The observed optic neuropathy in glaucoma patients results from the loss of retinal ganglion cells in a characteristic pattern.¹ Intraocular pressure (IOP) is currently the only modifiable risk factor, and IOP reduction is the only known treatment. However, despite our focus on IOP, epidemiologic and clinical evidence exists indicating additional risk factors for glaucoma beyond IOP.

In particular, microvasculature and blood flow may have a role in the pathophysiology of glaucoma.² Prior studies in patients with glaucoma have demonstrated reduced ocular blood flow in the optic nerve head (ONH), retina, choroid and retrobulbar circulations.^3-5

However, the lack of a reproducible and relevant in vivo quantitative assessment method limited the studies of both ocular perfusion and their microvascular networks.⁶

Despite the potential role that ischemia plays in apoptotic retinal ganglion cell death and the growing evidence that glaucoma patients have inadequate ocular blood flow, current diagnostic procedures and clinical management of glaucoma do not take these considerations into account. Each modern hemodynamic assessment technique examines a unique part of the ocular circulation, and none of them provides a complete description of the hemodynamic state of the eye.

Until now, clinicians and researchers had no methods at their disposal that could easily and reproducibly measure retinal vascular density and/or assess retinal blood flow — however, this may be changing thanks to the emergence of optical coherence tomography angiography (OCTA).

GLAUCOMA AND MICROVASCULATURE: WHAT IS NEW

OCTA is a recently introduced addition or “upgrade” to many current OCT platforms. This novel, noninvasive imaging strategy provides high-speed, three-dimensional, depth-encoded images of small- and large-caliber retinal vasculature within the eye by using a motion contrast method. This is based on comparison of repeat scans acquired at the same position in the retina to look for changes in the scan of blood flow.

Vascular mapping, created by comparing two or more OCT volumetric cubes, provides detailed vasculature of the retina and ONH in a noninvasive manner. Acquisition of OCTA images does not require the use of exogenous dye, which distinguishes it from other vascular imaging techniques like fluorescein angiography.⁷

In addition, OCTA provides highly repeatable and reproducible measurements from different retinal and optic nerve diseases, including glaucoma,⁸ and useful information regarding the microvascular network in the peripapillary and prelaminar area of glaucoma patients.

THE RESULTS ARE IN

David Huang, MD, co-inventor of OCT and colleagues developed a specific algorithm for OCTA: split-spectrum amplitude-decorrelation angiography (SSADA), and they were the first group to report on the use of OCTA in glaucoma.⁹ They used a swept light source with a central wavelength of 1050 nm. In their pilot study, they recruited four preperimetric glaucoma patients and four normal subjects to obtain ONH blood flow with OCTA. They found that, in early glaucoma, the reduction of ONH microvascular flow was much more dramatic than that of whole ONH circulation. They suggested that quantification performed on microvascular perfusion might be sensitive for detecting ONH circulatory changes in early glaucoma patients.

In a subsequent study, Dr. Huang’s research group compared the optic disc perfusion of 24 normal subjects and 11 patients with glaucoma using the same technology.¹⁰ They demonstrated that OCTA could detect reduced disc perfusion in those patients with early glaucoma with 100% sensitivity and specificity. They emphasized that the reduction in flow index is not a result of rim loss or cupping in glaucomatous eyes, and they showed a strong link between the disc flow index and the visual field (VF) pattern standard deviation.

LOTS OF POTENTIAL

Several others have studied OCTA’s potential for evaluating glaucoma:

• Akagi et al¹¹ compared the OCTA results of 60 eyes with primary open angle glaucoma (POAG) to 21 normal eyes. They found that the microvascular reduction was associated with visual field defects significantly in the peripapillary retina and partially in the optic disc.
• Lévêque et al¹² measured ONH perfusion using a spectral domain OCTA instrument in 43 patients with open angle glaucoma, seven patients with angle-closure glaucoma and 30 normal subjects. They reported a significant difference in ONH vascular density between glaucoma and normal patients in the total disc and temporal vascular areas.
• Liu et al¹³ studied OCTA images from 12 glaucomatous and 12 age-matched normal eyes and found significantly lower peripapillary flow index and peripapillary vessel density in glaucomatous eyes.
• Wang et al¹⁴ evaluated the disc flow and vessel density of OCTA on 62 eyes with open angle glaucoma, and 20 normal control eyes. They found that glaucomatous eyes showed a decrease in the disc flow index and vessel density. Additionally altered flow index and vessel density were found to be correlated with visual field mean deviation, RNFL thickness and ganglion cell layer thickness. They concluded that altered flow index and vessel density values could be good indicators of eyes with severe stages of open angle glaucoma.
• Yarmohammadi et al¹⁵ performed a prospective study for evaluation of peripapillary retinal vasculature on 23 healthy subjects, 37 glaucoma suspects, and 104 glaucoma patients. They measured the vessel density in the nerve fiber layer and found a significant difference among the three groups. Their study demonstrated that age-adjusted mean vessel density was significantly lower in open angle glaucoma eyes compared with glaucoma suspects and healthy eyes.
• Suh et al¹⁶ shared their results of vessel density measurements by OCTA in 82 POAG patients with and without focal lamina cribrosa (LC) defects matched by severity of visual field damage. In their study, OCTA measured vessel density was found to be significantly lower in POAG eyes with focal LC defects than in eyes without LC defect. They also showed the reduction of vessel density to be spatially correlated with the location of the LC defect.
• In a cross-sectional study by Rao et al¹⁷ the diagnostic ability of peripapillary vessel density measurements on OCTA was evaluated in POAG and primary angle-closure glaucoma (PACG). They had 48 eyes of 33 healthy control subjects, 63 eyes of 39 patients with POAG and 49 eyes of 32 patients with PACG underwent OCTA and RNFL imaging with spectral domain OCT.
  The diagnostic ability of peripapillary vessel density parameters of OCTA, especially the inferotemporal sector measurement, was found to be good in POAG and PACG. Diagnostic abilities of vessel density measurements were also demonstrated to be comparable to RNFL measurements in both POAG and PACG.
• The topographic relationship between the decreased parapapillary microvasculature and RNFL was investigated by Lee et al¹⁸ in POAG patients. The vascular impairment was found within the microvascular network of the retina in all POAG eyes and found to be correlated with the RNFL defect.
• Scripsema et al¹⁹ evaluated perfused peripapillary capillary density in POAG, normal tension glaucoma (NTG), and normal patients using OCTA. They compared the annular vascular vessel density between the groups and found that glaucoma groups had reduced values compared to healthy eyes. Their results also showed that the POAG group had reduced vessel density values as compared to the NTG group.

OCTA IN EARLY GLAUCOMA AND PREPERIMETRIC GLAUCOMA

Our group from Doheny UCLA recently reported on a prospective observational study that compared 20 eyes with very mild POAG, 20 eyes with pre-perimetric glaucoma and 16 normal age-matched eyes. ²⁰ We imaged the optic disc region with a 1050-nm wavelength swept-source OCT system (DRI OCT Triton, Topcon).

We measured retinal vessel densities in three areas: ONH defined as the area occupied by the vessels in the ONH, the 3-mm papillary region centered on and including the ONH and the peripapillary region, defined as a 700-μm wide elliptical annulus around the disc (so-called “donut” configuration), which excluded the ONH.

Retinal vessel density measurements in each area showed a stepwise decrease from normal eyes to preperimetric glaucoma eyes to early glaucoma eyes.

In this study, we noted the reduced retinal vascular density even in glaucomatous eyes characterized as preperimetric in addition to those with mild glaucoma. This allowed us to distinguish preperimetric and mild glaucoma cases from normal eyes based solely on reduced retinal vascular densities (see Figure 1).

We also found correlations between reduced OCT-derived RNFL thickness measurements and retinal vascular densities (and thus with the severity of glaucoma). Our study, along with other publications, supports the hypotheses that vascular attenuation (and possibly retinal blood flow) may be an early event in the development of glaucoma, rather than a late consequence of glaucomatous atrophy.

READY FOR PRIME-TIME? NOT QUITE

Despite promising results of research studies on the broad application and efficacy of OCTA in glaucoma, several challenges in both image acquisition and image interpretation may limit our ability to fully incorporate OCTA into daily clinical practice.

As with other OCT technologies, the potential presence of different types of artifacts can be present, which limit the reliable interpretation and analysis of OCTA images.²¹ To improve the quality of the images, we need post-acquisition software correction of images from the early versions of OCTA devices.

The implementation of eye-tracking software to newer version OCTA devices has already further eliminated some motion artifacts. However, projection artifacts from the superficial vessels onto the deeper structures makes the visualization and interpretation of the deeper vascular structures more difficult for clinicians. Fortunately, it appears that glaucoma tends to affect the superficial retinal layers preferentially — thus making the current OCTA technology usable despite projection artifacts.

Additionally, not all OCTA systems illustrate blood flow velocity in the retina or ONH. Rather, they provide retinal vascular densities or “retinal flow” indices.

On the interpretation side, one notable problem is the lack of a normative database as well as the large variation of retinal vascular densities and blood flow that are likely present in the population. Furthermore, it remains unclear whether systemic blood flow parameters or systemic anti-hypertensive medications would affect retinal vascular densities or retinal blood flow. However, further research with OCTA should provide solutions to these challenges because OCTA appears to provide a combination of structural and potentially functional data that would be useful in clinical practice.

THE FUTURE LOOKS BRIGHT

OCTA is an incredibly exciting newer technology for glaucoma evaluation, potentially enhancing our understanding of the role of microvasculature in the pathophysiology of the disease by allowing us to measure retinal vessel density and retinal blood flow. In the near future, these OCTA-derived measurements may serve as additional parameters that we could use in conjunction with currently used OCT-derived RNFL thickness measurements and VF indices in glaucoma evaluation and management. OM

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About the Author

Handan Akil, MD, is a research fellow at Doheny Image Reading Center, Doheny Eye Institute, Los Angeles, Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, Calif. E-mail her at HAkil@doheny.org.

Vikas Chopra, MD, is associate medical director, Doheny Image Reading Center, Doheny Eye Institute, Los Angeles, Calif., medical director, UCLA Doheny Eye Centers Pasadena and associate professor, Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles. E-mail him at VChopra@doheny.org.

Financial disclosures: The authors report no conflicting relationships.