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Pseudophakic cystoid macular edema and spectral-domain optical coherence tomography–detectable central macular thickness changes with perioperative prostaglandin analogs Andrew Walkden, MB ChB, Louise F. Porter, MB ChB, Jiten Morarji, MB ChB, Simon P. Kelly, FRCOphth, Evangelos Sioras, FRCOphth

Purpose: To define the incidence of cystoid macular edema (CME) and spectral-domain optical coherence tomography– detectable (SD-OCT) subclinical changes in central retinal thickness in patients using prostaglandin analog (PGA) eyedrops after phacoemulsification. Setting: Manchester Royal Eye Hospital, Manchester, United Kingdom.

Design: Prospective case series. Methods: A consecutive analysis of the incidence of postoperative CME after phacoemulsification by a single surgeon was performed in eyes of patients using PGA eyedrops between March 2010 and January 2014. The presence of CME was determined using SD-OCT (Cirrus) 3 weeks and 6 weeks postoperatively. Exclusion criteria included preexisting pathology known to predispose to CME and previous ophthalmic surgery. The paired Wilcoxon signed-rank test was used to compare central retinal

C

ystoid macular edema (CME) is a significant complication of modern cataract surgery and a primary cause of postoperative reduced vision. Reported incidences vary widely, ranging from 0.1% to 2.35%.1–3 The peak incidence occurs approximately 4 to 6 weeks postoperatively.4 Cystoid macular edema is characterized by thickening of the central retina resulting from fluid accumulation in the outer plexiform layer and abnormal perifoveal retinal capillary permeability. Differing definitions of CME make it difficult to determine accurately its incidence.1,5 Cystoid macular edema is divided into clinical CME, associated with decreased visual acuity, and angiographic CME,

thickness measurements at baseline and 3 weeks and 6 weeks postoperatively.

Results: All 48 patients (mean age 78.4 years; 60 eyes) had uneventful surgery. There were no cases of clinically significant CME. Subclinical CME detected by SD-OCT was confirmed in 2 eyes of different patients (3.3% of eyes), 1 eye 3 weeks postoperatively and another eye at 6 weeks. Subclinical CME resolved in both cases within 8 weeks. In both cases, the difference in central retinal thickness at baseline and 6 weeks postoperatively was statistically significant (P < .05).

Conclusions: The incidence of subclinical CME detectable on SD-OCT after routine phacoemulsification in patients using PGA eyedrops throughout the perioperative period was 3.3%. There were no cases of clinical CME. These findings might guide clinicians in their decision to use PGAs perioperatively. J Cataract Refract Surg 2017; 43:1027–1030 Q 2017 ASCRS and ESCRS

referring to CME without visual loss detected on fluorescein angiography. Cystoid macular edema can also be detected using optical coherence tomography (OCT).1 Spectral-domain OCT (SD-OCT) provides a safe and noninvasive objective imaging modality for quantifying clinical CME and subclinical CME.4,6 An increase in macular thickness that is not clinically symptomatic or detectable by slitlamp biomicroscopy has been noted using OCT after cataract surgery.7–9 Subclinical CME that does not result in visual impairment and is characterized by perifoveal edema and cystic spaces on SD-OCT has been described after uneventful phacoemulsification surgery in several studies.10,11

Submitted: February 27, 2017 | Final revision submitted: April 8, 2017 | Accepted: May 20, 2017 From Royal Bolton Hospital, Bolton (Walkden, Porter, Morarji, Kelly, Sioras) and the Department of Eye and Vision (Porter), Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom. Presented at the XXXIII Congress of the European Society of Cataract and Refractive Surgeons, Barcelona, Spain, September 2015. Corresponding author: Andrew Walkden, MB ChB, Manchester Royal Eye Hospital, Oxford Road, Manchester M13 9WL, United Kingdom. E-mail: walkdenandrew@ gmail.com. Q 2017 ASCRS and ESCRS Published by Elsevier Inc.

0886-3350/$ - see frontmatter http://dx.doi.org/10.1016/j.jcrs.2017.05.029

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Figure 1. Selection criteria (PGA Z prostaglandin analog; POAG Z primary open-angle glaucoma; SD-OCT Z spectraldomain optical coherence tomography).

Several ocular and systemic risk factors are known to contribute to the development of pseudophakic CME,5 and an increased risk has been reported in patients using a prostaglandin analog (PGA) eyedrop for glaucoma or ocular hypertension during the perioperative period.6,12–14 A large recent retrospective study3 was unable to associate an increased incidence of pseudophakic CME with PGA eyedrop use. Some authors advocate discontinuing PGAs in the perioperative period, in particular in patients deemed to be at higher risk for developing postoperative CME, including those with preexisting medical pathologies. These include previous retinal vein occlusion, uveitis, epiretinal membrane, and/or diabetes.15 To our knowledge, there are no prospective studies evaluating the incidence of CME in patients having phacoemulsification and IOL implantation while concurrently being treated with PGAs. Large variability in practice is observed in the United Kingdom with regard to PGA use during the perioperative period. Ahad and Mckee’s questionnaire study on behalf of the Royal College of Ophthalmologists16 found that 60% of surgeons continue PGAs during the perioperative period. Given the high volume of cataract surgery performed in the U.K., the high prevalence of glaucoma, and therefore the widespread use of PGAs in this patient demographic, there is clearly a need to determine the safety profile of PGAs in the period after routine cataract surgery. We sought to objectively determine, using clinical and SD-OCT imaging modalities, whether PGA use in the perioperative period was associated with an increased rate of postoperative clinical and subclinical CME development in a patient cohort using PGA eyedrops. PATIENTS AND METHODS Although no formal ethical review was required, approval for the study was granted by the local ethics committee review board. All patients provided written consent for cataract surgery in the format developed by the Royal College of Ophthalmologists and were provided with additional information about this study. Patients having routine phacoemulsification surgery with posterior chamber intraocular lens (IOL) insertion and receiving a Volume 43 Issue 8 August 2017

topical PGA were studied prospectively between March 1, 2010, and the January 1, 2014. The same consultant surgeon (E.S.) performed all cataract surgeries. All eyes included in the study were diagnosed with visually significant cataract that permitted a clear view of the fundus and were using a topical PGA for control of intraocular pressure in the context of primary open-angle glaucoma or ocular hypertension for at least 1 year before cataract surgery. All patients continued with the use of their PGA medication throughout the perioperative period. In addition, all patients were given prednisolone acetate 1.0% 4 times a day and chloramphenicol 0.5% 4 times a day routinely for 4 weeks after cataract surgery. Patients deemed to be at higher risk for postoperative CME were excluded (Figure 1). Full ocular clinical examinations, including corrected distance visual acuity using a standardized Snellen acuity chart, slitlamp biomicroscopy, Goldmann applanation tonometry, and dilated posterior segment evaluation, were performed at each visit. Central retinal thickness was recorded objectively by SD-OCT (Cirrus, Carl Zeiss Meditec AG) to look for evidence of CME scanning. The main outcome measures were the presence of clinical CME or presence of subclinical CME. Spectral-domain OCT examination was performed by experienced technicians through a dilated pupil. All SD-OCT images were reviewed by the consultant ophthalmologist to ensure scan quality. The images obtained had a laminar structure with 2 bands of high-intensity signal. The distance between the inner aspects of these bands was used as the measure of retinal thickness in concordance with previous publications.17 Subclinical macular edema was defined as low-intensity cystic spaces within the laminar structure of the retina. This cystic change could not be seen on slitlamp biomicroscopic examination and was not associated with reduced visual acuity. The acquired images were processed by the retinal map analysis of the SD-OCT instrument software. The SD-OCT imaging was performed preoperatively on the day of surgery and repeated at 3 weeks and 6 weeks postoperatively. Preoperative and postoperative retinal thickness measurements by SD-OCT in the study eyes were compared using a 2-tailed Wilcoxon signed-rank and SPSS software (version 19.0, International Business Machines Corp.). Preoperative retinal thickness was compared with postoperative thickness at 3 weeks and also separately with postoperative thickness at 6 weeks. A P value less than 0.05 was considered statistically significant.

RESULTS Sixty eyes of 48 patients were prospectively analyzed. The mean patient age was 78.4 years, and 39 patients (65%) were women. The PGA latanoprost was used in 42 eyes,

PSEUDOPHAKIC CME IN PATIENTS ON PGAS

bimatoprost (Lumigan) in 14 eyes, bimatoprost and timolol combination (Ganfort) in 3 eyes, and tafluprost (Saflutan) in 1 eye. No clinical CME was present, and slitlamp biomicroscopy retinal examinations were normal. No patient had a reduction in visual acuity. Two eyes (3.3%) of 2 different patients were found to have subclinical CME with low-intensity cystic spaces detected on SD-OCT. Spectral-domain OCT tomography testing detected CME 3 weeks postoperatively in the first case and 6 weeks postoperatively in the second case. Both patients were using a branded version of latanoprost, which was continued throughout the treatment period. Both patients’ CME resolved within 8 weeks with the use of topical nonsteroidal antiinflammatory and topical steroid therapy (bromfenac and prednisolone acetate ophthalmic suspension 1.0% every 2 hours during the day initially and then tapered according to clinical response). The mean preoperative central retinal thickness was 254.6 mm G 31.92 (SD) (95% confidence interval [CI], 26.9-43.5). The mean central retinal thickness was 267.7 G 30.85 mm (95% CI, 24.4-39.6) 3 weeks postoperatively and 268.2 G 34.5 mm at 6 weeks (95% CI, 30.2-44.5). The difference in central retinal thickness between preoperatively and 6 weeks postoperatively was statistically significant (P Z .01).

DISCUSSION There is a lack of consensus with regard to PGA eyedrop use in patients having cataract surgery,16 and it is not clear whether these drops are associated with an increased risk for CME. Previous authors18 have highlighted the lack of Oxford level-1 evidence on this subject. Because cataract surgery is the most commonly performed elective surgical procedure in the U.K.19 and PGA eyedrops are in widespread use, the risks associated with continuing PGAs postoperatively has to be accurately defined. To our knowledge, this is the first prospective study of the incidence of CME after cataract surgery in patients using PGAs. Our study provides incidence data for the rates of clinical and subclinical CME in a small cohort of patients using PGAs in the perioperative period. Although our sample remains smaller than in the aforementioned studies, our results suggest that PGAs can be used safely in the postoperative period without significantly altering the CME rate expected after routine phacoemulsification and IOL insertion. Our findings concur with those in a large retrospective analysis of cataract surgical outcomes. In a subgroup analysis, Chu et al.3 found that PGAs did not increase the risk for clinical CME. The incidence of CME in this study was 1.17% in patients without risk factors for CME. However, in this retrospective study, OCT or fluorescein angiographic imaging was performed in symptomatic patients only, in line with current U.K. clinical practice. The quoted incidence in this study therefore likely reflects the incidence of clinical CME with potential underreporting of subclinical CME discussed by Chu et al.,3 making direct comparison with our study difficult.

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Ching et al.17 described a cohort of 131 patients having phacoemulsification surgery, with all patients having preoperative and postoperative OCT evaluation. The CME rate was 3.05%, with all cases being clinical CME. However, that study included potential confounding factors, with 44 eyes (33.6%) having diabetes mellitus and 8 eyes (6.11%) having posterior capsule breaks during surgery. We did not have cases with either factor. Conversely, the above study found that retinal thickness decreased postoperatively. Unlike previous studies, our study used SD-OCT to detect subclinical CME in patients using PGAs having routine phacoemulsification and IOL insertion. The incidence of subclinical CME in this patient group had not been previously studied. Several predisposing risk factors for CME development are well known. With the use of our exclusion criteria, our patient cohort allowed us to more accurately establish the role PGAs might play in postoperative CME. The aim was to eliminate as many confounding factors as possible, including ensuring standard operating procedures, the same operating surgeon, and identical surgical equipment. A weakness of our study is that no control group was available. Although this would aid comparison within our own study, we believe that the incidence of OCT-proven CME has been assessed by others.17 A larger sample might more accurately define the incidence of CME. Central corneal thickness (CCT) was not measured in our study. It has been postulated that an increased CCT might limit the amount of PGA penetration into the anterior chamber.20 However, the results in our small patient cohort provide the highest level of evidence available to date on this topic. Further multicenter case-controlled studies are required to further establish the role of PGAs in CME development in the perioperative period and to help in the development of a working guideline for cataract surgeons. The results in such a study would aid decision-making in a large number of patients having cataract surgery.

WHAT WAS KNOWN  The incidence of CME after cataract surgery is highly variable, with a published incidence of between 0.1% and 2.35%. Perioperative use of a PGA eyedrop has been reported to contribute to the development of postoperative CME.  A recent large retrospective study did not show an increased risk for CME with PGA use at time of cataract surgery. Prospective studies ascertaining whether use of PGAs increases the risk for postoperative CME are limited. There is currently no agreed consensus on the use of PGAs in the perioperative period.

WHAT THIS PAPER ADDS  The incidence of subclinical pseudophakic CME detected on SD-OCT in eyes treated with a PGA in the perioperative period was 3.3%.  This prospective study could help surgeons decide whether to continue or discontinue a PGA eyedrop in the perioperative period.

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REFERENCES 1. Henderson BA, Kim JY, Ament CS, Ferrufino-Ponce ZK, Grabowska A, Cremers SL. Clinical pseudophakic cystoid macular edema; risk factors for development and duration after treatment. J Cataract Refract Surg 2007; 33:1550–1558 2. Powe NR, Schein OD, Gieser SC, Tielsch JM, Luthra R, Javitt J, Steinberg EP, for the Cataract Patient Outcome Research Team. Synthesis of the literature on visual acuity and complications following cataract extraction with intraocular lens implantation. Arch Ophthalmol 1994; 112:239– 252; erratum, 889 3. Chu CJ, Johnston RL, Buscombe C, Sallam AB, Mohamed Q, Yang YC, for the United Kingdom Pseudophakic Macular Edema Study Group. Risk factors and incidence of macular edema after cataract surgery; a database study of 81984 eyes. Ophthalmology 2016; 123:316–323. Available at: http://www.aaojournal.org/article/S0161-6420(15)01146-X/pdf. Accessed June 8, 2017 4. Wright PL, Wilkinson CP, Balyeat HD, Popham J, Reinke M. Angiographic cystoid macular edema after posterior chamber lens implantation. Arch Ophthalmol 1988; 106:740–744 5. Flach AJ. The incidence, pathogenesis and treatment of cystoid macular edema following cataract surgery. Trans Am Ophthalmol Soc 1998; 96:557–634. Available at: http://www.pubmedcentral.nih.gov/picrender .fcgi?artidZ1298410&blobtypeZpdf. Accessed June 8, 2017 6. Wand M, Gaudio AR, Shields MB. Latanoprost and cystoid macular edema in high-risk aphakic or pseudophakic eyes. J Cataract Refract Surg 2001; 27:1397–1401 7. Lobo CL, Faria PM, Soares MA, Bernardes RC, Cunha-Vaz JG. Macular alterations after small-incision cataract surgery. J Cataract Refract Surg 2004; 30:752–760 8. Nicholas S, Riley A, Patel H, Neveldson B, Purdie G, Wells AP. Correlations between optical coherence tomography measurement of macular thickness and visual acuity after cataract extraction. Clin Exp Ophthalmol 2006; 34:124–129 9. Perente I, Utine CA, Ozturker C, Cakir M, Kaya V, Eren H, Kapran Z, Yilmaz OF. Evaluation of macular changes after uncomplicated phacoemulsification surgery by optical coherence tomography. Curr Eye Res 2007; 32:241–247 10. Biro Z, Balla Z, Kovacs B. Change of foveal and perifoveal thickness measured by OCT after phacoemulsification and IOL implantation. Eye 2008; 22:8–12. Available at: http://www.nature.com/eye/journal/v22/n1 /pdf/6702460a.pdf. Accessed June 8, 2017

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11. Cagini C, Fiore T, Iaccheri B, Piccinelli F, Ricci MA, Fruttini D. Macular thickness measured by optical coherence tomography in a healthy population before and after uncomplicated cataract phacoemulsification surgery. Curr Eye Res 2009; 34:1036–1041 12. Yeh PC, Ramanathan S. Latanoprost and clinically significant cystoid macular edema after uneventful phacoemulsification with intraocular lens implantation. J Cataract Refract Surg 2002; 28:1814–1818 13. Lima MC, Paranhos A Jr, Salim S, Honkanen R, Devgan L, Wand M, Gaudio AR, Shields MB. Visually significant cystoid macular edema in pseudophakic and aphakic patients with glaucoma receiving latanoprost. J Glaucoma 2000; 9:317–321 14. Agange N, Mosaed S. Prostaglandin-induced cystoid macular edema following routine cataract extraction. J Ophthalmol 2010:690707. Available at: http://downloads.hindawi.com/journals/joph/2010/690707.pdf. Accessed June 8, 2017 15. Shrivastava A, Singh K. The effect of cataract extraction on intraocular pressure. Curr Opin Ophthalmol 2010; 21:118–122 16. Ahad MA, McKee HDR. Stopping prostaglandin analogues in uneventful cataract surgery. J Cataract Refract Surg 2004; 30:2644–2645 17. Ching H-Y, Wong AC, Wong C-C, Woo DC, Chan CW. Cystoid macular oedema and changes in retinal thickness after phacoemulsification with optical coherence tomography. Eye 2006; 20:297–303. Available at: http://www.nature.com/eye/journal/v20/n3/pdf/6701864a.pdf. Accessed June 8, 2017 18. Shrivastava A, Singh K. Prostaglandin analogs in the cataract surgery perioperative period. J Curr Glaucoma Pract 2008; 2:32–35. Available at: http:// www.jaypeebrothers.com/eJournalNEW/ShowText.aspx?IDZ161&TypeZ PAID&TYPZTOP&INZ_eJournals/Journal%20of%20Current%20Glaucoma %20Practice%20with%20DVD.jpg&IIDZ19&isPDFZYES. Accessed June 8, 2017 19. NHS Digital. Hospital Admitted Patient Care Activity 2015-16, published 09 November 2016. Available from: http://www.content.digital.nhs.uk /catalogue/PUB22378/hosp-epis-stat-admi-summ-rep-2015-16-rep.pdf. Accessed June 8, 2017 20. Brandt JD, Beiser JA, Gordon MO, Kass MA, and the Ocular Hypertension Treatment Study (OHTS) Group. Central corneal thickness and measured IOP response to topical ocular hypotensive medication in the Ocular Hypertension Treatment Study. Am J Ophthalmol 2004; 138:717–722

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

Pseudophakic cystoid macular edema and spectral-domain optical coherence tomography-detectable central macular thickness changes with perioperative prostaglandin analogs.

To define the incidence of cystoid macular edema (CME) and spectral-domain optical coherence tomography-detectable (SD-OCT) subclinical changes in cen...
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