Research Article: Retinal vessel density from optical coherence tomography angiography to differentiate early glaucoma, pre-perimetric glaucoma and normal eyes

Date Published: February 2, 2017

Publisher: Public Library of Science

Author(s): Handan Akil, Alex S. Huang, Brian A. Francis, Sirinivas R. Sadda, Vikas Chopra, Laura Frishman.

http://doi.org/10.1371/journal.pone.0170476

Abstract

To evaluate optic nerve vascular density using swept source optical coherence tomography angiography (OCTA) in patients with early primary open angle glaucoma (POAG), pre-perimetric glaucoma and normal eyes.

This is a prospective, observational study including 56 eyes in total and divided into 3 groups; 20 eyes with mild POAG, 20 pre-perimetric glaucoma eyes, and 16 age-matched normal eyes as controls. The optic disc region was imaged by a 1050-nm-wavelength swept-source OCT system (DRI OCT Triton, TOPCON). Vessel density was assessed as the ratio of the area occupied by the vessels in 3 distinct regions: 1) within the optic nerve head; 2) in the 3 mm papillary region around the optic disc; and 3) in the peripapillary region, defined as a 700-μm-wide elliptical annulus around the disc. The potential associations between vessel density and structural, functional measures were analyzed.

There was a statistically significant difference for the peripapillary vessel density, optic nerve head vessel density, and papillary vessel density among all the groups (p<0.001). Control eyes showed a significant difference for all measured vessel densities compared to glaucomatous eyes (p values from 0.001 to 0.024). There was a statistically significant difference between control and pre-perimetric glaucoma eyes for peripapillary, optic nerve head and papillary vessel density values (p values from 0.001 to 0.007). The optic nerve head vessel density, superior and inferior papillary area vessel density (Pearson r = 0.512, 0.436, 0.523 respectively) were highly correlated with mean overall, superior and inferior RNFL thickness in POAG eyes (p = 0.04, p = 0.02 and p = 0.04 respectively). Multiple linear regression analysis of POAG group showed that optic nerve head vessel density in POAG group was more strongly linked to RNFL thickness than to any other variables. Eyes with mild POAG could be differentiated from pre-perimetric glaucoma eyes, which also could be differentiated from normal eyes using OCTA-derived retinal vessel density measurements.

Partial Text

Glaucoma is a group of eye diseases that result in damage to the optic nerve and potentially leads to irreversible blindness [1]. The nerve damage involves loss of retinal ganglion cells in a characteristic pattern [2–5] with intraocular pressure (IOP) the only modifiable risk factor and IOP reduction the only treatment. Previous studies have reported that vascular factors may play a critical role in the development of glaucoma in addition to elevated IOP [3–7].

Our prospective, observational study was performed between February 2016 and May 2016 at the UCLA Doheny Eye Center glaucoma clinic. The research protocols were approved by the Institutional Review Board of UCLA, performed in accord with the tenets of the Declaration of Helsinki. Written informed consent was obtained from each participant.

Data are shown as a mean value with the standard deviation. The Kruskal-Wallis test was used to analyze the significance of differences among the 3 groups and if there was a difference T test was used to check where the difference came from. Multiple linear regression analysis was used to determine the relationships between the vessel density and traditional glaucoma measurements of structure (OCT-derived RNFL thickness) and function (VF mean deviation, VF pattern standard deviation [PSD]) in glaucomatous eyes. The receiver operating characteristic (ROC) curve for the disc parameters was plotted to determine the optimum cutoff point, and area under the ROC curve (AUC) was used to determine the discrimination power between the normal and POAG. Repeatability and reproducibility were analyzed by using the CV and the ICC between measurements. The CV is the standard deviation of the measurements divided by their mean, expressed as a percentage. The ICC measures the proportion of total variability in measurements contributed by variability in measurements between different subjects, and was determined using the random-effects mixed model. The significance level was set at p < 0.05. All analyses were performed with statistical software (SPSS for Windows, version 19.0; SPSS, Inc., Chicago, IL, USA). A total of 40 eyes from 40 patients were age-matched with 16 eyes from 16 normal controls. Kruskal Wallis testing was first performed to evaluate for overall differences among the groups. Table 1 summarized the baseline clinical characteristics of each group. No significant differences were found among these (p-values ranged from 0.421 to 0.7) except for IOP and number of glaucoma medications. As expected, the POAG patients were treated with medications, whereas the pre-perimetric glaucoma and normal eyes were not on glaucoma medications. For treatment in the POAG group, prostaglandin analogue once daily at bedtime was used in 10 eyes, while dorzolamide-timolol combination twice daily was used in 5 eyes, and brimonidine tartrate twice daily was used in 5 eyes. The duration of medication use was 3.5±2 years. Pairwise t-tests comparing POAG to suspects (p = 0.01) and POAG to normals (p = 0.09) confirmed that POAG patient had lower intraocular pressures which was consistent with the fact that they were under treatment. Use of an ocular antihypertensive eye drop or any subclass was not correlated with the vessel density measurements as determined by the Mann-Whitney U test. In our current study using OCT angiography, we were able to demonstrate lower retinal vessel densities for eyes with mild glaucoma compared with normal eyes, as well as, compared with pre-perimetric glaucoma eyes. In addition, one of the most revealing findings in our study is that we were able to demonstrate lower retinal vessel densities in our pre-perimetric glaucoma group (which includes patients with essentially normal perimetry testing but mild reduction in OCT-derived RNFL thickness measurements) compared with normal eyes. Thus, we were able to distinguish patients with pre-perimetric glaucoma from age-matched normal eyes using OCTA-derived vessel density measurements, and found correlation with mild reduction in OCT-derived RNFL thickness measurements. This may have important implications in increasing our understanding of the pathophysiology of glaucoma and its relationship with retinal vasculature, as previously suggested and in agreement with previous studies [10–13]. Furthermore, having novel structural parameters such as OCTA-derived retinal vascular measurements, in addition to the currently used RNFL and neuro-retinal rim thickness measurements, may enhance the clinician’s ability to detect early/mild glaucoma–which can often be challenging in the clinical setting, especially in cases with normal perimetry testing. To the best of our knowledge, our study is the first to report that retinal blood vessel density measures derived using non-invasive OCT angiography showed a stepwise decrease from normal eyes to pre-perimetric glaucoma eyes to mild POAG eyes. Furthermore, this difference in vessel density was seen in all three of the anatomic sites measured: optic nerve head, papillary, and peripapillary regions. Importantly, this difference was seen even though the POAG group in our study consisted only of mild disease, and lower retinal vessel density was also noted in our pre-perimetric glaucoma group. This shows that OCT angiography may provide new structural parameters that could potentially be used by clinicians to diagnose glaucoma at earlier stages. Our data suggest that retinal vascular changes may develop early in the glaucomatous process and may not develop solely as a result of advanced glaucoma damage. Even though the importance of retinal blood flow in glaucoma has been reported in prior research studies [10–24], the inability to get easily acquired measurement values has limited the wide-spread utility and applicability of these parameters in a clinical setting until now. Reduced retinal vessel density and/or retinal blood flow measurements using the evolving OCT angiography techniques may provide additional parameters that can be utilized in a clinical setting for glaucoma diagnosis and management.   Source: http://doi.org/10.1371/journal.pone.0170476

 

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