Changes in macular vasculature after uncomplicated phacoemulsification surgery: Optical coherence tomography angiography study

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ARTICLE

Changes in macular vasculature after uncomplicated phacoemulsification surgery: Optical coherence tomography angiography study Zhennan Zhao, MD, PhD, Wen Wen, MD, PhD, Chunhui Jiang, MD, PhD, Yi Lu, MD, PhD

Purpose: To use optical coherence tomography (OCT) angiography and a split-spectrum amplitude–decorrelation angiography algorithm to evaluate the changes in the macular vascular system after uncomplicated phacoemulsification.

Setting: Department of Ophthalmology, Eye and and Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China. Design: Prospective case series. Methods: Patients with senile cataracts were included. Retinal vessel density and thickness at the macular area were checked by OCT at baseline and at 1 week, 1 month, and 3 months after cataract surgery. Results: Thirty-two eyes (32 patients) were included in the final analysis. There was a significant increase in retinal vessel density, a decrease in the foveal avascular zone at the macular area after the cataract surgery (all P < .05, repeated-measures

C

ataract removal using phacoemulsification is one of the most common ophthalmic surgical procedures, usually resulting in a significant improvement in vision quality for elderly patients.1 Hilton et al.2 reported that ocular blood flow improved after cataract surgery, and they suggested that this improvement might be beneficial for eyes. However, their study focused on pulsatile ocular blood flow, which comes mainly from the choroid.2,3 Therefore, cataract surgery’s effects on the retinal vascular system are still not clear.

analysis of variance), and an increase in full and inner macular thickness, all of which extended to the end of the follow-up period. At 3 months postoperatively, there was a mean 6% and 3% increase in vessel density at the parafoveal and perifoveal regions, respectively, and a mean 27% reduction in the foveal avascular zone. The mean increase in inner retinal thickness was 15%, 10%, and 7% at the fovea, parafovea, and perifovea, respectively. Compared with the parafovea and perifovea, the fovea had a much higher percentage of change in retinal vasculature and inner retinal thickness (all P < .001).

Conclusions: Macular vessel density and thickness increased after cataract surgery. Whether these changes will persist over a longer period still needs to be studied. J Cataract Refract Surg 2018; -:-–- Q 2018 ASCRS and ESCRS

Supplemental material available at www.jcrsjournal.org.

Optical coherence tomography (OCT) is a noninvasive imaging technique that is used worldwide in the daily practice of ophthalmology. Jia et al.4 recently described a new method using high-speed OCT and a split-spectrum amplitude–decorrelation angiography algorithm to perform quantitative angiography of the retina. Previous studies have shown that OCT angiography with splitspectrum amplitude–decorrelation angiography offers results with good repeatability and reproducibility.5,6 This study was performed to evaluate the changes in retinal

Submitted: June 18, 2017 | Final revision submitted: January 30, 2018 | Accepted: February 5, 2018 From the Department of Ophthalmology and Vision Science (Zhao, Wen, Jiang, Lu), Eye and Ear, Nose, and Throat Hospital, Fudan University, Key Laboratory of Myopia of State Health Ministry and Key Laboratory of Visual Impairment and Restoration of Shanghai (Zhao, Wen, Jiang, Lu), and the Department of Ophthalmology (Jiang), Number 5 People’s Hospital of Shanghai, Shanghai, China. Drs. Zhao and Wen contributed equally to this work. Supported by research grants from the National Natural Science Foundation of China (Grant No. 81270989 and Grant No. 81200669) and the Scientific Research Program, Science and Technology Commission of Shanghai Municipality, Shanghai, China (Grant 14430721100). Corresponding authors: Yi Lu, MD, PhD and Chunhui Jiang, MD, PhD, Department of Ophthalmology and Vision Sciences and Key Laboratory of Myopia of State Health Ministry, Eye and ENT Hospital, Shanghai Medical College, Fudan University, 83 Fenyang Road, Shanghai 200031, China. Dr. Lu’s E-mail: [email protected]; Dr. Jiang’s E-mail: [email protected]. Q 2018 ASCRS and ESCRS Published by Elsevier Inc.

0886-3350/$ - see frontmatter https://doi.org/10.1016/j.jcrs.2018.02.014

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MACULAR VASCULATURE CHANGES AFTER CATARACT SURGERY

vasculature, especially macular vasculature, after uncomplicated phacoemulsification. PATIENTS AND METHODS Patients Patients were enrolled in this study from a tertiary eye clinic between December 2014 and April 2015. Cataract patients who planned to have phacoemulsification surgery with intraocular lens (IOL) implantation were enrolled. If both of the patient’s eyes qualified for the study, only the eye that was operated on first was enrolled. This study was approved by the Institutional Review Board and followed the tenets of the Declaration of Helsinki. All patients signed informed consent forms. All patients had complete ophthalmologic examinations, including the measurement of corrected distance visual acuity (CDVA) in logarithm of the minimum angle of resolution (logMAR), the measurement of intraocular pressure (IOP) with a noncontact tonometer, the measurement of axial length (AL) with partial coherence interferometry (IOLMaster), a slitlamp biomicroscopy, cataract grading with the Lens Opacities Classification System III,7 and a dilated fundus evaluation using a 3-mirror contact lens. Blood pressure was also measured and the mean arterial pressure was calculated as the diastolic blood pressure plus one third of the difference between the diastolic and the systolic blood pressure. The ocular perfusion pressure was determined by subtracting the IOP from two thirds of the mean arterial pressure. Each patient’s medical and family histories were also collected. The inclusion criteria for the study were the presence of a nuclear or cortical cataract (without a posterior subscapular or posterior polar cataract) with no concomitant intraocular disease, IOP of 21 mm Hg or lower, and an AL between 20.0 mm and 25.0 mm. Eyes with an AL longer than 25.0 mm or shorter than 20.0 mm, IOP higher than 21 mm Hg, a history of ocular trauma or intraocular surgery, or any abnormal intraocular findings were excluded. Poor OCT images because of severe cataracts or unstable fixation or any signs of intraoperative or postoperative complications were also grounds for exclusion. Optical Coherence Tomography Data Acquisition and Processing Optical coherence tomography angiography scans were obtained with the spectral domain system RTVue-XR Avanti (Optovue, Inc., software version: 2014.2.0.65). The macular area was covered by 6.0 mm  6.0 mm OCT angiography scans. En face retinal angiograms were created by projecting the signal from the inner limiting membrane (ILM) to the retinal pigment epithelium (RPE). For each patient, images with a signal strength index more than 40 and no residual motion artifacts were saved and used for further analysis.4,8 The foveal avascular zone was outlined and measured as previously described9 using ImageJ softwareA (Figure 1, A and B). During further analysis, the parafoveal region was defined as an annulus with an outer diameter of 3.0 mm and an inner diameter of 1.0 mm, and the perifoveal region was defined an annulus with an outer diameter of 5.0 mm and an inner diameter of 3.0 mm (Figure 1, C and D). The vessel density of these 2 areas was automatically provided by the OCT system. Macular Retinal Thickness Retinal thickness was obtained by the same OCT system at the same time as the retinal vasculature using the retina map mode, which covered a 6.0 mm  6.0 mm area centered at the fovea. The full retinal thickness was measured from the ILM to the middle of the RPE–Bruch membrane complex. The retina between the ILM and the outer boundary of the IPL was defined as the inner retina, and the retina between the outer boundary of the IPL and the middle of the RPE–Bruch membrane complex was defined as the outer retina. Retinal thickness referred to the mean thickness of that specific area. The fovea is the 1.0 mm ring area at Volume - Issue - - 2018

Figure 1. Measurements of the area of the foveal avascular zone (A and B) and vessel density of the macular region (C and D). The scan area is 6.0 mm  6.0 mm; A and C and B and D represent as baseline and 3 months postoperatively, respectively. The foveal avascular zone area is 0.50 mm2 and 0.39 mm2 for A and B, respectively. The vessel density at the parafovea (the annulus area between the red and green circles) is 62% and 67% for C and D, respectively; the vessel density at the perifovea (the annulus area between the green and yellow circles) is 63% and 67% for C and D, respectively. The diameter of red, green, and yellow circles is 1.0 mm, 3.0 mm, and 5.0 mm, respectively.

the center, and the parafovea and perifovea were defined in the same way that they were in the OCT angiogram. The OCT system automatically provided the mean full, inner, and outer retinal thicknesses of the 3 areas. The measurements of the OCT, AL, IOP, and CDVA were obtained before the phacoemulsification surgery. Optical coherence tomography, CDVA, and IOP measurements were also obtained 1 week, 1 month, and 3 months after surgery. To avoid the effects of diurnal variations, all measurements were obtained between 9:00 AM and 12:00 AM. Surgical Technique The cataract surgeries were performed using the Infinity Vision System (Alcon Laboratories, Inc.). Briefly, after topical anesthesia was administered, a 2.2 mm clear corneal self-sealing incision, continuous capsulorhexis, hydrodissection, phacoemulsification, and irrigation/aspiration of the residual lens cortex were sequentially performed. A foldable IOL (Tecnis ZCB00, Abbott Medical Optics, Inc.) was then implanted in the capsular bag. The effective phacoemulsification time (in seconds) and phacoemulsification energy (percentage) of the phacoemulsification machine were documented. Postoperative treatment consisted of prednisolone acetate 1.0% and levofloxacin 0.5% eyedrops administered 4 times a day for 2 weeks, and diclofenac sodium 0.1% eyedrops administered 4 times a day for 1 month. Statistical Analysis Statistical analyses were performed using SPSS for Mac software (version 20.0, IBM Corp.). The preoperative and postoperative measurements were compared using repeated measures analysis of variance tests with Bonferroni corrections. Pearson correlation

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analyses were performed to determine the relationships between the magnitude of the changes in retinal vasculature parameters from baseline to each timepoint and related factors. A P value less than 0.05 was considered statistically significant.

RESULTS Thirty-three eyes of 33 patients with senile cataract fulfilled the assessment visits at baseline and after surgery. One patient (3.03%) developed pseudophakic cystoid macular edema (CME) postoperatively and was excluded from further analysis. As a result, 32 eyes (32 patients [14 men, 18 women]) were included in the final analysis. The patients’ mean age was 66.25 years G 8.54 (SD), the mean AL was 23.26 G 1.12 mm, the mean nuclear opalescence was 1.71 G 0.47, the mean CDVA was 0.447 G 0.192, the mean effective phacoemulsification time was 39.48 G 18.38 seconds, and the mean phacoemulsification energy was 34.96% G 20.55%. After the cataract surgery, the CDVA was significantly improved and IOP decreased (all P ! .01) (Table S1, available at: http://jcrsjournal.org), whereas the mean arterial pressure and ocular perfusion pressure remained unchanged during all visits. At 3 months postoperatively, the mean decrease in IOP was 2.80 G 1.12 mm Hg. An increase in retinal thickness was found. At 1 month and 3 months after surgery, the full retinal thickness of the fovea, parafovea, and perifovea increased significantly (all P ! .05) (Table 1). This change was mainly confined to the inner layer. At 1 month and 3 months postoperatively, the inner retinal thickness in these 3 areas increased significantly (all P ! .0001) (Table 1), whereas the outer retinal thickness remained almost unchanged except for a slight decrease in the parafoveal and perifoveal regions 1 month after surgery (P Z .0295 and P Z .0366, respectively) (Table 1). At 3 months postoperatively, the mean increase in inner retinal thickness was 9.88 G 4.68 mm, 10.71 G 7.47 mm, and 7.53 G 4.17 mm (15% G 8%, 10% G 7%, and 7% G 4%) at the fovea, parafovea, and perifovea, respectively. There was also a significant change in the retinal vasculature. The retinal vessel density of the parafoveal and

perifoveal regions increased significantly at 1 week, 1 month, and 3 months after the cataract surgery (Table 2) (all P ! .05). At 3 months after surgery, there was a mean 6% G 11% and 3% G 10% increase in vessel density at the parafoveal and perifoveal regions, respectively (compared with the baseline). The foveal avascular zone decreased significantly at 1 week, 1 month, and 3 months after surgery (all P ! .05) (Table 2) and at 3 months after surgery, the mean reduction in the foveal avascular zone was 27% G 11%. The changes in retinal vasculature and thickness differed at different parts of the macula. Compared with the parafovea and the perifovea, the fovea had a much higher percentage of change in retinal vasculature and a greater increase in inner retinal thickness (P ! .001) (Table 3). The changes in retinal vasculature correlated with neither the changes in full, inner, nor outer retinal thickness at any regions at any timepoint nor with other factors such as age, sex, AL, effective phacoemulsification time/energy, or changes in CDVA, IOP, ocular perfusion pressure, and mean arterial pressure (Table S2, available at http://jcr sjournal.org). DISCUSSION In this study, the change in retinal vasculature at the macular area after cataract surgery was studied. A significant increase in vessel density at the parafovea and perifovea regions and a decrease in the foveal avascular zone were found after cataract surgery. An increase in macular thickness, which was mainly at the inner retina, was also recorded. These changes remained for at least 3 months after surgery. Various techniques have been used in several studies to assess blood flow in the large retinal vessels after cataract surgery, although inconsistent outcomes have been observed.10–12 Furthermore, the approaches they applied have their limitations and they only measured the blood flow in large retinal vessels but not local microcirculation in the eye. Although Doppler OCT has been able to obtain measurement of total retinal blood flow, it is not sensitive enough

Table 1. Macular thickness of the 32 eyes at baseline and 3 postoperative timepoints. Mean Macular Thickness (mm) ± SD Parameter Full Layer Fovea Parafovea Perifovea Inner Layer Fovea Parafovea Perifovea Outer Layer Fovea Parafovea Perifovea

Baseline

1 Wk Postop

1 Mo Postop

3 Mo Postop

252.8 G 16.69 318.0 G 11.30 291.1 G 12.95

250.8 G 14.79 316.4 G 10.65 288.1 G 12.48

256.4 G 16.39 322.1 G 10.68 293.4 G 12.99

266.2 G 13.99 331.1 G 18.45 302.8 G 10.59

64.4 G 7.59 115.6 G 6.97 107.9 G 6.24

66.4 G 9.06 115.6 G 6.96 110.8 G 5.81

71.1 G 10.01 127.2 G 5.79 116.1 G 6.39

74.2 G 9.58 126.3 G 6.64 115.5 G 6.32

188.2 G 11.13 202.2 G 11.88 182.9 G 10.14

184.9 G 9.22 199.6 G 10.18 178.9 G 8.97

185.2 G 8.69 194.8 G 10.37 177.1 G 9.582

189.5 G 8.06 203.6 G 11.73 186.8 G 10.45

P Value

Bonferroni Post Hoc Test

.0004 .0004 .0006

3 Mo O 1 Mo O1 Wk/Baseline 3 Mo O 1 Mo O1 Wk/Baseline 3 Mo O 1 Mo O1 Wk/Baseline

!.0001 !.0001 !.0001

3 Mo O 1 Mo O1 Wk/Baseline 3 Mo/1 Mo O1 Wk/Baseline 3 Mo/1 Mo O1 Wk/Baseline

.0734 .0295 .0366

d 1 Mo ! 3 Mo/1 Wk/Baseline 1 Mo ! 3 Mo/1 Wk/Baseline

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Table 2. Retinal vessel density and foveal avascular zone areas in the 32 eyes at baseline and 3 postoperative timepoints. Parameter Mean vessel density (%) G SD Parafovea Perifovea Mean foveal avascular zone (mm2) G SD

Baseline

1 Wk Postop

1 Mo Postop

3 Mo Postop

P Value

Bonferroni Post Hoc Test

61.59 G 7.75 62.88 G 8.22 0.569 G 0.112

63.12 G 7.46 66.65 G 6.83 0.487 G 0.128

66.76 G 6.70 66.76 G 7.76 0.441 G 0.126

65.12 G 9.45 64.65 G 9.37 0.417 G 0.112

.0281 .0126 !.0001

3 Mo/1 Mo/1 Wk O Baseline 3 Mo/1 Mo/1 Wk O Baseline 3 Mo/1 Mo ! 1 Wk ! Baseline

to accurately measure the flow of small vessels.5 Jia et al.4 recently described a new method of measuring local circulation using high-speed OCT to perform quantitative angiography. With the use of the split-spectrum amplitude–decorrelation angiography algorithm, flow in the macular can be quantified. Optical coherence tomography angiography with split-spectrum amplitude– decorrelation angiography is capable of measuring both macrocirculation and microcirculation (down to capillaries).4,5 This allows the OCT angiography to measure the microcirculation of specific regions of the eye. Wei et al.5 reported that this technique could measure macular flow in normal patients with excellent repeatability (1.3% intravisit and 2.1% intervisit coefficients of variation, respectively). The changes in retinal vasculature at the macula were documented via OCT angiograms after uncomplicated phacoemulsification. One might question whether cataracts would affect the OCT measurements. Amplitude decorrelation can be considered a metric for measuring fluctuations in the backscattered OCT signal amplitude (intensity) that does not depend on the mean signal level. In addition, all patients included had mild to moderate cataract (mean nuclear opalescence Z 1.71 G 0.47), and the quality of all OCT images was well screened (mean signal strength index baseline Z 53.00 G 7.22); thus, the results of this study should be reliable. The reason for the changes in retinal vasculature was not fully clear. One possibility was the decreases in IOP. Hilton et al.2 reported increased pulsatile ocular blood flow after cataract surgery; they thought that this increase was attributed to the 2.7 mm Hg (16.7%) decrease in IOP. Previously, Grunwald et al.13 reported that a drop in IOP could lead to a significantly faster leukocyte speed in the macula, and Weigert et al.14 reported that fundus pulsation amplitude decreased with an increase in IOP. Therefore, the mean

3 mm Hg (19.7%) decrease in IOP found in our group of patients could have contributed to the change in macular vasculature. However, other reasons should also be considered. One reason for the change might be postoperative inflammation. It was reported that the expression of proinflammatory genes and proteins, such as chemokine ligand 2 and interleukin-1b, were markedly upregulated and strongly detected in the neurosensory retina from mice that had lens extractions.15 These cytokines were reported to cause vessel dilation and a breakdown of the blood–retinal barrier.15–18 The CME case in our series was also in agreement with the elevation of inflammatory cytokines. It was reported that flare in the anterior chamber usually returns to baseline 1 month after surgery19,20; however, Zhu et al.21 reported elevated cytokines in the anterior chamber of the contralateral eye 1 month after cataract surgery. Therefore, the cytokines in operated eyes might remain elevated for even longer than 1 month. Another possible reason for the change in macular vasculature could be the increase in light exposure after cataract surgery. It has been estimated that a cataract might block 18% to 40% of light at different wavelengths.22 The increased light exposure after cataract removal has been proposed as one of the reasons for the relatively high incidence of age-related macular degeneration found in eyes that previously had cataract surgery.23,24 Whether increased light exposure could also lead to increased activity and more metabolic demands in the retina was not clear. Although the assertion that the retina requires more oxygen in the dark is generally accepted,25 the effect of increased light exposure, rather than a change from dark to light, on retinal oxygen demand was not clear. Hardarson et al.25 assessed this topic; however, the results of their study were inconclusive.

Table 3. Changes in retinal vasculature and thickness at different parts of the macula in the 32 eyes at 3 months postoperatively. Mean Change (%) ± SD Parameter Vasculature Macular thickness Full layer Inner layer

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Fovea

Parafovea

Perifovea

P Value

27 G 11

6 G 11

3 G 10

!.001

6G6 15 G 8

4G5 10 G 7

4G5 7G4

.663 .001

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Future research should be able to tell us more about this topic. Increases in macular thickness, which were mainly confined to the inner layer, were also observed 1 month after surgery and this increase remained 3 months after surgery (all P ! .01). This result was in accordance with the change in retinal vasculature, which was mainly located at the inner retina26 observed at this time. The increase of retinal thickness after cataract removal had been reported by others and was suggested to result from the breakdown of the blood–retinal barrier.27–29 However, the dilation of retinal vasculature and the opening of more retinal capillaries at the same time could also contribute to this result. We also found that the change in retinal vasculature and thickness differed at different parts of the macula. Lobo et al.30 reported that increase in retinal thickness after cataract surgery was located primarily in the central foveal area. This time we found that in addition to the increase in retinal thickness, the largest change in retinal vasculature was also located at the fovea. Although the area of the foveal avascular zone and vessel density did not share the same dimensions, the foveal avascular zone implies the nonvascularized area, therefore both measurements indicate the area of vessels in some way. The reason for the differences in different parts of the macula is not fully understood. The high metabolism and unique vascular pattern at the fovea might be involved. On the other hand, the highest changes in retinal vasculature and thickness were both found at the fovea and the photopic vision is fulfilled by cones, which are also mainly located at the fovea. This agreement in location might support our hypothesis that the increase of light exposure could contribute to the changes in retinal vasculature observed in this study. Hilton et al.2 reported increased pulsatile ocular blood flow after cataract surgery and they thought it could be beneficial for the eye. The increase in retinal vessels at the macular area after cataract removal was also recorded in our study; however, whether this is beneficial or could actually contribute to the development or progression of diabetic retinopathy,31,32 which has often been observed after cataract surgery, remains unclear. One limitation of this study is that whether and when the increased macular retinal vessel density and thickness will return to baseline levels, such as 12 months or more after surgery, is still unclear. Therefore, further investigations with a longer follow-up should be considered. In addition, evaluating the underlying mechanisms will be of great importance and interest. After cataract surgery, the retinal vessels at the macula increased significantly, and this increase was accompanied by an increase in inner macular thickness. Whether such changes might affect the retina in the long term still needs to be verified.

WHAT WAS KNOWN  Increases in macular thickness are detectable by several methods during the postoperative periods after cataract surgery. However, retinal vascular data regarding the effects of cataract surgery on the retina are limited.  Optical coherence tomography angiography with splitspectrum amplitude–decorrelation angiography can quantify retinal vascularization and offers results with good repeatability and reproducibility.

WHAT THIS PAPER ADDS  Senile cataract surgery increased the vessel density at the parafoveal and perifoveal areas and decreased the foveal avascular zone. An increase in macular thickness, which was mainly at the inner retina, was also detected. These changes remained for at least 3 months after surgery.  Detecting such changes by a high-speed swept-source OCT with the split-spectrum amplitude–decorrelation angiography algorithm was helpful toward understanding clinical findings in eyes after cataract surgery.

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Disclosures: None of the authors has a financial or proprietary interest in any material or method mentioned.