Diagnosing glaucoma

Considering the importance of early diagnosis, yet the difficulty in achieving it, reliable diagnosis of early-stage glaucoma remains an unmet clinical need¹

Given that the glaucoma disease process begins up to 20 years before diagnosis is possible, in which time irreversible vision loss may have already occurred, there is a need to develop techniques to diagnose glaucoma earlier, when treatment has a higher chance of improving clinical outcomes^2,3. While glaucoma is associated with increased intraocular pressure (IOP)⁴, and a primary treatment goal is to reduce IOP in order to prevent further optic nerve damage⁴, measuring changes in IOP and using those measurements to inform diagnosis, treatment and monitoring is problematic for several reasons.

Early glaucoma diagnosis with high specificity and sensitivity

Following age, elevated IOP is the strongest risk factor for primary open angle glaucoma⁵. However, research indicates that no single value of IOP is sufficiently sensitive or specific enough to detect glaucoma. For instance, although high IOP is a risk factor for glaucoma, high IOP in isolation is not indicative of glaucoma. Conversely, a person with normal IOP values can have glaucoma. IOP alone – in the absence of optic disc examination or visual field test – is therefore not an effective screening tool, and elevated IOP has been found to be a poor case-finding test for glaucoma^5,6.

While IOP measurements can help inform diagnosis, treatment and management of glaucoma, one-off IOP measurements taken in clinical practice can be problematic for the following reasons¹.

Diurnal variation

• IOP fluctuates throughout the day due to the circadian rhythm, with maximum and minimum levels typically occurring at daybreak and at the end of the afternoon, respectively. Given these peak fluctuations occurring outside standard clinic hours, it is difficult to detect the presence of increased IOP in this setting⁴
• If appointment times vary between clinic visits, IOP readings may be incomparable¹
• Although IOP variations in glaucomatous eyes tend to be higher than in healthy eyes, IOP can vary by as much as 5 mmHg per day in healthy eyes and be unrelated to disease progression or eye damage⁴

Factors influencing IOP

The following factors can influence IOP levels^1,4:

• Ocular factors (e.g. accommodation)
• Extraocular muscle action or blinking
• Corporal factors (e.g. physical exercise and blood pressure, body position, Valsalva manoeuvres)
• External factors (e.g. atmospheric pressure, tight neck ties)
• Some systemic medications
• The methods or observer measuring IOP in the clinic can affect the measurement obtained.

These factors suggest the need for devices that continuously monitor IOP levels, not only to gain insight into the range of IOP levels the optic nerve is exposed to, but also to monitor a patient’s response to treatment¹.

Other issues related to sensitivity and specificity that affect reliable early diagnosis¹:

• Research suggests that the sensitivity of current biomarkers can be improved in order to more accurately diagnose early disease. Examples include macular ganglion and nerve fibre layer imaging, and alternative visual field-testing protocols. However, few novel techniques have been explored to date.
• Glaucoma exists within a range of age-related neurodegenerative conditions which are also associated with retinal nerve fibre layer thinning, such as Parkinson’s and Alzheimer’s disease. Differentiating between these conditions can be difficult, and patients with Parkinson’s or Alzheimer’s disease may be misdiagnosed as having glaucoma and unlikely to benefit from IOP-lowering therapy further complicates the diagnosis of glaucoma.

The impact of socioeconomic factors and patient education on glaucoma

Several research studies indicate that a relationship exists between socioeconomic factors and glaucoma^7-10. According to a study of the global health burden of glaucoma, socioeconomic differences contributed to inequalities of provision of glaucoma care between countries¹¹. While early treatment can prevent glaucoma-related vision loss and change the disability adjusted life years burden, differences in access to healthcare and the difficulties associated with diagnosis – given that chronic glaucoma is largely asymptomatic in its early stages – are key unmet needs in glaucoma^11,12. Low levels of glaucoma awareness across the world impact the use of eyecare services, further contributing to the lack of early detection¹².

Affordable, effective screening approaches for glaucoma

In order to identify people at risk of losing visual function, affordable and effective screening approaches are required. Highly accurate glaucoma diagnosis based on one photograph has been achieved thanks to automated grading of optic disc photographs. Low-cost, widespread glaucoma diagnosis may be achieved by using fundus imaging with grading assisted by artificial intelligence. However, further research is needed to determine how to best apply these tools¹.

Considering the impacts of glaucoma when diagnosis is delayed, improvements in detection are needed, with calls for a proactive screening strategy to be implemented. While mass glaucoma screening has been cited as cost-prohibitive, China and India have reported population-based screenings that were cost-effective¹².

Figure 1 highlights key unmet needs in glaucoma diagnosis.

Figure 1. Unmet needs in glaucoma diagnosis. IOP, intraocular pressure.

In this video, Professor Anthony King discusses strategies for screening and diagnosing glaucoma. While there are numerous tools that can aid diagnosis, Professor King explains why glaucoma is known as the ‘silent thief of sight’, and highlights the importance of opportunistic case-finding.

Screening

Better screening, diagnosis, monitoring and management of glaucoma are possible thanks to technological advances and enhanced understanding of the disease¹³.

Guidelines for glaucoma screening vary between countries¹⁴. Due to a lack of effective screening programs globally, and the absence of widely accepted public guidelines and cost-effective screening tools, detection of glaucoma is usually opportunistic, relying largely on the general public’s health-seeking behaviour¹². In developed countries, glaucoma is commonly detected by opportunistic case finding, which typically occurs when a person receives an eye examination such as by an optometrist. Glaucoma suspects are then referred to ophthalmologists for diagnosis and management⁵.

According to a recent review, referring high-risk patients for a complete ophthalmic examination can reduce vision loss from glaucoma¹⁴.

Reference to association guidelines, such as those by the Asia-Pacific Glaucoma Society (APGS) and European Glaucoma Society (EGS), may assist healthcare professionals when considering screening strategies for glaucoma suspects¹³.

While the Asia-Pacific Glaucoma Society recommends screening people at risk of glaucoma, the European Glaucoma Society does not¹³

Glaucoma screening is defined by the Asia Pacific Glaucoma Society (APGS) as the “examination of asymptomatic people to classify them as likely or unlikely to have glaucoma”¹⁵. According to the APGS guidelines, opportunistic screening is preferable to universal, and healthcare professionals (HCPs) should conduct opportunistic screening for^13,15:

• people visiting ophthalmologists, using directed investigations and a comprehensive clinical examination
• people visiting a physician, optometrist or other HCP using more specific, rapid tests

To conduct screening of an individual for glaucoma, HCPs should¹³:

• assess their risk factors
• measure their IOP
• investigate any adverse effects from medications
• review quality of life factors
• conduct all basic investigations including an optic disc examination and visual field test

The endpoint of screening involves referring a person with a positive result to an ophthalmologist¹⁵.

The Early Manifest Glaucoma Trial Screening study found that people who had glaucoma detected during a screening program had less extensive visual field defects than those who had glaucoma detected in clinic, revealing the limitations of opportunistic case-finding¹³. However, there are currently no systematic reviews providing evidence for indirect or direct links between glaucoma screening and visual impairment, visual field loss, optic nerve damage, IOP or patient-reported outcomes¹⁶. While screening individuals for glaucoma remains unquestionably important¹³, the cost-effectiveness of population-based screening has been explored in economic simulation models, with inconclusive results, and there is no evidence of interventions, such as training, improving opportunistic case-finding¹⁶.

Debate on the optimal tests to screen for glaucoma is ongoing¹⁷, and even with an accurate test, screening for primary open angle glaucoma (POAG) tends to result in many false-positive referrals due to its relatively low prevalence¹⁸. A review conducted in the UK concluded that screening for POAG in adults is not recommended, and it did not find evidence to support improved outcomes with screening, compared with standard care, nor did it find screening tests with sufficient accuracy¹⁸. Similarly, the US Preventive Services Task Force (USPSTF) does not recommend population-based glaucoma screening for asymptomatic adults, although the recommendation is being revisited¹⁴. The recommendations made by the USPSTF in 2013 still apply, stating “current evidence is insufficient to assess the balance of benefits and harms of screening for primary open angle glaucoma in adults”¹⁹.

Researchers have recognised the need for development and implementation of inexpensive, accessible and effective pathway approaches for glaucoma screening, diagnosis, monitoring and management²⁰

Despite the lack of evidence for population-based screening, there is evidence of utility and cost-effectiveness for populations at high risk – such as people with a family history or of non-white race¹⁴. For people diagnosed with glaucoma, it is recommended that they receive regular monitoring for signs of disease progression. For example, people in the US at high risk of glaucoma are recommended to have a comprehensive ocular examination by an eye care professional to look for signs of glaucoma¹⁴.

An effective strategy may be to conduct targeted screening of a subset of the population with higher glaucoma prevalence. This may involve the use of deep learning image analysis and POAG polygenic risk prediction models to provide insight into identification of sub-populations that are glaucoma-enriched¹⁸.

Consistently, research has revealed an association between undetected glaucoma and lapse in or lack of eye examinations. In one study, adults who did not receive annual eye examinations for prescription glasses were nine times more likely to have undetected glaucoma¹². In countries such as the UK, which provide universal healthcare and free eye tests for people over 60 years of age, this may result in more cases of glaucoma being detected⁵.

In one study, people who had their last eye examination >3 years ago were 9.8 times more likely to have undetected glaucoma¹²

Diagnostic strategies

Typically, symptoms of open angle glaucoma appear only once the patient’s glaucoma has progressed to an advanced stage. In contrast, acute angle closure glaucoma exhibits symptoms, which may include visual impairment, nausea and vomiting, pain radiating from the eye and conjunctival hyperaemia¹³.

There are a variety of techniques and tools to diagnose glaucoma, with varying levels of evidence to support them. Table 1 outlines diagnostic techniques, their strength of recommendation according to the European Glaucoma Society, and the level of evidence that supports them.

Table 1. Techniques for glaucoma diagnosis including strength of recommendation and evidence^16,21-26. IOP, intraocular pressure; ONH, optic nerve head; RNFL, retinal nerve fibre layer. ^*Use of central corneal thickness-adjusted IOP not recommended. ^†Binocular observation under pupil dilation is preferable except in angle closure glaucoma. ^‡Glaucoma diagnosis cannot be made on the basis of optical coherence tomography alone.

Regular, periodic assessments are vital in order to detect progression early and adjust treatment as necessary, with the goal of preventing further vision loss²⁷. When monitoring glaucoma patients, there are a variety of tests and techniques that may be used. Table 2 outlines recommended tests used to monitor glaucoma, including the strength of recommendation.

Table 2. Recommended tests to monitor glaucoma, including strength of recommendation and evidence^{16,21, 23,24,26}. IOP, intraocular pressure; OCT, optical coherence tomography; RNFL, retinal nerve fibre layer. ^*The most important test to monitor progression; it is recommended to use software-based progression analysis and the same instrument and strategy for follow-up tests. ^†OCT progression analysis cannot replace visual field progression analysis; using the same instrument with software-based analysis may be helpful; OCT progression is not currently age-corrected; visual field progression does not always correlate with apparent OCT progression.

Glaucoma has a good prognosis and excellent vision can be retained when it is treated early¹². Continue to the next section to learn about glaucoma treatment strategies.

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Treating glaucoma