Postoperative macular edema (ME), also termed pseudophakic ME or “Irvine-Gass syndrome,”1,2 is a vision-limiting complication occurring after intraocular surgery. Its frequency is estimated at 1.2% after routine cataract extraction3 and is probably higher following complex anterior or posterior segment procedures. Diabetes, lens capsule rupture, history of epiretinal membrane, uveitis, retinal vein occlusion, or retinal detachment are known risk factors.3 On average, affected eyes harbor worse postoperative visual acuity (VA).3,4 Several treatments have been used, including oral acetazolamide,5 intravitreal triamcinolone acetonide,6 intravitreal anti-vascular endothelial growth factor,7–9 all off-label, and intravitreal dexamethasone implant (Ozurdex; Allergan, Parsippany, NJ).10–12 However, the exact mechanisms of chronic postoperative ME and its persistence are unclear. Inflammation, vitreous traction, and choroidal blood-flow changes and instability have been advanced.13–15
Oral mineralocorticoid receptor (MR) antagonists are efficient in reducing subretinal and intraretinal fluid in central serous chorioretinopathy (CSCR),16–19 in which vascular choroidal changes are recognized. Hypothesizing that both inflammation and vascular choroidal changes contribute to Irvine-Gass syndrome, we employed the combination of oral MR antagonists with dexamethasone drops in three cases of recalcitrant long-lasting Irvine-Gass.
A 76-year-old woman was referred 3 years after complicated cataract extraction for refractory postoperative ME. She had hypothyroidism, cardiac arrhythmia, and was on levothyroxine, metoprolol, and aspirin. In April 2013, she underwent pars plana vitrectomy (PPV), IOL removal, and anterior chamber IOL implantation due to posterior IOL dislocation 3 weeks after cataract surgery with posterior capsule rupture. Best-corrected VA (BCVA) recovered to 20/30, but 3 months later she developed Irvine-Gass syndrome, and her BCVA dropped to 20/100. She was treated with topical prednisolone acetate (four times/day) and oral acetazolamide (250 mg, three times/day) for 2 months without improvement. She then received three triamcinolone acetonide injections (4 mg), followed by BCVA improvement to 20/40 and partial ME reduction. Due to intraocular pressure (IOP) elevation, she then received nine intravitreal bevacizumab (Avastin; Genentech, South San Francisco, CA) injections (1.25 mg) during the following 12 months but did not respond, and BCVA progressively deteriorated to 20/200.
Upon referral, optical coherence tomography (OCT) showed large intraretinal cystoid cavities, a serous retinal detachment, focal photoreceptor atrophy, and intra- and subretinal hyperreflective dots (Figure 1A). Fluorescein angiography (FA) showed multiple hyperfluorescent spots indicating extensive outer blood-retinal barrier rupture, and mild inner barrier rupture at the macula (Figures 2A and 2B).
Progressive resolution of macular edema due to Irvine-Gass syndrome and visual improvement in a 76-year-old woman treated by oral eplerenone and topical dexamethasone drops 2 years after complicated cataract extraction, intraocular lens dislocation, and pars plana vitrectomy. (A) At presentation. (B) Anatomical and visual improvement were observed 1 month after initiating oral eplerenone 25 mg and topical dexamethasone drops (4 times daily). (C) Further anatomical and visual improvement were noted 3 months after treatment initiation with dexamethasone dose tapering (three times daily). (D) One month after progressive dose reduction of dexamethasone reached one drop per day, a recurrence of macular edema was observed. (E) Re-improvement was visible 1 month after increasing dexamethasone drops again at four times daily while continuing oral eplerenone. M = month; VA = visual acuity; CMT = central macular thickness.
Restoration of the outer and inner blood-retinal barrier on fluorescein angiography in a 76-year-old woman treated by oral eplerenone and topical dexamethasone drops 2 years after complicated cataract extraction. (A, B) At presentation, extensive outer blood-retinal barrier rupture manifested as diffuse hyperfluorescent spots (arrowheads), and inner blood-retinal barrier rupture at the macular manifested as fine telangiectasia in the early frames (A) and progressive filling of the cystoid cavities in the late frame (B) (arrows). An intense late diffusion at the disc indicated papillitis (B), a frequent finding in Irvine-Gass syndrome. (C, D) Three months after treatment initiation, all inflammatory signs had markedly declined, with fewer hyperfluorescent spots, a weaker diffusion at the macula, and a milder fluorescence at the disc still visible on the late frame (D). M = month.
She was prescribed oral eplerenone (Inspra; Pfizer, New York City, NY) (25 mg/day), with potassium level monitoring. One month later, ME and BCVA were unchanged, and she was additionally prescribed preservative-free topical dexamethasone four times/day. The following month, BCVA had improved to 20/60 and OCT showed a dramatic improvement of ME, with central macular thickness (CMT) reduction from 523 μm to 262 μm (Figure 1B). At the next monthly visit, BCVA and CMT had further improved. Due to IOP elevation, she was prescribed with topical brinzolamide (Azopt; Alcon, Fort Worth, TX), and topical dexamethasone was tapered to three times/day. Subsequent improvement was noted at the next visit (Figure 1C). The inner and outer blood-retinal barrier showed clear signs of restoration on FA (Figures 2C and 2D). Dexamethasone drops were progressively tapered to once daily, but ME recurred the following month (Figure 1D). Topical dexamethasone was re-increased (four times/day), and ME responded again (Figure 1E). Drops were progressively tapered to twice daily, without recurrence during a 4-month follow-up. Under eplerenone, subfoveal choroidal thickness (SFCT) decreased progressively from 284 μm to 214 μm.
An 80-year-old man was referred for refractory ME 18 months after PPV, IOL removal, and IOL implantation with scleral suture for posterior IOL dislocation. He had hypertension, asthma, and was on losartan (Cozaar; Merck, Kenilworth, NJ) and inhaled steroids. ME had developed 2 months before and persisted despite oral acetazolamide (125 mg, three times daily), topical bromfenac, and a 2-week course of oral prednisone (50 mg). Upon referral, BCVA was 20/100, OCT showed severe cystoid ME (Figure 3C), and FA showed diffuse blood-retinal barrier alterations (Figures 3A and 3B). He was prescribed with oral spironolactone 50 mg/day, with potassium level monitoring. The following month, ME and BCVA were unchanged. Spironolactone was continued, and preservative-free dexamethasone drops four times/day were initiated. Two months later, a marked improvement of ME, but no change in BCVA, was observed (Figure 3D). Dexamethasone drops were diminished to three times/day. During the following 3 months, a subsequent anatomical improvement was noted (Figure 3E), without visual improvement. Under spironolactone, SFCT decreased progressively from 304 μm to 268 μm.
Anatomical improvement in an 80-year-old man treated by oral spironolactone and topical dexamethasone for refractory postoperative macular edema 18 months after pars plana vitrectomy, dislocated intraocular lens removal, and intraocular lens suture to the sclera. (A, B) Fluorescein angiography showed inner and outer blood-retinal barrier rupture manifesting as fine paramacular telangiectasia (A) with late filling of cystoid cavities (B), and diffuse hyperfluorescent spots on late frames (B), respectively. There was a late hyperfluorescence at the disc (B) as usually observed in Irvine-Gass syndrome. (C) Optical coherence tomography at presentation showing marked, diffuse cystoid macular edema and a fine epiretinal membrane at the inner retinal surface. A few intraretinal hyperreflective dots were visible. (D) Two months after combined therapy associating oral spironolactone (50 mg/day) and topical dexamethasone (four times/day) was initiated, there was a clear reduction of macular edema. (E) Three months after tapering of dexamethasone drops at three times/day, macular edema further improved, but visual acuity remained unchanged. The square-shaped morphology of residual hyporeflective spaces suggests possible degenerative cavities. M = month; VA = visual acuity; CMT = central macular thickness.
A 69-year-old woman presented with long-standing ME 2 years after she underwent four PPV procedures and temporary silicone-oil tamponade for rhegmatogenous retinal detachment and proliferative vitreoretinopathy. ME had been refractory to one sub-Tenon's triamcinolone acetonide injection, and she was under topical dexamethasone (three times/day for 3 months then two times/day for 6 months) without effect. Eplerenone (25 mg) combined with dexamethasone four times/day was initiated. The next month, CMT had decreased from 438 μm to 311 μm, and ME cavities had regressed on OCT (Figure 4). This effect was maintained until the end of follow-up 2 months later, but BCVA did not improve (20/200). SFCT decreased from 366 μm to 347 μm.
Anatomical improvement in a 69-year-old woman presenting with long-standing macular edema treated by oral eplerenone and topical dexamethasone 2 years after pars plana vitrectomy and silicone-oil tamponade for rhegmatogenous retinal detachment with proliferative vitreoretinopathy. (A) At presentation. (B–C) Regression of cystoid edema cavities and decrease in central macular thickness after 1 month and 2 months since initiation of treatment with oral epleronone (50 mg/day) and topical dexamethasone (four times/day). M = month; VA = visual acuity; CMT = central macular thickness.
We report for the first time the efficacy of oral MR antagonists combined with topical dexamethasone in three cases of refractory postoperative ME. The reduction of macular thickness was observed 1 month after initiation, and was maximal after 2 months to 5 months in all subjects, with visual improvement in one subject. The only adverse effect was a mild IOP elevation observed in one case, managed with topical IOP-lowering medication.
All cases had received anti-inflammatory drops before referral. Two have been initially treated with a 1-month course of eplerenone or spironolactone alone, and one with dexamethasone drops three times daily alone, without improvement, which supports the notion that only the simultaneous administration of these treatments is synergically effective.
The pathophysiology of Irvine-Gass syndrome is not fully elucidated. Pronounced inner and outer blood-retinal barrier rupture results from pro-inflammatory mediators' release by uveal tissue, triggered by the causative procedure.4 The efficacy of intravitreal triamcinolone,6 dexamethasone implant, 10 to 12 hourly topical steroids,20 and interferon alpha21 in treating postoperative ME, as well as its effective prevention by non-steroidal anti-inflammatory drugs,22–24 are consistent with the central role of inflammation. In addition to the FA findings, suggesting advanced inflammatory outer blood-retinal barrier rupture, OCT showed intra- and subretinal hyperreflective dots, suggesting activation of microglia, a key marker of retinal inflammation.
Presence of MR in the retina was identified two decades ago.25,26 The MR pathway contributes to the homeostasis of water and electrolytes, particularly via Müller cells.27 In animal models, its deregulation leads to retinal vasculopathy28,29 and choroidopathy,30 reversed by MR antagonist treatment. Inflammatory mediators, possibly involving microglia, participate in MR deregulation.28
The coactivation of MR by corticosteroids, along with the glucocorticoid receptor, may explain why they lead to fluid accumulation in CSCR.30–32 Because MR binds to gluco- and mineralocortcoids with similar affinity, blocking MR enhances corticosteroid binding to glucocorticoid receptor, optimizing their pharmacological effect. Therefore, we assumed that blocking the MR pathway while administering topical corticosteroids, would allow to reduce their dose, a hypothesis consistent with the present clinical observations in Irvine-Gass syndrome. Here, the pharmacological action of MR antagonists is further supported by the SFCT reduction observed during treatment in both patients.
This first report of efficient combination therapy for severe Irvine-Gass syndrome opens therapeutic perspectives for these challenging cases, and will need confirmation by larger studies.
- Irvine S. A newly defined vitreous syndrome following cataract surgery. Am J Ophthalmol. 1953;36(5):599–619. doi:10.1016/0002-9394(53)90302-X [CrossRef]
- Gass JD, Norton EW. Fluorescein studies of patients with macular edema and papilledema following cataract extraction. Trans Am Ophthalmol Soc. 1966;64:232–249.
- Chu CJ, Johnston RL, Buscombe C, et al. Risk factors and incidence of macular edema after cataract surgery. Ophthalmology. 2016;123(2):316–323. doi:10.1016/j.ophtha.2015.10.001 [CrossRef]
- Grzybowski A, Sikorski B, Ascaso F, Huerva V. Pseudophakic cystoid macular edema: Update 2016. Clin Interv Aging. 2016;11:1221–1229. doi:10.2147/CIA.S111761 [CrossRef]
- Tripathi RC, Fekrat S, Tripathi BJ, Ernest JT. A direct correlation of the resolution of pseudophakic cystoid macular edema with acetazolamide therapy. Ann Ophthalmol. 1991;23(4):127–129.
- Benhamou N, Massin P, Haouchine B, Audren F, Tadayoni R, Gaudric A. Intravitreal triamcinolone for refractory pseudophakic macular edema. Am J Ophthalmol. 2003;135(2):246–249. doi:10.1016/S0002-9394(02)01938-4 [CrossRef]
- Spitzer MS, Ziemssen F, Yoeruek E, Petermeier K, Aisenbrey S, Szurman P. Efficacy of intravitreal bevacizumab in treating postoperative pseudophakic cystoid macular edema. J Cataract Refract Surg. 2008;34(1):70–75. doi:10.1016/j.jcrs.2007.08.021 [CrossRef]
- Mitropoulos PG, Chatziralli IP, Peponis VG, Drakos E, Parikakis EA. Intravitreal ranibizumab for the treatment of Irvine-Gass Syndrome. Ocul Immunol Inflamm. 2015;23(3):225–231. doi:10.3109/09273948.2014.898775 [CrossRef]
- Lin CJ, Tsai YY. Use of aflibercept for the management of refractory pseudophakic macular edema in Irvine-Gass syndrome and literature review. Retin Cases Brief Rep. 2016Sep8. [Epub ahead of print]
- Mayer WJ, Kurz S, Wolf A, et al. Dexamethasone implant as an effective treatment option for macular edema due to Irvine-Gass syndrome. J Cataract Refract Surg. 2015;41(9):1954–1961. doi:10.1016/j.jcrs.2015.10.025 [CrossRef]
- Klamann A, Böttcher K, Ackermann P, Geerling G, Schargus M, Guthoff R. Intravitreal dexamethasone implant for the treatment of postoperative macular edema. Ophthalmologica. 2016;236(4):181–185. doi:10.1159/000448057 [CrossRef]
- Sudhalkar A, Chhablani J, Vasavada A, et al. Intravitreal dexamethasone implant for recurrent cystoid macular edema due to Irvine–Gass syndrome: A prospective case series. Eye (Lond). 2016;30(12):1549–1557. doi:10.1038/eye.2016.205 [CrossRef]
- Nicholls J. Macular edema in association with cataract extraction. Am J Ophthalmol. 1954;37(5):665–672. doi:10.1016/0002-9394(54)91219-2 [CrossRef]
- Nicholls J. Concurrence of macular edema with cataract extraction. AMA Arch Ophthalmol. 1956;55(5):595–604. doi:10.1001/archopht.1956.00930030599001 [CrossRef]
- Welch R, Cooper J. Macular edema, papilledema, and optic atrophy after cataract extraction. AMA Arch Ophthalmol. 1958;59(5):665–675. doi:10.1001/archopht.1958.00940060049005 [CrossRef]
- Bousquet E, Beydoun T, Rothschild P, et al. Spironolactone for nonresolving central serous chorioretinopathy: A randomized controlled crossover study. Retina. 2015;35(12):2505–2515. doi:10.1097/IAE.0000000000000614 [CrossRef]
- Daruich A, Matet A, Dirani A, et al. Oral mineralocorticoid-receptor antagonists: Real-life experience in clinical subtypes of nonresolving central serous chorioretinopathy with chronic epitheliopathy. Transl Vis Sci Technol. 2016;5(2):2. doi:10.1167/tvst.5.2.2 [CrossRef]
- Salz DA, Pitcher JD 3rd, Hsu J, et al. Oral eplerenone for treatment of chronic central serous chorioretinopathy: A case series. Ophthalmic Surg Lasers Imaging Retina. 2015;46(4):439–444. doi:10.3928/23258160-20150422-06 [CrossRef]
- Ghadiali Q, Jung JJ, Yu S, Patel SN, Yannuzzi LA. Central serous chorioretinopathy treated with mineralocorticoid antagonists: A one-year pilot study. Retina. 2016;36(3):611–618. doi:10.1097/IAE.0000000000000748 [CrossRef]
- Campochiaro PA, Han YS, Mir TA, et al. Increased frequency of topical steroids provides benefit in patients with recalcitrant postsurgical macular edema. Am J Ophthalmol. 2017Sep20. pii: S0002-9394(17)30383-5. doi: . [Epub ahead of print]. doi:10.1016/j.ajo.2017.03.033 [CrossRef]
- Deuter CME, 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. Ocul Immunol Inflamm. 2011;19(3):216–218. doi:10.3109/09273948.2011.562341 [CrossRef]
- Kessel L, Tendal B, Jørgensen KJ, et al. Post-cataract prevention of inflammation and macular edema by steroid and nonsteroidal anti-inflammatory eye drops. Ophthalmology. 2014;121(10):1915–1924. doi:10.1016/j.ophtha.2014.04.035 [CrossRef]
- Wielders LHP, Lambermont VA, Schouten JSAG, et al. Prevention of cystoid macular edema after cataract surgery in nondiabetic and diabetic patients: A systematic review and meta-analysis. Am J Ophthalmol. 2015;160(5):968–981.e33. doi:10.1016/j.ajo.2015.07.032 [CrossRef]
- Allocco A, Ponce J, Quintana N, Magurno M. Non steroidal anti-inflammatory drugs in the prevention of cystoid macular edema after uneventful cataract surgery. Clin Ophthalmol. 2014;8:1209. doi:10.2147/OPTH.S61604 [CrossRef]
- Mirshahi M, Nicolas C, Mirshahi A, et al. The hormone receptor mineralocorticoid and action in the eye. Biochem Biophys Res Commun. 1996;219(1):150–156. doi:10.1006/bbrc.1996.0197 [CrossRef]
- Golestaneh N, Picaud S, Mirshahi M. The mineralocorticoid receptor in rodent retina: Ontogeny and molecular identity. Mol Vis. 2002;8:221–225.
- Zhao M, Valamanesh F, Celerier I, et al. The neuroretina is a novel mineralocorticoid target: Aldosterone up-regulates ion and water channels in Müller glial cells. FASEB J. 2010;24(9):3405–3415. doi:10.1096/fj.09-154344 [CrossRef]
- Wilkinson-Berka JL, Tan G, Jaworski K, Miller AG. Identification of a retinal aldosterone system and the protective effects of mineralocorticoid receptor antagonism on retinal vascular pathology. Circ Res. 2009;104(1):124–133. doi:10.1161/CIRCRESAHA.108.176008 [CrossRef]
- Liu Y, Hirooka K, Nishiyama A, et al. Activation of the aldosterone/mineralocorticoid receptor system and protective effects of mineralocorticoid receptor antagonism in retinal ischemia-reperfusion injury. Exp Eye Res. 2012;96(1):116–123. doi:10.1016/j.exer.2011.12.012 [CrossRef]
- Zhao M, Célérier I, Bousquet E, et al. Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy. J Clin Invest. 2012;122(7):2672–2679. doi:10.1172/JCI61427 [CrossRef]
- Daruich A, Matet A, Dirani A, et al. Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis. Prog Retin Eye Res. 2015;48:82–118. doi:10.1016/j.preteyeres.2015.05.003 [CrossRef]
- Behar-Cohen F, Zhao M. Corticosteroids and the retina: A role for the mineralocorticoid receptor. Curr Opin Neurol. 2016;29(1):49–54. doi:10.1097/WCO.0000000000000284 [CrossRef]