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| ORIGINAL ARTICLE |
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| Year : 2021 | Volume
: 8
| Issue : 1 | Page : 19-25 |
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Changes in peripapillary blood flow after dorzolamide 2%/timolol 0.5% versus latanoprost 0.005%/timolol 0.5% using optical coherence tomography angiography
Heba Magdy Ahmed El-Saied, Wael E. Abd Elhalim, Mohamed Abdelhamid, Kareem Bakr Elessawy
Department of Ophthalmology, Cairo University, Giza, Egypt
| Date of Submission | 20-Jul-2021 |
| Date of Acceptance | 26-Nov-2021 |
| Date of Web Publication | 27-Jan-2022 |
Correspondence Address:
Dr. Kareem Bakr Elessawy
3 Toman Bay Street, Ibn Sandr Square, Msr Elgdida, Cairo
Egypt
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/erj.erj_7_21
Purpose: The purpose is to compare the changes in the peripapillary blood flow in primary open-angle glaucoma (POAG) after administration of dorzolamide 2%/timolol 0.5% fixed combination versus latanoprost 0.005%/timolol 0.5% fixed combination, using spectral-domain optical coherence tomography angiography (OCTA). Patients and Methods: In this prospective, comparative, nonrandomized study, patients with POAG received simultaneous treatment with dorzolamide 2%/timolol 0.5% fixed combination in the right eye (Group 1) and latanoprost 0.005%/timolol 0.5% fixed combination in the left eye (Group 2) for 1 week. Intraocular pressure (IOP) was measured using applanation tonometry; and peripapillary capillary density and retinal nerve fiber layer (RNFL) thickness was assessed using OCTA before starting treatment and 1 week after the treatment. Results: IOP reduction was superior in Group 2; however, this was not statistically significant. Both groups showed an increase in the peripapillary capillary density and RNFL thickness after 1 week of the treatment as evaluated by OCTA angiography. However, this increase was not statistically significant. There was only a statistically positive correlation between IOP reduction and increase in the superior-hemiradial peripapillary capillary density (P = 0.037) in Group 1 and between IOP reduction and increase in the total RNFL thickness and superior hemi-RNFL thickness (P = 0.044, 0.032, respectively) in Group 1. Conclusion: Intraocular pressure decreased in both groups with no significant difference between both groups. There was more increase in radical peripapillary capillary density and RNFL thickness following treatment in dorzolamide 2%/timolol 0.5% group compared to the other groups; however, the difference between the two groups was not statistically significant.
Keywords: Dorzolamide 2%/timolol 0.5% - latanoprost 0.005%/timolol 0.5%, optical coherence tomography angiography, peripapillary blood flow
How to cite this article:
El-Saied HM, Elhalim WE, Abdelhamid M, Elessawy KB. Changes in peripapillary blood flow after dorzolamide 2%/timolol 0.5% versus latanoprost 0.005%/timolol 0.5% using optical coherence tomography angiography. Egypt Retina J 2021;8:19-25 |
How to cite this URL:
El-Saied HM, Elhalim WE, Abdelhamid M, Elessawy KB. Changes in peripapillary blood flow after dorzolamide 2%/timolol 0.5% versus latanoprost 0.005%/timolol 0.5% using optical coherence tomography angiography. Egypt Retina J [serial online] 2021 [cited 2023 Mar 25];8:19-25. Available from: https://www.egyptretinaj.com/text.asp?2021/8/1/19/336670 |
| Introduction | |  |
Primary open-angle glaucoma (POAG) is a progressive optic neuropathy with a slow progressive degeneration of retinal ganglion cells and their axons. Because the disease is treatable and because the visual impairment is irreversible, early detection is essential. New imaging tests can improve both detection and monitoring of the progression of the disease.[1]
Treatment of glaucoma is primarily directed toward lowering intraocular pressure (IOP) by conservative medical treatment, laser therapy, or surgery. Initially, the patients are treated with ocular hypotensive agents. If the IOP is not sufficiently lowered or the disease progresses, as estimated by the decay of visual fields or increasing excavation of the optic disc, more invasive techniques are performed.[2]
When the IOP is not adequately regulated with monotherapy, it is common practice to combine antiglaucoma drugs. When two agents are combined, an additional reduction of IOP of at least 15% is desirable. Drug combinations that act on different receptor sites or enzymes and have a different mode of action are preferred.[2]
Optical coherence tomography angiography (OCTA) is a functional extension of optical coherence tomography (OCT), which visualizes microvasculature by detecting motion contrast from flowing blood. It is a noninvasive method of imaging the optic nerve and retinal circulation providing a clear and continuous image of microvascular network.[3]
OCTA is reliable, objective tool; it relies much less on patient cooperation. OCTA differentiates between normal and glaucoma eyes. OCTA parameters were more strongly correlated with visual function than OCT parameters.[4]
OCTA shows reduced radical peripapillary capillary (RPC) density in POAG eyes when compared with the healthy control eyes.[5]
Peripapillary microvascular attenuation was greater in high tension glaucoma when compared to normal-tension glaucoma. Hence, IOP may have different effects on the peripapillary vessel density cases with open-angle glaucoma.[6]
The aim of this study is to compare the changes in the peripapillary blood flow in primary open-angle glaucoma (POAG) after administration of dorzolamide 2%/timolol 0.5% fixed combination versus latanoprost 0.005%/timolol 0.5% fixed combination, using spectral-domain optical coherence tomography (SD-OCT) angiography.
| Patients and Methods | | |
This is a prospective, comparative, nonrandomized, single-center, observational study. Twenty patients above age of 40 years old recently diagnosed as POAG were recruited in this study. Patients were recruited from the glaucoma clinic at our institutional hospital, starting from February 2018 to October 2018.
Diagnosis of PAOG was established in eyes with open angle on gonioscopy (>Grade 2), raised IOP (defined as an IOP >21 mmHg), glaucomatous optic neuropathy (defined as a vertical cup/disc (C/D) ratio >0.7 and/or C/D asymmetry >0.2 and/or focal notching), with compatible visual field loss on static automated perimetry (SITA standard algorithm with a 24-2 test pattern; Humphrey Visual Field Analyzer II; Carl Zeiss Meditec, Dublin, CA), defined as a glaucoma hemifield test outside normal limits, with an abnormal pattern and a standard deviation (SD) of P <5% in the healthy population and fulfilling test reliability criteria (fixation losses <20%, false positives <33%, and/or false negatives ≤33%). We aimed to include advanced cases to better assess the changes in the retinal nerve fiber layer (RNFL) and peripapillary capillary density.
Patients with previous history of antiglaucoma medication intake, history of previous ocular surgery other than noncomplicated cataract extraction, or past history of other ophthalmic (as retinal disease) or systemic disease (as neurological diseases) that is likely to significantly affect the OCTA test were excluded.
Forty eyes of the twenty patients were included in this study with no previous use of antiglaucoma medications. Choice of eye was randomly selected using closed envelope and revealed dorzolamide 2%/timolol 0.5% fixed combination in the right eye and latanoprost 0.005%/timolol 0.5% fixed combination in the left eye. All received simultaneous treatment with dorzolamide 2%/timolol 0.5% fixed combination in the right eye twice daily and latanoprost 0.005%/timolol 0.5% fixed combination in the left eye once at night for 1 week.
IOP was measured in each eye three times using applanation tonometer by the same investigator and the average value is recorded. OCT angiography of the optic nerve head also was done to measure the peripapillary capillary density and RNFL thickness before starting the treatment and 1 week after the treatment.
OCT and OCTA images of the optic disc and peripapillary region were done for all patients with the AngioVue system (Optovue RTVue XR Avanti; Optovue, Inc., Fremont, CA, USA). The imaging procedure was done as described previously by Rao et al. in 2016.[7] The system has an A-scan rate of 70.000 scans per second using light source centered on 840 nm and a bandwidth of 45 nm. The split-spectrum amplitude-decorrelation angiography algorithm was used to extract the OCT angiography information. In the optic disc scan, the software automatically fits an ellipse to the optic disc margin and calculates the average vessel density. We measured the papillary retinal vessel density, which could be defined as the total length of perfused vasculature per unit area in a region of measurement. It was automatically analyzed in the RPC segment (4.5 mm × 4.5-mm) and divided into three segments: the whole image, inside disc, and peripapillary. Inside disc vessel density was measured for the region inside the optic disc boundary. Whole en face vessel density was measured for the entire 4.5 mm × 4.5 mm image, while whole peripapillary vessel density was calculated for the region of 750 μm-wide elliptical annulus extending from the optic disc boundary. In addition, all patients underwent the traditional ONH, peripapillary RNFL, neuroretinal rim area, and macular ganglion cell complex (GCC) thickness measurements on RTVue-XR SD-OCT using the ONH and the GCC scans. Image quality was assessed for all OCTA and OCT scans. Poor quality images, which were defined as those with a signal strength index <45 or images with motion artifacts and segmentation errors, were excluded from the analysis. The scan was taken by two investigators, and the average reading was taken in the OCTA.
Sample size calculation
Assuming α = 0.05 (two-tailed), β = 0.05, a total sample size of 16 eyes, allocated equally into two groups (8/group), is required to detect an effect size (d) of 1.0 in the change between the two study groups with an actual power of 96.18%. Estimation of sample size was performed for t-tests of means of two dependent groups (two-tailed) using the computer program G * Power 3.1.9 (Franz Faul, Universität Kiel, Germany).
Statistical methods
Data were coded and entered using the Statistical Package for the Social Sciences version 25 (IBM Corp., Armonk, NY, USA) OCTA of right eye of one patient before starting treatment. Data were summarized using mean, standard deviation, median, minimum, and maximum in quantitative data and using frequency (count) and relative frequency (percentage) for categorical data. Comparisons between quantitative variables measured before and after treatment were done using the paired t-test 1. Correlations between quantitative variables were done using Spearman correlation coefficient 2. P < 0.05 was considered statistically significant.
Ethical consideration
An informed consent was obtained from the participant before the conduct of the study procedure. The participant was adequately informed about the study, risks, benefits, and alternative treatments, and they voluntarily agreed to participate in the study. Participants were free to choose to withdraw from the study at any time without any responsibility, even if the study has not been completed. The study protocol was revised and approved by the Research Ethical Committee and followed the tenets of the Helsinki Declaration.
| Results | | |
The patients' age ranged from 45 to 79 years with the average age value of 58.05 (± 8.89). Seventy-five percent were females and 25% were males. Fifty percent were diabetics. Thirty percent of patients were hypertensive. Central corneal thickness of all patients was within the normal range, mean central corneal thickness was 563.2 ± 37.6 μm using iPac pachymeter- Reichert.
There was no significant statistical difference in the pretreatment measurements between the two groups. The mean IOP, the mean peripapillary capillary density (total, superior-hemi, and inferior-hemi), and the mean RNFL thickness (total, superior-hemi, and inferior-hemi) in both groups before treatment were shown in [Table 1]. | Table 1: Descriptive data in both groups before and after 1 week of treatment
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The mean IOP, the mean peripapillary capillary density (total, superior-hemi, and inferior-hemi), and the mean RNFL thickness (total, superior-hemi, and inferior-hemi) in both groups after 1 week of the treatment were shown in [Table 1].
Comparison of the changes in each group before and after treatment
There was a significant reduction in IOP in the two Groups. The percentage of reduction was 18.9% and 24.01% in Group 1 and Group 2, respectively, as shown in [Table 2] (P < 0.001) (as seen in [Figure 1] and [Figure 2]). | Table 2: Comparison of the results between before and after treatment in each group
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 | Figure 2: OCTA of right eye of the same patient after one week of treatment
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The mean peripapillary capillary density (total, superior-hemi, and inferior-hemi) increased after 1 week of treatment in both groups, but the change was statistically insignificant, as shown in [Table 2].
The mean RNFL thickness (total, superior-hemi, and inferior-hemi) increased after 1 week of treatment in both groups, but the change was statistically insignificant, as shown in [Table 2].
Comparison between the two groups
IOP decreased in both groups with higher reduction in Group 2, the percentage of change in Group 1 was 18.9%, while in Group B was 24.01%, but the difference is statistically insignificant (P = 0.554) as shown in [Table 3].
The mean peripapillary capillary density (total, superior-hemi, and inferior-hemi) increased after 1 week of treatment in both groups with more increase in Group 1, the percentage of change was 2.5%, and 2.37%, in Group 1 and Group 2, respectively (P = 0.756). The increase in peripapillary capillary density was statistically insignificant between the two groups as shown in [Table 3].
The mean RNFL thickness (total, superior-hemi, and inferior-hemi) increased after 1 week of treatment in both groups, with more increase in Group 1. The percentage of change was 9.69% and 4.51%, in Group 1 and Group 2, respectively (P = 0.619). The increase in RNFL was statistically insignificant between the two groups as shown in [Table 3].
Correlation between Intraocular pressure reduction and radical peripapillary capillary density
There is a statistically positive correlation between IOP reduction and increase in the superior- hemiradial peripapillary capillary density (P = 0.037) in Group 1. No other relation was found between the change in the IOP and the increase in the radial peripapillary capillary density in both groups, as shown in [Table 4]. | Table 4: Correlation between intraocular pressure reduction and radical peripapillary capillary density in the two groups
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Correlation between intraocular pressure reduction and retinal nerve fiber layer
There is a statistically positive correlation between IOP reduction and increase in the total RNFL thickness and superior hemi-RNFL thickness (P = 0.044, 0.032, respectively) in Group 1. No other relation was found between the change in the IOP and the increase in the RNFL in both groups, as shown in [Table 5]. | Table 5: Correlation between intraocular pressure reduction and RNFL in the two groups
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| Discussion | | |
This prospective study aims to compare the changes in the peripapillary blood flow in patients with POAG after administration of dorzolamide 2%/timolol 0.5% fixed combination versus latanoprost 0.005%/timolol 0.5% fixed combination, using SD-OCT angiography.
OCTA can be used for the diagnosis of glaucoma and better understanding its pathophysiology. Reduction of the optic disc perfusion has been detected in glaucoma.[8] The reduced RPC density is a new parameter in OCTA that can detect early focal glaucoma damage.[9]
There is a strong association between POAG and both old age and African race. This was met in our group sample with mean of 58.05 ± 8.89 years. This was in agreement with other studies done on POAG.[10],[11],[12]
Although completely unintentional (since the subjects of the study were consecutive), 75% of patients were female. This was inconsistent with other studies as POAG is more common in males; this difference is probably due to the smaller sample size in our study.[10],[11],[12]
There was a significant reduction in IOP in the two groups. The percentage of reduction was 18.9% 24.01% in Group 1 and Group 2, respectively (P < 0.001). These results are comparable to previously established studies.[1],[13],[14],[15]
In our results, the mean peripapillary capillary density (total, superior-hemi, and inferior-hemi) increased after 1 week of treatment in both groups with more increase in Group 1. The percentage of change was 2.5% and 2.37%, in Group 1 and Group 2, respectively (P = 0.756). The increased peripapillary capillary density detected by OCTA in the current study after the treatment can be attributed to the improvement in peripaillary microcirculation with the reduction in IOP after the use of both combinations.
When IOP increases and exceeds the autoregulation mechanism of retinal vessels, the retinal blood flow decreases, while with IOP reduction after treatment, retinal vessels autoregulation is restored with increased blood flow leading to increase in the RNFL thickness and peripapillary capillary density.[16]
Although the result is not statistically significant, they are comparable to another study done by Siesky et al. in 2006 which assess ocular blood flow using confocal scanning laser Doppler flowmetry, color Doppler imaging, and scanning laser ophthalmoscopy. Furthermore, they found that fixed combination of timolol and dorzolamide significantly increased central retinal artery (CRA) end-diastolic blood flow velocity (P = 0.0168) and lowered resistance to flow (P = 0.0279).[1]
Importantly, the vasodilative activity of dorzolamide has been reported to be independent of reductions in IOP, and this also meets the results found that: in patients treated with dorzolamide 2%/timolol 0.5% fixed combination for 4 weeks; blood flow was significantly improved over baseline in the temporal principal component analysis and CRA measured by color Doppler imaging (P = 0.024).[17] While Martínez et al. 2006 found that significantly increased the end-diastolic volume in the ophthalmic artery and in the short posterior ciliary artery, P = 0.00012 and P = 0.00012, respectively, and decreased the resistance index in the ophthalmic and short posterior ciliary arteries, P = 0.00011 and P = 0.00031, respectively.[18] Furthermore, Harris et al. 2001 found that dorzolamide timolol combination increased arteriovenous passage time (superior temporal artery) of fluorescein dye (2.13 to 1.76 seconds, P < 0.01).[19]
Cennamo et al. 2017 state that OCT angiography can be considered a reliable, easy-to-perform method with which to evaluate microvascular changes of optic nerve head for the early diagnosis and follow-up of glaucoma. The flow index (P = 0.021) and vessel density (P = 0.001) were significantly lower in preperimetric glaucoma eyes versus normal eyes. Back to our results, (P = 0.596) baseline and (P = 0.697) posttreatment. This can be explained by our two groups being glaucomatous.[20]
According to Liu 2015, using OCTA, reduced peripapillary retinal perfusion in glaucomatous eyes can be visualized as focal defects and quantified as peripapillary flow index and peripapillary vessel density with high repeatability and reproducibility. Liu et al. in 2015 found the peripapillary vessel density, % area glaucomatous eyes is range from 57.89 to 93.87 with mean of 80.55 ± 11.10% compared to our results is range from 54.1 to 22.4 with mean of 43.83 ± 8.93. The difference may be due to the small size of Liu sample 12 patients only.[21] This is in line with Mansoori et al. in 2017 which demonstrated that there was symmetry in superior and inferior corresponding pair sectors with respect to the horizontal meridian.[22]
In Holló, 2017 case series, the influence of large medical IOP reduction on peripapillary angioflow vessel-density (PAFD) in the radial peripapillary capillaries layer was investigated on consecutive. He found that an IOP reduction >50% of the untreated baseline value resulted in an increase of PAFD in all cases. The difference of results between this study and ours can be explained by high IOP baseline and a large scale of glaucoma types (ocular hypertensive and pigment dispersion/glaucoma eyes).[23]
Increased RNFL thickness after IOP reduction either medically or surgically is thought to be due to the reversal of the physical compressive effect on the RNFL by the high IOP.[24] IOP reduction leads to a recovery of normal shape and size of the retinal ganglion cell axons with subsequent increase in RNFL thickness. Furthermore, hyptony after IOP reduction, especially after surgery may cause retinal and disc swelling with increased RNFL thickness.[25]
Dorzolamide decreases the resistance index of the ocular vessels, thus increasing ocular blood flow, and this will in turn increase the RNFL thickness and peripapillary capillary density.[26] While latanoprost has no or little effect on ocular blood flow, the increase in RNFL thickness and peripapillary capillary density after latanoprost could be related to its hypotensive effect.[27] Furthermore, latanoprost may cause uveitis with subsequent increase in RNFL thickness as reported by Din et al. in 2014 who noted increase in the RNFL thickness in uveitic eyes compared to control eyes.[28]
According to Ghasemi Falavarjani et al. in 2017 and Spaide et al. in 2015, image artifacts are common and can lead to incorrect interpretations of OCTA images. Our study faces this problem and it takes sometimes a long time to capture good quality images.[29],[30]
Furthermore, Rao et al. in 2016 state that diagnostic ability of the vessel density parameters of OCTA inside disc densities had significantly lower diagnostic abilities in POAG than the peripapillary density. Diagnostic abilities of vessel densities increased with increasing severity of glaucoma and that of ONH vessel density with higher pretreatment IOPs.[7]
| Conclusion | | |
Both fixed combinations of timolol and dorzolamide and latanoprost plus timolol therapy combinations were effective at reducing IOP in POAG patients with no statistically significant difference between the two combinations.
Furthermore, both fixed combinations of timolol and dorzolamide and latanoprost plus timolol therapy combinations showed an increase in the peripapillary capillary density and RNFL thickness after 1 week of the treatment as evaluated by OCT angiography. However, this increase was not statistically significant. There was only a statistically positive correlation between IOP reduction and increase in the superior-hemiradial peripapillary capillary density (P = 0.037) in Group 1 and between IOP reduction and increase in the total RNFL thickness and superior hemi-RNFL thickness (P = 0.044, 0.032, respectively) in Group 1. This correlation indicates increase in the superior peripapillary microvasculature after reduction of the IOP could be related to lower superior microvascular resistance to blood flow or more preserved superior microvasculature as glaucomatous damage is more common to start in the inferior area, but further longer-term studies are needed to properly investigate changes in ocular blood flow in glaucoma patients.
OCTA shows different changes in the microvascular network at the optic disc and peripapillary area. It is fast and noninvasive, and it acquires volumetric scans with simultaneous structural and functional information that can be segmented to specific depths, and that it provides accurate size and localization information.
The study is not free from limitations as the small sample size and the short-term nature of this study that limited the ability to detect differences between these two treatment combinations and the long-term therapeutic impact on OCTA findings. These findings should be evaluated in longer-duration studies and with larger patient populations and additional imaging technologies to confirm any medication-induced effects.
There are also several limitations associated with OCTA imaging itself. Unlike Doppler OCT, which provides absolute volumetric flow in μl/min, OCTA only yields a flow index in arbitrary units. Different types of artifacts may affect interpretation and measurements in OCTA images.
Compliance with ethical standards
An informed consent was obtained from the human participants before the conduct of any study procedure. The participant was adequately informed about the study, risks, benefits, and alternative treatments, and they voluntarily agreed to participate in the study. Participants were free to choose to withdraw from the study at any time without any responsibility, even if the study has not been completed. The study protocol was revised and approved by the Research Ethical Committee and followed the tenets of the Helsinki Declaration.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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