Article

Optical Coherence Tomography Angiography for Glaucoma Diagnosis and Follow-Up

Essential to practice or still a research tool?

Most ophthalmologists will have read or heard about optical coherence tomography angiography (OCTA) this year. But when new technologies make their first appearance in a medical field, it is not always immediately clear what additional information they will bring to the practitioner, or most importantly if they are clinically relevant and will find a place in daily practice. This review of the most recent literature will look into these questions, to allow general ophthalmologists and glaucoma specialists to make their own opinion as to where an OCTA can fit in their daily clinical practice.

The use of OCT in glaucoma diagnosis and follow-up has soared due to the images’ high resolution allowing detection of subtle changes in the retinal nerve fiber layer (RNFL), and to the absence of preparation, ionizing radiations or invasive procedures involved in the test.1 OCTA imaging relies on OCT technology, supplemented by motion detection capacities to detect blood vessels. This is achieved using techniques typically derived from 2 broad principles: phase variance, which detects variation in phases of the emitted light wave when it crosses the path of moving fluids, and amplitude decorrelation, which uses the difference in amplitudes between 2 rapid scans to localize moving red blood cells, and hence patent vessels.2 This permits blood flow detection and quantification of the flow-rate at specific depths within the retina, without the need for a dye or ionizing radiations. Each manufacturer has developed its own algorithm to obtain images and construct en-face and volumetric representations. More specifically, they include the split spectrum amplitude decorrelation angiography algorithm (SSADA) used by Optovue Inc., full-spectrum amplitude decorrelation algorithm (FS-ADA) by Heidelberg Inc., microangiography (OMAG) used by Zeiss Inc., and OCT angiography ratio analysis (OCTARA) used by Topcon.3

The OCTA technique was first described in 2012, by Jia Y et al in a study looking at optic head perfusion.4 Since then, OCTA has become a strong focus and a fast-moving field in ophthalmology research. Herein, we describe our knowledge of OCTA and make suggestions regarding its potential use in a daily glaucoma clinic.

Physiology

Mansoori et al showed that peripapillary capillary densities are naturally higher in the superior and inferior temporal quadrants of healthy eyes.5 More importantly, their study has highlighted the fact that, contrary to retinal nerve fibers, peripapillary capillary densities are not influenced by age, sex or disc size. Another study by Jiang et al goes on to show that, in an animal model, age did not directly affect capillary density, but rather capillary response to increasing IOPs.6 Younger animals were capable of maintaining their capillary function more steadily under increasing pressures, while elderly rats showed more variable responses, with reduced autoregulatory capacities and early loss of capillary function. This may contribute to the increased susceptibility to glaucoma as age increases.

Reliability

Recent reviews have shown relatively low coefficients of variation between OCTA repetitions, both for peripapillary and parafoveal vessel density assessment. Variation coefficients were consistently close to or lower than 7% across several studies and using all four main algorithms.7-10 Two observations can be drawn from this finding: (1) OCTA assessment of vessel density is repeatable and reproducible, and (2) variations under 7% should be interpreted with caution as they could potentially be accounted for by inter-test variations and not be clinically significant.

A study by Venugopal et al has highlighted that higher signal strength index had a significant positive impact on repeatability and vessel density values, thus reducing inter-test variations and improving OCTA clinical interpretation.11 Of note, Valsalva maneuver and breath-holding were shown not to affect OCTA results when analyzing vessel densities. This reduces the need for specific body-positioning or breathing instructions during the test.12

Figure 1. OCTA scans (left) (Avanti with AngioVue; Optovue), OCT RNFL thickness curve (middle) and automated visual field pattern deviation (right) of patients with a healthy optic disc (top), and showing moderate (middle) to advanced (bottom) glaucomatous defects. The correspondence in defects across the 3 tests is shown for the case of moderate glaucoma.

Figure 2. OCTA scan (Avanti with AngioVue; Optovue) of an optic nerve head vessels before (A) and 1 month after glaucoma surgery and restoration of physiologic IOP (B).

Results and Sensitivity

Primary Open-Angle Glaucoma

In primary open-angle glaucoma (POAG), vessel density defect has been shown to be anatomically associated with RNFL thinning and visual fields defects.13-16 A large number of studies has shown that optic disc, macular, and peripapillary vessel density analyses had stronger functional association than RNFL measurements, with significant correlations between OCTA results and visual fields (VF) mean defects (MD).17-21 In other words, while OCT RNFL analysis is purely a structural measurement, OCTA better reflects optical function.

Figure 3. OCTA scan (Avanti with AngioVue; Optovue) of macular vessels before (A) and 1 month after glaucoma surgery (B).

Figure 4. OCTA scan (A) (Avanti with AngioVue; Optovue) and photograph (B) of a filtration bleb 1 week after deep sclerectomy.

For diagnostic purposes, Rao et al found comparable diagnostic capacities between OCT RNFL analysis and OCTA peripapillary vessel density measurement in POAG and primary angle-closure glaucoma (PACG).22 Gopinath et al found OCT RNFL analysis to have a diagnostic sensitivity of 76% vs 81% for OCTA vessel density measurement.23 Interestingly, they assessed a system based on a combination of RNFL and peripapillary vessel density analysis, and achieved a sensitivity of 94.44% with a specificity of 91.67%. This highlights the fact that, while OCT and OCTA analyses have comparable diagnostic powers, a combination of the 2 methods adds considerable discriminatory power.

When it comes to POAG follow-up, Chen et al showed statistically significant reduction of the macular vessel density in POAG patients across a 13-month longitudinal cohort study, while healthy subjects maintained stable vessel densities.24 The vessel density reduction in the POAG group was always in keeping with the deterioration in visual field MD.

Rao et al also observed that RNFL analysis reaches its “floor effect” between -10 dB and -15 dB visual sensitivity loss vs -20 dB and -30 dB for OCTA vessel density analysis.25 This suggests a better diagnostic and follow-up capability of vessel density analysis than those of RNFL in advanced glaucoma.

Of note, recurrent disc hemorrhages were associated with significantly wider angles of choroidal microvascular loss on OCTA, at the same anatomic locations.26 Both choroidal vascular density loss and recurrent disc hemorrhages were strongly associated with glaucoma progression and had comparable prognostic values.

Pseudoexfoliative Glaucoma

Suwan et al showed more significant reduction in peripapillary capillary density in pseudoexfoliative glaucoma (PEXG) compared to POAG, when adjusted for age and stage of disease.27 This suggests that PEXG pathophysiology is intrinsically linked to some degree of vascular changes.

Ocular Hypertension

Studies have shown that OCTA was able to detect changes in the presence of ocular hypertension (OHT) in otherwise healthy eyes (normal VF MD and RNFL thickness).28,29 In these studies, substantial IOP reduction resulted in vessel density increase both in POAG and OHT eyes, which suggests that raised IOP affects blood flow in the eye, and that these changes can be partially reversed with normalization of the pressure.

Normal-Tension Glaucoma

Significant microvascular density reduction was noted in normal tension glaucoma (NTG), in correlation with RNFL and MD defects.30 This goes to show that vascular changes in glaucoma can occur even without elevation of IOP. Some studies have however noted some differences between POAG and NTG.31,32 When adjusted for age and advancement of the disease, the latter showed more severe vascular impairment, which suggests different pathophysiological processes in the 2 diseases.

Angle-Closure Glaucoma

In post-crisis acute angle-closure glaucoma (ACG), OCTA vessel density reduction was in line with visual field MD defect, both being more significantly affected than RNFL thickness.33 In early primary chronic ACG, however, OCTA parameters were less diagnostic than OCT RNFL thickness, which suggests a non-vascular origin of the disease. OCTA became more sensitive in advanced disease, when OCT reached its floor effect.

Treatment Effect

In one study, Alnawaiseh et al showed significant improvement in optic nerve head and macula flow density following cataract surgery with iStent MIGS, suggesting that OCTA could be used to assess glaucoma surgery success.34 The same outcome was observed by Chihara et al after treatment with topical ROCK inhibitor (ripasudil) in POAG and OHT eyes. No changes to OCTA measurements were noted after treatment with topical alpha-2 agonist (brimonidine).35

Area of Analysis

Optic Disc Capillary Density

Studies have shown that OCTA was able to discriminate glaucomatous from healthy eyes based on their optic disc head capillary density with a sensitivity between 93% and 100% in non-highly myopic eyes, the confidence of the results increasing with pretreatment IOP.36 No significant difference, however, was found in high myopia.19 This loss of discriminatory power in myopia could be due to optic disc morphology variations and the crowding of large vessels.

Macular Capillary Density

Study results are mixed about the diagnostic power of macular capillary density scans, with sensitivities varying between 69% and 98% between studies.37,38 In all studies, the most sensitive area to glaucoma damage was the superotemporal and inferotemporal outer areas that are located beyond the parafoveolar area. This could explain why studies using the 3 mm x 3 mm scan area found less significant glaucomatous changes than studies using a 6 mm x 6 mm area.

Peripapillary Capillary Density

Most studies on OCTA peripapillary capillary density analysis found it to have similar sensitivities to glaucoma changes to OCT RNFL measures (75% to 100% vs 76% to 97% respectively).39,40 As in macular changes, the 2 most sensitive areas to glaucoma changes were the superotemporal and inferotemporal sectors, where the OCTA was able to detect capillary density changes even at an early stage. Overall, out of the 3 regions studied, the peripapillary area was the most susceptible to show glaucoma alterations on OCTA.41

Figure 5. OCTA scan (A, B) (Avanti with AngioVue; Optovue) and optic nerve head photograph (C) showing optic nerve head hemorrhage and corresponding decrease in vessel density.

Layers

Changes were noted in both the superficial and the deep retinal layers, but were more significant in the superficial layers.42 Choroidal changes were also noted. They were associated with anatomical vascular changes that could be observed with indocyanine green angiography. Choroidal changes had a strong association with lamina cribrosa defects.43

Devices and Algorithms

Several studies have compared the different devices and algorithms used to assess capillary densities. In a review of 3 large OCTA studies, Van Melkebeke et al suggested that the OMAG algorithm was possibly more sensitive to microvascular density loss than SSADA. In another study, Munk et al have compared OCTA images obtained with 4 devices from the 4 main manufacturers (Zeiss, Topcon, Optovue, and Heidelberg) using different algorithms.44 Their outcomes suggested that SSADA causes more artifacts than other algorithms, but proprietary projection artifact removal modules were shown to significantly improve the scans’ accuracies. After postprocessing, all 4 devices evaluated achieved the same mean vessel density, but with large interdevice variations that can be accounted for by artifacts. With this regard, the OCTA scan and algorithm resulting in the fewest artifacts was Zeiss OMAG.

Clinical Applications

Visual field and OCT RNFL analyses have already found their place in ophthalmology clinics by allowing routine functional and structural assessment of glaucoma patients. OCTA has a similar sensitivity to OCT RNFL to differentiate between normal and glaucomatous eyes, but its delayed “floor effect” makes it a potent tool for the follow-up of advanced and late-stage glaucoma.

Moreover, the fact that individual discrimination powers of each of these 2 tests can be further increased by combining them suggests that the OCTA would find its role in combination with the OCT rather than as its replacement. This is further highlighted by the fact that OCTA and OCT studies focus on different structures, with the latter being more structurally descriptive and the former correlating more strongly with visual function, and thus VF impairment.

In comparison with VF testing, OCTA presents several advantages. First, as no patient input is required, it is less patient-dependent, more objective, and more repeatable than VF. Second, it is also, from a practical point of view, faster and easier to perform in patients with whom cooperation can be an issue. Third, OCTA is able to detect changes associated with glaucoma much earlier than VF. Finally, OCTA gives new perspectives on the pathophysiology of all anterior optic neuropathies, which may lead to a better understanding of those diseases, as well as new ways of diagnosing and differentiating them. In view of these recent findings, we strongly believe that OCTA may become, in the near future, an essential examination tool for the diagnosis and the follow-up of glaucoma patient and glaucoma suspects, alongside VF and OCT. GP

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