Cystoid macular edema related to cataract surgery and topical prostaglandin analogs: Mechanism, diagnosis, and management

      Abstract

      Cystoid macular edema (CME) is a form of macular retina thickening that is characterized by the appearance of cystic fluid-filled intraretinal spaces. It has classically been diagnosed upon investigation after a decrease in visual acuity; however, improvements in imaging technology make it possible to noninvasively detect CME even before a clinically significant decrease in central vision. Risk factors for the development of CME include diabetic retinopathy, retinal vein occlusion, uveitis, and cataract surgery. It has been proposed that eyes with elevated intraocular pressure after cataract surgery, including those treated with prostaglandin analog eye drops, may be at higher risk for the development of CME. We summarize the current knowledge of the molecular mechanisms underlying CME, the potential role of ocular surgery and topical glaucoma medication in increasing the risk of CME, the newly developed imaging methods for diagnosing CME, and the clinical management of CME.

      Keywords

      1. Introduction to cystoid macular edema

      Cystoid macular edema (CME) is characterized by retinal thickening at the macula, associated with cystic changes in the outer plexiform and inner nuclear layers.
      • Sigler E.J.
      • Randolph J.C.
      • Kiernan D.F.
      Longitudinal analysis of the structural pattern of pseudophakic cystoid macular edema using multimodal imaging.
      These cystic changes occur from the accumulation of fluid arising from inner and outer blood-retinal breakdown of the perifoveal capillaries, which is mediated by a number of inflammatory molecules.
      • Hernstadt D.J.
      • Husain R.
      Effect of prostaglandin analogue use on the development of cystoid macular edema after phacoemulsification using STROBE statement methodology.
      CME may be classified as acute or chronic, whereby CME is present for less or more than 6 months, respectively. Clinical CME is typically established after diagnostic evaluation following the patient's visual complaint and is associated with impaired visual acuity, usually less than 20/40. Conversely, angiographic CME is largely asymptomatic and is typically diagnosed using imaging-based diagnostic techniques.
      • Flach A.J.
      The incidence, pathogenesis and treatment of cystoid macular edema following cataract surgery.
      A summary of the risk factors for CME is provided in Table 1. In general, CME is considered to be related to ocular inflammation. It is typically associated with uveitis, diabetic retinopathy, and retinal vein occlusion and is a common complication of cataract surgery.
      • Law S.K.
      • Kim E.
      • Yu F.
      • Caprioli J.
      Clinical cystoid macular edema after cataract surgery in glaucoma patients.
      ,
      • Rotsos T.G.
      • Moschos M.M.
      Cystoid macular edema.
      Given the process of replacing the natural lens with an artificial intraocular lens during cataract surgery, CME that occurs after cataract surgery is referred to as pseudophakic CME. Pseudophakic CME, also known as Irvine-Gass syndrome, is one of the most common causes of decreased visual acuity after cataract surgery.
      • Flach A.J.
      The incidence, pathogenesis and treatment of cystoid macular edema following cataract surgery.
      ,
      • Kessel L.
      • Tendal B.
      • Jørgensen K.J.
      • et al.
      Post-cataract prevention of inflammation and macular edema by steroid and nonsteroidal anti-inflammatory eye drops: a systematic review.
      ,
      • Kim S.J.
      • Schoenberger S.D.
      • Thorne J.E.
      • Ehlers J.P.
      • Yeh S.
      • Bakri S.J.
      Topical nonsteroidal anti-inflammatory drugs and cataract surgery: a report by the American Academy of Ophthalmology.
      The incidence of clinical CME after cataract surgery is reported as 0.1–7.0% in studies where patients, including those with risk factors for CME, were assessed up to 4 months postoperatively.
      • Chu C.J.
      • Johnston R.L.
      • Buscombe C.
      • et al.
      Risk factors and incidence of macular edema after cataract surgery: a database study of 81984 eyes.
      ,
      • Flach A.J.
      The incidence, pathogenesis and treatment of cystoid macular edema following cataract surgery.
      ,
      • Lee K.M.
      • Lee E.J.
      • Kim T.-W.
      • Kim H.
      Pseudophakic macular edema in primary open-angle glaucoma: a prospective study using spectral-domain optical coherence tomography.
      ,
      • Packer M.
      • Lowe J.
      • Fine H.
      Incidence of acute postoperative cystoid macular edema in clinical practice.
      The observed incidence of pseudophakic CME is much greater when eyes are assessed with fluorescein angiography (FA) or optical coherence tomography (OCT) compared with that reported after the development of patients' visual complaints.
      • Grzybowski A.
      • Sikorski B.L.
      • Ascaso F.J.
      • Huerva V.
      Pseudophakic cystoid macular edema: update 2016.
      This suggests that there are many clinically unrecognized cases of CME. Although clinically significant macular edema develops in only up to 6% of patients without diabetes after cataract surgery, this may occur in up to 56% of patients with mild to moderate diabetic retinopathy who did not have macular edema preoperatively.
      • Wielders L.H.
      • Lambermont V.A.
      • Schouten J.S.
      • et al.
      Prevention of cystoid macular edema after cataract surgery in nondiabetic and diabetic patients: a systematic review and meta-analysis.
      In addition, pseudophakic CME is more likely to occur in eyes of patients with diabetes and preoperative diabetic retinopathy than in diabetic eyes without retinopathy.
      • Pollack A.
      • Leiba H.
      • Bukelman A.
      • Oliver M.
      Cystoid macular oedema following cataract extraction in patients with diabetes.
      Similarly, a history of retinal vein occlusion significantly increases the risk of developing CME after cataract surgery (odds ratio [95% confidence interval] = 47.12 [9.40–236.11]; P < 0.001).
      • Henderson B.A.
      • Kim J.Y.
      • Ament C.S.
      • Ferrufino-Ponce Z.K.
      • Grabowska A.
      • Cremers S.L.
      Clinical pseudophakic cystoid macular edema. Risk factors for development and duration after treatment.
      Although glaucoma itself is not considered a risk factor for the development of CME after cataract surgery, untreated elevated intraocular pressure (IOP) with glaucomatous optic nerve or retinal nerve fiber layer damage and associated glaucomatous visual field defect has been shown to increase the risk of postoperative pseudophakic CME.
      • Lee K.M.
      • Lee E.J.
      • Kim T.-W.
      • Kim H.
      Pseudophakic macular edema in primary open-angle glaucoma: a prospective study using spectral-domain optical coherence tomography.
      To date, studies have shown mixed results regarding the risk of pseudophakic CME after preoperative prostaglandin (PG) analog (PGA) use. Henderson and coworkers showed that, when patients with diabetes were excluded from the analysis as this was a confounding factor, preoperative use of PGAs significantly increased the risk of CME (P = 0.04); however, it was not stated if and when treatment was discontinued before surgery.
      • Henderson B.A.
      • Kim J.Y.
      • Ament C.S.
      • Ferrufino-Ponce Z.K.
      • Grabowska A.
      • Cremers S.L.
      Clinical pseudophakic cystoid macular edema. Risk factors for development and duration after treatment.
      In a retrospective study of 12 patients receiving latanoprost, 8 patients deliberately discontinued treatment 1 week preoperatively, and 4 patients continued treatment. CME did not develop in those who discontinued treatment, whereas CME developed in those who continued the treatment (P = 0.003).
      • Yeh P.C.
      • Ramanathan S.
      Latanoprost and clinically significant cystoid macular edema after uneventful phacoemulsification with intraocular lens implantation.
      Other studies have suggested that preoperative use of PGAs does not increase the risk of CME.
      • Chu C.J.
      • Johnston R.L.
      • Buscombe C.
      • et al.
      Risk factors and incidence of macular edema after cataract surgery: a database study of 81984 eyes.
      ,
      • Law S.K.
      • Kim E.
      • Yu F.
      • Caprioli J.
      Clinical cystoid macular edema after cataract surgery in glaucoma patients.
      PGAs are the current most commonly used standard-of-care medication option for patients with glaucoma. Given the potential association between the preoperative use of PGAs and the development of CME, this may indicate a risk for patients with glaucoma requiring cataract surgery.
      Table 1Summary of the risk factors for CME
      Conditions that may increase the risk of CME
      • Uveitis
        • Lardenoye C.W.T.A.
        • van Kooij B.
        • Rothova A.
        Impact of macular edema on visual acuity in uveitis.
      • Diabetic retinopathy
        • Chu C.J.
        • Johnston R.L.
        • Buscombe C.
        • et al.
        Risk factors and incidence of macular edema after cataract surgery: a database study of 81984 eyes.
        ,
        • Rotsos T.G.
        • Moschos M.M.
        Cystoid macular edema.
      • Retinal vein occlusion
        • Chu C.J.
        • Johnston R.L.
        • Buscombe C.
        • et al.
        Risk factors and incidence of macular edema after cataract surgery: a database study of 81984 eyes.
        ,
        • Rotsos T.G.
        • Moschos M.M.
        Cystoid macular edema.
      • Neovascular age-related macular degeneration
        • Shah N.
        • Maguire M.G.
        • Martin D.F.
        • et al.
        Angiographic cystoid macular edema and outcomes in the comparison of age-related macular degeneration treatments trials.
      • Retinitis pigmentosa
        • Hajali M.
        • Fishman G.A.
        • Anderson R.J.
        The prevalence of cystoid macular oedema in retinitis pigmentosa patients determined by optical coherence tomography.
      • Vitreous traction
        • Johnson M.W.
        Perifoveal vitreous detachment and its macular complications.
      • Preoperative treatment with paclitaxel or docetaxel
        • Yokoe T.
        • Fukada I.
        • Kobayashi K.
        • et al.
        Cystoid macular edema during treatment with paclitaxel and bevacizumab in a patient with metastatic breast cancer: a case report and literature review.
      • Use of omidenepag isopropyl on Japanese pseudophakic eyes
        • Duggan S.
        Omidenepag isopropyl ophthalmic solution 0.002%: first global approval.
        ,
        Santen Pharmaceutical Co., Ltd
        EYBELIS ophthalmic solution 0.002% package insert [Japanese].
      • Cataract surgery (3–12 weeks postoperatively)
        • Chu C.J.
        • Johnston R.L.
        • Buscombe C.
        • et al.
        Risk factors and incidence of macular edema after cataract surgery: a database study of 81984 eyes.
        ,
        • Rotsos T.G.
        • Moschos M.M.
        Cystoid macular edema.
      • The risk of CME with cataract surgery is increased with the following factors:
        • Surgery complicated with posterior capsule rupture and vitreous humor loss
          • Rotsos T.G.
          • Moschos M.M.
          Cystoid macular edema.
        • Diabetes mellitus or preoperative diabetic retinopathy
          • Pollack A.
          • Leiba H.
          • Bukelman A.
          • Oliver M.
          Cystoid macular oedema following cataract extraction in patients with diabetes.
          ,
          • Wielders L.H.
          • Lambermont V.A.
          • Schouten J.S.
          • et al.
          Prevention of cystoid macular edema after cataract surgery in nondiabetic and diabetic patients: a systematic review and meta-analysis.
        • Untreated elevated intraocular pressure
          • Lee K.M.
          • Lee E.J.
          • Kim T.-W.
          • Kim H.
          Pseudophakic macular edema in primary open-angle glaucoma: a prospective study using spectral-domain optical coherence tomography.
        • History of retinal vein occlusion
          • Henderson B.A.
          • Kim J.Y.
          • Ament C.S.
          • Ferrufino-Ponce Z.K.
          • Grabowska A.
          • Cremers S.L.
          Clinical pseudophakic cystoid macular edema. Risk factors for development and duration after treatment.
        • History of epiretinal membrane
          • Henderson B.A.
          • Kim J.Y.
          • Ament C.S.
          • Ferrufino-Ponce Z.K.
          • Grabowska A.
          • Cremers S.L.
          Clinical pseudophakic cystoid macular edema. Risk factors for development and duration after treatment.
        • Preoperative use of prostaglandin analogs
          • Henderson B.A.
          • Kim J.Y.
          • Ament C.S.
          • Ferrufino-Ponce Z.K.
          • Grabowska A.
          • Cremers S.L.
          Clinical pseudophakic cystoid macular edema. Risk factors for development and duration after treatment.
          ,
          The duration of treatment was not provided in this study.
        • Postoperative use of prostaglandin analogs and β-blockers
          • Wendel C.
          • Zakrzewski H.
          • Carleton B.
          • Etminan M.
          • Mikelberg F.S.
          Association of postoperative topical prostaglandin analog or beta-blocker use and incidence of pseudophakic cystoid macular edema.
          ,
          The duration of treatment was not provided in this study.
      CME, cystoid macular edema.
      The duration of treatment was not provided in this study.
      The emergence of improved imaging technologies has indicated that the risk of angiographic CME after cataract surgery may be higher than previously reported
      • Guo S.
      • Patel S.
      • Baumrind B.
      • et al.
      Management of pseudophakic cystoid macular edema.
      ; therefore, this review will cover how current diagnostic practice has led to a revised understanding of CME, the risk of CME after cataract surgery in patients with glaucoma on IOP-lowering treatment, and the implications for managing PGA-related pseudophakic CME.

      2. Diagnosis of CME

      The traditional methods for evaluating macular thickening include slit-lamp biomicroscopy, indirect ophthalmoscopy, and fundus photography.
      • Staurenghi G.
      • Invernizzi A.
      • de Polo L.
      • Pellegrini M.
      Diagnosis and detection.
      ,
      • Trichonas G.
      • Kaiser P.K.
      Optical coherence tomography imaging of macular oedema.
      Although these methods identify exudates, hemorrhages, and microaneurysms, their usefulness is limited in identifying specific anatomic details at the vitreoretinal interface, and they are dependent on the extent of edema and the observer's level of experience and skill.
      • Staurenghi G.
      • Invernizzi A.
      • de Polo L.
      • Pellegrini M.
      Diagnosis and detection.
      Therefore, postoperative CME is conventionally diagnosed by decreased visual acuity or by visualization of the accumulation of fluid in well-defined intraretinal spaces using FA or OCT.
      • Guo S.
      • Patel S.
      • Baumrind B.
      • et al.
      Management of pseudophakic cystoid macular edema.
      ,
      • Trichonas G.
      • Kaiser P.K.
      Optical coherence tomography imaging of macular oedema.
      Assessment by FA shows fluorescein leakage from the vasculature in a characteristic perifoveal petaloid pattern with or without fluid leakage from the optic disk, as well as fluorescein leakage from the macular capillaries and its pooling in the cystoid cavities.
      • Chetrit M.
      • Bonnin S.
      • Mané V.
      • et al.
      Acute pseudophakic cystoid macular edema imaged by optical coherence tomography angiography.
      ,
      • Guo S.
      • Patel S.
      • Baumrind B.
      • et al.
      Management of pseudophakic cystoid macular edema.
      The extent of fluid leakage observed does not always correlate with visual acuity, likely owing to the localization of the fluid accumulation.
      • Flach A.J.
      The incidence, pathogenesis and treatment of cystoid macular edema following cataract surgery.
      Although FA was the most commonly used technique for diagnosing CME until recent years, the observation of fluorescein leakage only provides qualitative information on vascular exudation.
      • Staurenghi G.
      • Invernizzi A.
      • de Polo L.
      • Pellegrini M.
      Diagnosis and detection.
      CME may also be detected by fundus autofluorescence (FAF), a noninvasive qualitative imaging technique that measures the fluorescence emitted by fluorophores of the retina at specific wavelengths. Blue FAF allows visualization of lipofuscin, which absorbs blue light at 470 nm and emits yellow/green light at 600–610 nm.
      • Banda H.K.
      • Shah G.K.
      • Blinder K.J.
      Applications of fundus autofluorescence and widefield angiography in clinical practice.
      In CME, FAF may be used to visualize displacement of macular pigment and consequently the cysts associated with CME. FAF patterns observed in patients with CME have been shown to correspond well with the petaloid pattern observed with FA images; however, caution may be advised with this method, as FAF hypoautofluorescence without the petaloid pattern is observed in patients with intraretinal fluid.
      • Peng X.-J.
      • Su L.-P.
      Characteristics of fundus autofluorescence in cystoid macular edema.
      This method is also limited by low signal strength, autofluorescence artifacts from the anterior segment, and the potential toxic effects of blue light excitation of the retina, including changes to circadian rhythm and dark adaption.
      • Banda H.K.
      • Shah G.K.
      • Blinder K.J.
      Applications of fundus autofluorescence and widefield angiography in clinical practice.
      Visualization of CME using FA and FAF is shown in Fig. 1.
      Figure thumbnail gr1
      Fig. 1Imaging of CME using fluorescein angiography and fundus autofluorescence. Fluorescein angiography images of an eye with CME in A: the early arteriovenous phase; B: the late arteriovenous phase; and C: the late angiography phase. The leakage of fluorescein into the CME spaces increases during the consecutive angiography phases. D: Shows the appearance of CME using fundus autofluorescence. CME, cystoid macular edema.
      In recent years, OCT has become the standard diagnostic technique for identifying CME.
      • Guo S.
      • Patel S.
      • Baumrind B.
      • et al.
      Management of pseudophakic cystoid macular edema.
      ,
      • Staurenghi G.
      • Invernizzi A.
      • de Polo L.
      • Pellegrini M.
      Diagnosis and detection.
      It has advantages over FA because it is a noninvasive and quantitative method that provides images of the retinal fluid-filled cystoid cavities as small, round, or oval hyporeflective spaces with highly reflective septa that bridge the retinal layers and separate the cavities.
      • Cunha-Vaz J.
      • Coscas G.
      Diagnosis of macular edema.
      ,
      • Staurenghi G.
      • Invernizzi A.
      • de Polo L.
      • Pellegrini M.
      Diagnosis and detection.
      The resulting image can be used to automatically quantify retinal thickness.
      • Chetrit M.
      • Bonnin S.
      • Mané V.
      • et al.
      Acute pseudophakic cystoid macular edema imaged by optical coherence tomography angiography.
      ,
      • Staurenghi G.
      • Invernizzi A.
      • de Polo L.
      • Pellegrini M.
      Diagnosis and detection.
      ,
      • Trichonas G.
      • Kaiser P.K.
      Optical coherence tomography imaging of macular oedema.
      OCT evaluation shows macular thickening and cystic spaces in the inner nuclear layer and the outer plexiform layer in patients with CME, which is in line with histopathological studies. These cystoid spaces may initially be observed as development of microcystoid spaces in the inner nuclear layer using spectral-domain OCT
      • Chetrit M.
      • Bonnin S.
      • Mané V.
      • et al.
      Acute pseudophakic cystoid macular edema imaged by optical coherence tomography angiography.
      ,
      • Guo S.
      • Patel S.
      • Baumrind B.
      • et al.
      Management of pseudophakic cystoid macular edema.
      ,
      • Sigler E.J.
      Microcysts in the inner nuclear layer, a nonspecific SD-OCT sign of cystoid macular edema.
      ; however, microcystoid spaces may also be observed in patients with advanced glaucoma and in patients with other forms of optic atrophy.
      • Hasegawa T.
      • Akagi T.
      • Yoshikawa M.
      • et al.
      Microcystic inner nuclear layer changes and retinal nerve fiber layer defects in eyes with glaucoma.
      This may lead to difficulties in differentiating microcysts associated with CME and those associated with forms of progressive retinal degeneration including optic nerve atrophy in patients with glaucoma.
      • Hasegawa T.
      • Akagi T.
      • Yoshikawa M.
      • et al.
      Microcystic inner nuclear layer changes and retinal nerve fiber layer defects in eyes with glaucoma.
      ,
      • Wolff B.
      • Basdekidou C.
      • Vasseur V.
      • Mauget-Faÿsse M.
      • Sahel J.-A.
      • Vignal C.
      Retinal inner nuclear layer microcystic changes in optic nerve atrophy: a novel spectral-domain OCT finding.
      Some studies have used methods such as OCT to differentiate pathologic causes of CME such as pseudophakic, uveitic, or diabetic CME; however, this application of OCT has not yet been validated, and in most cases, the patients' medical history provides sufficient information to determine the pathology.
      • Jo E.B.
      • Lee J.H.
      • Hwang Y.N.
      • Kim S.M.
      Comparison of evaluation parameters in the retinal layer between diabetic cystoid macular edema and postoperative cystoid macular edema after cataract surgery based on a hierarchical approach.
      ,
      • Munk M.R.
      • Sacu S.
      • Huf W.
      • et al.
      Differential diagnosis of macular edema of different pathophysiologic origins by spectral domain optical coherence tomography.
      Though the value of swept-source OCT in diagnosing CME has not yet been fully determined, this technique was used in one investigation to assess macular pathology after routine cataract surgery.
      • Zafar S.
      • Siddiqui M.A.R.
      • Shahzad R.
      • Shahzad M.H.
      Swept-source optical coherence tomography to screen for macular pathology in eyes having routine cataract surgery.
      The advantages of swept-source over spectral-domain OCT imaging comprise faster scanning speed, resulting in denser scan patterns and larger scan areas, and the use of a longer wavelength and reduced sensitivity roll-off, which improves signal detection and increases likelihood of detecting weak signals from the deeper layers.
      • Miller A.R.
      • Roisman L.
      • Zhang Q.
      • et al.
      Comparison between spectral-domain and swept-source optical coherence tomography angiographic imaging of choroidal neovascularization.
      Therefore, it is likely that this method may be more widely used in future diagnosis of CME.
      OCT angiography is an emerging noninvasive diagnostic technique that is increasingly used in clinical practice.
      • Sacconi R.
      • Corbelli E.
      • Carnevali A.
      • et al.
      Optical coherence tomography angiography in pseudophakic cystoid macular oedema compared to diabetic macular oedema: qualitative and quantitative evaluation of retinal vasculature.
      OCT angiography may be considered superior to FA owing to its ability to quantitatively measure retinal blood flow across separate layers, including the superficial capillary plexus and the deep capillary plexus, and can determine areas of decreased or absent retinal perfusion in the deep vascular plexus, localized to the cystoid spaces.
      • Sacconi R.
      • Corbelli E.
      • Carnevali A.
      • et al.
      Optical coherence tomography angiography in pseudophakic cystoid macular oedema compared to diabetic macular oedema: qualitative and quantitative evaluation of retinal vasculature.
      ,
      • Spaide R.F.
      Retinal vascular cystoid macular edema: review and new theory.
      A comparison of a healthy eye and an eye with CME as presented by OCT and OCT angiography is shown in Fig. 2.
      Figure thumbnail gr2
      Fig. 2Comparison of macular OCT angiography findings between eyes with and without CME. A: OCT angiography image of a healthy macula. The retinal vessels and the capillaries are clearly defined in the superficial and deep layers and in the outer retina except for the foveal avascular zone. The macular retina layers (middle row) are normal, and the perfusion is indicated with red pseudocolor. The color-coded perfusion map (bottom row) shows normal superficial retinal perfusion. B: OCT angiography image of an eye with CME. Macular perfusion is reduced in the superficial and deep layers and in the outer retina and choriocapillaries compared with the healthy macula (A). On the color-coded perfusion map (bottom left image), the reduced capillary perfusion is indicated by the dominance of blue color. These perfusion findings reflect the CME cavities (middle row). Images for both patients were obtained using an AngioVue OCT imaging system with the 3 mm diameter macular scan size. BRM, Bruch membrane; CME, cystoid macular edema; ETDRS, Early Treatment Diabetic Retinopathy Study; ILM, internal limiting membrane; IPM, inner plexiform layer; OCT, optical coherence tomography; OD, right eye; OPL, outer plexiform layer; RPE, retinal pigment epithelium; SLO, scanning laser ophthalmoscopy.

      3. Pathology and pathophysiology of CME

      Although the classic picture of CME is characterized by cysts in the outer plexiform layer, cysts initially form in the inner nuclear layer and, upon disease progression, they appear in the outer plexiform layer and the subretinal space.
      • Sigler E.J.
      • Randolph J.C.
      • Kiernan D.F.
      Longitudinal analysis of the structural pattern of pseudophakic cystoid macular edema using multimodal imaging.
      This is coupled with capillary loss, which is observed in both the superficial capillary plexus and the deep capillary plexus during pseudophakic CME, but normalizes upon CME resolution.
      • Chetrit M.
      • Bonnin S.
      • Mané V.
      • et al.
      Acute pseudophakic cystoid macular edema imaged by optical coherence tomography angiography.
      ,
      • Spaide R.F.
      Retinal vascular cystoid macular edema: review and new theory.
      This suggests that capillary nonperfusion in pseudophakic CME is temporary and that pseudophakic CME may have a different pathology compared with CME associated with retinal vascular occlusions.
      • Chetrit M.
      • Bonnin S.
      • Mané V.
      • et al.
      Acute pseudophakic cystoid macular edema imaged by optical coherence tomography angiography.
      CME also occurs in patients with a history of intraocular inflammation, such as uveitic syndromes; conditions that lead to predisposition to increased vascular permeability, such as diabetic retinopathy; or those with a history of intraocular surgery. Most studies agree that inflammation may play a key role in the development of CME, especially as inflammation may disrupt the blood-retinal and blood-aqueous barriers.
      • Cho H.
      • Madu A.
      Etiology and treatment of the inflammatory causes of cystoid macular edema.
      ,
      • Grzybowski A.
      • Sikorski B.L.
      • Ascaso F.J.
      • Huerva V.
      Pseudophakic cystoid macular edema: update 2016.
      A number of proinflammatory mediators contribute to inflammation and vascular permeability after cataract surgery. These include endogenous prostaglandins (PGs); complement components; platelet-activating factors; cytokines; nitric oxide; and growth factors, such as vascular endothelial growth factor (VEGF) and insulin-like growth factor-1.
      • Hernstadt D.J.
      • Husain R.
      Effect of prostaglandin analogue use on the development of cystoid macular edema after phacoemulsification using STROBE statement methodology.
      ,
      • Miyake K.
      • Ibaraki N.
      Prostaglandins and cystoid macular edema.
      It has been suggested that, after cataract surgery, inflammatory mediators that accumulate in the aqueous humor damage the blood-aqueous barrier and diffuse through the vitreous to the retina where they cause blood-retinal barrier disruption.
      • Miyake K.
      • Ibaraki N.
      Prostaglandins and cystoid macular edema.
      Taken together, this suggests that underlying inflammation, complicated cataract surgery, or use of proinflammatory medications such as PGAs may increase the risk of development of CME.

      4. CME in patients with glaucoma

      The risk of CME in patients who receive postoperative PGAs after IOP-lowering glaucoma surgery has not yet been characterized. There are limited reports on CME after incisional glaucoma surgeries like trabeculectomy. One small study reported CME after trabeculectomy combined with intraoperative mitomycin C in 1 of the 26 operated eyes (3.8%), all of which had post-keratoplasty glaucoma.
      • Ishioka M.
      • Shimazaki J.
      • Yamagami J.
      • Fujishima H.
      • Shimmura S.
      • Tsubota K.
      Trabeculectomy with mitomycin C for post-keratoplasty glaucoma.
      It has been reported, however, that trabeculectomy may lead to increased macular thickness. In one prospective study, clinically significant macular thickening, defined as ≥17 μm, was observed in 2 of 34 patients (5.8%) within 1 month after trabeculectomy.
      • Sesar A.
      • Cavar I.
      • Sesar A.P.
      • et al.
      Macular thickness after glaucoma filtration surgery.
      In this report, CME development was not significantly influenced by preoperative treatment with PGAs or the use of mitomycin C during surgery.
      • Sesar A.
      • Cavar I.
      • Sesar A.P.
      • et al.
      Macular thickness after glaucoma filtration surgery.
      Similarly, it has been shown that trabeculectomy in 45 eyes of 44 patients led to a statistically significant increase in macular thickness from 164 ± 20 μm before surgery to 173 ± 19 μm 1 month postoperatively (P < 0.0001).
      • Karasheva G.
      • Goebel W.
      • Klink T.
      • Haigis W.
      • Grehn F.
      Changes in macular thickness and depth of anterior chamber in patients after filtration surgery.
      In this study, macular thickness returned to the preoperative value (165 ± 16 μm) at 3 months, and no patients had hypotony for more than 5 days after surgery.
      EX-PRESS® shunt implantation and glaucoma drainage device surgery are also incisional IOP-lowering procedures. There have been few cases of CME reported in patients who underwent Baerveldt shunt implantation. In a retrospective case series investigating the implantation of the Baerveldt device in 24 eyes of 24 patients with uveitic glaucoma, CME occurred in 3 eyes (12.5%).
      • Ceballos E.M.
      • Parrish R.K.
      • Schiffman J.C.
      Outcome of Baerveldt glaucoma drainage implants for the treatment of uveitic glaucoma.
      In both studies, there was an increased risk of CME in patients because of underlying uveitis. There were no reports of CME after Baerveldt shunt implantation in patients without uveitis. In a retrospective chart review of 16 patients with complicated secondary glaucoma, one case of CME development was reported 4 months after a Molteno device implantation; this patient had not received glaucoma medication after surgery but had previously undergone extracapsular cataract extraction and anterior chamber intraocular lens implantation, penetrating keratoplasty, and vitrectomy. These factors all likely contributed to the development of CME.
      • Lotufo D.G.
      Postoperative complications and visual loss following Molteno implantation.
      There are no published reports of CME development after Ahmed glaucoma valve or EX-PRESS shunt implantation.
      There have been some instances of CME development after less invasive glaucoma procedures. Although few detailed studies have reported CME after selective laser trabeculoplasty, numerous case reports have been published. All but one reported case occurred in eyes that had previously undergone phacoemulsification with intraocular lens implantation, and the onset of the CME ranged from 12 hours to 4 weeks after laser treatment.
      • Örnek N.
      • Örnek K.
      • Oğurel T.
      • Büyüktortop Gökçınar N.
      Cystoid macular edema following selective laser trabeculoplasty in a patient with ocular hypertension.
      ,
      • Phillis C.A.
      • Bourke R.D.
      Bilateral subretinal fluid mimicking subretinal neovascularization within 24 hours after selective laser trabeculoplasty.
      ,
      • Wechsler D.Z.
      • Wechsler I.B.
      Cystoid macular oedema after selective laser trabeculoplasty.
      ,
      • Wu Z.Q.
      • Huang J.
      • Sadda S.
      Selective laser trabeculoplasty complicated by cystoid macular edema: report of two cases.
      In the case in which CME was recognized 12 hours after selective laser trabeculoplasty, the patient used travoprost before the procedure, but it had not been administered postoperatively before the development of CME. This patient also had foveal opalescence due to subretinal fluid. The finding of CME after selective laser trabeculoplasty was considered uncommon, and the additional observation of subretinal fluid suggested that this was not a typical case of CME.
      • Phillis C.A.
      • Bourke R.D.
      Bilateral subretinal fluid mimicking subretinal neovascularization within 24 hours after selective laser trabeculoplasty.
      In terms of other laser procedures, CME occurred in 1 of 20 eyes (5%) treated with transscleral diode laser cyclophotocoagulation for the reduction of IOP after a failed Baerveldt glaucoma implantation.
      • Panarelli J.F.
      • Banitt M.R.
      • Sidoti P.A.
      Transscleral diode laser cyclophotocoagulation after Baerveldt glaucoma implant surgery.
      In a small retrospective chart review of 10 eyes of 9 patients, combination of cyclophotocoagulation and glaucoma drainage device implantation led to CME in both eyes of 1 patient.
      • Shields S.R.
      • Chen P.
      Sequential or simultaneous cyclophotocoagulation and glaucoma drainage implant for refractory glaucoma.
      Although all other patients in this study had received cyclophotocoagulation and glaucoma drainage device implantation on separate occasions, this patient was the only individual to have received both treatments simultaneously. This may have been a contributing factor to the development of CME.
      There are few reports of CME in relation to minimally invasive glaucoma surgical procedures. In a retrospective study of 21 eyes in 20 patients with pseudoexfoliative glaucoma who underwent XEN45 implantation with subconjunctival mitomycin C and had a minimum postoperative follow-up period of 12 months, one case of CME was recorded; however, this patient had undergone combined XEN implantation and phacoemulsification.
      • Ibáñez-Muñoz A.
      • Soto-Biforcos V.S.
      • Chacón-González M.
      • et al.
      One-year follow-up of the XEN® implant with mitomycin-C in pseudoexfoliative glaucoma patients.
      There were no additional reports published on CME development for other minimally invasive glaucoma surgery devices and procedures except for one case reported in a patient with pseudoexfoliative glaucoma after Kahook dual blade goniotomy.
      • Arnljots T.S.
      • Economou M.A.
      Reversible cystoid macular edema following uneventful microinvasive Kahook Dual Blade goniotomy in a pseudophakic patient: a case report.
      The patient previously underwent an uncomplicated cataract surgery with intraocular lens implantation, had peripapillary hemorrhage, received multiple IOP-lowering treatments (including bimatoprost–timolol and brinzolamide–brimonidine fixed combinations, and oral carbonic anhydrase inhibitor medication), and two previous selective laser trabeculoplasty treatments. CME was reported 1 month after the Kahook dual blade goniotomy in this patient, but this could be attributable to the complicated ocular history.
      • Arnljots T.S.
      • Economou M.A.
      Reversible cystoid macular edema following uneventful microinvasive Kahook Dual Blade goniotomy in a pseudophakic patient: a case report.
      In a retrospective, single-center, cohort study in which patients who underwent uneventful cataract surgery alone (n = 234) were compared with patients for whom cataract surgery was performed in combination with ab-interno glaucoma surgery (trabecular aspiration or ab-interno trabeculotomy; n = 126), no significant difference in the incidence of CME between the two groups was found 48 weeks after cataract surgery (cataract surgery only, 16 of 234 eyes [6.8%]; cataract and ab-interno surgery, 7 of 126 eyes [5.5%]; P = 0.676). This result suggests that trabecular aspiration and ab-interno trabeculectomy did not increase the risk of CME compared with cataract surgery alone.
      • Schaub F.
      • Adler W.
      • Koenig M.C.
      • et al.
      Combined ab interno glaucoma surgery does not increase the risk of pseudophakic cystoid macular edema in uncomplicated eyes.
      There is evidence in the literature to suggest that there may be an association between cataract surgery and the development of CME in patients with glaucoma, and in those who receive topical PGA therapy.
      • Hernstadt D.J.
      • Husain R.
      Effect of prostaglandin analogue use on the development of cystoid macular edema after phacoemulsification using STROBE statement methodology.
      ,
      • Wendel C.
      • Zakrzewski H.
      • Carleton B.
      • Etminan M.
      • Mikelberg F.S.
      Association of postoperative topical prostaglandin analog or beta-blocker use and incidence of pseudophakic cystoid macular edema.
      The incidence of pseudophakic CME varies depending on the diagnostic method and the cataract surgery technique. A comparison of CME after different cataract extraction techniques showed that the incidence of clinically significant CME was higher after extracapsular cataract extraction compared with intracapsular cataract extraction and phacoemulsification. The incidence of angiographic CME was higher after intracapsular cataract extraction and phacoemulsification than after extracapsular cataract extraction when detected using FA.
      • Grzybowski A.
      • Sikorski B.L.
      • Ascaso F.J.
      • Huerva V.
      Pseudophakic cystoid macular edema: update 2016.
      However, no difference in the risk of CME was reported between femtosecond laser–assisted cataract surgery and conventional cataract surgery.
      • Levitz L.
      • Reich J.
      • Roberts T.V.
      • Lawless M.
      Incidence of cystoid macular edema: femtosecond laser-assisted cataract surgery versus manual cataract surgery.
      The frequency of CME after uncomplicated cataract surgery, as measured by spectral-domain OCT, is significantly greater in patients with primary open-angle glaucoma (44%, 31/70 eyes) than in patients without glaucoma (21%, 14/68 eyes) (P = 0.003).
      • Lee K.M.
      • Lee E.J.
      • Kim T.-W.
      • Kim H.
      Pseudophakic macular edema in primary open-angle glaucoma: a prospective study using spectral-domain optical coherence tomography.
      In this prospective study, the risk of CME in patients with glaucoma was highest in patients with primary open-angle glaucoma using PGAs compared with those who did not use PGAs (odds ratio = 5.51; P = 0.001).
      • Lee K.M.
      • Lee E.J.
      • Kim T.-W.
      • Kim H.
      Pseudophakic macular edema in primary open-angle glaucoma: a prospective study using spectral-domain optical coherence tomography.
      This suggests that PGAs can play a role in the development of pseudophakic CME.
      • Miyake K.
      • Ibaraki N.
      Prostaglandins and cystoid macular edema.

      5. The role of PGs in the development of pseudophakic CME

      Endogenous PGs are lipid mediators that are produced from the cleavage of membrane phospholipids by phospholipase A2 to arachidonic acid. Arachidonic acid is subsequently metabolized by the cyclooxygenase (COX) enzymes (COX1 and COX2) to eventually produce thromboxanes and PGs (PGD2, PGE2, PGI2, and PGF).
      • Ricciotti E.
      • FitzGerald G.A.
      Prostaglandins and inflammation.
      A summary of the ocular localization of PG receptors is provided in Table 2. Analogs of PGF are commonly used to lower IOP in patients with open-angle glaucoma by increasing uveoscleral outflow of aqueous humor. This is thought to be due to extracellular matrix remodeling and relaxation of the ciliary muscle.
      • Winkler N.S.
      • Fautsch M.P.
      Effects of prostaglandin analogues on aqueous humor outflow pathways.
      Table 2A summary of ocular prostaglandin receptors
      ProstaglandinProstaglandin receptorOcular localization
      PGD2DPCiliary epithelium/process, longitudinal and circular ciliary muscles, retinal choroid, and iris in human eye sections
      • Sharif N.A.
      • Williams G.W.
      • Davis T.L.
      Pharmacology and autoradiography of human DP prostanoid receptors using [3H]-BWA868C, a DP receptor-selective antagonist radioligand.
      PGE2EP1Highest expression in epithelia of the cornea, conjunctiva, lens, and ciliary body; also found in trabecular endothelial cells and meshwork, vascular endothelial cells of the iris, retinal ganglion cells and photoreceptor cells, cells lining Schlemm's canal, collector channels, and scleral aqueous veins
      • Schlötzer-Schrehardt U.
      • Zenkel M.
      • Nüsing R.M.
      Expression and localization of FP and EP prostanoid receptor subtypes in human ocular tissues.
      EP2Corneal epithelium, conjunctival epithelium at the limbus, and vascular endothelium of choriocapillaries. More abundant in the outer wall of Schlemm's canal and scleral cells, collector channels, and scleral aqueous veins than in the trabecular meshwork. Also found in the ciliary epithelium and ganglion cells and retinal nerve fiber layer
      • Schlötzer-Schrehardt U.
      • Zenkel M.
      • Nüsing R.M.
      Expression and localization of FP and EP prostanoid receptor subtypes in human ocular tissues.
      EP3Corneal endothelium, keratocytes, endothelial cells of the trabecular meshwork, ciliary epithelium, conjunctival and iridal stromal cells, and retinal Müller cells. Moderate levels in endothelial cells lining Schlemm's canal and collector channels
      • Schlötzer-Schrehardt U.
      • Zenkel M.
      • Nüsing R.M.
      Expression and localization of FP and EP prostanoid receptor subtypes in human ocular tissues.
      EP4Corneal endothelium, keratocytes, endothelial cells of the trabecular meshwork, ciliary epithelium, and conjunctival and iridal stromal cells. Also found in endothelial cells lining Schlemm's canal, the collector channels, aqueous veins, iridal vessels, and the retinal nerve fiber layer
      • Schlötzer-Schrehardt U.
      • Zenkel M.
      • Nüsing R.M.
      Expression and localization of FP and EP prostanoid receptor subtypes in human ocular tissues.
      PGFFPCorneal epithelium, ciliary epithelium, circular portion of the ciliary muscle, and the iridal stromal and smooth muscle cells. Moderate levels in the outer portions of the trabecular meshwork and endothelial cells of Schlemm's canal, collector channels, and aqueous veins. Also found in vascular endothelial cells and ciliary muscle vasculature, but not in capillaries in the ciliary processes
      • Schlötzer-Schrehardt U.
      • Zenkel M.
      • Nüsing R.M.
      Expression and localization of FP and EP prostanoid receptor subtypes in human ocular tissues.
      PGI2IPUnknown, but gene expression studies suggest that there is more gene expression present in Schlemm's canal cells than in the trabecular meshwork
      • Wang J.W.
      • Woodward D.F.
      • Stamer W.D.
      Differential effects of prostaglandin E2-sensitive receptors on contractility of human ocular cells that regulate conventional outflow.
      A role for PGs in inducing blood-aqueous barrier disruption has been described, and the proposed mechanisms by which PGAs and postsurgical endogenous PGs increase the risk of CME after cataract surgery are shown in Fig. 3. The ciliary processes actively uptake PGs from ocular fluids.
      • Bito L.Z.
      Accumulation and apparent active transport of prostaglandins by some rabbit tissues in vitro.
      ,
      • Bito L.Z.
      The effects of experimental uveitis on anterior uveal prostaglandin transport and aqueous humor composition.
      ,
      • Kraft M.E.
      • Glaeser H.
      • Mandery K.
      • et al.
      The prostaglandin transporter OATP2A1 is expressed in human ocular tissues and transports the antiglaucoma prostanoid latanoprost.
      This process was inhibited in a model of uveitis and led to accumulation of PGs in the anterior chamber, suggesting that active transport of PGs was interrupted.
      • Bito L.Z.
      The effects of experimental uveitis on anterior uveal prostaglandin transport and aqueous humor composition.
      Similarly, PGE2, which influences vascular permeability, was increased in both the aqueous humor and vitreous body of rabbits that underwent intracapsular cataract extraction and received topical epinephrine, compared with those that received epinephrine and indomethacin, or did not undergo cataract extraction but received topical epinephrine.
      • Miyake K.
      • Shirasawa E.
      • Hikita M.
      Active transport system of prostaglandins: clinical implications and considerations.
      This was attributed to impairment of ocular transport of PGE2 by the ciliary processes after cataract surgery. Epinephrine-induced PG production leads to COX-dependent blood-aqueous barrier disruption, which can be inhibited by the COX inhibitor indomethacin, suggesting a role for PGs in increasing vascular permeability.
      • Miyake K.
      • Shirasawa E.
      • Hikita M.
      Active transport system of prostaglandins: clinical implications and considerations.
      Elevation of PGE2 and PGF production levels in the aqueous humor immediately after cataract surgery has also been shown in humans.
      • Miyake K.
      • Ibaraki N.
      Prostaglandins and cystoid macular edema.
      ,
      • Schultz T.
      • Joachim S.C.
      • Kuehn M.
      • Dick H.B.
      Changes in prostaglandin levels in patients undergoing femtosecond laser-assisted cataract surgery.
      In addition, a pooled analysis of phase 2 and 3 studies (N = 267) investigating omidenepag isopropyl, a nonprostaglandin prostanoid EP2 receptor agonist approved in Japan for the treatment of glaucoma and ocular hypertension, found CME in 5.2% of the treated patients. All patients with treatment-related CME had previously had cataract surgery with intraocular lens implantation.
      • Duggan S.
      Omidenepag isopropyl ophthalmic solution 0.002%: first global approval.
      ,
      Santen Pharmaceutical Co., Ltd
      EYBELIS ophthalmic solution 0.002% package insert [Japanese].
      For this reason, according to the Japanese package insert, omidenepag isopropyl is contraindicated in patients who have undergone cataract surgery with intraocular lens implantation or who are aphakic.
      Santen Pharmaceutical Co., Ltd
      EYBELIS ophthalmic solution 0.002% package insert [Japanese].
      The lack of treatment-related CME in phakic eyes suggests that treatment-related risk of CME development may be specific to pseudophakic patients.
      Figure thumbnail gr3
      Fig. 3Proposed mechanism by which PGs increase the risk of CME after cataract surgery. After cataract surgery, lens epithelial cells and other anterior segment tissues are affected by surgical stress release inflammatory mediators. Postsurgical inflammation leads to inhibition of PG clearance from the aqueous humor by the ciliary processes, resulting in the accumulation of endogenous PG production in the anterior chamber. Accumulation of inflammatory mediators may result in blood-aqueous barrier breakdown. Transvitreal diffusion of inflammatory mediators to the retina may result in blood-retinal barrier breakdown and subsequent development of CME. CME, cystoid macular edema; PG, prostaglandin; PGA, prostaglandin analog.
      It is thought that the lens capsule acts as a diffusion barrier between the anterior and posterior segments and maintains topographical integrity of the anterior segment of the eye.
      • Miyake K.
      • Miyake T.
      • Miyake C.
      • Asakura M.
      • Maekubo K.
      Outward transport of fluorescein from the vitreous in aphakic eyes.
      ,
      • Miyake K.
      • Shirasawa E.
      • Hikita M.
      Active transport system of prostaglandins: clinical implications and considerations.
      Intraocular lens implantation in cataract surgery may induce changes in the lens epithelial cells and other tissues of the anterior segment subjected to surgical stress and lead to endogenous production of COX2, PGE2, and cytokines.
      • Jiang J.
      • Shihan M.H.
      • Wang Y.
      • Duncan M.K.
      Lens epithelial cells initiate an inflammatory response following cataract surgery.
      ,
      • Miyake K.
      • Ibaraki N.
      Prostaglandins and cystoid macular edema.
      Miyake and coworkers proposed that the secretion of proinflammatory molecules and changes in lens-related barrier function after cataract surgery may contribute to the development of aqueous humor flare.
      • Miyake K.
      • Ota I.
      • Maekubo K.
      • Ichihashi S.
      • Miyake S.
      Latanoprost accelerates disruption of the blood-aqueous barrier and the incidence of angiographic cystoid macular edema in early postoperative pseudophakias.
      Aqueous humor flare, which appears as light scattering caused by protein in the aqueous humor at slit-lamp examination, reflects the disruption of the blood-aqueous barrier several weeks after cataract surgery.
      • Miyake K.
      • Ota I.
      • Maekubo K.
      • Ichihashi S.
      • Miyake S.
      Latanoprost accelerates disruption of the blood-aqueous barrier and the incidence of angiographic cystoid macular edema in early postoperative pseudophakias.
      It has been suggested that accumulated PGs in the aqueous chamber influence the production of inflammatory mediators. The inflammatory mediators can reach the posterior part of the eye via transvitreal diffusion and disrupt the blood-retinal barrier, which causes fluid accumulation in the retina.
      • Miyake K.
      • Ibaraki N.
      Prostaglandins and cystoid macular edema.
      It is unlikely, however, that PGAs directly influence normal blood-aqueous barrier function. Rather, they may prolong the production of endogenous proinflammatory mediators after incisional eye surgery, such as those produced by the lens epithelial cells after cataract surgery.
      • Miyake K.
      • Ota I.
      • Maekubo K.
      • Ichihashi S.
      • Miyake S.
      Latanoprost accelerates disruption of the blood-aqueous barrier and the incidence of angiographic cystoid macular edema in early postoperative pseudophakias.
      This has been supported by data showing that latanoprost, travoprost, and bimatoprost had no statistically significant effect on the blood-aqueous barrier of phakic eyes with primary open-angle glaucoma or ocular hypertension, which may indicate a specific risk of CME development in pseudophakic patients.
      • Arcieri E.S.
      • Pierre Filho P.T.P.
      • Wakamatsu T.H.
      • Costa V.P.
      The effects of prostaglandin analogues on the blood aqueous barrier and corneal thickness of phakic patients with primary open-angle glaucoma and ocular hypertension.
      According to general clinical experience, the temporary increase in endogenous aqueous humor PG levels after uncomplicated cataract surgery does not affect the blood-retina barrier in a clinically significant manner; however, mild CME can frequently be detected with OCT after uncomplicated cataract surgery in patients without visual symptoms.
      • Meredith T.A.
      • Kenyon K.R.
      • Singerman L.J.
      • Fine S.L.
      Perifoveal vascular leakage and macular oedema after intracapsular cataract extraction.
      ,
      • Shelsta H.N.
      • Jampol L.M.
      Pharmacologic therapy of pseudophakic cystoid macular edema: 2010 update.
      By contrast, increased endogenous PG release after complicated cataract surgery or the cumulative effect of uncomplicated phacoemulsification and the use of topical PGAs in the early postoperative weeks may increase inflammation. This may lead to increased blood-aqueous and blood-retinal barrier permeability and clinically significant CME. In a randomized, double-masked trial, once-daily topical latanoprost (N = 37 eyes) significantly increased the incidence of fluorescein leakage into a cystic space, measured by FA, compared with topical placebo administration (N = 37 eyes) when both treatments were combined with topical corticosteroid (fluorometholone) drops (81% compared with 35%, respectively; P < 0.01).
      • Miyake K.
      • Ibaraki N.
      Prostaglandins and cystoid macular edema.
      By contrast, the incidence of fluorescein leakage in the same study was significantly lower when latanoprost was combined with diclofenac, a COX inhibitor, instead of fluorometholone (8.5% compared with 81%, respectively; P < 0.05). These results suggest that COX-mediated PG metabolism may have a role in increasing the risk of CME. It should be noted that because FA examination was done on all patients regardless of visual symptoms, CME may have been diagnosed in eyes without visual disturbance.
      • Miyake K.
      • Ibaraki N.
      Prostaglandins and cystoid macular edema.
      For this reason, caution should be exercised when treating high-risk eyes with PGAs. However, even in this population, the risk of visually significant CME is low; it developed in 5% of pseudophakic patients with additional risk factors after receiving latanoprost in a study of 40 patients.
      • Wand M.
      • Gaudio A.R.
      • Shields M.B.
      Latanoprost and cystoid macular edema in high-risk aphakic or pseudophakic eyes.
      It has been suggested that a risk-benefit analysis for each eye should be individually determined.
      • Hernstadt D.J.
      • Husain R.
      Effect of prostaglandin analogue use on the development of cystoid macular edema after phacoemulsification using STROBE statement methodology.
      Other studies showing increased occurrence of CME in pseudophakic patients receiving PGAs are described in the next section of this review. Although CME leads to a noticeable decrease in visual acuity, withdrawal of the PGA and treatment of the CME leads to recovery of visual functions in most cases.
      • Carrillo M.M.
      • Nicolela M.T.
      Cystoid macular edema in a low-risk patient after switching from latanoprost to bimatoprost.
      ,
      • Wand M.
      • Gaudio A.R.
      Cystoid macular edema associated with ocular hypotensive lipids.
      ,
      • Warwar R.E.
      • Bullock J.D.
      • Ballal D.
      Cystoid macular edema and anterior uveitis associated with latanoprost use. Experience and incidence in a retrospective review of 94 patients.
      ,
      • Yeh P.C.
      • Ramanathan S.
      Latanoprost and clinically significant cystoid macular edema after uneventful phacoemulsification with intraocular lens implantation.

      6. Clinical experience with CME in topical PGA users

      In one recent investigation, PGAs have recently been recommended for the prophylactic treatment of IOP elevation after uncomplicated cataract surgery.
      • Holm J.L.
      • Bach-Holm D.
      • Holm L.M.
      • Vestergaard A.H.
      Prophylactic treatment of intraocular pressure elevation after uncomplicated cataract surgery in nonglaucomatous eyes – a systematic review.
      As previously mentioned in this review, the use of PGAs typically does not cause CME in phakic patients with a normally functioning blood-ocular barrier but may increase the incidence of CME after cataract surgery.
      • Arcieri E.S.
      • Pierre Filho P.T.P.
      • Wakamatsu T.H.
      • Costa V.P.
      The effects of prostaglandin analogues on the blood aqueous barrier and corneal thickness of phakic patients with primary open-angle glaucoma and ocular hypertension.
      ,
      • Furuichi M.
      • Chiba T.
      • Abe K.
      • et al.
      Cystoid macular edema associated with topical latanoprost in glaucomatous eyes with a normally functioning blood-ocular barrier.
      ,
      • Yeom H.Y.
      • Hong S.
      • Kim S.S.
      • Kim C.Y.
      • Seong G.J.
      Influence of topical bimatoprost on macular thickness and volume in glaucoma patients with phakic eyes.
      In a retrospective study comprising data from 1659 cataract surgeries, preoperative use of PGAs was associated with a significant risk of the development of CME when patients with diabetes mellitus were excluded (odds ratio = 12.45).
      • Henderson B.A.
      • Kim J.Y.
      • Ament C.S.
      • Ferrufino-Ponce Z.K.
      • Grabowska A.
      • Cremers S.L.
      Clinical pseudophakic cystoid macular edema. Risk factors for development and duration after treatment.
      Similarly, a nested case-control study (N = 508 cases) found that postoperative use of bimatoprost or travoprost/travoprost-z in the year before diagnosis of pseudophakic CME was significantly associated with increased incidence of pseudophakic CME.
      • Wendel C.
      • Zakrzewski H.
      • Carleton B.
      • Etminan M.
      • Mikelberg F.S.
      Association of postoperative topical prostaglandin analog or beta-blocker use and incidence of pseudophakic cystoid macular edema.
      In the same investigation, there was no association found between pseudophakic CME and postsurgical use of latanoprost; however, the association was significant between overall PGA use (including latanoprost) and CME development (relative risk compared with no PGA use = 1.86). The difference between latanoprost and the other PGAs was not explained. In a prospective, randomized, observer-masked, 6-month trial in pseudophakic or aphakic patients with glaucoma, CME was detected using FA in 4 of 15 latanoprost-treated eyes (27%), 1 of 16 bimatoprost-treated eyes (6%), and 1 of 17 travoprost-treated eyes (6%) up to 6 months after treatment initiation.
      • Arcieri E.S.
      • Santana A.
      • Rocha F.N.
      • Guapo G.L.
      • Costa V.P.
      Blood-aqueous barrier changes after the use of prostaglandin analogues in patients with pseudophakia and aphakia: a 6-month randomized trial.
      There was no statistically significant difference between the three PGAs in the incidence of CME. The mean aqueous flare values throughout follow up were significantly higher in patients receiving bimatoprost, latanoprost, and travoprost compared with unoprostone (P < 0.02); however, there was no difference in aqueous flare between eyes treated with bimatoprost, latanoprost, or travoprost.
      • Arcieri E.S.
      • Santana A.
      • Rocha F.N.
      • Guapo G.L.
      • Costa V.P.
      Blood-aqueous barrier changes after the use of prostaglandin analogues in patients with pseudophakia and aphakia: a 6-month randomized trial.
      In another study, in patients with pseudoexfoliative glaucoma, CME occurred in 3 of 69 PGA-treated eyes (4.4%) after uncomplicated cataract surgery.
      • Gonnermann J.
      • Klamann M.K.J.
      • Maier A.-K.B.
      • Torun N.
      • Ruokonen P.C.
      • Bertelmann E.
      Influence of prostaglandin analogue on outcome after combined cataract surgery and trabecular aspiration in pseudoexfoliative glaucoma.
      However, the PGAs associated with CME and the time of the onset of CME after cataract surgery were not specified. CME has been reported in a patient who did not have glaucoma but who accidentally administered 6 doses of latanoprost for 7 days after uncomplicated phacoemulsification with intraocular lens implantation instead of the prescribed tobramycin-dexamethasone drops. In this case, the CME with latanoprost was closely linked with the cataract surgery and not underlying glaucoma.
      • Makri O.E.
      • Tsekouras I.K.
      • Plotas P.
      • Tsapardoni F.
      • Pallikari A.
      • Georgakopoulos C.D.
      Cystoid macular edema due to accidental latanoprost overdose after uncomplicated phacoemulsification.
      Regarding data on the relationship between individual PGAs and the development of CME, most publications concern latanoprost, the first and most widely used PGA in clinical practice. The incidence of CME during latanoprost treatment is reported between 1.2 and 5% of eyes that had previously undergone cataract surgery.
      • Lima M.C.
      • Paranhos A.
      • Salim S.
      • et al.
      Visually significant cystoid macular edema in pseudophakic and aphakic patients with glaucoma receiving latanoprost.
      ,
      • Warwar R.E.
      • Bullock J.D.
      • Ballal D.
      Cystoid macular edema and anterior uveitis associated with latanoprost use. Experience and incidence in a retrospective review of 94 patients.
      ,
      • Yeh P.C.
      • Ramanathan S.
      Latanoprost and clinically significant cystoid macular edema after uneventful phacoemulsification with intraocular lens implantation.
      ,
      • Wand M.
      • Gaudio A.
      • Shields B.
      Cystoid macular edema and latanoprost: a prospective study.
      CME has been reported to occur from 7 days after initiation of latanoprost treatment up to 11 months after treatment initiation
      • Ayyala R.S.
      • Cruz D.A.
      • Margo C.E.
      • et al.
      Cystoid macular edema associated with latanoprost in aphakic and pseudophakic eyes.
      ,
      • Callanan D.
      • Fellman R.L.
      • Savage J.A.
      Latanoprost-associated cystoid macular edema.
      ,
      • Heier J.S.
      • Steinert R.F.
      • Frederick A.R.
      Cystoid macular edema associated with latanoprost use.
      ,
      • Lima M.C.
      • Paranhos A.
      • Salim S.
      • et al.
      Visually significant cystoid macular edema in pseudophakic and aphakic patients with glaucoma receiving latanoprost.
      ,
      • Makri O.E.
      • Tsapardoni F.N.
      • Plotas P.
      • Ifantis N.
      • Xanthopoulou P.T.
      • Georgakopoulos C.D.
      Cystoid macular edema associated with preservative-free latanoprost after uncomplicated cataract surgery: case report and review of the literature.
      ,
      • Moroi S.E.
      • Gottfredsdottir M.S.
      • Schteingart M.T.
      • et al.
      Cystoid macular edema associated with latanoprost therapy in a case series of patients with glaucoma and ocular hypertension.
      ,
      • Warwar R.E.
      • Bullock J.D.
      • Ballal D.
      Cystoid macular edema and anterior uveitis associated with latanoprost use. Experience and incidence in a retrospective review of 94 patients.
      ,
      • Wand M.
      • Gaudio A.
      • Shields B.
      Cystoid macular edema and latanoprost: a prospective study.
      ; however, it is unknown if longer duration of latanoprost treatment increases the incidence of CME. A case report has described development of CME 1 month after switching isopropyl unoprostone to latanoprost in a pseudophakic eye with a history of surgical complications.
      • Watanabe K.
      • Hayasaka S.
      • Hayasaka Y.
      • Nagaki Y.
      • Watanabe K.
      Cystoid macular edema associated with latanoprost use in a pseudophakic eye with a history of surgical complications.
      Within 8 weeks of the treatment change, visual acuity decreased, and CME was detected. No association between CME and latanoprostene bunod has been reported. This may be because of a lack of experience with long-term use of this molecule in a wide population of patients, considering that it only became available at the end of 2017; however, the prescribing information states that, owing to the PGA component, it should be used cautiously in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, and in patients with known risk factors for macular edema.
      Bausch & Lomb Incorporated
      Vyzulta prescribing information.
      Two case reports have been published on two separate incidents of CME in patients who received topical tafluprost treatment after cataract surgery. It was not specified in either report whether the formulation used was preservative free or preserved. Because the preserved formulation contains a low concentration of benzalkonium chloride (BAK) (0.001%, as opposed to 0.02% in BAK-preserved latanoprost), it seems likely that these rare cases were attributable to the PGA component of the treatment rather than the preservative.
      • Matsuura K.
      • Uotani R.
      • Terasaka Y.
      Subtenon triamcinolone injection for postoperative cystoid macular edema associated with tafluprost.
      ,
      • Sacchi M.
      • Villani E.
      • Nucci P.
      Efficacy of preservative-free tafluprost in patients with normal-tension glaucoma previously treated with latanoprost.
      The role of BAK in the development of CME is discussed later in this review.
      Despite the evidence provided for the increased risk of pseudophakic CME by treatment with topical PGAs, in some publications the authors dispute the role of PGAs in increasing this risk. In a retrospective comparative case series of patients with uveitis and raised IOP, CME occurred only in 6 of 127 eyes (5%) on PGA medication and with a history of, or high risk for, CME, and in 9 of 96 eyes (9%) that had a similar history and risk but did not receive PGAs.
      • Chang J.H.
      • McCluskey P.
      • Missotten T.
      • Ferrante P.
      • Jalaludin B.
      • Lightman S.
      Use of ocular hypotensive prostaglandin analogues in patients with uveitis: does their use increase anterior uveitis and cystoid macular oedema?.
      Similar results were reported in a large retrospective database study of 3394 eyes that underwent cataract surgery. This study found that there was no statistically significant increase in the risk of clinically significant CME related to PGA use in the first 3 months after cataract surgery (relative risk to eyes that were not treated with PGAs was 1.11 [95% confidence interval 0.816–1.513]).
      • Chu C.J.
      • Johnston R.L.
      • Buscombe C.
      • et al.
      Risk factors and incidence of macular edema after cataract surgery: a database study of 81984 eyes.
      The reported retrospective studies have limitations including the nature of the retrospective study design. In addition, the studies only recorded clinically significant macular edema and have not systematically and continuously monitored patients using OCT or FA. Prospective studies on the relationship between PGAs and the development of CME are limited; however, a small, prospective, randomized controlled study has shown that treatment with latanoprost in the first month after cataract surgery (n = 76) significantly increased mean central macular thickness (±standard deviation) by 12 ± 49 μm from baseline (P = 0.03), but this returned to baseline by month 3. Changes from baseline were not significantly different from patients who discontinued latanoprost treatment after cataract surgery (n = 80).
      • Fakhraie G.
      • Mirghorbani M.
      • Katz L.J.
      • et al.
      Cystoid macular edema with prostaglandin analogue use after uneventful cataract surgery in glaucoma patients.
      Similarly, another small prospective study found that in 41 eyes of 31 patients treated with latanoprost for at least 4 months after cataract surgery, there was no significant change from baseline in central macular thickness, average macular thickness, or macular volume.
      • Moghimi S.
      • Zandian M.
      • Latifi G.
      • et al.
      Topical latanoprost does not cause macular thickening after uncomplicated cataract surgery.
      These data are not in agreement with most retrospective studies which found an overall association between PGA use and CME development; however, this may be explained by the findings of Wendel and coworkers,
      • Wendel C.
      • Zakrzewski H.
      • Carleton B.
      • Etminan M.
      • Mikelberg F.S.
      Association of postoperative topical prostaglandin analog or beta-blocker use and incidence of pseudophakic cystoid macular edema.
      who found an overall association between PGA use and CME development (N = 508) but did not observe this association with latanoprost specifically.

      6.1 PGA-timolol fixed combinations and CME

      Fixed combinations of a PGA and timolol are extensively used in clinical practice. Therefore, the relationship between the various PGA-timolol fixed-dose combinations and CME is of clinical importance. In a 6-week, prospective, randomized, open-label study, CME was not reported in patients who did not have recent cataract surgery and received a combination of latanoprost and timolol, whether taken as separate instillations (n = 58) or as a fixed-dose combination (n = 56).
      • Bhagat P.
      • Sodimalla K.
      • Paul C.
      • et al.
      Efficacy and safety of benzalkonium chloride-free fixed-dose combination of latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension.
      The macula was assessed using dilated fundoscopy, but it was not stated if patients were monitored for CME or if it was diagnosed after a visual complaint. Therefore, this study suggests that the addition of timolol does not increase the risk of CME in eyes treated with latanoprost that do not have a history of recent cataract surgery or ocular inflammation.
      • Bhagat P.
      • Sodimalla K.
      • Paul C.
      • et al.
      Efficacy and safety of benzalkonium chloride-free fixed-dose combination of latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension.
      In a prospective investigation of the use of latanoprost-timolol in the treatment of glaucoma or ocular hypertension, it was shown that treatment with latanoprost-timolol fixed-dose combination led to the development of CME in 8 of 974 PGA-naive patients with glaucoma (0.8%).
      • Alm A.
      • Grunden J.W.
      • Kwok K.K.
      Five-year, multicenter safety study of fixed-combination latanoprost/timolol (Xalacom) for open-angle glaucoma and ocular hypertension.
      However, no information on cataract surgery or pseudophakia was reported. In a retrospective study of 508 cases of CME in patients with a history of cataract surgery, 10 of 508 cases (1.97%) had been treated with β-blocker monotherapy, 25 of 508 cases (4.92%) with PGA monotherapy, and 5 of 508 cases (0.98%) with β-blocker and PGA.
      • Wendel C.
      • Zakrzewski H.
      • Carleton B.
      • Etminan M.
      • Mikelberg F.S.
      Association of postoperative topical prostaglandin analog or beta-blocker use and incidence of pseudophakic cystoid macular edema.
      The risk of CME development was not statistically different for PGA monotherapy or combined PGA and β-blocker treatment. A randomized, prospective, double-masked study found significantly increased aqueous humor flare in eyes treated with timolol and fluorometholone compared with preserved vehicle in the first week after cataract surgery, and compared with preservative-free vehicle up to 2 weeks after surgery (P < 0.05 for all).
      • Miyake K.
      • Ota I.
      • Ibaraki N.
      • et al.
      Enhanced disruption of the blood-aqueous barrier and the incidence of angiographic cystoid macular edema by topical timolol and its preservative in early postoperative pseudophakia.
      We found no data on CME development in eyes treated with bimatoprost-timolol, travoprost-timolol, or tafluprost-timolol fixed combinations. Overall, data regarding the risk of CME development with combined PGA and timolol treatment are lacking, and more studies are required to adequately conclude if combination treatments influence the risk of CME compared with PGA monotherapy.

      6.2 The role of preservatives in the development of CME

      Some published data suggest that BAK, a commonly used preservative in ophthalmic solutions, may increase the incidence of CME in pseudophakic eyes. A randomized, prospective, double-masked study found significantly increased aqueous humor flare in eyes treated with BAK-preserved vehicle and fluorometholone compared with preservative-free vehicle and fluorometholone (P < 0.05).
      • Miyake K.
      • Ota I.
      • Ibaraki N.
      • et al.
      Enhanced disruption of the blood-aqueous barrier and the incidence of angiographic cystoid macular edema by topical timolol and its preservative in early postoperative pseudophakia.
      The incidence of fluorescein leakage into a cystic space, measured by FA, was higher in eyes treated with BAK-preserved vehicle and fluorometholone than preservative-free vehicle and fluorometholone (26 of 28 eyes and 9 of 27 eyes, respectively; P < 0.01). Similarly, a prospective, randomized, investigator-masked study (N = 44) showed that artificial tears containing BAK increased aqueous humor flare compared with preservative-free artificial tears.
      • Abe R.Y.
      • Zacchia R.S.
      • Santana P.R.
      • Costa V.P.
      Effects of benzalkonium chloride on the blood-aqueous and blood-retinal barriers of pseudophakic eyes.
      Although there were no cases of CME in this small study, it was concluded that BAK may cause blood-aqueous barrier disruption but does not lead to blood-retinal barrier disruption. Sufficiently powered randomized investigations are necessary to clarify if BAK-preserved formulations of topical PGA and PGA-timolol fixed-dose combinations increase the risk of CME development compared with the corresponding preservative-free formulations in pseudophakic eyes.

      6.3 Overall consensus on the use of PGAs after cataract surgery

      Currently, there is a lack of prospective, controlled trials that investigate the risk of CME development in pseudophakic eyes. Overall, in the postoperative period, caution should be exercised in administering PGAs in eyes with risk factors for CME, and a risk-benefit analysis for the individual patient should be considered. Concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) with PGA treatment or close monitoring of the patient for CME should be considered.
      • Hernstadt D.J.
      • Husain R.
      Effect of prostaglandin analogue use on the development of cystoid macular edema after phacoemulsification using STROBE statement methodology.

      7. Management of pseudophakic CME

      PGA-related CME can be effectively treated with discontinuation of the PGA and appropriate treatment of the CME.
      • Arcieri E.S.
      • Santana A.
      • Rocha F.N.
      • Guapo G.L.
      • Costa V.P.
      Blood-aqueous barrier changes after the use of prostaglandin analogues in patients with pseudophakia and aphakia: a 6-month randomized trial.
      ,
      • Makri O.E.
      • Tsapardoni F.N.
      • Plotas P.
      • Ifantis N.
      • Xanthopoulou P.T.
      • Georgakopoulos C.D.
      Cystoid macular edema associated with preservative-free latanoprost after uncomplicated cataract surgery: case report and review of the literature.
      In pseudophakic CME, the most commonly used treatment strategy is to suppress postsurgical inflammation using topical NSAIDs or corticosteroids, either separately or as a combined treatment.
      • Grzybowski A.
      • Sikorski B.L.
      • Ascaso F.J.
      • Huerva V.
      Pseudophakic cystoid macular edema: update 2016.
      ,
      • Henderson B.A.
      • Kim J.Y.
      • Ament C.S.
      • Ferrufino-Ponce Z.K.
      • Grabowska A.
      • Cremers S.L.
      Clinical pseudophakic cystoid macular edema. Risk factors for development and duration after treatment.
      A summary of the medical interventions used to treat pseudophakic CME is provided in Table 3. Corticosteroids are commonly used to treat pseudophakic CME because of their well-known anti-inflammatory effects. It has been shown that within the first 2 months of treatment, intravitreal triamcinolone acetonide injection provides significant improvement in visual acuity and reduction of macular thickness compared with pars plana vitrectomy performed without the use of corticosteroids, but the differences are not sustained for 12 months.
      • Sevim M.S.
      • Sanisoglu H.
      • Turkyilmaz K.
      Intravitreal triamcinolone acetonide versus pars plana vitrectomy for pseudophakic cystoid macular edema.
      It has been reported, however, that there is a risk of CME recurrence 2–4 months after intravitreal administration of triamcinolone acetonide.
      • Benhamou N.
      • Massin P.
      • Haouchine B.
      • Audren F.
      • Tadayoni R.
      • Gaudric A.
      Intravitreal triamcinolone for refractory pseudophakic macular edema.
      Intravitreal triamcinolone may be beneficial in patients with long-term or persistent pseudophakic CME; however, a clinically significant sustained IOP elevation is frequently associated with this intervention.
      • Boscia F.
      • Furino C.
      • Dammacco R.
      • Ferreri P.
      • Sborgia L.
      • Sborgia C.
      Intravitreal triamcinolone acetonide in refractory pseudophakic cystoid macular edema: functional and anatomic results.
      ,
      • Conway M.D.
      • Canakis C.
      • Livir-Rallatos C.
      • Peyman G.A.
      Intravitreal triamcinolone acetonide for refractory chronic pseudophakic cystoid macular edema.
      ,
      • Jonas J.B.
      • Kreissig I.
      • Degenring R.F.
      Intravitreal triamcinolone acetonide for pseudophakic cystoid macular edema.
      ,
      • Koutsandrea C.
      • Moschos M.M.
      • Brouzas D.
      • Loukianou E.
      • Apostolopoulos M.
      • Moschos M.
      Intraocular triamcinolone acetonide for pseudophakic cystoid macular edema: optical coherence tomography and multifocal electroretinography study.
      Corticosteroid-induced elevations in IOP and inhibition of corneal wound healing have directed interest toward the use of topical NSAIDs to treat postoperative inflammation and CME.
      • Juthani V.V.
      • Clearfield E.
      • Chuck R.S.
      Non-steroidal anti-inflammatory drugs versus corticosteroids for controlling inflammation after uncomplicated cataract surgery.
      Table 3Medical treatment options for pseudophakic CME
      Drug classMoleculeType of CMEStudy design
      Number of eyes is equal to the patient number unless otherwise stated.
      Time to CME reduction (weeks)Clinical comment
      NSAIDTopical diclofenac sodium 0.1%Pseudophakic CMERandomized prospective study (N = 18)7.5
      • Rho D.S.
      Treatment of acute pseudophakic cystoid macular edema: diclofenac versus ketorolac.
      Effective in reducing the severity and duration of CME after uneventful phacoemulsification with posterior chamber IOL implantation
      • Rho D.S.
      Treatment of acute pseudophakic cystoid macular edema: diclofenac versus ketorolac.
      Topical ketorolac tromethamine 0.5%Pseudophakic CMERandomized prospective study (N = 16)8
      • Rho D.S.
      Treatment of acute pseudophakic cystoid macular edema: diclofenac versus ketorolac.
      Effective in reducing the severity and duration of CME after uneventful phacoemulsification with posterior chamber IOL implantation
      • Rho D.S.
      Treatment of acute pseudophakic cystoid macular edema: diclofenac versus ketorolac.
      Topical nepafenac 0.1%Chronic pseudophakic CMEProspective open-label pilot study (N = 15)4
      • Warren K.A.
      • Fox J.E.
      Topical nepafenac as an alternate treatment for cystoid macular edema in steroid responsive patients.
      ,
      At first follow up.
      All patients had previously responded to steroid treatment with an increase in intraocular pressure
      • Warren K.A.
      • Fox J.E.
      Topical nepafenac as an alternate treatment for cystoid macular edema in steroid responsive patients.
      CorticosteroidIntravitreal triamcinolone 1 mgRefractory chronic CMENonrandomized retrospective case review (N = 8)4–6
      • Conway M.D.
      • Canakis C.
      • Livir-Rallatos C.
      • Peyman G.A.
      Intravitreal triamcinolone acetonide for refractory chronic pseudophakic cystoid macular edema.
      Mean duration of CME before the intravitreal corticosteroid injection was 20 months; all eyes had been resistant to topical and periocular steroids
      • Conway M.D.
      • Canakis C.
      • Livir-Rallatos C.
      • Peyman G.A.
      Intravitreal triamcinolone acetonide for refractory chronic pseudophakic cystoid macular edema.
      Anti-VEGFIntravitreal bevacizumab 1.25 mgRefractory chronic CMERetrospective case series (N = 10)32
      • Barone A.
      • Russo V.
      • Prascina F.
      • Delle Noci N.
      Short-term safety and efficacy of intravitreal bevacizumab for pseudophakic cystoid macular edema.
      ,
      At first follow up.
      Patients had previously been treated with ketorolac alone, or with acetazolamide or prednisone. Final follow-up was at 6 months
      • Barone A.
      • Russo V.
      • Prascina F.
      • Delle Noci N.
      Short-term safety and efficacy of intravitreal bevacizumab for pseudophakic cystoid macular edema.
      Carbonic anhydrase inhibitorOral acetazolamideInflammatory CME (uveitic and pseudophakic)Retrospective review (N = 16; 19 eyes)12
      • Pepple K.L.
      • Nguyen M.H.
      • Pakzad-Vaezi K.
      • et al.
      Response of inflammatory cystoid macular edema to treatment using oral acetazolamide.
      ,
      At first follow up.
      Patients included were a mix of pseudophakic and uveitic CME
      • Pepple K.L.
      • Nguyen M.H.
      • Pakzad-Vaezi K.
      • et al.
      Response of inflammatory cystoid macular edema to treatment using oral acetazolamide.
      ImmunomodulatorInfliximabRefractory pseudophakic CMEOpen-label, uncontrolled, retrospective, interventional study (N = 7)12
      • Wu L.
      • Arevalo J.F.
      • Hernandez-Bogantes E.
      • Roca J.A.
      Intravitreal infliximab for refractory pseudophakic cystoid macular edema: results of the Pan-American Collaborative Retina Study Group.
      All eyes had been treated previously with topical nepafenac 0.1%, topical prednisolone acetate 1%, intravitreal triamcinolone (4 mg), and intravitreal bevacizumab (1.25 mg)
      • Wu L.
      • Arevalo J.F.
      • Hernandez-Bogantes E.
      • Roca J.A.
      Intravitreal infliximab for refractory pseudophakic cystoid macular edema: results of the Pan-American Collaborative Retina Study Group.
      Interferon-α 2aRefractory chronic CMEInterventional, retrospective case series (N = 3; 4 eyes)4
      • Deuter C.M.E.
      • Gelisken F.
      • Stübiger N.
      • Zierhut M.
      • Doycheva D.
      Successful treatment of chronic pseudophakic macular edema (Irvine-Gass syndrome) with interferon alpha: a report of three cases.
      This was an interventional case series
      • Deuter C.M.E.
      • Gelisken F.
      • Stübiger N.
      • Zierhut M.
      • Doycheva D.
      Successful treatment of chronic pseudophakic macular edema (Irvine-Gass syndrome) with interferon alpha: a report of three cases.
      Interferon-α 2bRefractory pseudophakic CMECase report4
      • Maleki A.
      • Aghaei H.
      • Lee S.
      Topical interferon alpha 2b in the treatment of refractory pseudophakic cystoid macular edema.
      Case report of one patient resistant to topical NSAIDs and multiple intravitreal bevacizumab injections over 9 months. The patient had adverse reactions to oral acetazolamide and intravitreal triamcinolone injections
      • Maleki A.
      • Aghaei H.
      • Lee S.
      Topical interferon alpha 2b in the treatment of refractory pseudophakic cystoid macular edema.
      CME, cystoid macular edema; IOL, intraocular lens; NSAID, nonsteroidal anti-inflammatory drug; VEGF, vascular endothelial growth factor.
      Number of eyes is equal to the patient number unless otherwise stated.
      At first follow up.
      Several investigations have shown that NSAIDs are useful in the treatment of pseudophakic CME; therefore, topical formulations have been developed.
      • Flach A.J.
      • Jampol L.M.
      • Weinberg D.
      • et al.
      Improvement in visual acuity in chronic aphakic and pseudophakic cystoid macular edema after treatment with topical 0.5% ketorolac tromethamine.
      ,
      • Rho D.S.
      Treatment of acute pseudophakic cystoid macular edema: diclofenac versus ketorolac.
      ,
      • Warren K.A.
      • Bahrani H.
      • Fox J.E.
      NSAIDs in combination therapy for the treatment of chronic pseudophakic cystoid macular edema.
      ,
      • Weisz J.M.
      • Bressler N.M.
      • Bressler S.B.
      • Schachat A.P.
      Ketorolac treatment of pseudophakic cystoid macular edema identified more than 24 months after cataract extraction.
      Topical application of NSAIDs leads to higher aqueous concentrations than systemic NSAID administration. The active molecules reach the retina via transvitreal diffusion from the aqueous humor.
      • Shelsta H.N.
      • Jampol L.M.
      Pharmacologic therapy of pseudophakic cystoid macular edema: 2010 update.
      ,
      • Sheppard J.D.
      Topical bromfenac for prevention and treatment of cystoid macular edema following cataract surgery: a review.
      Subsequently, topical NSAIDs are widely used to treat pseudophakic CME.
      • Shelsta H.N.
      • Jampol L.M.
      Pharmacologic therapy of pseudophakic cystoid macular edema: 2010 update.
      NSAIDs have been approved by the US Food and Drug Administration (FDA) for the treatment of postsurgical inflammation after cataract surgery; however, FDA guidance states that the use of topical NSAIDs beyond 14 days postoperatively may increase the risk of occurrence and severity of corneal abnormalities.
      U.S. Food & Drug Administration (FDA)
      NEVANAC: highlights of prescribing information (PI).
      U.S. Food & Drug Administration (FDA)
      VOLTAREN OPHTHALMIC: prescribing information (PI).
      A topical ophthalmic solution of nepafenac has been approved in the USA and Europe for the prevention and treatment of postoperative pain and inflammation associated with cataract surgery.
      electronic Medicines Compendium (eMC)
      Nevanac 3 mg/ml eye drops suspension: summary of product characteristics (SmPC).
      U.S. Food & Drug Administration (FDA)
      NEVANAC: highlights of prescribing information (PI).
      In addition, it is approved in Europe for the reduction in the risk of postoperative macular edema associated with cataract surgery in patients with diabetes.
      electronic Medicines Compendium (eMC)
      Nevanac 3 mg/ml eye drops suspension: summary of product characteristics (SmPC).
      Both ketorolac and diclofenac have also been shown to be effective in treating chronic pseudophakic CME. In this patient population, ketorolac has been shown to significantly improve distance visual acuity within 30 days of treatment compared with placebo.
      • Flach A.J.
      • Jampol L.M.
      • Weinberg D.
      • et al.
      Improvement in visual acuity in chronic aphakic and pseudophakic cystoid macular edema after treatment with topical 0.5% ketorolac tromethamine.
      In a randomized, prospective study, ketorolac and diclofenac similarly improved visual acuity in patients with chronic pseudophakic CME and resolved CME within approximately 13 weeks.
      • Rho D.S.
      Treatment of acute pseudophakic cystoid macular edema: diclofenac versus ketorolac.
      It has also been shown that ketorolac may be effective in treating CME that develops over 24 months after cataract surgery, but it may need to be administered for longer than 3 months to get a long-term therapeutic effect.
      • Weisz J.M.
      • Bressler N.M.
      • Bressler S.B.
      • Schachat A.P.
      Ketorolac treatment of pseudophakic cystoid macular edema identified more than 24 months after cataract extraction.
      A randomized study investigated the efficacy of the addition of different NSAIDs for the treatment of pseudophakic CME in 39 patients treated with intravitreal corticosteroid and VEGF. The study found that nepafenac is more effective for the treatment of chronic CME than diclofenac, ketorolac, or bromfenac.
      • Warren K.A.
      • Bahrani H.
      • Fox J.E.
      NSAIDs in combination therapy for the treatment of chronic pseudophakic cystoid macular edema.
      Nepafenac was the only adjunctive treatment to significantly lower retinal thickness and improve visual acuity compared with placebo (P = 0.004 and P = 0.02, respectively).
      In patients with PGA-related CME, it is important to discontinue the PGA treatment and to control IOP during CME treatment. NSAIDs have been demonstrated to be an effective alternative to topical corticosteroid medication in CME, and unlike topical corticosteroids, topical NSAIDs do not influence IOP. Thus, they may be the preferred treatment option in patients who are susceptible to corticosteroid-induced IOP elevations
      • Warren K.A.
      • Fox J.E.
      Topical nepafenac as an alternate treatment for cystoid macular edema in steroid responsive patients.
      ; however, the currently available data are insufficient to determine whether NSAIDs as a drug class are superior to corticosteroids in treating CME. One study demonstrated that nepafenac is more effective than subtenon triamcinolone acetonide in improving visual acuity in patients with pseudophakic CME.
      • Yüksel B.
      • Uzunel U.D.
      • Kerci S.G.
      • Sağban L.
      • Küsbeci T.
      • Örsel T.
      Comparison of subtenon triamcinolone acetonide injection with topical nepafenac for the treatment of pseudophakic cystoid macular edema.
      In this study, treatment with nepafenac resulted in a statistically significant improvement (P < 0.05) in best-corrected visual acuity at every time point (months 1, 2, 3, and 6), but treatment with triamcinolone acetonide only provided a significant improvement at months 2 and 6. Regarding combined topical NSAID and corticosteroid treatment, it has been suggested that combination of NSAIDs with corticosteroids is more effective than either treatment alone.
      • Heier J.S.
      • Topping T.M.
      • Baumann W.
      • Dirks M.S.
      • Chern S.
      Ketorolac versus prednisolone versus combination therapy in the treatment of acute pseudophakic cystoid macular edema.
      In this study, the combined treatment led to significantly more patients achieving two or more lines of improvement in Snellen visual acuity compared with corticosteroid monotherapy at every monthly study visit, and versus NSAID monotherapy at months 4 and 5 (P < 0.05 for all analyses). However, another study has shown that there was no statistically significant difference in visual acuity between treatment with ketorolac alone and ketorolac with adjuvant prednisolone treatments (mean Early Treatment Diabetic Retinopathy Study vision was 50.0 vs 54.7, respectively; P = 0.36).
      • Singal N.
      • Hopkins J.
      Pseudophakic cystoid macular edema: ketorolac alone vs. ketorolac plus prednisolone.
      The addition of NSAIDs to a corticosteroid and anti-VEGF complex treatment regimen for chronic CME resulted in significantly lower IOP elevation than the same treatment without NSAIDs.
      • Warren K.A.
      • Bahrani H.
      • Fox J.E.
      NSAIDs in combination therapy for the treatment of chronic pseudophakic cystoid macular edema.
      Intravitreal anti-VEGF treatment can also be used for CME owing to its effects on reducing blood-retinal barrier permeability.
      • Arevalo J.F.
      • Garcia-Amaris R.A.
      • Roca J.A.
      • et al.
      Primary intravitreal bevacizumab for the management of pseudophakic cystoid macular edema: pilot study of the Pan-American Collaborative Retina Study Group.
      ,
      • Arevalo J.F.
      • Maia M.
      • Garcia-Amaris R.A.
      • et al.
      Intravitreal bevacizumab for refractory pseudophakic cystoid macular edema: the Pan-American Collaborative Retina Study Group results.
      Bevacizumab, a VEGF inhibitor, reduces central macular thickness and improves visual acuity in patients with CME and has shown effectiveness in treating pseudophakic CME.
      • Arevalo J.F.
      • Garcia-Amaris R.A.
      • Roca J.A.
      • et al.
      Primary intravitreal bevacizumab for the management of pseudophakic cystoid macular edema: pilot study of the Pan-American Collaborative Retina Study Group.
      ,
      • Arevalo J.F.
      • Maia M.
      • Garcia-Amaris R.A.
      • et al.
      Intravitreal bevacizumab for refractory pseudophakic cystoid macular edema: the Pan-American Collaborative Retina Study Group results.
      ,
      • Barone A.
      • Russo V.
      • Prascina F.
      • Delle Noci N.
      Short-term safety and efficacy of intravitreal bevacizumab for pseudophakic cystoid macular edema.
      Although these studies do not provide information on the duration of treatment required for the resolution of CME, there has been a report of CME resolution 1 month after intravitreal bevacizumab injection and another report of substantial improvement after 1 month of intravitreal bevacizumab treatment, with complete resolution observed at a 6-month follow up after treatment initiation.
      • Arevalo J.F.
      • Maia M.
      • Garcia-Amaris R.A.
      • et al.
      Intravitreal bevacizumab for refractory pseudophakic cystoid macular edema: the Pan-American Collaborative Retina Study Group results.
      ,
      • Barone A.
      • Russo V.
      • Prascina F.
      • Delle Noci N.
      Short-term safety and efficacy of intravitreal bevacizumab for pseudophakic cystoid macular edema.
      Contradictory results were reported in a retrospective case series of 16 eyes; visual acuity remained unchanged in 12 eyes which were followed up for 14–82 weeks after intravitreal injection of bevacizumab.
      • Spitzer M.S.
      • Ziemssen F.
      • Yoeruek E.
      • Petermeier K.
      • Aisenbrey S.
      • Szurman P.
      Efficacy of intravitreal bevacizumab in treating postoperative pseudophakic cystoid macular edema.
      Treatment of pseudophakic CME with ranibizumab in a study of 7 eyes provided statistically significant improvements in best-corrected visual acuity and significantly decreased central retinal thickness (P < 0.001 for both).
      • Mitropoulos P.G.
      • Chatziralli I.P.
      • Peponis V.G.
      • Drakos E.
      • Parikakis E.A.
      Intravitreal ranibizumab for the treatment of Irvine-Gass syndrome.
      There are no data available on the effects of aflibercept treatment of pseudophakic CME.
      Where treatment with corticosteroids and NSAIDs has been unsuccessful, alternative approaches have been used. Acetazolamide is a carbonic anhydrase inhibitor that effects the elimination of fluid from the subretinal space across the retinal pigment epithelial cells, thereby lowering fluid accumulation.
      • Shelsta H.N.
      • Jampol L.M.
      Pharmacologic therapy of pseudophakic cystoid macular edema: 2010 update.
      A recent retrospective review of 4 eyes with pseudophakic CME and 15 eyes with uveitic CME showed that oral acetazolamide (500 mg twice daily) significantly reduced central macular subfield thickness and improved visual acuity within 3 months (P = 0.002 and P < 0.0001, respectively)
      • Pepple K.L.
      • Nguyen M.H.
      • Pakzad-Vaezi K.
      • et al.
      Response of inflammatory cystoid macular edema to treatment using oral acetazolamide.
      ; however, systemic side effects of acetazolamide were reported in several patients; paresthesia was reported by 10 patients, dysgeusia by 6 patients, fatigue by 5 patients, and diarrhea by 3 patients. One patient had treatment-related dehydration that required hospitalization. Similarly, in a retrospective study, infliximab, a tumor necrosis factor-α inhibitor, improved visual acuity and decreased central macular thickness in 7 eyes with refractory pseudophakic CME after 6 months of treatment.
      • Wu L.
      • Arevalo J.F.
      • Hernandez-Bogantes E.
      • Roca J.A.
      Intravitreal infliximab for refractory pseudophakic cystoid macular edema: results of the Pan-American Collaborative Retina Study Group.
      In this study, refractory CME was defined as persistent edema diagnosed by OCT or FA despite prior treatment of the CME. There were no systemic safety concerns reported in this study, which was underpowered for analysis of safety outcomes. One case of anterior uveitis was reported, which responded to topical steroid treatment.
      • Wu L.
      • Arevalo J.F.
      • Hernandez-Bogantes E.
      • Roca J.A.
      Intravitreal infliximab for refractory pseudophakic cystoid macular edema: results of the Pan-American Collaborative Retina Study Group.
      Few case reports on the effects of interferon-α 2 on CME have been published. In 4 eyes of 3 patients with pseudophakic CME refractory to local and systemic corticosteroids, treatment with interferon-α 2a led to resolution of CME within 4 weeks, and visual acuity improved in 3 of 4 eyes. A statistically significant improvement in mean best-corrected visual acuity was observed at 3 months (P < 0.05). No adverse events, aside from flu-like symptoms after the first dose and relapses of flu-like symptoms, were reported during follow up at 3–11 months.
      • Deuter C.M.E.
      • Gelisken F.
      • Stübiger N.
      • Zierhut M.
      • Doycheva D.
      Successful treatment of chronic pseudophakic macular edema (Irvine-Gass syndrome) with interferon alpha: a report of three cases.
      In another case report, when interferon-α 2b was used to treat pseudophakic CME resistant to multiple NSAIDs and corticosteroids, CME improved after 4 weeks of treatment and resolved after 12 weeks. Visual acuity and macular structure were restored, and this effect was sustained throughout a 36-week follow-up period.
      • Maleki A.
      • Aghaei H.
      • Lee S.
      Topical interferon alpha 2b in the treatment of refractory pseudophakic cystoid macular edema.
      Where pharmacologic options fail, surgical intervention may be an alternative treatment. If vitreous loss occurs during cataract surgery, vitreous strands may adhere to structures in the anterior segment. Lysing these adhesions using lasers or vitrectomy may reduce existing CME by restoring retinal vascular stability, thereby lowering vascular leakage.
      • Rotsos T.G.
      • Moschos M.M.
      Cystoid macular edema.
      ,
      • Shelsta H.N.
      • Jampol L.M.
      Pharmacologic therapy of pseudophakic cystoid macular edema: 2010 update.
      In a small study conducted on 14 eyes with CME after complicated cataract surgery with vitreous incarceration in the corneoscleral wound, the vitreous strands were cut using neodymium-yttrium-aluminum-garnet laser. This treatment improved visual acuity in all eyes, of which 11 had visual acuities of 20/40 or better after follow up at 1–9 months.
      • Katzen L.E.
      • Fleischman J.A.
      • Trokel S.
      YAG laser treatment of cystoid macular edema.
      Conversely, in a different study carried out in 29 patients with CME, with vitreous incarceration in the corneoscleral wound, 55% of eyes achieved two or more lines of stable visual improvement, 17% improved but had fluctuating levels of vision and persistent edema, and 28% failed to improve owing to other coexisting ocular pathology.
      • Steinert R.F.
      • Wasson P.J.
      Neodymium: YAG laser anterior vitreolysis for Irvine-Gass cystoid macular edema.
      In a retrospective analysis of 23 patients with pseudophakic CME without vitreous incarceration in the corneoscleral wound, but with persistent CME unresponsive to medical treatment, pars plana vitrectomy was performed.
      • Pendergast S.D.
      • Margherio R.R.
      • Williams G.A.
      • Cox M.S.
      Vitrectomy for chronic pseudophakic cystoid macular edema.
      Vitreomacular traction was present in 4 eyes. The median best-corrected visual acuity improved from 20/200 to 20/60 (P < 0.0001) after a mean follow up of 30 months, with CME resolving in a mean period of 3.3 months. In conclusion, vitrectomy may be useful for patients with CME when vitreous traction is responsible for the development of CME which does not respond to medical treatment.

      7.1 Prophylactic treatments for CME

      There is currently no official FDA- or European Medical Agency-approved strategy for the prevention of pseudophakic CME. Although most surgeons use topical steroids with or without topical NSAIDs postoperatively, prophylaxis of CME by prescribing topical NSAIDs after cataract surgery is recommended in numerous studies.
      • Hoffman R.S.
      • Braga-Mele R.
      • Donaldson K.
      • et al.
      Cataract surgery and nonsteroidal antiinflammatory drugs.
      ,
      • Kessel L.
      • Tendal B.
      • Jørgensen K.J.
      • et al.
      Post-cataract prevention of inflammation and macular edema by steroid and nonsteroidal anti-inflammatory eye drops: a systematic review.
      ,
      • Wielders L.H.
      • Lambermont V.A.
      • Schouten J.S.
      • et al.
      Prevention of cystoid macular edema after cataract surgery in nondiabetic and diabetic patients: a systematic review and meta-analysis.
      ,
      • Yannuzzi L.A.
      • Landau A.N.
      • Turtz A.I.
      Incidence of aphakic cystoid macular edema with the use of topical indomethacin.
      In some investigations, the authors suggest that NSAIDs are significantly more effective in preventing CME than corticosteroids, and preoperative prophylactic use may be beneficial.
      • Kessel L.
      • Tendal B.
      • Jørgensen K.J.
      • et al.
      Post-cataract prevention of inflammation and macular edema by steroid and nonsteroidal anti-inflammatory eye drops: a systematic review.
      ,
      • Wielders L.H.
      • Lambermont V.A.
      • Schouten J.S.
      • et al.
      Prevention of cystoid macular edema after cataract surgery in nondiabetic and diabetic patients: a systematic review and meta-analysis.
      ,
      • Yavas G.F.
      • Oztürk F.
      • Küsbeci T.
      Preoperative topical indomethacin to prevent pseudophakic cystoid macular edema.
      It has also been shown that administration of NSAIDs as an adjunctive to topical corticosteroids is more beneficial than prophylactic corticosteroids alone.
      • Shelsta H.N.
      • Jampol L.M.
      Pharmacologic therapy of pseudophakic cystoid macular edema: 2010 update.
      ,
      • Wolf E.J.
      • Braunstein A.
      • Shih C.
      • Braunstein R.E.
      Incidence of visually significant pseudophakic macular edema after uneventful phacoemulsification in patients treated with nepafenac.
      Based on the currently available data, no general conclusion on the prophylactic benefits of the different topical treatment regimens can be drawn.
      • Grzybowski A.
      • Sikorski B.L.
      • Ascaso F.J.
      • Huerva V.
      Pseudophakic cystoid macular edema: update 2016.
      ,
      • Juthani V.V.
      • Clearfield E.
      • Chuck R.S.
      Non-steroidal anti-inflammatory drugs versus corticosteroids for controlling inflammation after uncomplicated cataract surgery.
      ,
      • Lim B.X.
      • Lim C.H.
      • Lim D.K.
      • Evans J.R.
      • Bunce C.
      • Wormald R.
      Prophylactic non-steroidal anti-inflammatory drugs for the prevention of macular oedema after cataract surgery.
      The long-term prophylactic effects of NSAIDs for treatment periods of more than 1 year have not been investigated.
      • Grzybowski A.
      • Sikorski B.L.
      • Ascaso F.J.
      • Huerva V.
      Pseudophakic cystoid macular edema: update 2016.
      ,
      • Shelsta H.N.
      • Jampol L.M.
      Pharmacologic therapy of pseudophakic cystoid macular edema: 2010 update.
      Prophylaxis using anti-VEGF treatments has also been suggested; prophylactic treatment with pegaptanib (N = 250) administered after cataract surgery together with dexamethasone-tobramycin administered 4 times daily led to a significantly lower incidence of CME (0.4%) compared with dexamethasone-tobramycin treatment alone (N = 250; 4.4%) after uncomplicated cataract surgery (P = 0.009).
      • Gallego-Pinazo R.
      • Arévalo J.F.
      • Udaondo P.
      • García-Delpech S.
      • Dolz-Marco R.
      • Díaz-Llopis M.
      Prophylaxis of pseudophakic cystoid macular edema with intraoperative pegaptanib.
      Although there were no reported safety concerns in this study, there are added costs and risks associated with intravitreal injections. In addition, as preoperative use of PGAs has been identified as a risk factor, there is a need for guidance in clinical practice regarding possible withdrawal of PGA treatment in patients with mild glaucoma undergoing cataract surgery and the appropriate duration of this withdrawal to minimize the likelihood of postoperative development of CME.

      8. Expert opinion and conclusions

      Pseudophakic CME seems to be more common than previously appreciated and may be underreported after cataract surgery. In several published studies and case reports, CME was detected only upon the report of decreased visual acuity; however, advances in OCT and OCT angiography technology allow noninvasive detection, quantification, and monitoring of CME. This makes it possible to assess CME objectively, but independently from central visual function. In addition, this means that CME may be detected in high-risk populations ahead of the development of vision loss, allowing for early treatment initiation and minimizing the risk of vision loss. Although angiographic CME observed using imaging techniques may resolve without intervention, prevention of visually significant CME is clinically important in patients who are at high risk for CME, including those with underlying ocular inflammation, retinal vascular diseases, elevated IOP, or who undergo cataract surgery. As such, these imaging techniques could be used more readily in these high-risk patient populations. Although the literature is still not clear on the relationship between PGAs and the development of CME, patients who require topical PGA administration or use of fixed combinations of a PGA and a β-receptor blocker in the early postoperative period after cataract surgery, especially when the eye is inflamed, may be at increased risk for CME. Therefore, to control postoperative IOP elevation in the early postoperative period after cataract surgery, the use of non-PGA IOP-lowering topical medication should be used at the physician's discretion following a benefit-risk assessment based on available data. Carbonic anhydrase inhibitors may theoretically be an alternative hypotensive treatment, given the use of topical formulations as IOP-lowering medications and the use of oral formulations in the treatment of refractory CME
      • Pepple K.L.
      • Nguyen M.H.
      • Pakzad-Vaezi K.
      • et al.
      Response of inflammatory cystoid macular edema to treatment using oral acetazolamide.
      ; however, the IOP-lowering efficacy of topical carbonic anhydrase inhibitors is considerably less than that provided by PGAs.
      • van der Valk R.
      • Webers C.A.B.
      • Schouten J.S.A.G.
      • Zeegers M.P.
      • Hendrikse F.
      • Prins M.H.
      Intraocular pressure-lowering effects of all commonly used glaucoma drugs.
      In addition, there are safety concerns associated with the use of oral formulations to treat CME,
      • Pepple K.L.
      • Nguyen M.H.
      • Pakzad-Vaezi K.
      • et al.
      Response of inflammatory cystoid macular edema to treatment using oral acetazolamide.
      and data on the use of topical ophthalmic solutions in treating pseudophakic CME are limited.
      Further research is needed to provide guidance on the use of prophylactic treatment for CME. Improvements in cataract surgery technique and additional care to prevent vitreous humor loss are necessary to minimize the risk of the development of pseudophakic CME. There is significant need for new topical IOP-lowering therapy options that provide clinically significant IOP reductions comparable to PGAs but at the same time do not increase the risk of CME and do not worsen its severity even in the early postoperative period after cataract surgery. Currently, careful glaucoma and cataract surgery, prophylactic treatment with NSAIDs, and avoidance of the use of topical PGAs in patients at high risk for CME are considered important clinical factors in preventing the development of clinically significant CME and the related decrease of central vision.

      9. Method of literature search

      • A thorough literature search was done on Medline from 1950 to 2019 using the main search term “(cystoid macular edema) OR (cystoid macular oedema OR CME OR CMO)” AND the following terms “prostaglandin AND cataract surgery”, “prostaglandin”, “bimatoprost”, “travoprost”, “latanoprost”, “tafluprost”, “unoprostone”, “phakic”, “(phakic) AND (glaucoma)”, “diagnosis”, “(prostaglandin) AND (management)”, “management”, “(treatment) AND pseudophakic”, “glaucoma filtration surgery”, “glaucoma filtration surgery AND prostaglandin”, “selective laser trabeculoplasty”, “laser trabeculoplasty”, “selective laser trabeculoplasty AND prostaglandin”, “trabeculectomy AND prostaglandin”, and “glaucoma AND cataract surgery”.
      • A narrative search was also completed on Google Scholar to substantiate some of the data discussed.
      • References were also obtained from citations in papers found in the original search.
      Non-English language articles were obtained if a translated version was available.

      10. Disclosures

      G Holló is a consultant for Mundipharma, Novartis, and Santen. T Aung is a consultant for Alcon, Allergan, Belkin Laser, Mundipharma, Novartis, ONL Therapeutics, PH Pharma, Santen, and Sun Pharma and has received grant support from Allergan , Novartis , and Santen. L Cantor is a consultant for Carl Zeiss Meditec and Santen and has received grant support from Allergan , Bausch and Lomb , and InnFocus. M Aihara is a consultant for Santen and has received grants and personal fees from Alcon Japan , Pfizer , Santen , Sato Pharmaceutical , and SENJU Pharmaceutical and has received personal fees from Astellas Pharma Inc, Canon, Carl Zeiss Meditec, CREWT Medical systems, Glaukos, HOYA, InnFocus, IRIDEX, Ivantis, Johnson & Johnson, Kowa Pharmaceutical, NIDEK, Nitten Pharmaceutical, Novartis, Ono Pharmaceutical, Otsuka Pharmaceutical, Santen, TOMEY, and Wakamoto Pharmaceutical. Medical writing support was provided by Sandra Callagy, PhD, Helios Medical Communications, Cheshire, UK, which was funded by Santen .

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