Most clinicians are already familiar with conventional structural optical coherence tomography (OCT),1 which provides measurements of the optic disc, peripapillary nerve fiber layer (NFL) thickness and macular ganglion cell complex (GCC) thickness that have become indispensable to the diagnosis and monitoring of glaucoma. However, visual field (VF) remains the standard way to evaluate visual function in glaucoma, despite the obvious drawbacks of poor reproducibility due to its subjective nature and reliance on good patient cooperation and attention.
The new optical coherence tomographic angiography (OCTA) technology opens a new window into glaucoma by looking at tissue perfusion, which is more tightly linked to tissue metabolism and function.
We will show in this article that OCTA parameters are better correlated with VF results and, therefore, could be a better way to assess disease severity and monitor progression than structural OCT parameters. Furthermore, reduced tissue perfusion may precede tissue thinning — therefore OCTA could detect glaucoma earlier than OCT in some cases.
It is time for clinicians to make an acquaintance with this new technology that is likely to become more and more important as a tool for glaucoma evaluation in the coming years.
THE NUTS AND BOLTS OF OCTA
OCTA uses the motion of blood cells as intrinsic contrast to produce high-resolution images of microvascular networks of the optic disc, retina and choroid. Because it is a software extension of OCT technology, OCTA does not require any hardware modification of standard OCT devices, which are already used extensively in the evaluation of glaucoma and retina diseases.2
Because OCTA requires consecutive repetitive cross-sectional scans at each location, it works better with higher-speed devices. Commercially available OCTA systems are implemented on relatively high-speed (68,000 axial scans per second or faster) platforms.
This article focuses on the AngioVue OCTA system (Optovue), which has the capability of making vessel density (VD) measurements relevant to glaucoma evaluation. AngioVue is based on the Avanti spectral-domain OCT device, which has a speed of 70,000 axial scans per second. AngioVue uses a very efficient OCTA algorithm called “split-spectrum amplitude decorrelation angiography” (SSADA),3 which generates high-quality angiograms using only two cross-sectional scans at each scan location. AngioVue can acquire standard-definition (304 × 304 transverse pixels) OCTA volumes in 2.7 seconds or high-definition (400 × 400 transverse pixels) OCTA volumes in 4.7 seconds.
BOOSTING DIAGNOSTIC ACCURACY
Though Jia et al. showed that glaucoma reduces perfusion both in the superficial disc and in the deeper lamina cribrosa,4 identifying glaucomatous perfusion defects in the optic disc is hampered by pervasive shadowing by large blood vessels and high-population variability in the size and shape of the optic nerve head.
A more robust diagnostic strategy is to use OCTA to evaluate the peripapillary retinal circulation. Liu et al. reported significantly lower peripapillary retinal VD in glaucomatous eyes than in normal eyes with good diagnostic accuracy — areas under the receiver operating characteristic curve (AROC) was 0.938.5
Yarmohammadi et al. reported similar results with a larger study sample size.6 They showed that radial peripapillary capillary (RPC) plexus VD measured over a larger 4.5-mm square area has superior diagnostic accuracy (AROC=0.94) compared with VD measured in a 0.7-mm wide annulus just outside the disc (AROC=0.83).
A NEW SOFTWARE GETS SPECIFIC
To help clinicians detect and monitor glaucoma using OCTA, Optovue developed a commercially available quantification software called AngioAnalytics, which is available on the AngioVue system. (We were not involved in the development of this software.) This new capability enables clinicians to quantify the density of blood perfusion in different slabs of the retina.
AngioAnalytics provides automated segmentation of the OCTA angiogram and focuses on the RPC, which is the most superficial vascular plexus that supplies the NFL. Glaucoma reduces VD in the RPC more than in the deep vascular complex.7 The AngioAnalytics software provides RPC-VD and capillary density (CD, which is the vascular density measured after excluding larger vessels from analysis) (Figures 1, 2). The RPC-VD parameters include the overall, hemispheric and eight sectoral averages, which will help clinicians make glaucoma diagnosis and determine the location of glaucoma focal damage. These parameters could also be followed over time to detect glaucoma progression.
AngioVue OCTA can also be used to evaluate glaucoma damage in the macula. Using a projection-resolved OCTA (PR-OCTA) algorithm, our group revealed focal capillary dropout in the superficial vascular complex (SVC) but not the intermediate capillary plexus and deep capillary plexus in glaucomatous eyes (Figure 3). This is to be expected, as glaucoma damages the ganglion cells supplied by the SVC. The SVC-VD has an excellent diagnostic accuracy for distinguishing glaucoma from normal controls and had a sensitivity of 96.7% and a specificity of 95%, achieving AROC 0.983.8
Also, note that this high diagnostic accuracy requires the larger scan area of 6 mm × 6 mm. Macular retinal VD based on 3 mm × 3 mm scan had a poor diagnostic accuracy (AROC=0.69).9 Glaucoma clinicians should use larger macular scans of at least 6 mm × 6 mm and avoid smaller scans that could miss the peripheral macular areas that are more commonly affected by glaucoma.
WHAT IT MEANS TO GLAUCOMA EVALUATION
While both structural OCT and OCTA can detect glaucoma damage, we believe that OCTA could provide better glaucoma evaluation in the early and late stages of the disease. In the early stages of glaucoma, reduced macular and peripapillary retinal VD could be detected in patients with glaucoma prior to visual field damage.10-12 A series of articles also showed OCTA parameters to correlate better with VF compared with structural OCT parameters.5,8,11,13
In the first paper of peripapillary retinal perfusion in glaucoma, we found that peripapillary retinal VD had a Pearson correlation R2 of 0.74 with glaucoma stage (Enhanced Glaucoma Staging System GSS2 based on both VF mean deviation [MD] and pattern standard deviation [PSD]), compared to R2 of 0.10 between mean NFL thickness and glaucoma stage.5 In a larger study (153 eyes) the peripapillary retinal VD was found to have an R2 of 0.50 with VF MD, compared to a R2 of 0.35 between NFL thickness and VF MD.13
Therefore, we believe that the reduced perfusion in glaucoma reflects reduced metabolic activity that correlates very closely with the VF function. OCTA may be able to detect dysfunctional nerve fibers or ganglion cells before cell death and tissue thinning occurs — which would allow for earlier diagnosis of glaucoma.
In the later stages of glaucoma, OCTA may be able to monitor progression better than conventional structural OCT measures such as the NFL thickness. The relationship between NFL thickness with VF is highly nonlinear. NFL thins at a high rate with decreasing MD in early glaucoma. But because of the presence of residual glial or non-neural tissue including blood vessels, NFL approaches a floor value in more advanced stages, which is called the “floor effect.”7 The NFL floor effect causes inability of NFL thickness to monitor structural progression in moderate to advanced glaucoma.
The peripapillary retinal VD has less floor effect and better linear correlation with VF MD.6,14 Thus, OCTA has the potential for improving monitoring of progression in moderate to advanced glaucoma.
OCTA is a novel noninvasive imaging technology that allows glaucoma clinicians to evaluate tissue perfusion with high precision, which had never been possible before. OCTA is implemented on ordinary OCT devices, which are economical and widely accessible. Ophthalmologists can use this technology to measure glaucomatous changes in the perfusion of the macular and peripapillary retina.
While clinical data on this new technology is still limited, preliminary results show the potential for earlier glaucoma diagnosis and improved monitoring of disease progression rate.
Recent advances in commercial instrumentation have made it possible for any clinician to begin using this powerful new tool in their practice. OM
- Jia Y, Bailey ST, Hwang TS, et al. Quantitative optical coherence tomography angiography of vascular abnormalities in the living human eye. Proceedings of the National Academy of Sciences of the United States of America 2015;112:E2395-402.
- Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science 1991;254:1178-1181.
- Jia Y, Tan O, Tokayer J, et al. Split-spectrum amplitude-decorrelation angiography with optical coherence tomography. Opt Express 2012;20:4710-4725.
- Jia Y, Wei E, Wang X, et al. Optical coherence tomography angiography of optic disc perfusion in glaucoma. Ophthalmology. 2014;121:1322-1332.
- Liu L, Jia Y, Takusagawa HL, et al. Optical coherence tomography angiography of the peripapillary retina in glaucoma. JAMA Ophthalmology. 2015;133:1045-1052.
- Yarmohammadi A, Zangwill LM, Diniz-Filho A, et al. Optical coherence tomography angiography vessel density in healthy, glaucoma suspect, and glaucoma eyes. Invest Ophthalmol Vis Sci. 2016;57:OCT451-459.
- Edmunds B, Liu L, Jia Y, et al. Projection-resolved optical coherence tomography angiography of the peripapillary retina in glaucoma. Investigative Ophthalmology & Visual Science. 2017;58:721.
- Takusagawa HL, Liu L, Ma KN, et al. Projection-resolved optical coherence tomography angiography of macular retinal circulation in glaucoma. Ophthalmology. 2017;124:1589-1599.
- Rao HL, Pradhan ZS, Weinreb RN, et al. Regional comparisons of optical coherence tomography angiography vessel density in primary open-angle glaucoma. Am J Ophthalmol. 2016;171:75-83.
- Yarmohammadi A, Zangwill LM, Manalastas PIC, et al. Peripapillary and macular vessel density in patients with primary open-angle glaucoma and unilateral visual field loss. Ophthalmology. 2018;125:578-587.
- Yarmohammadi A, Zangwill LM, Diniz-Filho A, et al. Peripapillary and macular vessel density in patients with glaucoma and single-hemifield visual field defect. Ophthalmology. 2017;124:709-719.
- Suh MH, Zangwill LM, Manalastas PI, et al. Optical coherence tomography angiography vessel density in glaucomatous eyes with focal lamina cribrosa defects. Ophthalmology. 2016;123:2309-2317.
- 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;123:2498-2508.