Trends in macular and optic nerve head vessel density following myopic photorefractive keratectomy

doi:10.21203/rs.3.rs-4891785/v1

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Research Article

Trends in macular and optic nerve head vessel density following myopic photorefractive keratectomy

https://doi.org/10.21203/rs.3.rs-4891785/v1

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Purpose

We aimed to apply Optical Coherence Tomography Angiography (OCTA) to comprehensively assess changes in the optic nerve head (ONH) and macular perfusion before and after the myopic photorefractive keratectomy (PRK).

Methods

A total of 26 myopic patients eligible for PRK were included based on specific criteria, with meticulous exclusion criteria in place to minimize potential confounders. Participants underwent OCTA assessments of the ONH and macula using the Spectralis OCT (Heidelberg) before, as well as at 1 and 3months after PRK. MATLAB software was utilized for image analysis.

Results

The average age at the time of surgery was 31.3 ± 5.82years with 26.9% of participants being male. The mean intraocular pressure before the surgery was 15.84 ± 2.46 mmHg. Significant alterations were observed in macular vessel density, emphasizing regional variations in vascular response. Regarding Large vessel density (LVD), there was a significant decrease in Superficial Vascular Complex (SVC) (from 24.21–18.67%, P = 0.011) and deep vascular complex (DVC) (from 26.93% to 21.81, P = 0.003) between before surgery and 3 months later. Similarly, in Capillary Vessel Density (CVD (, significant changes were observed between before surgery and 3 months later in SVC (from 18.22–21.16%, P = 0.004) and DVC (from16.89–21.44%, P = 0.002). In comparison to the macula, vascular densities were more stable overtime in optic nerve head. In both LVD and CVD, only DVC had significant decrease between before surgery and 3 months after (P = 0.008, and 0.038 respectively).

Conclusions

While PRK appears to maintain the integrity of certain ocular structures, alterations in macular and optic nerve head perfusion post-PRK suggest potential effects on retinal blood supply.

Long-term monitoring is crucial to understand the implications of these changes, particularly in the context of conditions such as diabetes.

OCT angiography

PRK

vessel density

Unaddressed refractive errors, particularly myopia, are the leading cause of global visual impairment. ^1–3 Laser corneal refractive procedures provide an effective alternative to glasses or contact lenses, with a focus on treating myopia. Various surgical methods have been developed to reshape the cornea by precisely removing corneal tissue using a photoablative approach. ^{4, 5} Photorefractive keratectomy (PRK) is the pioneering technique in corneal refractive surgery, utilizing excimer lasers with over 25 years of successful practice. PRK is a widely used and safe method for correcting refractive errors. ^{6, 7}

During PRK, an excimer laser is used to remove corneal tissue, specifically targeting the anterior stroma. This process changes the cornea's refractive power in proportion to the amount of tissue ablation. PRK is effective for correcting low to moderate myopia, but it is important to note that myopia is a risk factor for developing primary open-angle glaucoma. ^8–10 Additionally, patients undergoing PRK often require long-term steroid use, which can increase the risk of glaucoma. Previous studies have investigated changes in intraocular pressure (IOP) and retinal nerve fiber layer (RNFL) thickness following myopic PRK. ^{10, 11} However, the impact of PRK on retinal vasculature has not been evaluated. This study aimed to assess the effects of PRK on macula and optic nerve head circulation using OCT angiography in patients with myopia.

This research is a practical prospective cohort study aiming to assess the effects of PRK on Optic Nerve Head (ONH) and macular perfusion in 26 myopic patients eligible for PRK. Inclusion criteria involve myopic patients eligible for PRK, while exclusion criteria include individuals with central corneal thickness below 500 microns, a history of herpes simplex virus (HSV) keratitis, retinal, optic nerve, or systemic diseases, such as diabetes and high blood pressure, or use of drugs with retinal toxicity. The study involves using OCT angiography of ONH and macula and the OCT Glaucoma module, with data collected before PRK and at 1month and 3 months post-PRK using Spectralis OCT (Heidelberg Co) to determine vascular density as well as macular and optic nerve head analysis. OCT Angiography images were analyzed using MATLAB software. Noise was reduced with adaptive median filtering.

Total Vessel Density (TVD) and Large Vessel Density (LVD) were obtained from binary outputs using local adaptive and global thresholding. Capillary Vessel Density (CVD) was calculated as TVD minus LVD. (Figs. 1(A, B))

Photorefractive keratectomy (PRK)

The standard surgical technique of PRK was employed, as described elsewhere, using TECNOLAS Perfect Vision GmbH (TENEO 317 software version 1.25; Bausch & Lomb) ¹². Postoperatively, patients were prescribed topical levofloxacin four times daily for one week and loteprednol four times daily for one week, gradually tapering over the course of four months. Importantly, none of the patients experienced haze or encountered any other surgery-related complications.

Optical Coherence Tomography (OCT)

Spectral domain optical coherence tomography (SD-OCT) assessed macular retinal anatomy using the Heidelberg Engineering Spectralis HRA®OCT device. Patients' pupils were dilated with eye drops, and they fixated on a target light.

An infrared camera tracked foveal fixation, while retinal mapping software measured macular thickness within the central ring.

Optical Coherence Tomography Angiography (OCT-A)

A 3x3 mm OCTA image, centered on the fovea, was captured using advanced swept-source (SS)-OCTA technology from Heidelberg Engineering, Germany. Operating at 1060 nm, this system offers swift scanning capabilities and delivers high-resolution images. Automated segmentation precisely delineated the superficial retinal layer, including the superficial capillary plexus. Additionally, Spectralis® OCT scans employed a 15º x 15º optic nerve head protocol, utilizing Spectralis® software for en face OCTA images of the superficial and deep vascular complexes. Segmentation defined the upper and lower limits of the superficial vascular complex (SVC) and deep vascular complex (DVC). SVC spanned from the internal limiting membrane to 17 µm above the inner plexiform layer, while DVC ranged from 17 µm above the inner plexiform layer to the outer plexiform layer's extremity.

Statistical Analysis

The collected data were analyzed using SPSS version26.0 (IBM Corp, Armonk, New York, USA). Figures were created using Excel (Microsoft®, Redmond, Washing-ton, USA). Categorical data were presented as numbers and percentages. Continuous data were tested for normality using the Shapiro-Wilks test with a P > 0.05 considered as normal data distribution. Normally distributed variables analyzed by Repeated measures and presented as mean ± standard deviation (SD), while non parametric data were analyzed by the Friedman test and expressed as median and inter-quartile range (IQR). When Repeated measures test or Friedman test identified statistically significant differences, post hoc multiple comparisons using Bonferroni adjusted tests were performed to detect significant pairs. A p-value of 0.05 or less was considered statistically significant.

Twenty-six eyes of 26 myopic patients who underwent Photorefractive Keratectomy (PRK) were enrolled in this study. The average age at the time of surgery was 31.3 ± 5.82years (range 21–41 years) with 26.9% of participants being male. The mean intraocular pressure (IOP) before the surgery was 15.84 ± 2.46 mmHg (range 10–20 mmHg) and corneal topography (Pentacam®) showed a mean thinnest point of 539.57 ± 25.68 µm (range 486–594 µm) and a mean Kmax of 45.83 ± 1.45 D (range 42.7–48.5 D) prior to the surgery (Table 1). The mean total, superior, and inferior retinal thickness were not significantly different before and after the surgery (p = 0.09, p = 0.14, and p = 0.33 respectively) (as shown in Table 2). Additionally, peripapillary retinal nerve fiber layer (ppRNFL) thickness measurements indicated significant changes in the global (p = 0.02) and supranasal (p = 0.01) regions during evaluations conducted preoperatively, one month postoperatively, and three months postoperatively.

Table 1

Patients characteristics and corneal topography measurements before PRK surgery
Variable	Value (n = 26)
Male gender, %	26.9%
Age at surgery time (years), mean ± SD	31.3 ± 5.82
Pre operation IOP (mmHg), mean ± SD	15.84 ± 2.46
Axis refraction(D), median [IQR]	101.5[12.5,169.75]
Cylinder refraction(D), median [IQR]	-1.5[-1.56,-0.93]
Sphere refraction(D), median [IQR]	-2.50[-3.37,-1.68]
Thinnest point(µm), mean ± SD	539.57 ± 25.68
Kmax(D), mean ± SD	45.83 ± 1.45
n: number, D: Diopter, µm: micrometer, IOP: intraocular
-pressure, Kmax: maximal keratometry

Table 2

Comparison of average retinal thickness and peripapillary retinal nerve fiber layer(ppRNFL) thickness before and after the PRK surgery in patients with myopia (n = 26)
Variable	Pre-operation	1 Month post-operation	3 Months Post-operation	P-value*
ART(µm)
Total	77.42 ± 2.39	76.75 ± 1.76	76.83 ± 1.74	0.09
Superior	78.08 ± 2.87	77.08 ± 2.32	77.31 ± 2.09	0.14
Inferior	76.92 ± 2.01	76.31 ± 1.43	76.54 ± 1.85	0.33
Peripapillary RNFLT(µm)
Global	102.77 ± 11.46	102.08 ± 11.92	103.77 ± 12.91	0.02
superior temporal	139.31 ± 22.03	137.62 ± 18.54	140 ± 20.46	0.26
Temporal	72 ± 11.71	71.31 ± 11.56	73 ± 12.36	0.09
inferior temporal	151.69 ± 16.87	150 ± 16.53	152.92 ± 17.58	0.30
superior nasal	124.92 ± 29.24	122.15 ± 30.63	125.85 ± 31.64	0.01
Nasal	85.08 ± 16.52	85.46 ± 17.45	86.69 ± 18.74	0.07
inferior nasal	113.46 ± 21.57	115.85 ± 23.74	113.23 ± 20.76	0.31
ART: average retinal thickness, RNFLT: retinal nerve fiber layer thickness, (µm): micrometer
*Friedman test

P-values < 0.05 were considered as statically significant, all data were presented as mean ± standard deviation.

Vascular changes in the macula following PRK surgery:

Vascular changes are shown in Table 3 and Fig. 2(A). The data displays the levels of macular OCT-A markers before surgery, as well as at 1- and 3-months post-surgery follow-up for all patients. Changes in total vessel density (TVD), superficial vascular complex (SVC) and avascular complex (AC) were not significant between timepoints (P = 0.43, and 0.96 respectively). However, there was a significant decrease in the amount of deep vascular complex (DVC) between 1 and 3 months after surgery(P = 0.038).

Regarding Large Vessel Density (LVD), changes in AC were not significant between timepoints(P = 0.89). However, there was a significant decrease in SVC (from 24.21–18.67%, P = 0.011) and DVC (from 26.93% to 21.81, P = 0.003) between before surgery and 3 months later. Similarly, in Capillary Vessel Density (CVD (, significant changes were observed between before surgery and 3 months later in SVC (from 18.22–21.16%, P = 0.004) and DVC (from16.89–21.44%, P = 0.002).

Table 3

Comparison of macular optical coherence tomography angiography vessel density in myopic patients before and after PRK (n = 26).
	Pre-operation	1 Month post-operation	3 Months Post-operation	P-value
TVD (%)
SVC	40.75 ± 3.6	40.33 ± 3.1	39.59 ± 3.8	0.43€
DVC	43.48[42.64,44.78]	43.91[42.94,45.18]	42.79[41.85,43.9]	0.028*§
AC	49.08[47.93,50.67]	49.31[48.54,50.93]	49.35[48.12,52.26]	0.96*
LVD (%)
SVC	24.21[18.26, 29.15]	23.89[16.23,25.89]	18.67[14.6,24.25]	0.014*†
DVC	26.93[21.71, 29.16]	25.46[21.28, 28.12]	21.81[16.87,23.39]	0.004*†
AC	27.93[26.55,30.39]	28.15[26.51,30.78]	27.74[26.9,31.56]	0.89*
CVD (%)
SVC	18.22[13.8,20.34]	18.99[16.36,20.65]	21.16[17.59,23.18]	0.006*†
DVC	16.89[15.4,22.18]	18.74[16.99,21.55]	21.44[19.49,24.13]	0.002*†
AC	21.39[20.48,22.66]	21.12[20.14,22.64]	21.49[20.53,22.87]	0.49*
n: number, TVD: total vessel density, LVD: large vessel density, CVD: capillary vessel density, SVC: Superficial Vascular Complex, DVC: Deep Vascular Complex, AC: avascular complex
* P-values by Friedman test and data were presented as median [IQR]

€ P-values by repeated measures and data were presented as mean ± SD

P-values < 0.05 were considered as statically significant

Vascular changes in the optic nerve head following PRK surgery:

Vascular changes are presented in Table 4 and Fig. 2(B). The data shows the levels of optic nerve head OCT-A markers before surgery as well as 1- and 3-months post-surgery for all participants. In comparison to the macula, vascular densities were more stable overtime in optic nerve head. For TVD, all vascular markers (SVC, DVC, and AC) remained consistent throughout the timepoints (P = 0.076,0.446, and 0.607 respectively). In both LVD and CVD, only DVC had significant changes between before surgery and 3 months after (P = 0.008, and 0.038 respectively).

Additional statistical analysis was conducted with a significance level of p < 0.05 to identify statistically significant differences. Post-hoc comparisons were then performed using Bonferroni adjustment for multiple comparisons, &: statically significant differences between before the surgery and 1-month post-surgery, †: statically significant differences between before the surgery and 3 months post-surgery, and, §: statically significant differences between 1month after the surgery and 3 months post-surgery.

P-values < 0.05 were considered as statically significant. Additional statistical analysis was conducted with a significance level of p < 0.05 to identify statistically significant differences. Post-hoc comparisons were then performed using Bonferroni adjustment for multiple comparisons, &: statically significant differences between before the surgery and 1-month post-surgery, †: statically significant differences between before the surgery and 3 months post-surgery, and, §: statically significant differences between 1month after the surgery and 3 months post-surgery.

Table 4

Comparison of optic nerve head optical coherence tomography angiography vessel density in myopic patients before and after PRK surgery at 1 and 3 months after the surgery(n = 26).
	Pre-operation	1 Month post-operation	3 Months Post-operation	P-value
TVD (%)
SVC	51.86[49.17,54.19]	49.45[46.46,52.02]	50.71[48.18,52.6]	0.076*
DVC	37.63[35.87,39.74]	36.85[35.73,38.55]	37.13[35.95,38.05]	0.446*
AC	49.22[47.96,52.34]	49.43[47.24,52.29]	48.8[48.1,51.64]	0.607*
LVD (%)
SVC	43.75[40.77,49.05]	38.4[35.3,44.84]	41.08[36.3,44.11]	0.056*
DVC	14.5 ± 4.5	12.27 ± 4.3	10.28 ± 4.8	0.003€ †
AC	26.67[23.31,28.59]	25.25[21.36,30.95]	24.09[20.27,25.69]	0.76*
CVD (%)
SVC	11.16 ± 4.3	12.3 ± 3.4	12.99 ± 3	0.156€
DVC	23.63[21.62,25.52]	24.42[22.44,26.72]	25.57[24.82,26.18]	0.04*†
AC	26.33[22.59,28.36]	25.81[22.79,29.88]	27.28[25.34,29.12]	0.135*
n: number, TVD: total vessel density, LVD: large vessel density, CVD: capillary vessel density, SVC: Superficial Vascular Complex, DVC: Deep Vascular Complex, AC: avascular complex
* P-values by Friedman test and data were presented as median [IQR]

€ P-values by repeated measures and data were presented as mean ± SD

Figure 2(A). Column charts illustrating macular OCT-A vessel density (Median [IQR], %) in patients with myopia before and after PRK surgery at 1 and 3 months after the surgery. TVD: total vessel density, LVD: large vessel density, CVD: capillary vessel density, SVC: Superficial Vascular Complex, DVC: Deep Vascular Complex, AC: avascular complex. †: statically significant differences between before the surgery and 3 months post-surgery, and, §: statically significant differences between 1month after the surgery and 3 months post-surgery. n = 26.

Figure 2(B). Column charts illustrating optic nerve head OCT-A vessel density (Median [IQR], %) in patients with myopia before and after PRK surgery at 1 and 3 months after the surgery. TVD: total vessel density, LVD: large vessel density, CVD: capillary vessel density, SVC: Superficial Vascular Complex, DVC: Deep Vascular Complex, AC: avascular complex. †: statically significant differences between before the surgery and 3 months post-surgery. n = 26.

While photorefractive keratectomy (PRK) is commonly seen as a simple procedure for correcting myopia, several studies have pointed out potential complications. These studies have shown an increase in intraocular pressure and changes in various parameters related to the optic nerve head and retinal nerve layer after this surgery ^{10, 13}. Changes in the blood supply to the optic nerve head and macula may occur as potential side effects of PRK. Therefore, the current study was conducted to evaluate the blood supply to the optic nerve head and macula in myopic patients who had PRK. In this study, the overall average thickness of the retina did not show a significant change compared to preoperative measurements, which is in line with previous findings. However, there was a noticeable decrease in the thickness of the upper layer of the retina one month after the surgery, contrary to earlier observations¹⁴. Importantly, this decrease was temporary, as shown by subsequent measurements at three months post-surgery, which did not differ significantly from preoperative or one-month postoperative values. This temporary decrease in the thickness of the upper retinal layer one month after the surgery emphasized the dynamic nature of retinal changes following PRK. Furthermore, significant changes in retinal nerve fiber layer (RNFL) thickness were observed globally and in the superior nasal region at one- and three-months post-surgery. These finding are consistent with previous studies, emphasizing the importance of monitoring RNFL changes in patients undergoing PRK. ¹⁰ In the analysis of macular total vessel density (TVD) following PRK surgery, changes in the superficial vascular complex (SVC) and avascular complex (AC) between timepoints were not significant. However, there was a significant decrease in the deep vascular complex (DVC) between 1 and 3 months postoperatively. Interestingly, a significant reduction in DVC was observed when comparing preoperative evaluations to one-month postoperative evaluations, but this decrease did not persist at the three-month postoperative mark. This finding suggests a transient decline in blood supply to the macular large vessels following PRK surgery. Similarly, in the analysis of Large Vessel Density (LVD), changes in the avascular complex (AC)

between timepoints were not significant. However, significant decreases were observed in the SVC and DVC when comparing preoperative evaluations to those conducted three months postoperatively. For Capillary Vessel Density (CVD), similar significant changes were noted. There were significant decreases in both the SVC and DVC when comparing preoperative evaluations to those conducted three months postoperatively. These findings raise concerns about the safety of PRK surgery, particularly regarding its impact on the vascular structures of the eye. Regarding the blood supply to the optic nerve head (ONH), vascular densities were more stable between time points compared to the macula. In total vessel density (TVD), all vascular markers, including the SVC, DVC, and AC, remained consistent throughout the time points. In both LVD and CVD, only the DVC showed significant changes when comparing preoperative evaluations to those conducted three months postoperatively. In general, most abnormalities observed in this study were related to the first month postoperatively. By three months after the operation, these values had generally returned to their preoperative levels. These issues may be attributed to the use of topical steroids within the first month after the operation, which can result in a significant increase in intraocular pressure (IOP) following PRK. The use of steroids after refractive surgery poses a risk of glaucoma in steroid responders. ¹⁵ The route of administration and the formulation of the steroid medication play a role in penetration in ocular tissues, resulting in high IOP. In a study conducted by Fakhraie et al,they demonstrated that eyes with higher baseline IOP and lower baseline CCT are at increased risk of steroid-induced IOP rise of more than 5 mmHg after PRK and should be monitored more frequently. (11) On the other hand, although it is proposed that the laser used in PRK does not penetrate beyond the cornea, the shockwave generated by the laser could potentially affect the retina and its blood supply. Therfore, we should have a special concern for patients at risk of vascular damage. Our study has both strengths and limitations. To the best of our knowledge, this is the first study designed to evaluate the trend of macular and ONH vascular changes following myopic PRK.

However, one of the limitations of the study is the relatively short follow up period and small number of patients. Therefore, a longer follow- up with a larger study population is suggested. On the other hand, although we excluded all patients with a history of vascular problems such as diabetes mellitus,

hypertension and ischemic heart disease, there may be some patients who were unaware of their diseases or in subclinical stages which could potentially influence the macular and optic nerve head vascular changes.

Our study revealed vessel density in the macula and optic nerve head particularly large vessel density, decreased after myopic PRK. This decrease may be primarily caused by a steroid-induced rise in IOP. Therefore, patients who are at a higher risk of increase IOP and those who are susceptible to vascular issues should be monitored regularly.

Acknowledgments: The authors will acknowledge all participants of the study.

Funding: None.

Conflicts of interest/Competing interests: None declared.

Availability of data and material: We provide the data with a reasonable request.

Ethics approval: This study has approved by the Ethics Committee of Shiraz University of

Medical Sciences.

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No competing interests reported.

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You are reading this latest preprint version

Trends in macular and optic nerve head vessel density following myopic photorefractive keratectomy

Status:

Version 1

Abstract

Figures

INTRODUCTION

METHODS

Photorefractive keratectomy (PRK)

Optical Coherence Tomography (OCT)

Optical Coherence Tomography Angiography (OCT-A)

Statistical Analysis

RESULTS

Vascular changes in the macula following PRK surgery:

Vascular changes in the optic nerve head following PRK surgery:

DISCUSSION

Declarations

References

Additional Declarations

Status:

Version 1