How accurate are screening tests in identifying those at risk of developing primary angle closure glaucoma?

Why is improving the diagnosis of primary angle closure glaucoma important?
Glaucoma is a group of eye diseases that cause damage to the optic nerve at the back of the eye. If untreated, glaucoma can lead to blindness. Primary angle closure glaucoma is a type of glaucoma, where the drainage route for the fluid inside the eye (known as the angle) is narrowed or blocked, leading to raised eye pressure and loss of the field of vision. Primary angle closure glaucoma accounts for a quarter of all cases of glaucoma globally and it is more likely to lead to vision loss than the more common form, primary open angle glaucoma.

A variety of non-invasive tests are available to identify people at risk of primary angle closure glaucoma in a community or non-specialist clinical setting. Those who test positive are referred for further specialist investigation and possible treatment. Failure to detect this condition (a false negative result) may result in an increased risk of progressive optic nerve damage and blindness. An incorrect diagnosis (a false positive result) could lead to unnecessary and costly investigation.

What is the aim of this review?
The aim of this review was to find out how accurate non-invasive screening tests are in identifying those at risk of developing primary angle closure glaucoma.

What was studied in this review?
Five non-invasive tests were studied. These range from simple tests that require either a pen torch or a widely available piece of clinical equipment known as a slit -lamp microscope (oblique flashlight test; limbal anterior chamber depth (LACD)) to more sophisticated imaging equipment (anterior segment optical coherence tomography (AS-OCT), Scheimpflug photography and scanning peripheral anterior chamber depth analyser (SPAC)) that can scan and measure the dimensions of the drainage angle.

What were the main results in this review?
The review included 47 relevant studies, with a total of 26,151 participants. Twenty-seven studies assessed AS-OCT, 17 studies assessed LACD, nine studies Scheimpflug photography, six studies SPAC and five studies evaluated the flashlight test.

The overall diagnostic performance of LACD was similar to the more advanced imaging technologies, AS-OCT, Scheimpflug photography and SPAC, however, the flashlight test showed an inferior performance. Using LACD as an example, if this test was performed on 1000 people, of whom 100 were at risk of primary angle closure, an estimated 83 would be correctly identified and 17 cases would be missed (false negatives). The test would correctly identify 792 of the 900 not at risk of angle closure glaucoma and incorrectly classify 108 (12%), who would be unnecessarily referred (false positives).

How reliable were the results of the studies in this review?
Most studies were of low quality due to the way that the participants were recruited or how the tests were performed. This could have led to the tests appearing more accurate than what they really are. We can therefore not be sure that the tests will always produce the reported results.

What are the implications of this review?
The studies included in this review were mostly conducted in Asia, which carries the greatest burden of primary angle closure glaucoma. The results of this review have shown that LACD, which is a quick and simple test that can be performed with a minimal amount of training, can identify people at risk of primary angle closure glaucoma, leading to early and appropriate treatment. Although this test could potentially miss approximately one in six of those at risk of the condition and lead to an over referral of 12%, the test could be useful for targeted screening in areas with a high prevalence of the condition.

How up to date is this review?
Evidence in this review is current to 3 October 2019.

Authors' conclusions: 

The finding that LACD performed as well as index tests that use sophisticated imaging technologies, confirms the potential for this test for case-detection of occludable angles in high-risk populations. However, methodological issues across studies may have led to our estimates of test accuracy being higher than would be expected in standard clinical practice. There is still a need for high-quality studies to evaluate the performance of non-invasive tests for angle assessment in both community-based and secondary care settings.

Read the full abstract...
Background: 

Primary angle closure glaucoma (PACG) accounts for 50% of glaucoma blindness worldwide. More than three-quarters of individuals with PACG reside in Asia. In these populations, PACG often develops insidiously leading to chronically raised intraocular pressure and optic nerve damage, which is often asymptomatic. Non-contact tests to identify people at risk of angle closure are relatively quick and can be carried out by appropriately trained healthcare professionals or technicians as a triage test. If the test is positive, the person will be referred for further specialist assessment.

Objectives: 

To determine the diagnostic accuracy of non-contact tests (limbal anterior chamber depth (LACD) (van Herick test); oblique flashlight test; scanning peripheral anterior chamber depth analyser (SPAC), Scheimpflug photography; anterior segment optical coherence tomography (AS-OCT), for identifying people with an occludable angle.

Search strategy: 

We searched the following bibliographic databases 3 October 2019: CENTRAL; MEDLINE; Embase; BIOSIS; OpenGrey; ARIF and clinical trials registries. The searches were limited to remove case reports. There were no date or language restrictions in the searches.

Selection criteria: 

We included prospective and retrospective cross-sectional, cohort and case-control studies conducted in any setting that evaluated the accuracy of one or more index tests for identifying people with an occludable angle compared to a gonioscopic reference standard.

Data collection and analysis: 

Two review authors independently performed data extraction and quality assessment using QUADAS2 for each study. For each test, 2 x 2 tables were constructed and sensitivity and specificity were calculated. When four or more studies provided data at fixed thresholds for each test, we fitted a bivariate model using the METANDI function in STATA to calculate pooled point estimates for sensitivity and specificity. For comparisons between index tests and subgroups, we performed a likelihood ratio test comparing the model with and without the covariate.

Main results: 

We included 47 studies involving 26,151 participants and analysing data from 23,440. Most studies were conducted in Asia (36, 76.6%). Twenty-seven studies assessed AS-OCT (analysing 15,580 participants), 17 studies LACD (7385 participants), nine studies Scheimpflug photography (1616 participants), six studies SPAC (5239 participants) and five studies evaluated the oblique flashlight test (998 participants). Regarding study quality, 36 of the included studies (76.6%) were judged to have a high risk of bias in at least one domain.The use of a case-control design (13 studies) or inappropriate exclusions (6 studies) raised patient selection concerns in 40.4% of studies and concerns in the index test domain in 59.6% of studies were due to lack of masking or post-hoc determination of optimal thresholds. Among studies that did not use a case-control design, 16 studies (20,599 participants) were conducted in a primary care/community setting and 18 studies (2590 participants) in secondary care settings, of which 15 investigated LACD.

Summary estimates were calculated for commonly reported parameters and thresholds for each test; LACD ≤ 25% (16 studies, 7540 eyes): sensitivity 0.83 (95% confidence interval (CI) 0.74, 0.90), specificity 0.88 (95% CI 0.84, 0.92) (moderate-certainty); flashlight (grade1) (5 studies, 1188 eyes): sensitivity 0.51 (95% CI 0.25, 0.76), specificity 0.92 (95% CI 0.70, 0.98) (low-certainty); SPAC (≤ 5 and/or S or P) (4 studies, 4677 eyes): sensitivity 0.83 (95% CI 0.70, 0.91), specificity 0.78 (95% CI 0.70, 0.83) (moderate-certainty); Scheimpflug photography (central ACD) (9 studies, 1698 eyes): sensitivity 0.92 (95% CI 0.84, 0.96), specificity 0.86 (95% CI 0.76, 0.93) (moderate-certainty); AS-OCT (subjective opinion of occludability) (13 studies, 9242 eyes): sensitivity 0.85 (95% CI 0.76, 0.91); specificity 0.71 (95% CI 0.62, 0.78) (moderate-certainty).

For comparisons of sensitivity and specificity between index tests we used LACD (≤ 25%) as the reference category. The flashlight test (grade 1 threshold) showed a statistically significant lower sensitivity than LACD (≤ 25%), whereas AS-OCT (subjective judgement) had a statistically significant lower specificity. There were no statistically significant differences for the other index test comparisons. A subgroup analysis was conducted for LACD (≤ 25%), comparing community (7 studies, 14.4% prevalence) vs secondary care (7 studies, 42% prevalence) settings. We found no evidence of a statistically significant difference in test performance according to setting.

Performing LACD on 1000 people at risk of angle closure with a prevalence of occludable angles of 10%, LACD would miss about 17 cases out of the 100 with occludable angles and incorrectly classify 108 out of 900 without angle closure.

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