Numerous therapies exist to control IOP, delay glaucoma progression

Glaucoma is still the leading cause of irreversible blindness in the world because of its insidious onset.

 

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Glaucoma, a word derived from the Greek “glaukos,” appeared in the works of Homer around the 8th century BC, describing a sparkling silver glare. By the 4th century BC, the word “glaucosis” was used in Aphorisms by Hippocrates to describe “dimness of vision” among the infirmities of the age. Throughout the Roman era, the term glaucoma was used to describe a greenish or bluish hue (a dull sheen or “glaze”) of blindness, specifically a condition for what is now known as cataract.

It was not until 1622 when Richard Bannister, MD, distinguished glaucoma from cataracts with clinical features of eye tension, a fixed pupil and blindness. However, it was more than 2 more centuries until Sir William Lawrence gave a complete description of glaucoma in his A Treatise of Diseases of the Eye in 1832.

The modern era in the understanding and management of glaucoma truly began in the early 19th century with a clear definition from a few prominent ophthalmologists of the day such as William McKenzie, MD; Franciscus Cornelis Donders, MD; and Albrecht Von Graefe, MD, facilitated by the invention of the ophthalmoscope in 1851 by Hermann van Helmholtz. Interestingly, McKenzie was against the use of the ophthalmoscope because of its potential harmful effects to the retina, a light toxicity issue that is still being debated today.

What is glaucoma?

Current understanding defines glaucoma as a chronic, progressively degenerative optic neuropathy with multiple etiologies resulting in damage and death of ganglion cells, enlarging of the optic nerve cup and loss of vision. Typically, peripheral vision is affected first, followed by encroaching loss of central vision; however, complete blindness can occur if glaucoma is left untreated.

 

Although glaucoma is no longer diagnosed solely on elevated intraocular pressure, the majority of glaucoma patients have abnormal IOP of above 21 mm Hg; therefore, tonometry remains one of the most important tests for glaucoma diagnosis and management. The normal range for IOP is between 10 mm Hg and 21 mm Hg. IOP of greater than 21 mm Hg is chosen as an indicator of high IOP because it is two standard deviations over the mean of 15.5 mm Hg. Normally, IOP is regulated by aqueous humor production from the ciliary body and the two outflow pathways, the major corneoscleral outflow and the minor uveoscleral outflow. The disruption or increased resistance to drainage systems is largely responsible for abnormally elevated IOP rather than an increase in aqueous humor production. In addition to maintaining the normal structure and pressure of the eye, aqueous humor production serves as a circulatory system for the anterior segment of the eye by providing essential nutrients to the crystalline lens, iris and cornea.

As an optic neuropathy, glaucoma can be differentiated from other optic neuropathies by a few distinct clinical features such as a pink neuroretinal rim, rim thinning and optic nerve cupping. Optic nerve pallor and cupping are not often seen in other optic neuropathies, except cupping may be observed in rare cases of longstanding arteritic anterior ischemic optic neuropathy or giant cell arteritis.

Classification

Glaucoma is classified into two major categories based on the appearance of the iridocorneal angle: open-angle glaucoma (OAG) and closed-angle glaucoma (CAG). Although the angle or drainage pathway may appear open or normal, the aqueous flow is impeded by abnormalities in the trabecular meshwork. Glaucoma can be primary, when it arises spontaneously and is not associated with or caused by a known disease or injury, or secondary, when it is caused by an earlier disease, injury or event such as exfoliation, pigment dispersion, trauma or inflammatory cause.

The age of glaucoma onset can also be part of the classification; for instance, congenital or developmental glaucoma is diagnosed at birth or within the first few years of life and often associated with syndromes such as aniridia or the Axenfeld-Rieger syndrome. Juvenile-onset glaucoma occurs between the ages of 3 and 40 years old. Adult-onset glaucoma arises after 40 years of age.

Another term used to describe glaucoma is whether the disease is acute or chronic. Acute glaucoma is caused by a sudden spike in IOP up to as high as 70 mm Hg in some cases, usually secondary to pupillary block or severe ocular trauma. Inflammatory glaucoma and glaucomatocyclitic crisis (Posner Schlossman syndrome) can also induce acute IOP spike, which requires immediate management to minimize rapid damage to the retinal ganglion cells. On the contrary, chronic glaucoma progresses insidiously, and IOP often goes beyond 30 mm Hg, but the patient is asymptomatic for many years even without treatment.

Race has been shown to be a factor associated with a certain type of glaucoma. Primary open-angle glaucoma (POAG) accounts for about three-fourths of all glaucomas in the world and is the predominant form of glaucoma in North America. A subset of POAG patients maintain a normal IOP range of below 21 mm Hg and are considered to have normal-tension glaucoma (NTG). Interestingly, Japanese people have the highest rates of NTG. While POAG is also the major form of glaucoma in Asia, primary angle-closure glaucoma (PACG) is more common in Chinese people than Caucasians.

An important group of patients that does not fit into any of the above categories is individuals with ocular hypertension when their IOPs are consistently higher than 21 mm Hg (2 standard deviations above an average IOP of 15.5 mm Hg) but they do not suffer from progressive neuropathy or visual field loss. Ocular hypertension is relatively common, affecting 3% to 5% of the population older than 40 years. As indicated by the Ocular Hypertension Treatment Study (OHTS), less than 10% of subjects presenting with ocular hypertension per se developed POAG over 5 years. On the contrary, more than half of POAG cases had a mean IOP of less than 21 mm Hg. Although IOP by itself is a poor diagnostic marker for glaucoma, it remains an important predictor of POAG development and progression as found in the OHTS and the Barbados Eye Studies. Therefore, it is important to monitor ocular hypertensive patients closely at least for the first few years to minimize misdiagnosis.

Prevalence, incidence

As primary eye care providers, optometrists diagnose and manage glaucoma probably on a daily basis, as it is one of the most common ocular disorders. Data from the World Health Organization in 2010 estimated that approximately 2% of visual impairment and 8% of global blindness were caused by glaucoma. It is the second leading cause of vision loss in the world after cataract. In the U.S., more than 2.2 million Americans are affected by glaucoma, and more than 120,000 patients are blind from glaucoma, accounting for about 10% of all cases of blindness. Thus, glaucoma imposes a significant economic impact in the U.S. and the world. Prevalence data provide a guide on how to allocate resources to fight the disease, whereas incidence data is important to understand how commonly glaucoma occurs over a period of time. Additionally, incidence can be used to estimate the individual risk of getting glaucoma.

Incidence data, however, are more difficult to obtain because an incidence study requires several years to complete. Glaucoma incidence studies have shown that in a predominantly white population in Melbourne, Australia, the 5-year incidence of POAG was 0.5% and in a predominantly black population in Barbados, the 9-year incidence of POAG was 4.4%, or 0.5% per year. Thus, the risk for POAG was higher blacks than in whites. Moreover, the relative risk for Hispanics has been shown to lie between these two populations.

Risk factors for glaucoma

Cumulative studies over the past few decades have provided convincing evidence that increasing age, elevated IOP, black race, a first-degree relative with glaucoma, myopia and low diastolic perfusion pressure are among the strong risk factors for POAG. Additionally, a thinner-than-average central cornea is also a major risk factor for individuals with increased IOP. Other risk factors such as diabetes mellitus, hypertension or migraine have been reported, but are less consistent.

A recent review indicated that African-Americans are five times more likely to have POAG than age-adjusted Asian and European Americans. Furthermore, POAG is the leading cause of blindness in African-Americans. Unfortunately, up to half of all cases of glaucoma remain undetected in Western countries. Moreover, the rate of undiagnosed glaucoma could be much higher in developing countries where routine eye care is not readily accessible. For example, only 4% of POAG was diagnosed in a Nepal population-based study.

The biggest challenge with glaucoma is that it is generally asymptomatic until a substantial loss of nerve fibers or late in the disease course. Even with a diagnosis, many patients tend to be in denial and do not accept the diagnosis because the disease has not affected their daily activities. On top of that, medical treatment does not provide any beneficial effect for the expense, but irritating side effects, so many patients have poor compliance and adherence to ophthalmic drops.

Late detection and poor compliance with treatment increase the risk of blindness. In addition, the rate of progression varies considerably among patients, making it difficult to determine a prognosis. The OHTS studies, however, provide valuable data to estimate POAG progression. A few versions of a 5-year risk calculator are available online to aid clinicians in prognosis and patient education (http://ohts.wustl.edu/risk/calculator.html or www.deverseye.org/grc). Further, it can serve as a tool for patient education because it is an evidence-based prognosis.

Pathophysiology

Despite more than a century of active research, the pathophysiology of POAG remains to be fully elucidated. Increased IOP, however, is one of the common clinical features among patients with POAG. Regardless of the cause, the rise in IOP triggers a series of cellular events leading to the eventual death of retinal ganglion cells (RGCs). The optic nerve head is made up of a collagenous sieve-like structure, lamina cribosa, where the unmyelinated prelaminar RGC axons emerge and innervate the whole retina. Additionally, non-neuronal supporting cells such as microglia, astrocytes and retinal vasculature intersperse with RGC.

 

Within the neuron, axonal transport is critical to its survival because the axon does not contain cellular organelles for protein synthesis, so nutrients and proteins must be transported from the neuronal cell body (soma) down along the axon (anterograde) or from axon to the cell body (retrograde) for neuronal function. Elevated IOP has been found to reduce retrograde axoplasmic flow and induce RGC stress and death from deprivation of brain-derived neurotrophic factors. Additionally, blood perfusion to the optic nerve head is also reduced, leading to neuronal hypoxia and death.

Activation of glial cells, such as microglia and astrocytes, by elevated IOP accelerates the degradation of extracellular matrix and remodeling of the optic nerve head, rendering it more fragile. At the molecular level, tumor necrosis factor a (TNF-a), a proinflammatory cytokine, has been suggested as a mediator of RGC damage because deletion of the genes encoding TNF-a or its receptor increased RGC survival, whereas intravitreal injection of TNF-a leads to RGC loss even in the absence of elevated IOP in a mouse model of glaucoma.

Studies in human glaucomatous retina and optic nerve head have detected TNF-α immunohistochemically supporting the importance of glial-activated TNF-a production as mediators of RGC damages. The initial site of glaucomatous damage is at the lamina cribrosa, and axonal damage occurs first before triggering apoptotic death of the neuronal cell body about 1 to 2 months later in a mouse model. Collectively, several factors contributed to RGC death, including mechanical pressure on the axons at the lamina cribrosa, stasis in axoplasmic flow, low perfusion and ischemia to the optic nerve head.

Natural course

The natural path of POAG is variable, albeit time dependent. A majority of cases are identified initially as suspects during a routine eye exam when the patients have elevated IOP accompanying moderate to large cup-to-disc (C/D) ratio and/or family history. In addition, diagnostic markers such as visual field loss corresponding to nerve fiber layer loss are usually necessary to confirm diagnosis.

Once the diagnosis is made, POAG is treated medically to lower the IOP in an attempt to delay or stop progression of visual field loss. In most cases of POAG the disease progresses slowly even without treatment, and patients remain unaware of the disease until the advanced stage several years later. In contrast, some types of secondary OAG such as pigmentary, pseudoexfoliation or traumatic glaucoma can progress more rapidly because of the acute nature of the disease, with extreme IOP spike.

A recent review identified a number of prognostic factors for glaucomatous visual field progression. Older patients, more loss in baseline visual field, higher baseline IOP and presence of exfoliation syndrome are prone to glaucomatous progression. Similarly, disc hemorrhages are definitely associated with progression in patients with NTG.

Despite medical treatment, many patients continue to progress and thus require surgical intervention in the later stage of the disease. Even with the available medical and surgical armamentarium to manage glaucoma in developed countries, a significant portion, approximately 5%, of patients, end up blind in one or both eyes due to glaucoma. Higher figures of 6% in both eyes within 15 years and 22% within 20 years have been reported in retrospective studies. Fortunately, glaucoma can be managed quite effectively when it is diagnosed early, and most patients do not go completely blind with treatments; thus, optometrists play a crucial role in fighting this stealthy thief of sight.

Screening

Current epidemiological evidence suggests a staggering number of patients with glaucoma remain unidentified – more than half in the developed countries and up to 90% in developing countries. The large number of people with undiagnosed glaucoma remains a public health issue, and numerous challenges to glaucoma screening exist. For example, there is no single test or marker to diagnose glaucoma, and a relatively low prevalence of glaucoma makes public screening cost prohibitive in the developed world.

 

In 2005, the U.S. Preventive Services Task Force concluded that there was insufficient evidence to recommend glaucoma screening. Glaucoma screening is not recommended in the United Kingdom, either. Nevertheless, screening for glaucoma continues to be conducted throughout the U.S., usually at various public events. The effectiveness in identifying individuals with undetected glaucoma during these independent public screenings at health fairs and church gatherings remains uncertain and controversial because it is not a comprehensive eye exam or glaucoma work-up, but the individual may interpret it as such and may skip a regular vision exam. On the other hand, many individuals who fail the screening test or are glaucoma suspects do not pursue further testing for a definite diagnosis.

A study after a community screening in Portland, Ore., reported that less than 70% of those with a positive screen sought free definitive evaluation. Therefore, the consensus about glaucoma screening is to target high-risk populations, such as the elderly and African-Americans, and to have a mechanism to assure follow-up and treatment once glaucoma is suspected or diagnosed.

Selection of which glaucoma test to use is also important in the screening process. A recent systematic review of published reports of screening tests for glaucoma by Mowatt and colleagues identified frequency doubling technology (FDT) C20-1, oculokinetic perimetry and Heidelberg retinal tomography (HRT) to have good sensitivity, specificity and a diagnostic odds ratio. On the contrary, ophthalmoscopy, standard automated perimetry, retinal photography and applanation tonometry were found to be poor screening tests.

Diagnosis

Once individuals are suspected of having glaucoma from a screening event or routine eye exam, they undergo a diagnostic work-up consisting of examination of the angle via gonioscopy, measurement of IOP via tonometry, optic nerve head imaging and visual field testing. Although elevated IOP is often seen in POAG, IOP measurement alone is not sufficient to diagnose glaucoma because it may miss up to half of the patients with glaucoma, and its measurement is also subjected to inter-observer and intra-observer variability. Gonioscopy is crucial to evaluate whether the iridocorneal angle is open or closed, in addition to ruling out angle neovascularization or other anatomical changes. For further training in gonioscopy, Wallace L.M. Alward, MD, has generously shared his expertise online (www.gonioscopy.org).

Optic nerve examination is the next essential step in diagnosing glaucoma and is usually performed after pupillary dilation for optimal stereoscopic view using one of the high-plus lenses: 60 D, 78 D or 90 D. An average optic nerve head is about 1.7 mm to 1.8 mm in diameter. The C/D ratio is the first clinical parameter to measure by estimating the area of the optic hole as a fraction of the optic nerve head horizontally and vertically. C/D ratio is relatively stable over time because NFL loss due to the normal aging process is slow. In glaucoma, accelerated and progressive loss of optic nerve axons leads to enlargement of the C/D ratio, and optic nerve cupping is considered to be pathognomonic of glaucoma. Asymmetry of C/D ratio >0.2 between eyes also raises suspicion of glaucomatous loss. As a consequence of axonal loss, the lamina cribrosa becomes more apparent as fenestrated mesh or “laminar dot sign.”

The next step is to assess the shape, contour and color of the neuroretinal rim, applying the “ISNT” rule. In a normal optic disc, the inferior rim at 6 o’clock is thickest, followed next by the superior, nasal and temporal portions of the rim. Violating the “ISNT” rule or pallor of the neuroretinal rim is a red flag for glaucomatous optic atrophy. For example, if visual field testing is unreliable and C/D ratio is used alone as a diagnostic sign, a 0.8 mm vertical C/D ratio is a good cutoff for the 99.5th percentile because only 0.5% of normals have such a large vertical C/D.

Before the arrival of advanced optic nerve imaging technology, retinal NFL defects were assessed under red-free illumination, which can still be important as part of the glaucoma work-up. Other clinical signs to pay attention to are Drance hemorrhage, bayonet vessel, baring of circumlinear vessel and nasalization of vessel. An excellent illustration of some of these signs has been shared online by Philipp Franko Zeitz, MD (www.zeitzfrankozeitz.de/tl_files/Bilder/Dictionary/glaucoma%20optic%20disc%20pt2.jpg).

 

Finally, an additional sign relevant to glaucoma is peripapillary atrophy, with the b zone overlapping the temporal crescent and a zone adjacent to the b zone. The peripapillary atrophy area has been found to be larger in patients with glaucoma than in controls.

Early glaucomatous loss is difficult to detect because reserve is built into the optic nerve, compensating for the initial NFL loss and, hence, the patient is asymptomatic. As the disease progresses, functional loss starts to appear, but it may take up to half of the optic nerve fiber loss before a visual field defect is picked up on standard automated perimetry. Nonetheless, visual field testing still is an integral part of the glaucoma work-up and management.

Although several automated perimeters are available for testing visual field, Humphrey and Octopus automated perimeters are most commonly used by clinicians because they integrate the Swedish Interactive Threshold Algorithm (SITA) to shorten the length of the test, with similar or better reproducibility than the full-threshold strategy. The SITA Standard takes about 7 minutes per eye and is good for glaucoma diagnosis and management, whereas SITA Fast takes about 4 minutes per eye and is useful for screening purposes. The 30-2 program tests 76 points, whereas the 24-2 program tests 54 points. Perimeters with an alternate target using frequency doubling technology are also widely used, with evidence that they have a high sensitivity and specificity for early detection of glaucoma. The test duration is relatively short, taking only 5 minutes for a comprehensive field and 1 minute for a screening field. The C-20 measures 17 target locations, whereas the N-30 measures 19 target locations.

Taking a visual field test is not a simple task for the first time because it requires high concentration and manual dexterity. It often requires a few tests to get reliable and reproducible results; therefore, it is important that the diagnosis of glaucoma is not based on a single visual field test but after a few tests showing repeatable field defects. For example, on a Humphrey field analyzer 24-2 SITA Standard, an abnormal glaucoma hemifield test or a reproducible cluster of three nonedge abnormal points at the 5% level is considered an abnormal visual field. Additionally, the severity of glaucoma can be graded based on the mean deviation (MD): mild MD is less than or equal to -6 dB; moderate is -6 dB to -12 dB; and advanced is greater than -12 dB. In contrast, a simpler ICD-10 classification defines mild as no visual field loss, moderate as any visual field loss not within 5 degrees of fixation in one hemifield and severe as field loss in both hemifields or within 5 degrees of fixation. Typical glaucomatous field defects to look for include nasal step, arcuate defect and paracentral scotoma.

In the last few years, a number of studies have shown that glaucoma damages the RGCs throughout the retina, and macular RGCs can be affected early in the course of the disease. One of the newer analytic features available in the spectral or Fourier domain ocular coherence tomography (SD-OCT) for glaucoma diagnosis is the ganglion cell complex (GCC) analysis. Visual field testing with 10-2 strategy testing every 2° has been found to be better in detecting these early macular changes than 24-2 strategy testing every 6°. The estimation was that approximately 16% of patients with central field defects were missed when 24-2 tests were done alone. Therefore, 10-2 central field testing should be considered as an important part of glaucoma diagnosis and management.

Therapeutic goals, approaches to reducing IOP

The main goal of glaucoma management is to delay or stop progression of visual field loss and ultimately maintain functional vision throughout the patient’s lifetime. At the moment, the only way to delay glaucoma progression is by lowering IOP. Numerous studies over the years have confirmed that lowering IOP significantly decreased glaucomatous progression. Once the diagnosis of glaucoma is confirmed, a target pressure is set as a guide to gauge the effectiveness of medical therapy.

For example, the target pressure is set to at least a 20% reduction from baseline IOP or less than 21 mmHg for early-stage glaucoma, whereas for advanced glaucoma the target pressure is desirably set to at least a 30% reduction from baseline IOP or less than 15 mmHg. These target pressures only serve as a guide for initial treatment of glaucoma to delay or prevent progression. So, if patients do not meet the initial target pressure with good medical compliance or show signs of progression on follow-up visits even though the target pressure has been reached, lowering the target pressure and adding another glaucoma drop may be necessary. In general, the younger the patient and the more severe the glaucoma, the lower the target pressure must be set.

 

Lowering of IOP to meet target pressure can be achieved by medical therapy, laser treatment, and surgical means. The first line of glaucoma management usually starts with IOP lowering ophthalmic drops. Generally, the two ways to lower IOP are by reducing aqueous humor production or increasing outflow.

Timoptic (timolol 0.25% and 0.50%, Santen), Alphagan (brimonidine 0.1% and 0.15%, Allergan), Trusopt 2% (dorzolamide, Santen) and Azopt 1% (brinzolamide, Alcon) inhibit aqueous production, where the prostaglandin analogs such as Lumigan (bimatoprost 0.01%, Allergan), Xalatan (latanoprost 0.005%, Pfizer), Travatan Z (travoprost 0.004%, Alcon) and Zioptan (tafluprost 0.0015%, Merck) increase aqueous outflow. Prostaglandin analogs and carbonic anhydrase inhibitors such as brinzolamide are known to have good 24-hour IOP lowering efficacy, whereas beta-blockers (timolol) and alpha-agonists (brimonidine) have poor nocturnal efficacy.

Another important point to keep in mind for glaucoma patients who have ocular surface disease or are sensitive to preservatives: a few preservative-free glaucoma medications are available, including Zioptan, Timoptic in Ocudose (Santen) and Cosopt (dorzolamide HCl–timolol maleate, Santen). Finally, a recent review on the effects of antiglaucoma drugs on blood flow of the optic nerve head reported that betaxolol, latanoprost and dorzolamide can increase blood flow to the optic nerve head, ranging from 5% to 30%, but further study is needed to examine its potential significance in glaucoma progression.

When IOP still does not meet the target with multiple glaucoma drops, a laser procedure, such as selective laser trabeculoplasty (SLT), is recommended as a next line of therapy. Surgical intervention, such as trabeculectomy (filtration surgery) or drainage implants (Molteno, Baerveldt or Ahmet) is typically reserved for patients with uncontrolled glaucoma despite multiple forms of therapies. Although laser and surgical interventions for glaucoma have been found to be more effective in reducing IOP than medical therapy, surgery may be associated with more ocular discomfort and cataract development.

Minimally invasive glaucoma surgery (MIGS) is the latest trend in the management of glaucoma. MIGS is performed through a small corneal incision similar to cataract surgery, thus minimally invasive, and spares the conjunctiva. Hence, it is often combined with cataract surgery by solving two problems with one surgery. A growing body of knowledge in the last few years indicates that MIGS can maintain an average IOP of 15.2 mm Hg at 5 years. Therefore, the procedure is recommended for patients with mild or moderate glaucoma with a target IOP in the mid- to upper teens. Patients who need an IOP in the lower teens or below 10 mm Hg will typically require a trabeculectomy or tube shunt surgery. Examples of MIGS options approved by the U.S. Food and Drug Administration are the Glaukos iStent, the NeoMedix Trabectome and the Endo Optiks ECP.

Glaucoma is a chronic disease that requires lifelong management with regular monitoring for structural changes (imaging) and functional deterioration (visual field). Patients with stable or mild glaucoma should be scheduled for follow-up every 6 to 12 months, and those with more advanced stages should be seen every 2 to 4 months.

On the horizon

A few exciting developments in the management of glaucoma for the near future include 24-hour IOP monitoring, sustained slow release of glaucoma medications and a new class of glaucoma medication.

The Sensimed Triggerfish is a contact lens sensor that measures the circumferential changes at the corneoscleral junction that are converted as changes to IOP over a 24-hour period. Latanoprost and travoprost punctal plug delivery systems are in phase 2 clinical trials with QLT Inc. and Ocular Therapeutix Inc., respectively. Latanoprost-eluting contact lenses were able to release the medication slowly over a month as reported recently by researchers at the Massachusetts Eye and Ear Infirmary in Boston. Lastly, Rho-associated protein kinase (ROCK) inhibitors are a new class of compounds that target cells in the trabecular meshwork to encourage aqueous humor outflow. Aerie Pharmaceutical’s product AR-13324, which was able to reduce IOP by 5 mm Hg in a phase 2 study, now moves forward to phase 3 study.

Glaucoma is still the leading cause of irreversible blindness in the world because of its insidious onset. More than half of affected individuals may not know they have the disease until it reaches the moderate or severe stage. Fortunately, there are numerous effective therapies to control IOP and delay glaucoma progression and burden. Additionally, new understanding and discoveries are made over time to conquer this visually debilitating disease. Therefore, clinicians must keep up to date with the literature and be vigilant in catching this silent thief of sight early, followed by effective management to prevent further damage to vision.