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.
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.
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
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.
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.
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.
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.
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.
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.
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
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.
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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- Munk MR, Giannakaki-Zimmermann H, Berger L, et al. OCT-angiography: a qualitative and quantitative comparison of 4 OCT-A devices. PLoS ONE. 2017;12(5):e0177059.
- Jia Y, Tan O, Tokayer J, et al. Split-spectrum amplitude-decorrelation angiography with optical coherence tomography. Opt Express. 2012;20(4):4710-4725.
- Mansoori T, Sivaswamy J, Gamalapati JS, Balakrishna N. Radial peripapillary capillary density measurement using optical coherence tomography angiography in early glaucoma. J Glaucoma. 2017;26:483-443.
- Jiang X, Johnson E, Cepurna W, et al. The effect of age on the response of retinal capillary filling to changes in intraocular pressure measured by optical coherence tomography angiography. Microvasc Res. 2018;115:12-19.
- Chansangpetch S, Lin SC. Optical coherence tomography angiography in glaucoma care. Curr Eye Res. 2018;43(9):1067-1082.
- Venugopal JP, Rao HL, Weinreb RN, et al. Repeatability of vessel density measurements of optical coherence tomography angiography in normal and glaucoma eyes. Br J Ophthalmol. 2018 Mar;102(3):352-357.
- Chen FK, Menghini M, Hansen A, Mackey DA, Constable IJ, Sampson DM. Intrasession repeatability and interocular symmetry of foveal avascular zone and retinal vessel density in OCT angiography. Transl Vis Sci Technol. 2018;7(1):6.
- Pilotto E, Frizziero L, Crepaldi A, et al. Repeatability and reproducibility of foveal avascular zone area measurement on normal eyes by different optical coherence tomography angiography instruments. Ophthalmic Res. 2018;59(4):206-211.
- Venugopal JP, Rao HL, Weinreb RN, et al. Repeatability of vessel density measurements of optical coherence tomography angiography in normal and glaucoma eyes. Br J Ophthalmol. 2018;102(3):352-357.
- Holló G. Valsalva maneuver and peripapillary OCT angiography vessel density. J Glaucoma. 2018 Jul;27(7):e133-e136.
- Liu L, Jia Y, Takusagawa HL, et al. Optical coherence tomography angiography of the peripapillary retina in glaucoma. JAMA Ophthalmol. 2015;133(9):1045-1052.
- Chihara E, Dimitrova G, Amano H, Chihara T. Discriminatory power of superficial vessel density and prelaminar vascular flow index in eyes with glaucoma and ocular hypertension and normal eyes. Invest Opthalmol Vis Sci. 2017;58(1):690-697.
- Geyman LS, Garg RA, Suwan Y, et al. Peripapillary perfused capillary density in primary open-angle glaucoma across disease stage: an optical coherence tomography angiography study. Br J Ophthalmol. 2017;101(9):1261-1268.
- Takusagawa HL, Liu L, Ma KN, et al. Projection-resolved optical coherence tomography angiography of macular retinal circulation in glaucoma. Ophthalmology. 2017;124(11):1589-1599.
- Yarmohammadi A, Zangwill LM, Diniz-Filho A, et al. Relationship between optical coherence tomography angiography vessel density and severity of visual field loss in glaucoma. Ophthalmology. 2016;123(12):2498-2508.
- Kumar RS, Anegondi N, Chandapura RS, et al. Discriminant function of optical coherence tomography angiography to determine disease severity in glaucoma. Invest Opthalmol Vis Sci. 2016;57(14):6079-6088.
- Akagi T, Iida Y, Nakanishi H, et al. Microvascular density in glaucomatous eyes with hemifield visual field defects: an optical coherence tomography angiography study. Am J Ophthalmol. 2016;168:237-249.
- Holló G. Relationship between OCT angiography temporal peripapillary vessel-density and octopus perimeter paracentral cluster mean defect. J Glaucoma. 2017;26(5):397-402.
- Yarmohammadi A, Zangwill LM, Diniz-Filho A, et al. OCT angiography vessel density in normal, glaucoma suspects and glaucoma eyes: structural and functional associations in the Diagnostic Innovations in Glaucoma Study (DIGS). Invest Ophthalmol Vis Sci. 2016;57(9):2958.
- Rao HL, Pradhan ZS, Weinreb RN, et al. Relationship of optic nerve structure and function to peripapillary vessel density measurements of optical coherence tomography angiography in glaucoma. J Glaucoma. 2017;26(6):548-554.
- Gopinath K, Sivaswamy J, Mansoori T. Automatic glaucoma assessment from angio-OCT images. Proc Int Symp Biomed Imaging. 2016;193-196.
- Chen CL, Zhang A, Bojikian KD, et al. Peripapillary retinal nerve fiber layer vascular microcirculation in glaucoma using optical coherence tomography-based microangiography. Invest Opthalmol Vis Sci. 2016;57(9):OCT475-OCT485.
- Rao HL, Pradhan ZS, Weinreb RN, et al. Vessel density and structural measurements of optical coherence tomography in primary angle closure and primary angle closure glaucoma. Am J Ophthalmol. 2017;177:106-115.
- Park HL, Kim JW, Park CK. Choroidal microvasculature dropout is associated with progressive retinal nerve fiber layer thinning in glaucoma with disc hemorrhage. Ophthalmology. 2018 Jul;125(7):1003-1013.
- Suwan Y, Geyman LS, Fard MA, et al. Peripapillary perfused capillary density in exfoliation syndrome and exfoliation glaucoma versus POAG and healthy controls: an OCTA study. Asia Pac J Ophthalmol (Phila). 2018;7(2):84-89.
- Holló G. Vessel density calculated from OCT angiography in 3 peripapillary sectors in normal, ocular hypertensive, and glaucoma eyes. Eur J Ophthalmol. 2016;26(3):e42-e45.
- Holló G. Influence of large intraocular pressure reduction on peripapillary OCT vessel density in ocular hypertensive and glaucoma eyes. J Glaucoma. 2017;26(1):e7-e10.
- Lee EJ, Kim S, Hwang S, Han JC, Kee C. Microvascular compromise develops following nerve fiber layer damage in normal-tension glaucoma without choroidal vasculature involvement. J Glaucoma. 2017;26(3):216-222.
- Ma J, Nesper P, Anchala A, Fawzi AA. Optical coherence tomography angiography in glaucoma. Invest Ophthalmol Vis Sci. 2017;58:1678.
- Zhu D, Reznik A, Chen C-L, Wang RK, Puliafito CA. Evaluation of optic disc perfusion in normal-tension glaucoma patients by optical coherence tomography angiography. Invest Ophthalmol Vis Sci. 2015;56:2745.
- Wang X, Jiang C, Kong X, Yu X, Sun X. Peripapillary retinal vessel density in eyes with acute primary angle closure: an optical coherence tomography angiography study. Graefes Arch Clin Exp Ophthalmol. 2017;255(5):1013-1018.
- Alnawaiseh M, Müller V, Lahme L, Merte RL, Eter N. Changes in flow density measured using optical coherence tomography angiography after iStent insertion in combination with phacoemulsification in patients with open-angle glaucoma. J Ophthalmol. 2018;2018:2890357.
- Chihara E, Dimitrova G, Chihara T. Increase in the OCT angiographic peripapillary vessel density by ROCK inhibitor ripasudil instillation: a comparison with brimonidine. Graefes Arch Clin Exp Ophthalmol. 2018;256(7):1257-1264.
- Jia Y, Wei E, Wang X, et al. Optical coherence tomography angiography of optic disc perfusion in glaucoma. Ophthalmology. 2014;121(7):1322-1332.
- Chen HS, Liu CH, Wu WC, Tseng HJ, Lee YS. Optical coherence tomography angiography of the superficial microvasculature in the macular and peripapillary areas in glaucomatous and healthy eyes. Invest Opthalmol Vis Sci. 2017;58(9):3637-3645.
- Kurysheva NI, Maslova E, Trubilina AV, Likhvantseva VG, Fomin AV, Lagutin MB. OCT angiography and color Doppler imaging in glaucoma diagnostics. Int J Pharm Sci Res. 2017;9(5):527-536.
- Liu L, Jia Y, Takusagawa HL, et al. Optical coherence tomography angiography of the peripapillary retina in glaucoma. JAMA Ophthalmol. 2015;133:1045.
- Schweitzer C, Dutheil C, De Bosredon Q, Roseng S, Georges N, Fard A, et al: Peripapillary retina nerve fiber layer (RNFL) vascular microcirculation using optical coherence tomography based microangiography to discriminate glaucoma or glaucoma suspect and healthy control patients. Invest Ophthalmol Vis Sci. 2017;58:720.
- Liu L, Jia Y, Tan O, et al. Radial peripapillary capillary plexus perfusion and regional visual field loss in glaucoma. Invest Ophthalmol Vis Sci. 2017;58:3394.
- Richter GM, Madi I, Chu Z, et al. Structural and functional associations of macular microcirculation in the ganglion cell-inner plexiform layer in glaucoma using optical coherence tomography angiography. J Glaucoma. 2018;27(3):281-290.
- Lee EJ, Lee KM, Lee SH, Kim TW. Parapapillary choroidal microvasculature dropout in glaucoma: a comparison between optical coherence tomography angiography and indocyanine green angiography. Ophthalmology. 2017;124(8):1209-1217.
- Munk MR, Giannakaki-Zimmermann H, Berger L, et al. OCT-angiography: a qualitative and quantitative comparison of 4 OCT-A devices. PLoS One. 2017;12(5):e0177059.