Pseudophakic cystoid macular edema (PCME), also known as Irvine-Gass syndrome, is a common cause of vision loss following cataract surgery.1 It manifests as macular thickening caused by fluid accumulation, which, if sufficient, can interfere with retinal function and cause a loss of visual acuity.1,2 Patients with diabetes, particularly those with diabetic retinopathy, are at an increased risk of developing PCME, and the edema may take longer to resolve than in patients without diabetes.1–5 Insulin dependence, a long duration of diabetes (> 10 years), the presence of diabetic macular edema (DME) at baseline, a history of treatment for clinically significant macular edema (ME), and greater severity of diabetic retinopathy all increase the risk of developing macular thickening and loss of vision following cataract surgery.2,6 Whether the ME that develops following cataract surgery in patients with diabetes is PCME or a worsening of DME may be impossible to determine, but the risk to vision and the need for effective treatment are clear.
At this time, there is no standardized treatment or prophylactic regimen for PCME, but topical nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are often used prophylactically and are the most common first-line treatments for acute PCME.1,7 Several studies suggest that these topical therapies can be effective in many patients with PCME, but they are not effective in all patients1,7 and have not been systematically evaluated in patients with diabetes. Treatment options being investigated for eyes with PCME that persists despite topical therapy include periocular or intravitreal corticosteroids and intravitreal anti–vascular endothelial growth factor (VEGF) agents.1,7 However, there is very little clinical evidence to support the use of any of these treatments, and most are limited by either a short duration of action or adverse effects.1,7 For patients with persistent PCME, especially those with the added complication of diabetes, there is an important need for an effective therapy that can be safely administered for long periods of time.
The dexamethasone intravitreal implant (DEX implant; Ozurdex; Allergan, Irvine, CA) was approved by the United States Food and Drug Administration for the treatment of ME secondary to retinal vein occlusion and for noninfectious uveitis affecting the posterior segment of the eye.8–11 It has been shown to produce improvements in visual acuity and retinal thickness in eyes with ME associated with a variety of inflammatory retinal vascular disorders,8,12 including DME,13,14 RVO,9,10 noninfectious uveitis affecting the posterior segment of the eye,11,15 and PCME.16,17 The prophylactic use of the DEX implant has also been shown to help prevent the worsening of DME following cataract surgery in diabetic patients.17 In all of these studies, the clinical benefits of the DEX implant are seen as early as 7 days postinjection and may persist for up to 6 months.
The purpose of this prospective, interventional case series was to evaluate the effects of DEX implant in patients with diabetes who developed PCME following uncomplicated cataract surgery despite ongoing prophylactic treatment with topical anti-inflammatory agents.
Patients and Methods
This prospective, interventional case series evaluated the effect of a single treatment with the DEX implant (0.7 mg) in patients with diabetes who developed PCME within 4 to 10 weeks following uncomplicated cataract surgery. Patients were required to have best corrected visual acuity (BCVA) between 20/40 and 20/200 for enrollment. Inclusion criteria also included optic nerve staining and petaloid leakage within the macula on fluorescein angiography. Exclusion criteria included a history of vitrectomy surgery; use of systemic, periocular, or intraocular corticosteroids within 30 days of enrollment; and moderate or severe glaucoma (defined as the use of > two topical ocular hypertensive medications). This trial was registered with ClinicalTrials.gov (identifier NCT01284478).
At baseline (day 0), the study eye was anesthetized and prepared according to standard clinical protocols for intravitreal injection. The DEX implant (0.7 mg) was then inserted into the vitreous using a single-use 22-G applicator. Ophthalmic evaluations were conducted at baseline (prior to treatment) and on days 7, 30, 60, 90, and 180. The prospectively defined primary outcome measure was the change in BCVA from baseline to day 180 (using the standardized Early Treatment Diabetic Retinopathy Study protocol).18 Secondary outcome measures were the proportion of patients achieving at least a 10-letter improvement in BCVA from baseline to day 180, central subfoveal thickness as measured by optical coherence tomography (Heidelberg Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany), macular volume (Heidelberg Spectralis HRA+OCT), and safety parameters. Safety measures included intraocular pressure (IOP), slit-lamp biomicroscopy, ophthalmoscopy, and adverse events.
The mean values for visual acuity, IOP, retinal thickness, and retinal volume at baseline and each follow-up visit were compared using the one-sample t test. A P value less than .05 was considered statistically significant. Calculations were conducted in R 214 (R Foundation for Statistical Computing, Vienna, Austria).
Statement of Ethics
The authors certify that this study was conducted in compliance with all institutional and governmental regulations concerning the ethical use of human volunteers and the Declaration of Helsinki. Approval was obtained from the El Camino Institutional Review Board (Mountain View, CA) before the study was initiated, and informed consent was obtained from all patients prior to enrollment.
Six patients with diabetic retinopathy who developed PCME following cataract surgery were enrolled in this study. The demographic and baseline characteristics of the study participants are summarized in the Table. The average age of the patients was 69 years. Two (33%) of the patients had mild nonproliferative diabetic retinopathy, two (33%) had moderate nonproliferative diabetic retinopathy, and two (33%) had regressed proliferative diabetic retinopathy. Five (83%) of the patients had been previously treated for clinically significant macular edema; treatments included focal laser (83%) and intravitreal injection of anti-VEGF agents (33%). All patients had uncomplicated cataract surgery with phacoemulsification. All patients had been prescribed a topical NSAID (33% on ketorolac and 66% on nepafenac) and a topical steroid (prednisolone acetate) immediately following cataract surgery as prophylaxis for cystoid macular edema and were still using this treatment at study entry. The mean time until diagnosis of ME following cataract surgery was 45.3 ± 4.4 days. The mean time from ME diagnosis to treatment with the DEX implant was 10.7 ± 15.4 days. The mean retinal thickness at baseline was 454 ± 131 µm.
Patient Demographics, Treatment History, and Baseline Characteristics
Changes in Visual Acuity
Baseline BCVA ranged from 53 to 73 letters (20/80 to 20/40) with a mean (± standard deviation [SD]) of 66 ± 9 letters (Snellen equivalent, 20/50). In all but one patient (patient 3), BCVA improved to 80 letters or greater (20/40 to 20/20) by day 180 (Figure 1A).The mean BCVA on day 180 for all patients was 79 ± 6 letters (Snellen equivalent, 20/25), and four of six patients (67%) had at least a 10-letter improvement from baseline BCVA on day 180. A statistically significant mean increase from baseline BCVA was observed as soon as day 60 (P = .01) and was maintained through day 180 (P = .03, Figure 1B). The mean change from baseline to day 180 was 14 letters (P = .03).
BCVA over 6 months after treatment with an intravitreal DEX implant. (A) Individual patient data. Patient 3 (in gray) had an epiretinal membrane at baseline. (B) The mean change from baseline. Error bars represent the SD of the mean. A significant improvement in visual acuity was observed as early as day 60 and was maintained through day 180 (*P < .05).
Baseline central retinal thickness (CRT) ranged from 363 to 718 µm with a mean (± SD) of 454 ± 131 µm. Central retinal thickness decreased by day 30 and remained below baseline through day 180 in all patients (Figure 2A). In general, the greatest decrease in retinal thickness was noted between day 30 and day 90 posttreatment. Central retinal thickness gradually increased thereafter but remained below baseline in all patients on day 180. The mean decrease from baseline CRT was 100 µm (P < .01 vs baseline) on day 30 and remained significantly below baseline through day 180 (P ≤ .005); the mean decrease from baseline to day 180 was 72 µm (P = .004, Figure 2B).
Central retinal thickness (CRT) over 6 months after treatment with an intravitreal DEX implant. (A) Individual patient data. Patient 3 (in gray) had an epiretinal membrane at baseline. (B) The mean change from baseline. Error bars represent the SD of the mean. A significant decrease in CRT was observed on day 30 and maintained through day 180 (*P < .05).
At baseline, the mean (± SD) retinal volume was 9.99 ± 1.25 mm3 (range: 8.49–11.91 mm3). Following treatment, there was at least a transient decrease in retinal volume in all patients, but volume returned to near baseline levels in half of the patients (Figure 3A). The mean change from baseline in retinal volume was statistically significant from day 30 through day 90 (P = .01, Figure 3B).
Retinal volume over 6 months after treatment with an intravitreal DEX implant. (A) Individual patient data. Patient 3 (in gray) had an epiretinal membrane at baseline. (B) The mean change from baseline. Error bars represent the standard deviation of the mean. A significant decrease in retinal volume was observed as early as day 30 and was maintained through day 90 (P < .001) but was not significantly different from baseline on day 180 (P = .08).
There was no statistically significant change from baseline in mean IOP at any time during the study. There was no increase in IOP that exceeded 8 mm Hg, and no patient experienced an IOP greater than 22 mm Hg at any time during the study. No patient required treatment to lower their IOP. No other adverse events occurred during the study.
In this study, a single DEX implant produced clinically meaningful improvements in vision in diabetic patients who developed PCME following uncomplicated cataract surgery despite topical treatment with NSAIDs and steroid eye drops. Improvements in vision were accompanied by reductions in CRT and volume, and all benefits were sustained for 3 to 6 months posttreatment. Treatment was well tolerated, and no adverse events were reported.
By the final study visit on day 180, vision was restored to normal or near normal levels in all but one patient (five/six). It is important to note that the one patient (patient 3) who did not have a visual acuity of 20/25 or better on day 180 did experience a transient improvement in vision (to 83 letters on day 60). Patient #3 had an epiretinal membrane at baseline that may have played a role in his macular edema and the lack of a robust response to treatment with the DEX implant. Across all patients, the improvement in the mean BCVA from baseline to day 180 was statistically significant despite the one patient who did not experience a sustained response to treatment. The visual gains (67% with a > 10-letter improvement on day 180) were similar to those seen in the subgroup analysis of patients with inflammatory ME enrolled in an earlier phase 2 study. In that subgroup analysis, 46% (6/13 patients) had a greater than 10-letter improvement with the DEX implant (0.7 mg) at 180 days posttreatment.15 However, that analysis included patients with ME caused by either PCME or uveitis and is therefore not directly comparable with this study. A small, retrospective study that only evaluated patients with refractory ME caused by PCME also found that a single treatment with the DEX implant produced statistically significant improvements from baseline in both BCVA and foveal thickness that were maintained for up to 6 months after treatment.16
In the present study, the improvements in vision following treatment with the DEX implant were accompanied by sustained improvements in CRT. Even the patient who failed to maintain a sustained improvement in visual acuity experienced a marked reduction in CRT that was sustained through day 180. In all patients, retinal thickness decreased as early as day 30 posttreatment and continued to decrease through days 60 to 90. After day 90, retinal thickness began to gradually increase but remained below baseline in all patients on day 180.
The results of the present study build on the findings of an earlier randomized controlled trial that demonstrated that the DEX implant could effectively prevent DME progression following cataract surgery in patients with diabetes (18 eyes of 16 patients).17 In this prophylaxis study, the DEX implant was placed in the vitreous at the beginning of the phacoemulsification procedure. The eyes that received the prophylactic DEX implant had a significantly greater improvement in vision and a decrease in central macular thickness than did untreated eyes at every follow-up visit through 24 weeks. All untreated eyes experienced increases in central macular thickness, and seven of nine (78%) required an intravitreal injection of triamcinolone acetonide (IVTA) to control their ME; none of the eyes treated with the DEX implant required IVTA.17
Taken together, the results of this earlier study17 and the present study suggest that the DEX implant may be a promising therapy for both the prevention and treatment of vision loss due to ME following cataract surgery in patients with diabetes. Prophylaxis with DEX implant may be considered when a patient is at high risk for developing PCME but could result in some patients receiving an unnecessary treatment. The results of the present study suggests that the majority of eyes in patients with diabetes who develop PCME may respond favorably to treatment with the DEX implant, suggesting that treating all diabetic patients with the DEX implant prophylactically may not be warranted.
To our knowledge, no other intravitreal therapy has been prospectively evaluated for the treatment of PCME following cataract surgery in eyes with diabetic retinopathy. IVTA has been evaluated for the treatment of refractory PCME in a retrospective case review of eight patients, including three with diabetes.19 Vision improved in all patients, but multiple injections were required (the mean interval between injections was 8 weeks). Moreover, the response to IVTA became less impressive with repeated injections, and there was a trend toward resistance.19 The usefulness of intravitreal anti-VEGF agents (bevacizumab and pegaptanib) has also been evaluated in retrospective studies of eyes with PCME, but the results have been mixed and the relevance to patients with diabetes is unclear.20–22 Intravitreal anti-VEGF agents are short-acting therapies that, like IVTA, may need to be repeated every 1 to 2 months.
The strengths of this study include the prospective study design, the use of standardized Early Treatment Diabetic Retinopathy Study visual acuity measurements, and the inclusion of a particularly difficult-to-treat patient population with an unmet medical need. The main limitations of the present study are the small sample size and the lack of a control arm. Acute PCME (< 4 months in duration) may improve spontaneously without any further treatment. However, all patients in this study developed ME despite prophylactic and ongoing treatment with topical NSAIDs and steroids and had significant retinal thickening (average 454 µm). Therefore, it is unlikely that they would have improved without an additional intervention. It should also be noted that it is not possible to determine how much of the ME observed in these patients represents a worsening of their DME rather than the development of PCME. Five of the six patients had previous treatment for DME, and it is not known how much ME was present before cataract surgery.1 However, all patients had a component of PCME as optic nerve staining and petaloid leakage within the macula on fluorescein angiography (which was part of the inclusion criteria). This is a minor limitation, however, because both conditions require treatment to prevent visual deterioration and the approach to treatment is similar. Another potential limitation is that all enrolled eyes had relatively minor visual impairment. This means that the results may not be applicable to a broader population of eyes with more severe vision loss, but the findings may help to define those patients most likely to respond to treatment. The visual impairment seen in the enrolled patients was consistent with a recent, large study of diabetic patients who developed ME following cataract surgery.6
In conclusion, the results of the present study suggest that the DEX implant may be a promising treatment option for diabetic patients who develop PCME following cataract surgery. Controlled studies with larger sample sizes should be performed to confirm these preliminary findings.
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- Kim SJ, Equi R, Bressler NM. Analysis of macular edema after cataract surgery in patients with diabetes using optical coherence tomography. Ophthalmology. 2007;114:881–889. doi:10.1016/j.ophtha.2006.08.053 [CrossRef]
- Krepler K, Biowski R, Schrey S, Jandrasits K, Wedrich A. Cataract surgery in patients with diabetic retinopathy: visual outcome, progression of diabetic retinopathy, and incidence of diabetic macular oedema. Graefes Arch Clin Exp Ophthalmol. 2002;240:735–738. doi:10.1007/s00417-002-0530-7 [CrossRef]
- Schmier JK, Halpern MT, Covert DW, Matthews GP. Evaluation of costs for cystoid macular edema among patients after cataract surgery. Retina. 2007;27:621–628. doi:10.1097/01.iae.0000249577.92800.c0 [CrossRef]
- Sivaprasad S, Bunce C, Crosby-Nwaobi R. Non-steroidal anti-inflammatory agents for treating cystoid macular oedema following cataract surgery. Cochrane Database Syst Rev. 2012;(1):CD004239. pub3.
- Baker CW, Almukhtar T, Bressler NM, et al. Macular edema after cataract surgery in eyes without preoperative central-involved diabetic macular edema. JAMA Ophthalmol. 2013Jul1;131(7):870–9. doi:10.1001/jamaophthalmol.2013.2313 [CrossRef]
- Shelsta HN, Jampol LM. Pharmacologic therapy of pseudophakic cystoid macular edema: 2010 update. Retina. 2011;31:4–12. doi:10.1097/IAE.0b013e3181fd9740 [CrossRef]
- Robinson MR, Whitcup SM. Pharmacologic and clinical profile of dexamethasone intravitreal implant. Expert Rev Clin Pharmacol. 2012;5:629–647. doi:10.1586/ecp.12.55 [CrossRef]
- Haller J, Bandello F, Belfort R Jr, et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010;117:1134–1146. doi:10.1016/j.ophtha.2010.03.032 [CrossRef]
- Haller J, Bandello F, Belfort R Jr, et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology. 2011;118:2453–2460. doi:10.1016/j.ophtha.2011.05.014 [CrossRef]
- Lowder C, Belfort R Jr, Lightman S, et al. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol. 2011;129:545–553. doi:10.1001/archophthalmol.2010.339 [CrossRef]
- Kuppermann BD, Blumenkranz MS, Haller JA, et al. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol. 2007;125:309–317. doi:10.1001/archopht.125.3.309 [CrossRef]
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- Williams GA, Haller JA, Kuppermann BD, et al. Dexamethasone posterior-segment drug delivery system in the treatment of macular edema resulting from uveitis or Irvine-Gass syndrome. Am J Ophthalmol. 2009;147:1048–1054. doi:10.1016/j.ajo.2008.12.033 [CrossRef]
- Medeiros MD, Navarro R, Garcia-Arumi J, Mateo C, Corcóstegui B. Dexamethasone intravitreal implant for treatment of patients with recalcitrant macular edema resulting from Irvine-Gass Syndrome. Invest Ophthalmol Vis Sci. 2013;54:3320–3324 doi:10.1167/iovs.12-11463 [CrossRef]
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Patient Demographics, Treatment History, and Baseline Characteristics
|Pt.||Agea (yrs)||Sex||Eye||DR Severity||Other Macular Pathology||Previous CSME Treatment||Current Topical Treatment||Time to CMEb (days)||Time From Diagnosis to DEX (days)||VAc (Snellen letters)||CRT (µm)||IOP (mm Hg)|
|1||77||F||OS||Moderate NPDR||None||Focal Laser #2, Intravitreal bevacizumab||Ketorolac Pred||41||38||56 (20/80)||392||17|
|2||70||F||OS||Moderate NPDR||None||Focal Laser #2||Ketorolac pred||48||20||53 (20/80)||430||16|
|3||77||M||OS||Mild NPDR||ERM||None||Nepafenac pred||44||4||69 (20/40)||718||10|
|4||73||M||OD||Mild NPDR||None||Focal laser||Nepafenac pred||40||0||72 (20/40)||401||13|
|5||67||M||OD||PDR||None||Focal laser||Nepafenac pred||48||2||73 (20/40)||419||18|
|6||55||M||OS||PDR||None||Focal laser #2, Intravitreal ranibizumab||Nepafenac pred||51||0||70 (20/40)||363||14|