October 2019


EyeWorld Journal Club
Review of “Cystoid macular edema following prostaglandin analogue use after uncomplicated cataract surgery in glaucoma patients: A randomized clinical trial”

by Geoffrey Rodriguez, MD, Alexander Dillon, MD, Daniel Kornberg, MD, Christiana Gandy, MD, Mahmood Khan, MD, Michelle Sun, MD, Jason Chien, MD, Stephanie Engelhard, MD, Karina Somohano, MD, Grace Sun, MD

Grace Sun, MD
Ophthalmology residency program director
Weill Cornell Medicine

Weill Cornell residents, from left: Daniel Kornberg, MD, Alexander Dillon, MD, Geoffrey Rodriguez, MD, Mahmood Khan, MD, Stephanie Engelhard, MD, Christiana Gandy, MD, Michelle Sun, MD,
Jason Chien, MD, Christina Grassi, MD


Pseudophakic cystoid macular edema (PME) is one of the most common causes of vision loss after cataract surgery.1 First described by A. Ray Irvine Jr., MD, in 1953 as a “change in the vitreous humor following cataract surgery,” PME was further characterized by J. Donald M. Gass, MD, in 1966 using fluorescein angiography (FA).2,3 While FA is considered the gold standard in its diagnosis, PME can be detected by OCT or clinically as decreased visual acuity 4–6 weeks postoperatively. Recent studies evaluating clinical PME after small incision phacoemulsification report incidence rates ranging from 0.1–2.35%.4 However, with the use of OCT imaging, the detection of PME is greater, with several studies citing incidence rates from 4–11%.5,6
Surgical complications, including vitreous loss, iris trauma, and posterior capsule rupture, can increase the risk of developing PME.7 Other risk factors include history of diabetic macular edema, active uveitis, and use of topical glaucoma medications.8 In particular, the association of prostaglandin analogue (PGA) use and increased risk of PME is controversial with existing literature presenting conflicting evidence.
In this study, Fakhraie et al. report the results of their prospective single-masked, randomized clinical trial with parallel assignment, evaluating the effect of postoperative latanoprost administration on the development of PME in glaucoma patients undergoing uncomplicated cataract surgery. This study addresses an issue encountered by many ophthalmologists, because latanoprost is one of the most commonly used medications for the treatment of primary open angle glaucoma.9 Given the high global prevalence of open angle glaucoma—the population age 40–80 years is estimated to be 3.54%—and the high incidence of cataract surgery, a significant number of patients undergoing cataract surgery may be on latanoprost preoperatively.10,11
The primary outcome measure in this study was the change in central macular thickness (CMT) between preoperative and postoperative measurements by OCT imaging at 1 and 3 months. Secondary outcome measures included the incidence of clinical PME on fundus examination, incidence of significant increase in CMT (here defined as >50 µm) compared to baseline, visual acuity, IOP, and number of glaucoma medications at both time points.
Eligible glaucoma patients in need of cataract surgery who were on topical latanoprost 0.005% for a minimum of 6 months alone or in combination with other topical glaucoma medications were randomized to either continue or discontinue latanoprost following uncomplicated cataract surgery on postop day 1. Surgeon and outcome assessors were masked to the treatment allocation; however, patients were aware of their assigned treatment group. Following enrollment, study participants underwent complete ocular examination, including measurement of CMT by OCT at baseline as well as at 1 and 3 months postop. Data was analyzed using a variety of statistical methods.
A total of 156 eyes from 156 patients were included in the study. No differences were found in baseline demographics and preop data (age, sex, type of glaucoma, VA baseline, IOP baseline, central corneal thickness, medication baseline, CMT baseline, cup to disc ratio baseline, and mean deviation of visual field baseline) between the latanoprost group and the discontinue (DC) group. Regarding the primary outcome, the latanoprost group showed a significant increase in CMT detected by OCT from baseline to 1 month post-cataract extraction, but no significant difference in CMT from baseline to 3 months postop. The DC group showed no significant difference in CMT from baseline to 1 month and 3 months postop. Regarding secondary outcomes, no differences in prevalence of clinical PME, incidence of a significant increase in CMT, and IOP reduction were found between latanoprost and DC groups at 1 month and 3 months postop. Visual acuity improvement occurred significantly more in DC group compared to latanoprost group at 1 month and 3 months postop. The number of medications significantly decreased in the latanoprost group at 1 and 3 months postop.
The conclusion of this study was that although latanoprost was associated with a significant increase in CMT at 1 month, there was no difference in CMT at 3 months, indicating that latanoprost is relatively safe for use after cataract surgery. The authors suggest that that PGAs can be continued after uneventful cataract surgery. However, the authors do note there was less improvement in visual acuity in PGA users after at 1 month postop and to a lesser extent 3 months postop, which they attributed to transient increase in CMT. They hypothesized that this difference in visual acuity compared to non-PGA users would dissipate if comparing visual acuity at 6 months or later after surgery, because the transient CMT resolves and visual acuity improves.
The strengths of this study lie in its design as a randomized clinical trial and that it was single masked. From a methodology standpoint, this decreases bias related to confounding factors via a control group, selection bias via randomization, and interpretation bias via masking. Furthermore, study participants theoretically would comprise good and poor responders to interventions, so that the average therapeutic response is mitigated. All of the operations were performed by the same expert surgeon, minimizing variability in surgical technique and ability. An additional strength is that recruited eyes did not have risk factors for the development of PME in cases with uneventful cataract surgery. The study also assessed patients at appropriate time points for the development of PME. Follow-up was at 1 and 3 months postop, which falls within the usual time course for the onset of PME, typically 4–12 weeks after surgery, reaching a peak incidence 4–6 weeks postoperatively.12 Lastly, patients included were also on treatment for at least 6 months with topical latanoprost 0.005% eye drops.
There are several limitations of this study. As the authors acknowledged, the study size was not large enough to elicit a statistically significant difference in clinical PME between treatment arms, given its relatively low incidence rate. The use of potential confounding medications like acetazolamide (a treatment for PME) were not controlled for or matched between arms, and neither were use of iris manipulators during surgery, which may increase inflammation and possibly PME as a result. The applicability of this study to practices that routinely use topical NSAIDs pre- and postop may be limited, because NSAIDs were not routinely used in this study, and steroid use was more frequent than is typical (specifically betamethasone every 2 hours for 1 week followed by a taper). 
While investigators were blinded to patients’ treatment arms, patients were not (there was no use of a placebo control). One could argue that this could be of limited importance in determination of the primary endpoint, an objective anatomical measurement. That said, it could influence a more subjective measurement such as visual acuity. On that note, neither visual acuity (pre- or postop) or preoperative cataract grade were reported or controlled for between treatment arms. Furthermore, the primary endpoint, as well as the secondary outcome of significant CMT increase from baseline, are of only indirect clinical significance. That is, one may presumably have some unknown degree of CMT without experiencing a functional decline. A larger, double-blinded, placebo-controlled study with postop regimens that more closely mirror mainstream practice patterns explicitly reporting differential functional outcomes may further inform cataract surgeons’ perioperative management of patients on PGAs.
Current evidence of a possible association between the development of PME after uncomplicated cataract surgery and the postoperative use PGAs is sparse and often conflicting. Studies that support a potential causative relationship include a prospective interventional case series by Walkden et al., which demonstrated an increased incidence of PME at 6 weeks postoperatively.13 Similarly, a retrospective study by Yeh et al. reported an association between latanoprost and the development of PME after uneventful cataract surgery. 14 Wand et al. conducted a prospective cohort study, which demonstrated the development of clinically symptomatic and angiographically documented PME in post-cataract patients treated with latanoprost.15 Arcieri et al. documented a statistically significant difference in foveal thickness between patients treated with latanoprost compared to placebo.16 A case-control study by Wendel et al. showed an increased relative risk of PME development with postop use of the PGAs travoprost and bimatoprost, although the study was unable to prove a similar relationship with latanoprost.17 Opposing evidence comes from a prospective interventional case series conducted by Moghimi et al., which found that use of latanoprost later than 4 months after uncomplicated cataract surgery does not predispose to increased macular thickness or PME.18 Likewise, a systematic literature review by Hernstadt et al. concluded that PGA use was not associated with the development of clinically significant PME after cataract surgery regardless of the time point, suggesting that there is no evidence to support stopping PGA perioperatively.19
In summary, this study indicates that patients who continued latanoprost in the postop period experienced a transient increase in CMT at 1 month, which resolved by 3 months, suggesting that patients without additional risk factors for PME can continue their PGA glaucoma medication after cataract surgery without additional risk to vision. As the authors note, further studies with larger sample sizes will be necessary to compare rates of incidence of clinical PME.

Editor’s note: The authors would like to acknowledge Dr. Paul Petrakos and Dr. Sarah Van Tassel for their support and guidance with this review.

Do topical prostaglandin analogues increase the risk of CME, and should we discontinue them prior to performing cataract surgery on glaucoma patients? I invited the Weill Cornell residents to review this new randomized study that is published in this month’s JCRS.
—David F. Chang, MD EyeWorld Journal
Club Editor


1. Henderson BA, et al. Clinical pseudophakic cystoid macular edema. Risk factors for development and duration after treatment. J Cataract Refract Surg. 2007;33(9):1550–1558.
2. Irvine SR. A newly defined vitreous syndrome following cataract surgery. Am J Ophthalmol. 1953;36:599–619.
3. Gass JDM, Norton EWD. Fluorescein studies of patients with macular edema and papilledema following cataract extraction. Trans Am Ophthalmol Soc 1966;64:232–249.
4. Loewenstein A, Zur D. Postsurgical cystoid macular edema. Dev Ophthalmol. 2010;47:148–159.
5. Belair ML, et al. Incidence of cystoid macular edema after cataract surgery in patients with and without uveitis using optical coherence tomography. Am J Ophthalmol. 2009;148(1):128–135.
6. Perente I, et al. Evaluation of macular changes after uncomplicated phacoemulsification surgery by optical coherence tomography. Curr Eye Res. 2007;32(3):241–247.
7. Flach AJ. The incidence, pathogenesis and treatment of cystoid macular edema following cataract surgery. Trans Am Ophthalmol Soc. 1998;96:557–634.
8. Yonekawa Y, et al. Pseudophakic cystoid macular edema. EyeWiki. https://eyewiki.aao.org/Pseudophakic_Cystoid_Macular_Edema_(Irvine-Gass_Syndrome). Accessed 8/14/2019.
9. Connor AJ, Fraser SG. Glaucoma prescribing trends in England 2000 to 2012. Eye (Lond). 2014 Jul;28(7):863–869.
10. Tham Y, et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040. Ophthalmology. 2014;121(11):2081–2090.
11. Gollogly HE, et al. Increasing incidence of cataract surgery: Population-based study. J Cataract Refract Surg. 2013;39(9):1383–1389.
12. Lally DR, Shah CP. Pseudophakic cystoid macular edema. Review of Ophthalmology. 2014. Accessed 8/14/2019.
13. Walkden A, et al. Pseudophakic cystoid macular edema and spectral-domain optical coherence tomography-detectable central macular thickness changes with perioperative prostaglandin analogs. J Cataract Refract Surg. 2017;43:1027–1030.
14. 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.
15. Wand M, et al. Latanoprost and cystoid macular edema in high-risk aphakic or pseudophakic eyes. J Cataract Refract Surg. 2001;27:1397–1401.
16. Arcieri ES, et al. Influence of topical latanoprost on foveal thickness in eyes that underwent uneventful cataract surgery. Arquivos Brasileiros de Oftalmologia. 2008;71:629–634.
17. Wendel C, et al. Association of postoperative topical prostaglandin analog or beta-blocker use and incidence of pseudophakic cystoid macular edema. J Glaucoma. 2018;27:402–406.
18. Moghimi S, et al. Topical latanoprost does not cause macular thickening after uncomplicated cataract surgery. Journal Ophthalmic Vis Res. 2012;7:289–294.
19. Hernstadt DJ, Husain R. Effect of prostaglandin analogue use on the development of cystoid macular edema after phacoemulsification using STROBE statement methodology. J Cataract Refract Surg. 2017;43:564–569.

Contact information

Sun: grs2003@med.cornell.edu

Review of “Cystoid macular edema following prostaglandin analogue use after uncomplicated cataract surgery in glaucoma patients: A randomized clinical trial” Review of “Cystoid macular edema following prostaglandin analogue use after uncomplicated cataract surgery
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