye test that uses a microscope with a focused beam of light to examine the front of your eye and the back of your eye with the aid of special lenses.
• Gonioscopy. “Gonio” means angle. Gonioscopy is a specialized eye examination that allows an ophthalmologist to visualize the anterior chamber drainage angle, the space between the iris and the cornea where fluid drains out of the eye. Gonioscopy is a crucial part of diagnosing and monitoring glaucoma and other eye conditions. Eye doctors regularly examine the drainage angle to see if there is any visible obstruction to fluid leaving the eye through the trabecular meshwork. A special lens (gonioscopy lens) is needed to examine the trabecular meshwork. The gonioscopy lens is gently placed against the surface of the cornea and allows eye doctors to see the trabecular meshwork in the drainage angle. Gonioscopy determines whether the diagnosis is considered “open” or “closed” angle glaucoma. Gonioscopy is an acquired skill that allows the ophthalmologist to visualize the angle between the cornea and iris and determine if it is open. The angle between the iris and cornea should be 20° to 45° to be considered “open” so that aqueous humor can circumvent the posterior chamber to the anterior chamber ³⁸⁴.

If your eye specialist has a reason to suspect damage to your retina and/or optic nerve, they may also use additional types of eye imaging. These include:

• Optical coherence tomography (OCT). Optical Coherence Tomography (OCT) measures the reflection of low-coherence infrared light directed toward the back of the eye, and the path of scattered photons helps recreate an image of the retina. Optical coherence tomography (OCT) provides high-resolution cross-sectional imaging of the retina, optic nerve, and anterior segment. Using optical coherence tomography (OCT) a 3D reconstruction of the optic nerve can be created. Optical coherence tomography (OCT) is valuable for monitoring morphological changes in the optic nerve and retinal nerve fiber layer, especially in patients with ocular hypertension and early-to-moderate glaucoma ¹¹⁷. OCT is highly reproducible and is widely used as an adjunct in routine glaucoma patient management. The most recent advances of OCT include OCT-A or OCT-Angiography, whereby the blood flow to vessels surrounding the optic nerve and in the macula can be measured. This is still an active area of research, but scientists do know that some patients’ optic nerves are very vulnerable to changes in optic nerve blood flow, and this new measurement may be useful in evaluating these patients. Peripapillary retinal nerve fiber layer (RNFL) analysis can show thinning in this layer. As the most commonly used scanning protocol for glaucoma diagnosis, optical coherence tomography (OCT)  samples retinal ganglion cells (RGCs) from the entire retina ³⁹³. Some of the drawbacks included variability in optic nerve head morphology from patient to patient. The macular thickness is proposed as a means of glaucoma detection, given that 50% of retinal ganglion cells (RGCs) are found in the macula, and retinal ganglion cell (RGC) bodies are thicker than their axons and potentially easier to detect ³⁹⁴. Retinal nerve fiber layer (RNFL), macular thickness measurements, and visual field results are key in managing cases.
• Heidelberg Retina Tomograph (HRT): Heidelberg Retina Tomograph (HRT) is also a laser that can produce a 3D representation of the optic nerve.
• Nerve Fiber Analyzer (GDx): Nerve Fiber Analyzer (GDx) uses laser light to measure the thickness of the nerve fiber layer.
• Fluorescein angiography. Fluorescein angiography is a diagnostic test used to examine the blood vessels in the retina and choroid of the eye. Fluorescein angiography involves injecting a fluorescent dye into the bloodstream and taking photographs of your retina and its blood vessels as the dye circulates, revealing potential blockages, leaks, or other abnormalities in the blood vessels. Fluorescein angiography is often recommended to find and diagnose eye disease including ¹¹⁸:
  • macular edema (swelling in the retina that distorts vision)
  • diabetic retinopathy (damaged or abnormal blood vessels in the eye caused by diabetes)
  • macular degeneration
  • blockage of veins inside the eye, called branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO)
  • macular pucker (a wrinkle in the retina caused by a buildup of fluid behind it)
  • ocular melanoma (a type of cancer affecting the eye)
  • rack changes in eye disease over time
  • target treatment areas
• Less commonly, ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI).

The following triad is the cornerstone of Open Angle Glaucoma diagnosis ³⁹⁵:

1. Optic disc or retinal nerve fiber layer changes
2. Visual field changes
3. Elevated intraocular pressure (IOP)

Open-angle glaucoma differential diagnoses

Open angle glaucoma differential diagnoses should include ³³⁵:

• Optic nerve head diseases
  • Physiological cup: Deep cup with healthy neuroretinal rim is seen with normal retinal nerve fiber layer thickness and no visual field defect; disc size may be large
  • Optic disc drusen
  • Optic disc coloboma
  • Anomalous optic disc
  • Tilted disc
  • Ischemic optic neuropathy
• Retinal diseases causing similar visual field defects
  • Branch retinal vein occlusion (BRVO)
  • Branch retinal artery occlusion (BRAO)
  • Retinitis pigmentosa
  • Panretinal photocoagulation
• Central nervous system diseases
  • Pituitary tumor: Neuroretinal rim is typically pale, pallor more than cupping, and bitemporal hemianopia exists, which respects the vertical line passing through the fixation (contrary to glaucoma, whose visual field respects the horizontal meridian)
  • Intracranial hypotension due to cerebrospinal fluid shunts or other neurologic pathologies
  • Foster Kennedy Syndrome is a rare neurological condition characterized by optic atrophy in one eye and papilledema (swelling of the optic disc) in the other eye, often accompanied by anosmia (loss of smell). Foster Kennedy Syndrome is usually caused by a mass lesion compressing the optic nerve on one side, leading to optic atrophy, and increased intracranial pressure causing swelling of the optic disc on the other side.
  • Cerebrovascular pathologies or traumas
  • Multiple sclerosis

Open-angle glaucoma treatment

The main goal of treating glaucoma is to keep it from getting worse by lowering the pressure inside your eye (IOP) ³³⁶, ³⁹⁶. Below a certain upper limit of intraocular pressure (IOP), it is estimated that the visual field, the optic nerve head, and retinal nerve fiber layer (RNFL) parameters will not deteriorate. This helps to maintain a patient’s quality of life.

Some of the most likely treatments for this include:

• Medications. This mainly involves medications that lower pressure inside your eye. They can prevent glaucoma from developing if you have higher-than-normal intraocular pressure (ocular hypertension) or keep it from worsening enough to cause damage and symptoms.
• Glaucoma surgeries. These mainly focus on improving the drainage of aqueous humor fluid to lower pressure inside your eye. Surgery options include trabeculectomy, tube shunts, laser therapy and minimally invasive glaucoma surgeries (MIGS).

There is no strong evidence supporting which of medication, laser or surgical therapy should be given initially. Your eye specialist can tell you more about your treatment options and help you choose one that fits your needs best.

The Collaborative Initial Glaucoma Treatment Study (CIGTS) showed no significant difference in outcome between patients randomized to either medical therapy or trabeculectomy ⁷⁷, ⁸⁴. Commonly, patients are started on medical therapy with possible add-on (adjunctive) laser therapy, and only if these measures fail surgery considered.

Unfortunately, some primary open-angle glaucoma (POAG) patients continue to progress despite lowering of intraocular pressure (IOP). This provides some evidence that there are intraocular pressure (IOP)-independent mechanisms at play ³³⁶. Therefore, searching for other reversible risk factors for primary open-angle glaucoma is essential ³³⁶. For example, this may come from epidemiological study of primary open-angle glaucoma and identifying lifestyle or nutritional risk factors associated with primary open-angle glaucoma ³³⁶.

Open-angle glaucoma prognosis

Advanced open-angle glaucoma may cause optic atrophy and no perception of light, though most open-angle glaucoma patients will not lose vision in their lifetime ³³⁵. One study in St Lucia found that 35% of untreated eyes progressed to end-stage disease over 10 years ³⁹⁷. There is strong evidence that lowering intraocular pressure (IOP) can reduce the rate of progression significantly. During 6 years of the Early Manifest Glaucoma Trial, 53% progressed, though treatment reduced the rate of progression by half, and for each mmHg of intraocular pressure (IOP) lowering achieved, the rate was reduced by 10%. However, the rate of progression and risk of blindness may be hard to predict in individual patients ³³⁶.

Risk factors for progression of open-angle glaucoma include ³⁹⁸:

• Old age
• Elevated intraocular pressure (IOP)
• Increased cup-to-disc ratio or small optic rim area
• Beta peripapillary atrophy
• Disc hemorrhage
• Thin central corneal thickness
• Reduced corneal hysteresis
• Low ocular perfusion pressure
• Poor compliance with therapy
• Pseudoexfoliation.

Angle closure glaucoma

Figure 17. Gonioscopy (the drainage angle is examined using a special lens)

Footnotes: Gonioscopy. (A) and (B) Gonioscopy lens. (C) The gonioscopy lens is gently held against the cornea. Eye doctors look through the gonioscopy lens to see the drainage angle.

Figure 18. Humphrey Field Analyzer

Optic Nerve

The optic nerve should be evaluated using a slit lamp and 90D or 78D lens so that the three-dimensional features of the optic nerve are appreciated ³³⁵. The inferior neuroretinal rim (neuroretinal rim) is the thickest, followed by superior, nasal, and temporal neuroretinal rim; this is called the ISNT rule (inferior [I] ≥ superior [S] ≥ nasal [N] ≥ temporal [T] rule) ⁴⁶⁰, ⁴⁶¹. The ISNT rule (inferior [I] ≥ superior [S] ≥ nasal [N] ≥ temporal [T]) refers to the characteristic pattern of neuroretinal rim width in a normal optic disc ⁴⁶⁰. In a healthy eye, the neuroretinal rim is typically broadest inferiorly, followed by superiorly, nasally, and thinnest temporally ⁴⁶⁰. This pattern, represented as inferior [I] ≥ superior [S] ≥ nasal [N] ≥ temporal [T], can be used as a reference point for evaluating optic disc rim changes, especially in the context of glaucoma diagnosis. In open-angle glaucoma, the superior and inferior neuroretinal rim are thinned, breaking the ISNT rule ³³⁵. The optic cup should be determined by its contour and not color. A recent Journal of the Americal Medical Association Rational Clinical Examination systematic review of primary open-angle glaucoma diagnosis found that the risk of glaucoma was highest when an examination revealed an increased cup-disk ratio (CDR), cup-disk ratio asymmetry, disc hemorrhage, or elevated intraocular pressure (IOP) ⁴⁶².

Typical optic nerve head changes in open-angle glaucoma include ³³⁵:

• Diffuse or focal narrowing (notching/shelving) of the neuroretinal rim precisely at the superior or inferior part of the optic disc
• Symmetrically enlarged cup-to-disc ratios greater than 0.5
• Increased vertical cup-to-disc ratio and thinning of neuroretinal rim
• Asymmetry of cup-disk ratio (CDR) of 0.2 or more
• Hemorrhage at or around the optic disc
• Peripapillary atrophy
• Baring of circumlinear vessels (the gap between the superficial vessels and disc margin)
• Bayonetting of vessels (the vessel first goes back and then climbs along the wall of the deep cup and then angles again on the disc margin)
• Very deep (excavated) cup with bean-pot cupping and laminar dot sign
• Nasalization of optic disc vessels
• Diffuse or focal (arcuate) thinning/defect of the retinal nerve fiber layer contiguous with an area of neuroretinal rim-notch
• The neuroretinal rim is typically pink and not pale in open-angle glaucoma. The pallor of the neuroretinal rim usually denotes an atrophic optic nerve, as seen in primary angle closure glaucoma (POAG).

Figure 19. ISNT rule

Footnotes: ISNT rule for a normal optic nerve. The ISNT rule is that optic disc rim thickness shows a characteristic configuration of inferior (I) greater than or equal to superior (S) greater than or equal to nasal (N) greater than or equal to temporal (T) (or inferior [I] ≥ superior [S] ≥ nasal [N] ≥ temporal [T]).

Figure 20. Glaucomatous Optic Nerve

Footnotes: (A) Normal optic nerve. The pink area of neural tissue forms the neuroretinal rim, whereas the central empty space corresponds to the cup. (B) Glaucomatous optic nerve showing loss of superior neural retinal rim (thinning) and excavation with enlargement of the cup. The arrowheads point to an associated retinal nerve fiber layer defect, which appears as a wedge-shaped dark area emanating from the optic nerve head. The superior neural losses correspond to the inferior defect (black scotoma) seen on the visual field. There is also a small retinal nerve fiber layer defect inferiorly, but the corresponding hemifield of the visual field remains within normal limits. (C) More extensive neural tissue loss from glaucoma with severe neuroretinal rim loss, excavation, and enlargement of the cup. There is severe loss of visual field both in the superior as well as in the inferior hemifield.

Figure 21. Optical Coherence Tomography (OCT) of Glaucomatous Optic Nerve

Footnotes: (A) The arrowheads point to a retinal nerve fiber layer (RNFL) defect. (B) Areas of thicker retinal nerve fiber layer (RNFL) appear in yellow and red. Arrowheads point to the retinal nerve fiber layer (RNFL) defect. A deviation map compares the retinal nerve fiber layer (RNFL) thickness values with a normative database and highlights the defect. (E) Arrowheads point to a visual field defect.

Visual Field

Perimetry also known as visual field testing is an important diagnostic tool that maps out your visual field on a printout, making it helpful and necessary in diagnosing and managing open-angle glaucoma. Perimetry testing provides a baseline visual field for glaucoma suspects and confirmed open-angle glaucoma cases so clinicians can track disease progression ³³⁵.

To make a diagnosis of acquired glaucomatous visual field defect, Hoddap–Parrish–Anderson criteria are used ⁴⁶³:

• Glaucoma hemifield test outside normal limits on at least 2 fields.
• A cluster of 3 or more non-edge points in a location typical for glaucoma, all of which are depressed on the pattern deviation plot at a perimetry (P) <5% and one of which is depressed at a perimetry (P) <1% on 2 consecutive fields.
• A corrected pattern standard deviation that occurs in less than 5% of normal fields on 2 consecutive fields.

Static automated threshold perimetry is used with white stimulus on a white background. Most studies used the Humphrey Field Analyzer, but other perimeters like Octopus have also been used successfully. Non-conventional perimetry like SWAP (short-wavelength automated perimetry using blue stimulus on yellow background), pulsar perimetry, rarebit, Matrix and frequency-doubling technology have been proposed in earlier studies for the detection of early glaucoma visual field loss, however, tend not to be used in routine clinical practice ⁴⁶⁴, ⁴⁶⁵, ⁴⁶⁶, ⁴⁶⁷, ⁴⁶⁸, ⁴⁶⁹, ⁴⁷⁰.

The visual field must be reliable, and defects should be repeatable on at least 2 fields. When treating patients long-term, it is preferable to use the same machine, the same degree of field, and protocol (eg, 24-2, 30-3, or 10-2) to compare the fields to note for progression or stability. At least 40% to 50% ganglion cell loss is needed to reliably show visual field defects in threshold perimetry ⁴⁷¹, ⁴⁷².

Structural changes of the optic nerve and retinal nerve fiber layer (RNFL) tend to occur earlier than functional change (visual field loss) in most patients with open-angle glaucoma. This is relevant to the concept of preperimetric glaucoma, which is defined as ‘the presence of characteristic glaucomatous changes in the optic disc and increased vulnerability to damage in the retinal nerve fiber layer (RNFL), without the presence of visual field defects detectable with standard automated perimetry ⁴⁷³. For patients with risk factors, suspect optic discs, and/or ocular hypertension, periodic visual field and optical coherence tomography (OCT) testing are recommended to detect early visual field defects and changes to determine whether therapy is needed.

Typical visual field changes in open-angle glaucoma include ³³⁵:

• Increased variability of responses in an area that later developed field defects
• Asymmetry of the visual field between the eyes
• Paracentral scotoma- commonly superonasal
• Roenne’s nasal step- an area of depression above or below the horizontal meridian on the nasal side
• Temporal wedge
• Sickle-shaped (Seidel) scotoma
• Bjerrum scotoma or arcuate scotoma
• Annular or ring scotoma when arcuate scotoma is present on both above and below the horizontal meridian
• General constriction of peripheral field
• A temporal island of the visual field.

Figure 22. Hoddap–Parrish–Anderson criteria

Abbreviations: MD = mean deviation; dB = decibels (refers to the logarithmic scale used to measure visual sensitivity and it represents the intensity of light stimuli that a person can see at a specific location in their visual field)

Intraocular Pressure

Intraocular pressure (IOP) is measured with tonometry and several different tonometers are used ⁴⁷⁴, ⁴⁷⁵. The gold standard for intraocular pressure (IOP) measurement is Goldmann Applanation Tonometry (GAT) ⁴⁷⁶. However, Goldmann Applanation Tonometry is not available in all instances, and non-contact tonometry is also frequently used. In the UK, this is certainly true in the community where optometrists’ preferred method of IOP measurement is non-contact ³³⁶.

When determining the intraocular pressure (IOP) of a patient using tonometry, certain variables must be considered. Tonometry measurements can, for example, vary between examiners by approximately 10% per individual, translating to a difference in intraocular pressure (IOP) measurement of 1 mm Hg to 2 mm Hg ⁴⁷⁷.

An individual’s corneal thickness measured with pachymetry or diurnal variations of intraocular pressure (IOP) (eg, higher intraocular pressure (IOP) in early morning hours or other times of the day or variability in the time of day of maximal intraocular pressure (IOP) between patients) can also have a tremendous effect on the accuracy of intraocular pressure (IOP) measurements. Study results have shown that intraocular pressure (IOP) is overestimated in individuals with thick corneas or central corneal thickness (CCT) while underestimated in those with thinner corneas ⁴⁷⁸, ⁴⁷⁹. Newer methods of IOP measurement aim to overcome variations in corneal biomechanics and give a more accurate estimate of true IOP. These include the Reichert Ocular Response Analyzer (ORA) and the Pascal Dynamic Contour Tonometer (DCT). The ORA is a non-contact tonometer that measures a biomechanical attribute of the cornea termed hysteresis. The DCT uses uses principle of contour matching instead of applanation to reduce the effect of corneal biomechanics. Furthermore, multiple measurements should be taken and correlated with optic nerve and visual field examinations when a patient is suspected of elevated intraocular pressure (IOP).

If previous tonometry measurements are available, they should be reviewed and compared to the most recent ones. Also, the intraocular pressure (IOP) may be different on different days, and different instruments may capture different values of intraocular pressure (IOP). If a difference of 3 mm Hg or more is noted between the 2 eyes, there is an increased suspicion of glaucoma ³³⁵. Clinicians should expect approximately 10% variation between individual and repeat measurements over 2 to 3 occasions before deciding on the treatment ³³⁵.

Elevated intraocular pressure (IOP) is an important and modifiable risk factor; however, it is not a diagnostic factor for open-angle glaucoma. An ophthalmologist should check the patient’s intraocular pressure (IOP) using applanation tonometry, remaining aware that the applanation tonometry test causes patients to squeeze their eyes and elevate their pressure readings. Normal intraocular pressure (IOP) should range between 12 mm Hg and 21 mm Hg ³³⁵. Approximately 75% of patients with elevated intraocular pressure (IOP) never develop glaucomatous optic nerve atrophy or visual field deficits. When a patient has recorded a reliably high intraocular pressure (IOP) reading above 21 mm Hg, they are deemed patients with glaucoma or patients with ocular hypertension ³⁸⁴, ⁴⁸⁰.

Corneal Photokeratoscopy

Corneal photokeratoscopy or corneal topography, is a potential biological marker to monitor patients with primary open-angle glaucoma (POAG). Preliminary results have shown a forward shift of the posterior and anterior corneal surfaces; this is correlated with more advanced stages of functional damage, indicating a link between corneal structural changes and the duration and intensity of elevated IOP. Further studies are needed to validate this marker in patients with primary open-angle glaucoma (POAG) ⁴⁸¹.

Glaucoma Stages

The Americal Academy of Ophthalmology’s classifies the severity of glaucomatous damage into different categories ³⁹⁸:

• Mild: Definite optic disc or retinal nerve fiber layer (RNFL) abnormalities consistent with glaucoma as detailed above and a normal visual field tested with standard automated perimetry (SAP) are seen.
• Moderate: Definite optic disc or retinal nerve fiber layer (RNFL) abnormalities consistent with glaucoma, as detailed above, are seen, and visual field abnormalities in one hemifield are not within 5° of fixation as tested with standard automated perimetry (SAP).
• Severe: Definite optic disc or retinal nerve fiber layer (RNFL) abnormalities consistent with glaucoma as detailed above are seen, and visual field abnormalities in both hemifields or loss within 5° of fixation in at least one hemifield as tested with standard automated perimetry (SAP).
• Indeterminate: Definite optic disc or retinal nerve fiber layer (RNFL) abnormalities consistent with glaucoma, as detailed above, are seen, and the patient cannot perform visual field testing, has unreliable or uninterpretable visual field test results, or has not performed visual fields yet.

Several other different staging systems are recognized based on visual field damage, optic disc cupping, and retinal nerve fiber layer (RNFL) defects with optical coherence tomograpy (OCT), some of which are applicable in a routine clinical setting or clinical trials ⁴⁸², ⁴⁸³, ⁴⁸⁴, ⁴⁸⁵, ⁴⁸⁶, ⁴⁸⁷.

Glaucoma treatment

The main goal of treating glaucoma is to keep it from getting worse by lowering the pressure inside your eye (IOP).

Some of the most likely treatments for this include:

• Medications. This mainly involves medications that lower pressure inside your eye. They can prevent glaucoma from developing if you have higher-than-normal intraocular pressure (ocular hypertension) or keep it from worsening enough to cause damage and symptoms.
• Glaucoma surgeries. These mainly focus on improving the drainage of aqueous humor fluid to lower pressure inside your eye. Surgery options include trabeculectomy, tube shunts, laser therapy and minimally invasive glaucoma surgeries (MIGS).

Other treatments are possible, depending on what type of glaucoma you have, how it’s affecting your eye and other factors. Your eye specialist can tell you more about your treatment options and help you choose one that fits your needs best.

Table 1. Glaucoma medications

Eye drops

Glaucoma treatment often starts with prescription eye drops. Some may decrease eye pressure by improving how fluid drains from your eye. Others decrease the amount of fluid your eye makes. Depending on how low your eye pressure needs to be, more than one eye drop may be prescribed.

Prescription eye drop medicines include:

• Prostaglandins. These increase the outflow of the fluid in your eye, helping to reduce eye pressure (IOP). Medicines in this category include latanoprost (Xalatan), travoprost (Travatan Z), tafluprost (Zioptan), bimatoprost (Lumigan) and latanoprostene bunod (Vyzulta). Possible side effects include mild reddening and stinging of the eyes, darkening of the iris, darkening of the pigment of the eyelashes or eyelid skin, and blurred vision. This class of medicine is prescribed for once-a-day use.
• Beta blockers. These reduce the production of fluid in your eye, helping to lower eye pressure. Examples include timolol (Betimol, Istalol, Timoptic) and betaxolol (Betoptic S). Possible side effects include difficulty breathing, slowed heart rate, lower blood pressure, impotence and fatigue. This class of medicine can be prescribed for once- or twice-daily use depending on your condition.
• Alpha-adrenergic agonists. These reduce the production of the fluid that flows throughout the inside of your eye. They also increase the outflow of fluid in the eye. Examples include apraclonidine (Iopidine) and brimonidine (Alphagan P, Qoliana). Possible side effects include irregular heart rate; high blood pressure; fatigue; red, itchy or swollen eyes; and dry mouth. This class of medicine is usually prescribed for twice-daily use but sometimes can be prescribed for use three times a day.
• Carbonic anhydrase inhibitors. These medicines reduce the production of fluid in your eye. Examples include dorzolamide and brinzolamide (Azopt). Possible side effects include a metallic taste, frequent urination, and tingling in the fingers and toes. This class of medicine is usually prescribed for twice-daily use but sometimes can be prescribed for use three times a day.
• Rho kinase inhibitor. This medicine lowers eye pressure by suppressing the rho kinase enzymes responsible for fluid increase. It is available as netarsudil (Rhopressa) and is prescribed for once-a-day use. Possible side effects include eye redness and eye discomfort.
• Miotic or cholinergic agents. These increase the outflow of fluid from your eye. An example is pilocarpine (Isopto Carpine). Side effects include headache, eye pain, smaller pupils, possible blurred or dim vision, and nearsightedness. This class of medicine is usually prescribed to be used up to four times a day. Because of potential side effects and the need for frequent daily use, these medicines are not prescribed very often anymore.

Combination drugs:

• Timolol/Brinzolamide (Azarga-not available in the US)
• Timolol/Dorzolamide (Cosopt)
• Timolol/Latanoprost (Xalacom-not available in the US)
• Timolol/Bimatoprost (Ganfort-not available in the US)
• Timolol/Brimonidine (Combigan)
• Brinzolamide/Brimonidine (Simbrinza)

Because some of the eye drop medicine is absorbed into the bloodstream, you may experience some systemic side effects unrelated to your eyes. To minimize this absorption, close your eyes for 1 to 2 minutes after putting the drops in. You also may press lightly at the corner of your eyes near your nose to close the tear duct for 1 to 2 minutes. Wipe off any unused drops from your eyelid.

You may be prescribed multiple eye drops or need to use artificial tears. Make sure you wait at least five minutes in between using different drops.

Never change or stop taking your glaucoma medications without talking to your ophthalmologist. If you are about to run out of your medication, ask your ophthalmologist if you should have your prescription refilled.

Alpha agonists for glaucoma

Alpha agonists also called alpha2-adrenergic agonists work by reducing the amount of fluid your eye produces. Alpha agonists also increase the amount of fluid that drains out of the eyes. This helps lower eye pressure and, hopefully, saves your vision.

Possible side effects of alpha agonists include:

• red, stinging or painful eyes after using drops
• blurry vision
• allergy (redness, itching, tearing and swelling of the eye)
• a large (dilated) pupil
• headaches
• dry mouth
• feeling tired, weak or dizzy
• decreased blood pressure
• a fast or irregular heartbeat
• feeling nervous

Blurry vision, stinging, and redness may improve with time. But if the side effects still bother you, call your ophthalmologist. They may be able to lower your dose or change your medicine. Most side effects go away when the medicine is stopped. If you feel you need to stop taking this medication due to side effects or other concerns, please discuss with your doctor.

Beta-blockers for glaucoma

Beta-blockers also called beta-adrenergic antagonists work by reducing the amount of fluid your eye produces. This helps lower pressure in your eye and, hopefully, saves your vision.

Possible side effects of beta-blockers include:

• red, stinging or painful eyes after using drops.
• blurry vision
• breathing problems in people with asthma, emphysema, or chronic obstructive pulmonary disease (COPD)
• a slow or irregular heartbeat
• feeling tired
• depression
• dizziness
• a change in sex drive or sexual function
• getting overly tired during exercise
• in people with diabetes, low blood sugar symptoms becoming difficult to notice

Blurry vision, stinging, and redness may improve with time. But if the side effects still bother you, call your ophthalmologist. They may be able to lower your dose or change your medicine. Most side effects go away when the medication is stopped. Never suddenly quit taking your medicine unless your doctor tells you to.

Carbonic anhydrase inhibitors for glaucoma

Carbonic anhydrase inhibitors work by reducing the amount of fluid your eye produces. This helps lower eye pressure and, hopefully, saves your vision. Your ophthalmologist may have you take this medicine as an eye drop or by mouth as a pill.

Possible side effects of carbonic anhydrase inhibitors include:

• stinging eyes after putting drops in.
• red eyes
• blurry vision
• a skin rash (especially in people who are allergic to sulfa drugs)
• changes in how things taste to you (especially with carbonated drinks)
• bad taste or upset stomach (nausea)
• feeling tired
• decreased energy
• increase in urination (with the pills)
• tingling around the mouth and fingertips (with the pills)
• lower potassium (with the pills)

Blurry vision, stinging, and redness may improve with time. But if the side effects still bother you, call your ophthalmologist. They may be able to lower your dose or change your medicine. Most side effects go away when the medication is stopped. Never suddenly quit taking your medicine unless your doctor tells you to.

Miotics for glaucoma

Miotics also called cholinergic agents make your pupil constrict (get smaller or miosis), increasing the amount of fluid that drains out of the eye. This helps lower eye pressure and, hopefully, helps protect your vision.

Possible side effects of miotics include:

• blurred vision
• nearsightedness (trouble focusing on distant objects)
• dim vision with difficulty seeing in the dark or at night
• headache or brow ache (aching around eye)

While very rare, there is the possibility that your retina could detach. This is when the light-sensitive tissue lining the back of the eye pulls away. You would suddenly notice dark specks or spots (floaters) or flashing lights in your vision. If you have these symptoms, see your ophthalmologist immediately.

Side effects may go away after you take the medicine for a while. But if the side effects still bother you, call your ophthalmologist. They may be able to lower your dose or change your medicine. If you feel you need to stop taking this medication due to side effects or other concerns, please discuss with your doctor.

Prostaglandin analogs for glaucoma

Prostaglandin analogs also called prostaglandin F2a analogues work by increasing the drainage of fluid out of your eye. This helps lower eye pressure and, hopefully, saves your vision.

Possible side effects of prostaglandin analogs include:

• red, stinging or painful eyes after using drops.
• feeling like something is in your eye
• blurry vision
• a permanent change in your eye color (occurs mostly in hazel eyes)
• an increase in thickness, number and length of eyelashes
• darkening of the eyelid
• worsening of existing angina and asthma
• joint aches
• light sensitivity
• eyes gradually sinking deeper into their sockets, keeping eyelids from working properly

Blurry vision, stinging, and redness may improve with time. But if the side effects still bother you, call your ophthalmologist. They may be able to lower your dose or change your medicine. Most side effects go away when the medication is stopped. Never suddenly quit taking your medicine unless your doctor tells you to.

Oral medicines

Eye drops alone may not bring eye pressure down to the desired level. So an eye doctor also may prescribe oral medicine. This medicine is usually a carbonic anhydrase inhibitor. Possible side effects include frequent urination, tingling in the fingers and toes, depression, stomach upset, and kidney stones.

Surgery, laser and other therapies

Other treatment options include laser therapy and surgery. The following techniques may help to drain fluid within the eye and lower eye pressure:

• Laser trabeculoplasty is an option if eye drops can’t be tolerated. Laser trabeculoplasty also may be used if medicine hasn’t slowed the progression of the glaucoma. An eye doctor also may recommend laser surgery before using eye drops. It’s done in the eye doctor’s office. An eye doctor uses a small laser to improve the drainage of the tissue located at the angle where the iris and cornea meet. It may take a few weeks before the full effect of this procedure becomes apparent.
• Laser iridotomy. Laser iridotomy is for people who have angle-closure glaucoma. The ophthalmologist uses a laser to create a tiny hole in the iris. This hole helps fluid flow to the drainage angle.
• Glaucoma filtration surgery also called a trabeculectomy. The eye doctor (ophthalmologist) creates an opening in the white of your eye, which also is known as the sclera. This is where your eye surgeon creates a tiny flap in the sclera. They will also create a bubble like a pocket in the conjunctiva called a filtration bleb. It is usually hidden under the upper eyelid and cannot be seen. Aqueous humor will be able to drain out of the eye through the flap and into the bleb, lowering eye pressure. In the bleb, the fluid is absorbed by tissue around your eye.
• Drainage tubes. In this procedure, the eye surgeon inserts a small drainage tube in your eye to drain excess fluid to lower eye pressure. The glaucoma drainage implant sends the fluid to a collection area called a reservoir. Your eye surgeon creates this reservoir beneath the conjunctiva. The fluid is then absorbed into nearby blood vessels.
• Minimally invasive glaucoma surgery (MIGS). An eye doctor may suggest a minimally invasive glaucoma surgery (MIGS) procedure to lower eye pressure. This procedure generally require less immediate postoperative care and have less risk than trabeculectomy or using a drainage device. A minimally invasive glaucoma surgery (MIGS) procedure is often combined with cataract surgery. There are a number of minimally invasive glaucoma surgery (MIGS) techniques available.
• Cataract surgery. For some people with narrow angles, removing the eye’s natural lens can lower eye pressure. With narrow angles, the iris and the cornea are too close together. This can cover (block) the eye’s drainage channel. Removing the eye’s lens with cataract surgery creates more space for fluid to leave the eye. This can lower eye pressure.

After your procedure, you’ll need to see your eye doctor for follow-up exams. You can expect to visit your ophthalmologist about every 3 to 6 months. However, this can vary depending on your treatment needs. And you may eventually need to undergo additional procedures if your eye pressure begins to rise or other changes happen in your eye.

Living with glaucoma

If you have glaucoma, the best thing you can do is follow your eye specialist’s guidance on treating and managing your glaucoma. Your eye specialist may also recommend making certain changes to your life, habits or routine. These can include:

• Not ignoring new symptoms or vision changes
• Reaching and maintaining a weight that’s healthy for you
• Staying physically active (but be sure to ask about which activities to avoid, as some can increase eye pressure)
• Seeing your eye specialist as recommended

You should also see your eye specialist if you notice new symptoms, if treatments aren’t as effective or if you have treatment side effects that are disrupting your life.

Glaucoma prognosis

Without treatment, glaucoma inevitably causes permanent vision loss and blindness. With treatment, it’s possible to slow the progress of your glaucoma or stop it entirely. The higher the intraocular pressure (IOP) and the duration of elevated IOP, the greater the risk of damaging the optic nerve. But because the range of possibilities can vary so widely between indivuals, your eye specialist is the best person to talk to about this. Your eye doctor can tell you the likely prognosis (outlook) for your specific case and what you can do to help tilt the scales in your favor. Timely diagnosis plays a critical role in mitigating glaucomatous eye damage, and early intervention is crucial in preventing and slowing down vision loss progression. Effective treatment, especially in maintaining low intraocular pressure (IOP) levels, can often lead to positive outcomes, preserving visual field integrity and halting disease advancement ²⁸.

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