Myopia is a common condition that affects a significant portion of the world's population.1,2 The prevalence of myopia is highest in Asia at approximately 50%. By 2050, myopia and high myopia will affect 4.95 billion (52%) and 0.93 billion (10%) of the world's population, respectively.3 High myopia can cause serious, sight-threatening retinal damage, such as myopic choroidal neovascularization and lacquer cracks, and carries an increased risk of developing glaucoma and cataracts.4,5 Interestingly, high myopic individuals have decreased retinal vessel caliber and decreased superficial and deep retinal microvasculature density.6–8
Corneal refractive surgery is an effective surgical option to correct myopia. Procedures include photorefractive keratectomy, laser in situ keratomileusis (LASIK), laser epithelial keratomileusis, femtosecond lenticule extraction, and small-incision lenticule extraction (SMILE).9,10 SMILE, first reported by Shah and Sekundo 2011,11,12 is a type of corneal refractive surgery that involves the use of a femtosecond laser to create an intrastromal lenticule followed by lenticule removal through a small peripheral corneal tunnel incision to reshape the cornea and correct refractive error.13,14 In contrast to LASIK, SMILE does not require a corneal flap. Thus, SMILE theoretically causes less morphological and biomechanical disruption of the corneal surface. Because of the safe, effective, and predictable quality of this surgical procedure, SMILE has gained widespread acceptance.
Clinically, it is well documented that there are significant increases in intraocular pressure (IOP) during refractive surgery. In a study with donated human eyes, mean IOP levels during flap creation with a 200 kHz femtosecond laser (Carl Zeiss Meditec AG), a 60 kHz femtosecond laser (Abbott Medical Optics, Inc.), and a microkeratome (Ziemer Ophthalmic Systems AG) were 81 ± 18 mm Hg (SD), 179 ± 14 mm Hg, and 220 ± 53 mm Hg, respectively. Although there was lower IOP elevation during the femtosecond laser flap creation than LASIK flap creation using microkeratomes, a longer procedure time is required than during microkeratome flap creation. The duration of the cutting phase was longest for procedures performed using the 200 kHz femtosecond laser (91 ± 9 seconds).15
The transient IOP spikes during the creation of corneal flaps or intrastromal lenticules may cause harm to the optic nerve and retina, particularly in myopic patients. First, spikes in IOP during refractive surgery may have an impact on optic nerve function. Myopia itself is a risk factor for open-angle glaucoma, and the effects of transient increases in IOP are of particular concern in these patients.16 Iester et al.17 demonstrated that a 45-second acute increase in IOP, such as during LASIK (microkeratome) suction, did not decrease the retinal nerve fiber layer (RNFL) thickness in normal eyes. However, the effect of IOP elevation after SMILE surgery on the RNFL and ganglion cell-inner plexiform layer (GCIPL) still remains largely unexplored. Second, the sudden elevation in IOP during LASIK has been reported to cause retinal tears, retinal detachments, and macular holes.18,19 Finally, the IOP elevation during corneal refractive surgeries may cause transient ischemia of the retinal and optic nerve.20 Previous studies have shown that during refractive surgery procedures in rabbit or porcine eyes, the IOP was elevated.21,22 Myopic individuals who already have morphologic changes in their retinal vasculature, such as reduced vessel density, may be more susceptible to ischemic events secondary to transient intraoperative increases in IOP. However, to date, no studies have specifically focused on the alterations in the retinal vasculature after refractive surgery in myopic individuals.
Although SMILE has been widely used to correct myopia and its predictability and stability have been documented in long-term follow-ups,23 a gap exists in the understanding of the immediate effect of IOP elevation during SMILE on the retinal neurovasculature. In this work, we aimed to bridge this gap using optical coherence tomography angiography (OCTA) to explore the effect of IOP elevation during SMILE on RNFLs and the vasculature. In addition, a new strategy was developed to evaluate retinal safety after SMILE based on the application of OCTA.
This study was approved by the Institutional Review Board for Human Research of the Second Affiliated Hospital of Guangzhou Medical University. Written informed consent was obtained from all patients. All patients were treated according to the tenets of the Declaration of Helsinki. The patients were enrolled at the Ophthalmic Center, the Second Affiliated Hospital of Guangzhou Medical University. The data were processed and analyzed in the Bascom Palmer Eye Institute, University of Miami Miller School of Medicine.
A total of 38 patients with myopia (−10 diopters [D] ≤ spherical equivalent < −1.0 D) were recruited. The inclusion criteria were age older than 18 years, central corneal thickness 480 µm or greater, and target of postoperative refraction of plano. Patients were excluded if they had a history of corneal trauma or surgery, suspicion of keratoconus, severe dry eye, glaucoma, progressive corneal degeneration, cataract, uveitis, retinal vessel occlusions, and systemic disease, such as autoimmune disease or diabetes mellitus. One eye of each patient was randomly selected if both eyes were eligible for this study. All patients underwent a comprehensive ophthalmic examination that included corrected distance visual acuity (CDVA), uncorrected distance visual acuity (UDVA), slitlamp examination, corneal tomography as measured by Pentacam Scheimpflug tomography (OCULUS Optikgeräte GmbH), and IOP as measured by a noncontact tonometer (Cannon TX-F), which was adjusted as corrected IOP (IOP) based on the corneal thickness as obtained by Pentacam at baseline preperatively (PRE), postoperative day (POD) 1, and POD 7.
All surgeries were performed by one experienced surgeon (X.S.). The VisuMax femtosecond laser system (Carl Zeiss Meditec AG) was used for SMILE with a pulse energy of 130 nJ to 160 nJ and a repetition rate of 500 kHz. The intended SMILE parameters were cap thickness between 110 µm and 120 µm, lenticule diameter between 6.0 mm and 7.0 mm, and cap diameter 1.0 mm larger than the stromal lenticule. The refractive stromal lenticule was extracted using surgical forceps through a superior side cut with a circumferential length of 2.1 mm. Postoperative medications included levofloxacin 0.5% (Cravit) 4 times a day for 2 weeks, sodium hyaluronate 0.3% (Hialid) 4 times a day for 3 weeks, and tobramycin 0.3% and dexamethasone 0.1% (Tobradex) 4 times a day for 1 week, before switching to fluorometholone 0.1% (Flumetholon) 4 times a day for 1 week. Fluorometholone was then tapered to 2 times a day for 3 weeks.
GCIPL and RNFL Thickness Measurement
To measure the thickness of the GCIPL and the peripapillary retinal nerve fiber layer (pRNFL), the 512 × 128 scanning protocol was used in a high-definition optical coherence tomography (OCT) with an AngioPlex OCTA device (Carl Zeiss Meditec) (Figure 1). The GCIPL thickness was measured using an elliptical partition, and the pRNFL thickness was measured using a quadrantal partition; measurements were obtained from OCT reports. GCIPL and RNFL thicknesses were measured at baseline PRE, POD 1, and POD 7.
Retinal Microvasculature Imaging
The retinal vessels were imaged using a 3 × 3 mm scan on a high-definition OCT device (Figure 2). It acquires the retinal vasculature using a scan rate of 68 000 A-scans per second with an optical source centered at a wavelength of 840 nm and a bandwidth of 90 nm. The OCTA images are generated by analyzing differences in both the intensity and phase information between a number of B-scan images acquired at the same locations. Angiographic images of the superficial vascular plexus (SVP) and deep vascular plexus (DVP) were exported for further processing. To measure the vessel area density (VAD), a custom Matlab (Mathworks, Inc.) software program was used to extract the vessels using a series of image-processing procedures as described previously.24–26 OCTA images were standardized, cropped, and binarized. In each binary image, large vessels were defined as vessels with a diameter of 25 µm or larger, whereas the remaining vessels were defined as small vessels. The small vessels of the SVP and DVP were analyzed. The annulus from 0.6 to 2.5 mm was analyzed. The VAD was calculated as a unitless proportion of the total image area occupied by the detected OCTA signal (binarized as white pixels) compared with the total area of the retina (the total number of pixels). Skeletonized images were created by iteratively deleting the pixels in the outer boundary of the binarized, white-pixelated vasculature unit 1 pixel remained along the width direction of the vessels. The vessel skeleton density (VSD) was calculated based on the skeletonized images. The vessel diameter index, which represents the average vessel caliber, was calculated by dividing the total vessel area in the binarized image by the total vessel length in the skeletonized image.27 Fractal dimension (Dbox) of each skeletonized image could then be calculated by using a fractal analysis toolbox (TruSoft Benoit Pro 2.0; TruSoft International, Inc.). OCTA images were measured at baseline PRE, POD 1, and POD 7. Images of poor quality were excluded from the current study.
Statistical analysis was performed using IBM SPSS Statistics for Windows software (version 25, IBM Corp.). The Shapiro-Wilks test was used to test the data normality. Generalized estimating equation models (repeated measures) were conducted to evaluate the variations in each group at different time points: PRE, POD 1, and POD 7. Pearson correlation coefficients were used to evaluate the linear correlation between changes in corrected IOP and retinal neurovasculature parameters. All data were presented as mean ± SD, and P values less than .05 were considered statistically significant.
Study Population and Baseline Clinical and Structural Parameters
Thirty-eight eyes of 38 myopic patients were included. The mean age of the patients was 28.1 ± 4.9 years. The mean spherical equivalent of the patients was −4.71 ± 1.50 D. Baseline demographic and clinical data are shown in Table 1.
Clinical and Structural Parameters After SMILE
All patients had a significant improvement in UDVA and no loss of CDVA at the final follow-up (POD 7). No patient experienced any serious adverse events. Slitlamp examination showed there was no clinically significant corneal edema at POD 1 and POD 7.
Compared to baseline, the patients had decreased Km (P < .05), decreased central corneal thickness (P < .05), and decreased corneal volume (P < .05) (Table 2). Although the cornea was slightly thicker at POD 1 than at POD 7, there was no significant difference in corneal volumes at POD 1 and POD 7. The patients showed an increase in the GCIPL thickness after SMILE at POD 1 and POD 7 (P < .05) (Figure 3). Compared to baseline, superior temporal, superior, superior nasal, inferior, and inferior temporal quadrants of the GCIPL thickness were significantly increased at POD 1 (Table 3). At POD 7, each quadrant of the GCIPL thickness reverted to the baseline level except the superior nasal quadrant (P < .05). As shown in Figure 4, the VAD, VSD, and Dbox of the SVP and DVP were decreased at POD 1 in both groups (P < .05), but not at POD 7. As shown in Figure 5, the VDI in total vessels of the DVP was increased at POD 7 (P < .05), and the VDI in small vessels of the SVP and DVP was decreased at POD 1 (P < .05). Compared to PRE, the VDI in big vessels of the DVP at POD 1 and POD 7 was decreased (P < .05). As shown in Figure 6, the Dbox of the SVP and DVP were decreased at POD 1 in both groups (P < .05), but not at POD 7. Representative patient images at various time points, PRE, POD 1, and POD 7, are shown in Figure 7.
Correlations Between Clinical and Structural Parameters
Correlational analyses were performed between changes in clinical (corrected IOP and logarithm of the minimum angle of resolution) and structural OCTA (layer thickness, VAD, VSD, and Dbox) parameters at various time points, PRE, POD 1, and POD 7. Changes in corrected IOP were not significantly correlated with changes in the pRNFL thickness (r = 0.039, P = .738). Changes in corrected IOP were positively correlated with changes in the GCIPL thickness (r = 0.385, P = .001), negatively correlated with changes in the VAD of small vessels in the DVP (r = −0.300, P = .008), and negatively correlated with changes in the Dbox of total vessels in the DVP (r = −0.348, P = .002). Changes in corrected IOP were negatively correlated with the VSD of small vessels in the DVP (r = −0.231, P = .045). Changes in corrected IOP were negatively correlated with the VDI of big vessels in the SVP (r = −0.240, P = .037) and the VDI of small vessels in the DVP (r = −0.291, P = .011) (Table 4).
OCTA is a noninvasive imaging modality based on OCT that allows for the visualization of functional blood vessels in the eye by using the variable backscattering of light from different static structural tissues and moving particles (ie, red blood cells). The images obtained from OCTA are essentially motion-contrast images of such high-resolution that they approach a histological level of resolution. Because of the degree of high-resolution images that OCTA can provide, this imaging modality can provide in-depth information about the retinal neurovasculature. This unprecedented resolution coupled with the simple, fast, and noninvasive nature of this imaging platform has allowed a host of basic and clinical research applications.28
Studies have demonstrated that OCTA is subject to low intravisit and intervisit flow index variability as well as good repeatability of vessel density measurements.29,30 In the current study, OCTA was performed by the same technician who had been trained well. Patients with poor images were excluded. In addition, the vascular parameters were measured in a circular area (ϕ 2.5 mm) centered on the fovea, which decreases variability because of motion and macular area tilt between tests.30
This study quantitatively characterized the retinal neuro-vasculature in patients with myopia after SMILE using OCTA. To our knowledge, this is the first study to directly evaluate the transient fluctuations of the retinal neurovasculature after SMILE. All patients had a significant improvement in UDVA and no loss of CDVA at the final follow-up, which indicated that the patients had good visual acuity outcome and no serious adverse effect after SMILE surgery. In this study, we used OCTA to objectively measure retinal neural structures (GCIPL and the pRNFL) and retinal vascular perfusion in the SVP and DVP at baseline and up to a week after SMILE surgery.
Because of the various degrees of degenerative alterations in the retinas of myopic patients and the susceptibility of this population to chronic open-angle glaucoma, the risk of retinal complications of SMILE in myopic patients is increased. Most studies have focused on the effect of corneal refractive surgery on nerve fiber loss, particularly in the GCIPL and pRNFL (Table 5).31–37 However, studies to date have failed to demonstrate a significant decrease in the pRNFL or GCIPL thickness after refractive surgery when compared with baseline. In agreement with previous studies, our results confirmed previous findings that the transient IOP increase during the flap preparation was unlikely to create consequent loss of retinal nerve fibers. By contrast, our study found that the thickness of the GCIPL was transiently increased after SMILE surgery. It is possible that acute high IOP can cause axoplasmic flow disorder in retinal ganglion cells, causing cell dysfunction or death, which could cause the thickness of the GCIPL to transiently increase after SMILE surgery during the early stages.22,38
IOP fluctuations during refractive surgery, including LASIK, FS-LASIK, and SMILE,39–43 can cause ocular complications, especially in the retina. A potential source of damage to the vitreous and retina is from the pulsed energy applied to the cornea. When the suction ring induces an elevation in IOP that is then suddenly released, the anterior segment is quickly drawn into a vacuum chamber with subsequent rapid shape deformation. All structures posterior to the suction ring are also rapidly compressed and decompressed in sequence. Intraoperative vacuum suction caused by transient elevated IOP may cause optic nerve and retinal circulatory ischemia, and the sudden drop of IOP after stopping the suction may cause ischemia–reperfusion dysfunction.44,45 Transient changes in retinal hemodynamics may cause vascular endothelial spasm or dysfunction.17,38
Significant alterations in retinal hemodynamics after SMILE surgery appear to be mediated by fluctuation in IOP. Specifically, the vessel density (VAD, VSD, and Dbox) and vessel caliber (VDI) in the SVP and DVP were decreased at POD 1, likely in response to surgical factors such as IOP elevation during flap preparation. These effects appeared to be transient in nature at POD 1. During the capillary reperfusion procedure, the VDI of small vessels in both the SVP and DVP was increased at POD 7, and the VDI of big vessels in the DVP was decreased at POD 7. The dynamic regulation of the vessel density and vessel caliber between small and big vessels also demonstrated the retinal hemodynamics during transient ischemia–reperfusion spasm after suction.
Although the changes in the retinal neurovasculature were attributed to IOP changes during refractive surgery, other factors may also affect the retinal neurovasculature during and after SMILE. Liu et al. found that approximately 34% of eyes had corneal edema immediately after SMILE. However, all eyes in this series had a resolution of this edema within 6 hours to 24 hours.46 In agreement with this finding, the current study did not observe any operative corneal edema at POD 1 and POD 7. Although frank postoperative edema was not observed, the corneal thickness was slightly higher at POD 1 than at POD 7. In animal models, keratocyte death and proliferation, inflammatory infiltration, and extracellular matrix remodeling predominately take place during the first POD after refractive surgery.47,48 Compared to LASIK, the SMILE procedure elicits virtually identical and minimal keratocyte activation, cell death, and inflammation.49 During corneal wound healing, inflammation responses may affect corneal ultrastructure, which may cause the changes in densitometry of the cornea. Thus, inflammation responses during corneal wound healing may contribute to vessel density reduction at POD 1. Further studies may be necessary to more clearly elucidate the cause of these transient retinal neurovasculature changes.
As with all studies, our findings must be considered in light of its limitations. First, although the present study demonstrated reversible fluctuations in the retinal neurovasculature in myopic patients after SMILE, this should be repeated with a larger sample size. Second, the alterations in the corneal curvature and corneal edema might influence the accurate measurement of the retinal parameters. Third, we did not measure the intraoperative IOP or immediate postoperative IOP, which may have more significant clinical relevance of the changes in IOP between retinal neurovasculature parameters. The final limitation is the lack of longer follow-up to truly show return to baseline. Long-term alterations in the retina need to be further explored in the future.
In summary, this study demonstrated surgical-related fluctuations in the retinal neurovasculature in patients with myopia after SMILE. The transient reversible fluctuations in the retinal neurovasculature may represent a characteristic pattern of homeostasis in patients after refractive surgery. Our findings may lead to further validation for using the retinal neurovasculature in clinical research aimed at the detection and monitoring of the retinal neurovasculature after refractive surgery, which could provide a predictor model for evaluating the retinal safety of refractive surgery.
WHAT WAS KNOWN
- Myopia is projected to affect 50% of the world's population by 2050. Small-incision lenticule extraction (SMILE) has gained widespread acceptance. The effect of SMILE on the retinal neurovasculature remains unexplored.
WHAT THIS PAPER ADDS
- There are transient retinal neurovasculature fluctuations after SMILE. Changes in the ganglion cell-inner plexiform layer thickness were positively correlated with changes in corrected intraocular pressure (IOP). Changes in the vasculature of the superficial vascular plexus and deep vascular plexus were negatively correlated with changes in corrected IOP.
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