EFFICACY AND SAFETY OF DEXAMETHASONE INTRAVITREAL IMPLANT FOR PERSISTENT UVEITIC CYSTOID MACULAR EDEMA RAHUL N. KHURANA, MD,*† TRAVIS C. PORCO, PHD† Purpose: To investigate dexamethasone intravitreal implant (DEX Implant 0.7 mg, Ozurdex; Allergan, Inc, Irvine, CA) as a treatment for persistent cystoid macular edema (CME) secondary to uveitis. Methods: Treatment and outcomes data were collected retrospectively for 18 eyes from 13 consecutive patients treated with the DEX Implant for persistent, noninfectious uveitic CME. Outcome measures included the cumulative incidence of resolution of CME, visual acuity, central retinal thickness (measured by spectral domain optical coherence tomography), and vitreous haze score. Results: After a single DEX Implant, there was no detectable CME in 89% and 72% of eyes at 1 month and 3 months, respectively. The median time to recurrence of CME (±standard error) was 201 ± 62 days. The percentage of eyes with no recurrence of CME was 35% at 6 months and 30% at 12 months. At 3 months, there was a significant improvement from baseline in mean visual acuity (+2.1 lines, P , 0.01). Eyes with an epiretinal membrane at baseline had shorter time to recurrence of CME and smaller improvements in visual acuity and central retinal thickness than eyes without an epiretinal membrane. At least 1 episode of intraocular pressure .25 mmHg occurred within the first 3 months in 11% (2 of 18) of eyes; all effectively managed with topical hypotensive medications. Conclusion: A single DEX Implant produced sustained improvements in both visual acuity and retinal thickness in the majority of eyes with persistent uveitic CME. Uveitic CME did gradually recur in most eyes; however, close posttreatment monitoring is recommended. RETINA 35:1640–1646, 2015
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Many different interventions have been used in the treatment uveitic CME—including a variety of corticosteroid therapies, anti-vascular endothelial growth factor treatments, and immunomodulatory agents— but there is very little evidence to support the efficacy of any of these treatments.6 In some patients, uveitic CME may persist despite multiple interventions.6 The dexamethasone intravitreal implant (DEX Implant; Ozurdex; Allergan, Inc, Irvine, CA) is approved by the United States Food and Drug Administration for the treatment of macular edema (ME) secondary to retinal vein occlusion and noninfectious uveitis affecting the posterior segment of the eye.7–10 In both these indications, the DEX Implant produces statistically and clinically significant improvements in both best-corrected visual acuity (BCVA) and central retinal thickness (CRT).9,10 In addition, the first randomized, controlled clinical trial of the DEX Implant demonstrated that the
veitis is an uncommon disorder, with an estimated prevalence of only 38 to 714 cases per 100,000,1 yet it is estimated to account for 10% of all cases of total blindness worldwide.2–4 The leading cause of visual impairment in eyes with uveitis is cystoid macular edema (CME),5 which is often difficult to treat and may persist despite adequate control of the uveitis itself. From the *Northern California Retina Vitreous Associates, Mountain View, California; and †Department of Ophthalmology, University of California, San Francisco, San Francisco, California. Paper presented at the 2014 American Society of Retina Specialists Meeting, San Diego, CA. None of the authors have any financial/conflicting interests to disclose. Amy Lindsay, PhD (Lindsay Biomedical Communications, Inc) provided professional writing assistance (funded by Allergan, Inc). Reprint requests: Rahul N. Khurana, MD, Northern California Retina Vitreous Associates, 2485 Hospital Drive, Suite #200, Mountain View, CA 94040; e-mail: [email protected]
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DEXAMETHASONE IMPLANT FOR UVEITIC CME KHURANA AND PORCO
DEX Implant could produce significant improvements in both BCVA and CRT in eyes with persistent ME because of any of a variety of causes including uveitis.11 A subgroup analysis of those eyes with ME because of either uveitis or Irvine–Gass syndrome confirmed that the DEX Implant could produce improvements in BCVA in this subgroup of patients but did not report anatomical outcomes and only included five eyes treated with the DEX Implant for ME because of uveitis.12 These studies suggest that it would be worthwhile to investigate the DEX Implant as a treatment for eyes with uveitic CME. The purpose of this retrospective chart review was to document the effects of a single DEX Implant in eyes with persistent CME secondary to uveitis.
Methods This was a retrospective, noncomparative consecutive interventional case series. Thirteen consecutive patients (18 eyes) who had been treated with the DEX Implant for noninfectious uveitic CME between July 2011 and November 2012 were identified in the clinical databases of Northern California Retina Vitreous Associates. The Institutional Review Board (IRB) approval was obtained from the El Camino IRB (Mountain View, CA). All study procedures conformed to the tenets of the Health Insurance Portability and Accountability Act and the Declaration of Helsinki for research involving human subjects. Patients were included in the study if they were older than 18 years of age, had been treated with the DEX Implant for CME secondary to noninfectious uveitis, and had been followed for at least 3 months after treatment. Persistent uveitic CME was defined as the presence of intraretinal cysts on spectral domain optical coherence tomography (SD-OCT) and macular leakage on fluorescein angiography for greater than 3 months before DEX Implant treatment.13 Before each treatment with DEX Implant, the eye was anesthetized and prepared according to standard clinical protocols for intravitreal injection. The DEX Implant was inserted into the vitreous using a singleuse 22-gauge applicator. Data for BCVA (Snellen scale), CRT as measured by SD-OCT (Cirrus, Model 4000; Carl Zeiss, Dublin, CA), vitreous haze score, intraocular pressure (IOP), and adverse events were collected for each patient at each follow-up visit. The OCT measurements consisted of standard macular imaging with the Macular Cube (512 ·128) and the 5-line raster scanning protocols (Carl Zeiss, Dublin, CA). The presence or absence of an epiretinal membrane (ERM), which was defined as
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a thin, smooth hyperreflective layer between the neural retina and the vitreous involving the foveal area, was determined by SD-OCT. The main outcome measure was the cumulative incidence of resolution of CME at the 1-month and 3-month visits after the first DEX Implant. Recurrence of CME was defined as the presence of intraretinal cysts on SD-OCT. Retreatment with DEX implant was performed if there was recurrence of CME on SD-OCT and a decrease in visual acuity as compared with previous visits. Secondary outcome measures included change in visual acuity, change in CRT, and adverse events. Data Analysis and Statistical Methods All visual acuity measurements were converted to logarithm of the minimum angle of resolution (logMAR) units for comparison and analysis. Changes in visual acuity, CRT, and IOP with two-sided values of P , 0.05 were considered statistically significant. Because the presence of an ERM may limit the response to medical therapy in uveitic CME,14 the anatomical outcomes involving CRT, the time to recurrence of CME, and visual acuity were calculated separately for the eyes without an ERM (n = 13) and with an ERM (n = 5). Linear mixed-effects regression was used to model the change scores. Because of the small number of patients, multivariate analysis was not performed. Nonparametric maximum likelihood estimates for the survival curves for the interval-censored event-time data were computed using the vertex exchange algorithm (R Package, Icens, R Foundation for Statistical Computing, Vienna, Austria). Parametric survival analysis was conducted using the Weibull model; all analyses were repeated using the lognormal distribution as a sensitivity analysis (results not shown). Median survival was computed from the estimated distribution, with standard errors (SEs) computed by the delta method. All computations were conducted in R v. 3.1 for MacIntosh (R Foundation for Statistical Computing, Vienna, Austria, http://www.r-project.org). Results Study Population The key patient population characteristics at the time of the first DEX implant are listed in Table 1. The median age was 54 years, and most of the patients included in this study were female (77%) and white (67%). Three patients (23%) were current or former smokers. Patients presented with a variety of different inflammatory diagnoses, including intermediate uveitis (39%), birdshot chorioretinitis (22%), and sarcoidosis (22%), among others.
1642 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES Table 1. Patient Characteristics Demographic characteristics (n = 13 patients) Age, years Mean Median Range Sex, n (%) female Race, n (%) White Latino Asian History of smoking, n (%) Current Former Medical history (n = 20 eyes) Diagnosis, n (%) Intermediate uveitis Birdshot chorioretinitis Sarcoidosis Other Duration of CME Median in months (range) Previously treated, n (%) Any treatment More than 2 treatments Baseline values (n = 18 eyes) Visual acuity, n (%) 10/30–10/50 10/60–10/80 10/100–10/150 CRT, mm Median Range ERM present, n (%) IOP, mmHg Median Range Vitreous haze score, n (%) 0 1 2
48 54 27–72 10 (77) 8 (62) 2 (15) 3 (23) 2 (15) 1 (8) 7 4 4 3
(39) (22) (22) (17)
16.5 (4–39) 14 (78) 10 (56) 9 (50) 7 (39) 2 (11) 453 314–778 5 (28) 15.5 7–22 10 (56) 6 (33) 2 (11)
The median duration of CME before treatment with DEX Implant was 16.5 months (range, 4–39 months). Seventy-eight percent of eyes had been managed with at least another therapy for uveitic CME before being treated with the DEX Implant. Most eyes (72%), however, were not receiving any treatment for uveitis at the time of the first DEX implant. Among 28% of eyes that were receiving immunosuppression at the time of the DEX Implant injection, the medications included infliximab (2 eyes), prednisone (1 eye), adalimumab (1 eye), and methotrexate (1 eye). The most common previous treatments were corticosteroids (either systemic, periocular, or intravitreal) and immunomodulatory therapies (including methotrexate, infliximab, adalimumab, etanercept, and rituximab). In addition, 9 eyes (50%) had received either a periocular or
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intravitreal injection (of either corticosteroid or bevacizumab) for treatment of uveitic CME in the past. Ten eyes (56%) had no vitreal inflammation. Five patients (38%) had bilateral CME that was treated with bilateral DEX Implants. Five eyes (28%) had an ERM present involving the fovea in addition to the CME at baseline. Anatomical Changes After a single DEX Implant, there was complete resolution of CME in 89% (95% confidence interval, 70%–95%) of eyes at 1 month posttreatment and 72% (95% confidence interval, 43%–84%) of eyes at 3 months posttreatment. In uveitic CME without an ERM, the mean CRT was 502 mm at baseline and this improved to 288 mm by 1 month posttreatment. The mean change from baseline in CRT was −190 mm (first quartile to third quartile: −275 to −129 mm) at Month 1 and −228 mm (first quartile to third quartile: −295 to −161 mm) at Month 3. This improvement was statistically significant at both Month 1 (P = 0.00048) and Month 3 (P = 0.0039). In uveitic CME with an ERM, the mean CRT was 399 mm at baseline and this improved to 298 mm by 1 month posttreatment. The mean change from baseline in CRT was −100 mm (first quartile to third quartile: −129 to −38 mm) at Month 1 and −33 mm (first quartile to third quartile: −66 to −1 mm) at Month 3. This change was not statistically significant at both Month 1 (P = 0.063) and Month 3 (P = 0.50). The reductions in CRT from baseline were greater in the eyes without an ERM at baseline than those with an ERM at baseline after DEX Implant treatment (P = 0.00078). In all patients with uveitic CME (including those with and without an ERM), the median time (±SE) to recurrence of CME was 201 ± 62 days. Figure 1 shows the estimated survival curve for the time to recurrence of CME for the entire study population after a single DEX Implant. Green bars occur where there was insufficient information to locate the survival curve (because of interval censoring); the wide SEs have been omitted for clarity. Note that 65% and 70% of eyes had recurrence of CME at 6 months and 12 months, respectively, after a single DEX implant treatment. In patients with an ERM at baseline, the median time to recurrence of CME was 110 days in comparison with 338 days for patients without an ERM present at baseline (P = 0.0053). Visual Acuity In all patients with uveitic CME, mean BCVA was 0.449 logMAR (Snellen equivalent, 20/60) and this improved to 0.238 logMAR (Snellen equivalent,
DEXAMETHASONE IMPLANT FOR UVEITIC CME KHURANA AND PORCO
Fig. 1. Estimated survival curve of the time to recurrence of CME after a single dexamethasone implant. Green bars are regions of uncertainty where there was insufficient information to locate the survival curve because of interval censoring.
20/30) by 1 month posttreatment. The mean change from baseline in BCVA was 2.0 lines (first quartile to third quartile: 3.0–1.0 lines) and 2.1 lines (first quartile to third quartile: 3.3–1.2 lines) at 1 month and 3 months posttreatment, respectively. These improvements were statistically significant at both Month 1 (P = 0.0016) and Month 3 (P = 0.0051). In addition, 47% and 50% of eyes gained 2 lines or more at 1 month and 3 months posttreatment, respectively. At 6 months after treatment, the visual acuity improved 2.1 lines (first quartile to third quartile: 3.5–0.4 lines; P = 0.014), and at 12 months, the visual acuity improved 1.4 lines (first quartile to third quartile: 1.9–0.6 lines; P = 0.11). In uveitic CME without an ERM at baseline, mean BCVA was 0.456 logMAR (Snellen equivalent, 20/60) and this improved to 0.203 (Snellen equivalent, 20/30) by 1 month posttreatment. The mean change from baseline in BCVA was 2.4 lines (first quartile to third quartile: 3.2–1.2 lines) and 2.5 lines (first quartile to third quartile: 3.9–1.8 lines) at 1 month and 3 months posttreatment, respectively. These improvements were statistically significant at both Month 1 (P = 0.0076) and Month 3 (P = 0.0078). In addition, 58% and 67% of eyes gained 2 lines or more at 1 month and 3 months posttreatment, respectively. At 6 months after treatment, the visual acuity improved 2.3 lines (first quartile to third quartile: 3.9–0.8 lines; P = 0.022), and at 12 months, the visual acuity improved 2.1 lines (first quartile to third quartile: 2.3–0.8 lines; P = 0.036). In uveitic CME with an ERM at baseline, mean BCVA was 0.429 logMAR (Snellen equivalent,
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20/50) and this improved to 0.321 (Snellen equivalent, 20/40) by 1 month posttreatment. The mean change from baseline in BCVA was 1.1 lines (first quartile to third quartile: 1.3–0.67 lines) and 0.9 lines (first quartile to third quartile: 1.4–0.6 lines) at 1 month and 3 months posttreatment, respectively. These changes in vision were not statistically significant at both Month 1 (P = 0.10) and Month 3 (P = 0.37). In addition, 20% and 20% of eyes gained 2 lines or more at 1 month and 3 months posttreatment, respectively. At 6 months after treatment, the visual acuity improved 1.5 lines (first quartile to third quartile: 2.2–0.8 lines; P = 0.40), and at 12 months, the visual acuity worsened 0.8 lines (first quartile to third quartile: 0.4–1.1 lines; P = 0.60), but these changes were not statistically significant. Eyes without an ERM at baseline had better improvements in visual acuity than those eyes with an ERM (P = 0.046). Ocular Inflammation At baseline, vitreous haze of Grade 1 was detected in 6 eyes (33%) and of Grade 2 was detected in 2 eyes (11%). The vitreous haze was Grade 0 at Months 1, 3, 6, and 12 follow-up visits. Number of Treatments Received The number of DEX implant treatments received per patient during the course of follow-up ranged from 1 to 4; 56% (10 of 18) needed 2 or more DEX implant treatments. Among those who received a second treatment, the median time (±SE) to retreatment was 300 ± 71 days. Safety No serious adverse events occurred in any of the evaluated patients. There was no statistically significant change in mean IOP at 1 month (+3.0 mmHg, P = 0.10), 3 months (+0.8 mmHg, P = 0.44), 6 months (+1.0 mmHg, P = 0.41), or 12 months (+1.5 mmHg, P = 0.40) posttreatment. Two eyes (11%) experienced an IOP of 25 mmHg or greater, and 0 eyes experienced an IOP of 35 mmHg or greater at some point during the first 90 days after the first DEX Implant. One eye (6%) had an increase of IOP . 10 mmHg from baseline. All increases in IOP were transient and effectively managed with topical hypotensive medications. Four patients initiated IOP medications during follow-up (all at the 1-month follow-up visit), but none required surgery to lower their IOP. Among the 10 eyes that were phakic at baseline, 1 (10%) had an increase in lens opacity during the
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follow-up period (progression of an existing cataract) and this occurred approximately 9 months after treatment with a single DEX Implant. There were no episodes of retinal detachment, hypotony, or anterior chamber migration of the DEX implant.15
Discussion Cystoid macular edema secondary to uveitis is difficult to treat and may persist despite multiple interventions.6 All of the patients included in this retrospective study had persistent uveitic CME (median duration, 16.5 months), and most had been unsuccessfully treated with multiple therapies in the past. In this study population, the majority of eyes (72%) had complete resolution of CME 3 months after a single treatment with DEX Implant. The resolution of CME was accompanied by statistically and clinically significant improvements in CRT and BCVA at both 1 month and 3 months posttreatment. The effect of the DEX implant was durable, with a median (±SE) time to recurrence of CME greater than 6 months (201 ± 62 days). Our findings are consistent with a recent retrospective study of 13 patients with persistent uveitic CME and a history of pars plana vitrectomy that were treated with the DEX Implant.16 In that study, all eyes experienced improvements in CRT after a single treatment with DEX Implant.16 The mean decrease in CRT was approximately 190 mm at 1 month posttreatment and 112 mm after 3 months. This is similar to the decrease of 190 mm at Month 1 and of 228 mm at Month 3 seen in this study. Unfortunately, this earlier study did not report the percentage of eyes with complete resolution of CME nor the time to recurrence of CME among those eyes that experienced complete resolution. The reductions in CRT reported in a large Phase 3 clinical trial of the safety and efficacy of DEX implant for the treatment of noninfectious posterior uveitis were somewhat smaller than observed in this study; a decrease of 99 mm at Week 8 and 68 mm at Week 16.10 In that study, the main outcome measure was vitreous haze; and uveitic CME was not part of the inclusion criteria. As a result, mean CRT at baseline was lower than that in this study (344 mm as compared with 473 mm), and this may explain the difference in the reduction in retinal thickening. The improvements in visual acuity seen in this study were also similar to those seen in the study of DEX Implant in vitrectomized eyes.16 In that study, the median improvement in BCVA was 1 line at 1 month posttreatment and 2 lines after 3 months.16 This is similar to the mean improvement of approximately 2 lines (at both Months 1 and 3) seen in this study. In
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addition, 53% of vitrectomized eyes experienced at least a 2-line improvement in BCVA by 3 months posttreatment,16 which is also consistent with 50% of eyes that gained at least 2 lines in this study. Although DEX Implant produced effective and sustained improvements in uveitic CME, visual acuity, and retinal thickness in the majority of eyes in this case series, uveitic CME did eventually recur in most eyes; only 35% of eyes had no recurrence of CME at 6 months posttreatment. Fifty-five percent of eyes required retreatment with the DEX Implant, and the median time to retreatment was 300 days. This is consistent with a recent retrospective study involving 27 patients who were treated with the DEX implant for noninfectious uveitis.17 The median time to relapse after the first DEX implant was 6 months (range, 2–42 months); and the overall relapse rate was 69%. In that study, relapse was defined as the first follow-up with foveal thickening (average retinal thickness plus one standard deviation) and/or doubling of the visual angle. Eyes that had an ERM at baseline had a worse prognosis, with CME recurring faster than in those eyes that did not have an ERM present (110 days vs. 338 days; P = 0.0053). Eyes with an ERM did not achieve improvements in visual acuity nor in CRT with DEX Implant treatment. It is possible that the mechanical component of uveitic CME caused by the ERM may be less affected by the DEX Implant. Caution is recommended when interpreting this data because of the small sample size and retrospective analysis. However, it is consistent with a previous report that showed the potential negative effect of ERM on visual function gain in eyes with uveitic CME treated with intravitreal triamcinolone acetonide.18 Furthermore, a recent study demonstrated that the presence of an ERM may limit the response to medical therapy in uveitic CME.14 Further studies should be done to explore the effect of ERM on outcomes in uveitic CME. The definition of recurrence of uveitic CME in this study was stringent and included the presence of any intraretinal cysts on SD-OCT. In 2004, the Standardization of Uveitis Nomenclature Working Group, an expert consensus panel, defined ME based on clinical observations.13 The panel also recommended ancillary testing to aid in the diagnosis but did not indicate a preference between OCT and fluorescein angiography.13 The noninvasive aspect and quantitative measurements provided by OCT have made it the most common method to detect CME in research studies and in the clinical management of retinal diseases. Previous studies that looked at CME have used time domain OCT, which is not as sensitive as SD-OCT in detecting intraretinal cysts and CME.19,20 In this study, all the patients
DEXAMETHASONE IMPLANT FOR UVEITIC CME KHURANA AND PORCO
were evaluated with SD-OCT at each follow-up visit, which allowed for earlier detection of intraretinal cysts after treatment. However, the presence of intraretinal cysts on OCT does not always correlate with vision loss.21 In this study, the median time to retreatment was longer than the median time to recurrence of CME (300 days vs. 201 days), because treatment was delayed until there was retinal thickening and/or vision loss in addition to the appearance of intraretinal cysts. The DEX Implant seemed to be well tolerated in this study. There were no serious adverse effects, and the incidence of elevated IOP (11% with IOP . 25 mmHg) was similar to what has been reported in earlier large Phase 3 studies of the use of the DEX Implant in nonvitrectomized eyes.8–10 Importantly, all increases in IOP were effectively managed with topical medications, and no patients required surgery to lower their IOP. This was a better safety profile than was seen in the study in vitrectomized eyes treated with the DEX Implant for uveitic CME.16 In that study, 40% of eyes experienced an increase in IOP to .25 mmHg and 6% of eyes required filtering surgery to lower their IOP.16 It is possible that vitrectomized eyes are at a higher risk for steroid-induced IOP increases than nonvitrectomized eyes.22 It is difficult to compare the results of this small study with DEX Implant with the results of studies of other interventions for uveitic CME. Most of the studies are small, and the study designs, outcome measures, and definitions of CME vary widely.6 In this study, resolution of CME (as measured by SD-OCT) was 89% and 72% at 1 month and 3 months posttreatment, respectively. In comparison, in a large retrospective cohort study of 126 patients who were treated with periocular triamcinolone acetonide for uveitic CME, the clinical resolution of CME at 1 month and 3 months was 53% and 57%, respectively, after a single injection.23 It is important to note that time domain OCT was used in the majority of those cases treated with periocular triamcinolone. Intravitreal triamcinolone acetonide is also used in the treatment of uveitic CME.18 In a prospective interventional study of 29 eyes treated with intravitreal triamcinolone acetonide for uveitic CME, the percentage of eyes with resolution of CME (as measured by SD-OCT) was 72% at 1 month and 45% at 3 months posttreatment.18 The DEX Implant and other local corticosteroid therapies should be investigated in prospective, comparative clinical trials to determine relative efficacy. The main limitations of this study are the retrospective study design and the small sample size, which makes multivariate analysis difficult. The strength of this study is that it provides the first report of anatomical outcomes after DEX Implant treatment in
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eyes with persistent CME secondary to uveitis. Other strengths of this study are the inclusion of many eyes with CME that had persisted despite multiple interventions, and the use of SD-OCT to determine CME recurrence rates. In conclusion, the results of this small retrospective study suggest that the DEX Implant may be a particularly promising treatment for persistent CME secondary to uveitis, even in those cases of uveitic CME that have been unresponsive to other treatments. Further prospective studies should be done to confirm these findings and compare them with other treatments for uveitic CME. Key words: dexamethasone intravitreal implant, cystoid macular edema, Ozurdex, uveitis, epiretinal membrane, spectral domain optical coherence tomography, intraocular pressure. References 1. De Smet M, Taylor S, Bodaghi B, et al. Understanding uveitis: the impact of research on visual outcomes. Prog Retin Eye Res 2011;30:452–470. 2. Gritz DC, Wong IG. Incidence and prevalence of uveitis in northern California; the northern California Epidemiology of uveitis study. Ophthalmology 2004;111:491–500. 3. McCluskey PJ, Towler HM, Lightman S. Management of chronic uveitis. BMJ 2000;320:555–558. 4. Nussenblatt RB. The natural history of uveitis. Int Ophthalmol 1990;14:303–308. 5. Okhravi N, Lightman S. Cystoid macular edema in uveitis. Ocul Immunol Inflamm 2003;11:29–38. 6. Karim R, Sykakis E, Lightman S, Fraser-Bell S. Interventions for the treatment of uveitic macular edema: a systematic review and meta-analysis. Clin Ophthalmol 2013;7:1109–1144. 7. Robinson MR, Whitcup SM. Pharmacologic and clinical profile of dexamethasone intravitreal implant. Expert Rev Clin Pharmacol 2012;5:629–647. 8. Haller J, Bandello F, Belfort R Jr, et al. Randomized, shamcontrolled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010;117:1134–1146. 9. 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. 10. Lowder C, Belfort R Jr, Lightman S, et al. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol 2011;129:545–553. 11. 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. 12. 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. 13. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of
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14.
15.
16.
17.
18.
the First International Workshop. Am J Ophthalmol 2005;140: 509–516. Lehpamer B, Moshier E, Pahk P, et al. Epiretinal membranes in uveitic macular edema: effect on vision and response to therapy. Am J Ophthalmol 2014;157:1048–1055. Khurana RN, Appa SN, McCannel CA, et al. Dexamethasone implant anterior chamber migration: risk factors, complications, and management strategies. Ophthalmology 2014;121:67–71. Adán A, Pelegrín L, Rey A, et al. Dexamethasone intravitreal implant for treatment of uveitic persistent cystoid macular edema in vitrectomized patients. Retina 2013;33:1435–1440. Tomkins-Netzer O, Taylor SR, Bar A, et al. Treatment with Repeat dexamethasone implants results in Long-Term Disease control in eyes with noninfectious uveitis. Ophthalmology 2014;121:1649–1654. Munk MR, Bolz M, Huf W, et al. Morphologic and functional evaluations during development, resolution, and relapse of uveitisassociated cystoid macular edema. Retina 2013;33:1673–1683.
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19. Sayanagi K, Sharma S, Yamamoto T, Kaiser PK. Comparison of spectral-domain versus time-domain optical coherence tomography in management of age-related macular degeneration with ranibizumab. Ophthalmology 2009;116:947–955. 20. Khurana RN, Dupas B, Bressler NM. Agreement of timedomain and spectral-domain optical coherence tomography with fluorescein leakage from choroidal neovascularization. Ophthalmology 2010;117:1376–1380. 21. Taylor SR, Lightman SL, Sugar EA, et al. The impact of macular edema on visual function in intermediate, posterior, and panuveitis. Ocul Immunol Inflamm 2012;20:171–181. 22. Yamashita T, Uemura A, Kita H, Sakamoto T. Intraocular pressure after intravitreal injection of triamcinolone acetonide following vitrectomy for macular edema. J Glaucoma 2007;16: 220–224. 23. Leder HA, Jabs DA, Galor A, et al. Periocular triamcinolone acetonide injections for cystoid macular edema complicating noninfectious uveitis. Am J Ophthalmol 2011;152:441–448.
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Many different interventions have been used in the treatment uveitic CME—including a variety of corticosteroid therapies, anti-vascular endothelial growth factor treatments, and immunomodulatory agents— but there is very little evidence to support the efficacy of any of these treatments.6 In some patients, uveitic CME may persist despite multiple interventions.6 The dexamethasone intravitreal implant (DEX Implant; Ozurdex; Allergan, Inc, Irvine, CA) is approved by the United States Food and Drug Administration for the treatment of macular edema (ME) secondary to retinal vein occlusion and noninfectious uveitis affecting the posterior segment of the eye.7–10 In both these indications, the DEX Implant produces statistically and clinically significant improvements in both best-corrected visual acuity (BCVA) and central retinal thickness (CRT).9,10 In addition, the first randomized, controlled clinical trial of the DEX Implant demonstrated that the
veitis is an uncommon disorder, with an estimated prevalence of only 38 to 714 cases per 100,000,1 yet it is estimated to account for 10% of all cases of total blindness worldwide.2–4 The leading cause of visual impairment in eyes with uveitis is cystoid macular edema (CME),5 which is often difficult to treat and may persist despite adequate control of the uveitis itself. From the *Northern California Retina Vitreous Associates, Mountain View, California; and †Department of Ophthalmology, University of California, San Francisco, San Francisco, California. Paper presented at the 2014 American Society of Retina Specialists Meeting, San Diego, CA. None of the authors have any financial/conflicting interests to disclose. Amy Lindsay, PhD (Lindsay Biomedical Communications, Inc) provided professional writing assistance (funded by Allergan, Inc). Reprint requests: Rahul N. Khurana, MD, Northern California Retina Vitreous Associates, 2485 Hospital Drive, Suite #200, Mountain View, CA 94040; e-mail: [email protected]
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DEX Implant could produce significant improvements in both BCVA and CRT in eyes with persistent ME because of any of a variety of causes including uveitis.11 A subgroup analysis of those eyes with ME because of either uveitis or Irvine–Gass syndrome confirmed that the DEX Implant could produce improvements in BCVA in this subgroup of patients but did not report anatomical outcomes and only included five eyes treated with the DEX Implant for ME because of uveitis.12 These studies suggest that it would be worthwhile to investigate the DEX Implant as a treatment for eyes with uveitic CME. The purpose of this retrospective chart review was to document the effects of a single DEX Implant in eyes with persistent CME secondary to uveitis.
Methods This was a retrospective, noncomparative consecutive interventional case series. Thirteen consecutive patients (18 eyes) who had been treated with the DEX Implant for noninfectious uveitic CME between July 2011 and November 2012 were identified in the clinical databases of Northern California Retina Vitreous Associates. The Institutional Review Board (IRB) approval was obtained from the El Camino IRB (Mountain View, CA). All study procedures conformed to the tenets of the Health Insurance Portability and Accountability Act and the Declaration of Helsinki for research involving human subjects. Patients were included in the study if they were older than 18 years of age, had been treated with the DEX Implant for CME secondary to noninfectious uveitis, and had been followed for at least 3 months after treatment. Persistent uveitic CME was defined as the presence of intraretinal cysts on spectral domain optical coherence tomography (SD-OCT) and macular leakage on fluorescein angiography for greater than 3 months before DEX Implant treatment.13 Before each treatment with DEX Implant, the eye was anesthetized and prepared according to standard clinical protocols for intravitreal injection. The DEX Implant was inserted into the vitreous using a singleuse 22-gauge applicator. Data for BCVA (Snellen scale), CRT as measured by SD-OCT (Cirrus, Model 4000; Carl Zeiss, Dublin, CA), vitreous haze score, intraocular pressure (IOP), and adverse events were collected for each patient at each follow-up visit. The OCT measurements consisted of standard macular imaging with the Macular Cube (512 ·128) and the 5-line raster scanning protocols (Carl Zeiss, Dublin, CA). The presence or absence of an epiretinal membrane (ERM), which was defined as
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a thin, smooth hyperreflective layer between the neural retina and the vitreous involving the foveal area, was determined by SD-OCT. The main outcome measure was the cumulative incidence of resolution of CME at the 1-month and 3-month visits after the first DEX Implant. Recurrence of CME was defined as the presence of intraretinal cysts on SD-OCT. Retreatment with DEX implant was performed if there was recurrence of CME on SD-OCT and a decrease in visual acuity as compared with previous visits. Secondary outcome measures included change in visual acuity, change in CRT, and adverse events. Data Analysis and Statistical Methods All visual acuity measurements were converted to logarithm of the minimum angle of resolution (logMAR) units for comparison and analysis. Changes in visual acuity, CRT, and IOP with two-sided values of P , 0.05 were considered statistically significant. Because the presence of an ERM may limit the response to medical therapy in uveitic CME,14 the anatomical outcomes involving CRT, the time to recurrence of CME, and visual acuity were calculated separately for the eyes without an ERM (n = 13) and with an ERM (n = 5). Linear mixed-effects regression was used to model the change scores. Because of the small number of patients, multivariate analysis was not performed. Nonparametric maximum likelihood estimates for the survival curves for the interval-censored event-time data were computed using the vertex exchange algorithm (R Package, Icens, R Foundation for Statistical Computing, Vienna, Austria). Parametric survival analysis was conducted using the Weibull model; all analyses were repeated using the lognormal distribution as a sensitivity analysis (results not shown). Median survival was computed from the estimated distribution, with standard errors (SEs) computed by the delta method. All computations were conducted in R v. 3.1 for MacIntosh (R Foundation for Statistical Computing, Vienna, Austria, http://www.r-project.org). Results Study Population The key patient population characteristics at the time of the first DEX implant are listed in Table 1. The median age was 54 years, and most of the patients included in this study were female (77%) and white (67%). Three patients (23%) were current or former smokers. Patients presented with a variety of different inflammatory diagnoses, including intermediate uveitis (39%), birdshot chorioretinitis (22%), and sarcoidosis (22%), among others.
1642 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES Table 1. Patient Characteristics Demographic characteristics (n = 13 patients) Age, years Mean Median Range Sex, n (%) female Race, n (%) White Latino Asian History of smoking, n (%) Current Former Medical history (n = 20 eyes) Diagnosis, n (%) Intermediate uveitis Birdshot chorioretinitis Sarcoidosis Other Duration of CME Median in months (range) Previously treated, n (%) Any treatment More than 2 treatments Baseline values (n = 18 eyes) Visual acuity, n (%) 10/30–10/50 10/60–10/80 10/100–10/150 CRT, mm Median Range ERM present, n (%) IOP, mmHg Median Range Vitreous haze score, n (%) 0 1 2
48 54 27–72 10 (77) 8 (62) 2 (15) 3 (23) 2 (15) 1 (8) 7 4 4 3
(39) (22) (22) (17)
16.5 (4–39) 14 (78) 10 (56) 9 (50) 7 (39) 2 (11) 453 314–778 5 (28) 15.5 7–22 10 (56) 6 (33) 2 (11)
The median duration of CME before treatment with DEX Implant was 16.5 months (range, 4–39 months). Seventy-eight percent of eyes had been managed with at least another therapy for uveitic CME before being treated with the DEX Implant. Most eyes (72%), however, were not receiving any treatment for uveitis at the time of the first DEX implant. Among 28% of eyes that were receiving immunosuppression at the time of the DEX Implant injection, the medications included infliximab (2 eyes), prednisone (1 eye), adalimumab (1 eye), and methotrexate (1 eye). The most common previous treatments were corticosteroids (either systemic, periocular, or intravitreal) and immunomodulatory therapies (including methotrexate, infliximab, adalimumab, etanercept, and rituximab). In addition, 9 eyes (50%) had received either a periocular or
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intravitreal injection (of either corticosteroid or bevacizumab) for treatment of uveitic CME in the past. Ten eyes (56%) had no vitreal inflammation. Five patients (38%) had bilateral CME that was treated with bilateral DEX Implants. Five eyes (28%) had an ERM present involving the fovea in addition to the CME at baseline. Anatomical Changes After a single DEX Implant, there was complete resolution of CME in 89% (95% confidence interval, 70%–95%) of eyes at 1 month posttreatment and 72% (95% confidence interval, 43%–84%) of eyes at 3 months posttreatment. In uveitic CME without an ERM, the mean CRT was 502 mm at baseline and this improved to 288 mm by 1 month posttreatment. The mean change from baseline in CRT was −190 mm (first quartile to third quartile: −275 to −129 mm) at Month 1 and −228 mm (first quartile to third quartile: −295 to −161 mm) at Month 3. This improvement was statistically significant at both Month 1 (P = 0.00048) and Month 3 (P = 0.0039). In uveitic CME with an ERM, the mean CRT was 399 mm at baseline and this improved to 298 mm by 1 month posttreatment. The mean change from baseline in CRT was −100 mm (first quartile to third quartile: −129 to −38 mm) at Month 1 and −33 mm (first quartile to third quartile: −66 to −1 mm) at Month 3. This change was not statistically significant at both Month 1 (P = 0.063) and Month 3 (P = 0.50). The reductions in CRT from baseline were greater in the eyes without an ERM at baseline than those with an ERM at baseline after DEX Implant treatment (P = 0.00078). In all patients with uveitic CME (including those with and without an ERM), the median time (±SE) to recurrence of CME was 201 ± 62 days. Figure 1 shows the estimated survival curve for the time to recurrence of CME for the entire study population after a single DEX Implant. Green bars occur where there was insufficient information to locate the survival curve (because of interval censoring); the wide SEs have been omitted for clarity. Note that 65% and 70% of eyes had recurrence of CME at 6 months and 12 months, respectively, after a single DEX implant treatment. In patients with an ERM at baseline, the median time to recurrence of CME was 110 days in comparison with 338 days for patients without an ERM present at baseline (P = 0.0053). Visual Acuity In all patients with uveitic CME, mean BCVA was 0.449 logMAR (Snellen equivalent, 20/60) and this improved to 0.238 logMAR (Snellen equivalent,
DEXAMETHASONE IMPLANT FOR UVEITIC CME KHURANA AND PORCO
Fig. 1. Estimated survival curve of the time to recurrence of CME after a single dexamethasone implant. Green bars are regions of uncertainty where there was insufficient information to locate the survival curve because of interval censoring.
20/30) by 1 month posttreatment. The mean change from baseline in BCVA was 2.0 lines (first quartile to third quartile: 3.0–1.0 lines) and 2.1 lines (first quartile to third quartile: 3.3–1.2 lines) at 1 month and 3 months posttreatment, respectively. These improvements were statistically significant at both Month 1 (P = 0.0016) and Month 3 (P = 0.0051). In addition, 47% and 50% of eyes gained 2 lines or more at 1 month and 3 months posttreatment, respectively. At 6 months after treatment, the visual acuity improved 2.1 lines (first quartile to third quartile: 3.5–0.4 lines; P = 0.014), and at 12 months, the visual acuity improved 1.4 lines (first quartile to third quartile: 1.9–0.6 lines; P = 0.11). In uveitic CME without an ERM at baseline, mean BCVA was 0.456 logMAR (Snellen equivalent, 20/60) and this improved to 0.203 (Snellen equivalent, 20/30) by 1 month posttreatment. The mean change from baseline in BCVA was 2.4 lines (first quartile to third quartile: 3.2–1.2 lines) and 2.5 lines (first quartile to third quartile: 3.9–1.8 lines) at 1 month and 3 months posttreatment, respectively. These improvements were statistically significant at both Month 1 (P = 0.0076) and Month 3 (P = 0.0078). In addition, 58% and 67% of eyes gained 2 lines or more at 1 month and 3 months posttreatment, respectively. At 6 months after treatment, the visual acuity improved 2.3 lines (first quartile to third quartile: 3.9–0.8 lines; P = 0.022), and at 12 months, the visual acuity improved 2.1 lines (first quartile to third quartile: 2.3–0.8 lines; P = 0.036). In uveitic CME with an ERM at baseline, mean BCVA was 0.429 logMAR (Snellen equivalent,
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20/50) and this improved to 0.321 (Snellen equivalent, 20/40) by 1 month posttreatment. The mean change from baseline in BCVA was 1.1 lines (first quartile to third quartile: 1.3–0.67 lines) and 0.9 lines (first quartile to third quartile: 1.4–0.6 lines) at 1 month and 3 months posttreatment, respectively. These changes in vision were not statistically significant at both Month 1 (P = 0.10) and Month 3 (P = 0.37). In addition, 20% and 20% of eyes gained 2 lines or more at 1 month and 3 months posttreatment, respectively. At 6 months after treatment, the visual acuity improved 1.5 lines (first quartile to third quartile: 2.2–0.8 lines; P = 0.40), and at 12 months, the visual acuity worsened 0.8 lines (first quartile to third quartile: 0.4–1.1 lines; P = 0.60), but these changes were not statistically significant. Eyes without an ERM at baseline had better improvements in visual acuity than those eyes with an ERM (P = 0.046). Ocular Inflammation At baseline, vitreous haze of Grade 1 was detected in 6 eyes (33%) and of Grade 2 was detected in 2 eyes (11%). The vitreous haze was Grade 0 at Months 1, 3, 6, and 12 follow-up visits. Number of Treatments Received The number of DEX implant treatments received per patient during the course of follow-up ranged from 1 to 4; 56% (10 of 18) needed 2 or more DEX implant treatments. Among those who received a second treatment, the median time (±SE) to retreatment was 300 ± 71 days. Safety No serious adverse events occurred in any of the evaluated patients. There was no statistically significant change in mean IOP at 1 month (+3.0 mmHg, P = 0.10), 3 months (+0.8 mmHg, P = 0.44), 6 months (+1.0 mmHg, P = 0.41), or 12 months (+1.5 mmHg, P = 0.40) posttreatment. Two eyes (11%) experienced an IOP of 25 mmHg or greater, and 0 eyes experienced an IOP of 35 mmHg or greater at some point during the first 90 days after the first DEX Implant. One eye (6%) had an increase of IOP . 10 mmHg from baseline. All increases in IOP were transient and effectively managed with topical hypotensive medications. Four patients initiated IOP medications during follow-up (all at the 1-month follow-up visit), but none required surgery to lower their IOP. Among the 10 eyes that were phakic at baseline, 1 (10%) had an increase in lens opacity during the
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follow-up period (progression of an existing cataract) and this occurred approximately 9 months after treatment with a single DEX Implant. There were no episodes of retinal detachment, hypotony, or anterior chamber migration of the DEX implant.15
Discussion Cystoid macular edema secondary to uveitis is difficult to treat and may persist despite multiple interventions.6 All of the patients included in this retrospective study had persistent uveitic CME (median duration, 16.5 months), and most had been unsuccessfully treated with multiple therapies in the past. In this study population, the majority of eyes (72%) had complete resolution of CME 3 months after a single treatment with DEX Implant. The resolution of CME was accompanied by statistically and clinically significant improvements in CRT and BCVA at both 1 month and 3 months posttreatment. The effect of the DEX implant was durable, with a median (±SE) time to recurrence of CME greater than 6 months (201 ± 62 days). Our findings are consistent with a recent retrospective study of 13 patients with persistent uveitic CME and a history of pars plana vitrectomy that were treated with the DEX Implant.16 In that study, all eyes experienced improvements in CRT after a single treatment with DEX Implant.16 The mean decrease in CRT was approximately 190 mm at 1 month posttreatment and 112 mm after 3 months. This is similar to the decrease of 190 mm at Month 1 and of 228 mm at Month 3 seen in this study. Unfortunately, this earlier study did not report the percentage of eyes with complete resolution of CME nor the time to recurrence of CME among those eyes that experienced complete resolution. The reductions in CRT reported in a large Phase 3 clinical trial of the safety and efficacy of DEX implant for the treatment of noninfectious posterior uveitis were somewhat smaller than observed in this study; a decrease of 99 mm at Week 8 and 68 mm at Week 16.10 In that study, the main outcome measure was vitreous haze; and uveitic CME was not part of the inclusion criteria. As a result, mean CRT at baseline was lower than that in this study (344 mm as compared with 473 mm), and this may explain the difference in the reduction in retinal thickening. The improvements in visual acuity seen in this study were also similar to those seen in the study of DEX Implant in vitrectomized eyes.16 In that study, the median improvement in BCVA was 1 line at 1 month posttreatment and 2 lines after 3 months.16 This is similar to the mean improvement of approximately 2 lines (at both Months 1 and 3) seen in this study. In
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addition, 53% of vitrectomized eyes experienced at least a 2-line improvement in BCVA by 3 months posttreatment,16 which is also consistent with 50% of eyes that gained at least 2 lines in this study. Although DEX Implant produced effective and sustained improvements in uveitic CME, visual acuity, and retinal thickness in the majority of eyes in this case series, uveitic CME did eventually recur in most eyes; only 35% of eyes had no recurrence of CME at 6 months posttreatment. Fifty-five percent of eyes required retreatment with the DEX Implant, and the median time to retreatment was 300 days. This is consistent with a recent retrospective study involving 27 patients who were treated with the DEX implant for noninfectious uveitis.17 The median time to relapse after the first DEX implant was 6 months (range, 2–42 months); and the overall relapse rate was 69%. In that study, relapse was defined as the first follow-up with foveal thickening (average retinal thickness plus one standard deviation) and/or doubling of the visual angle. Eyes that had an ERM at baseline had a worse prognosis, with CME recurring faster than in those eyes that did not have an ERM present (110 days vs. 338 days; P = 0.0053). Eyes with an ERM did not achieve improvements in visual acuity nor in CRT with DEX Implant treatment. It is possible that the mechanical component of uveitic CME caused by the ERM may be less affected by the DEX Implant. Caution is recommended when interpreting this data because of the small sample size and retrospective analysis. However, it is consistent with a previous report that showed the potential negative effect of ERM on visual function gain in eyes with uveitic CME treated with intravitreal triamcinolone acetonide.18 Furthermore, a recent study demonstrated that the presence of an ERM may limit the response to medical therapy in uveitic CME.14 Further studies should be done to explore the effect of ERM on outcomes in uveitic CME. The definition of recurrence of uveitic CME in this study was stringent and included the presence of any intraretinal cysts on SD-OCT. In 2004, the Standardization of Uveitis Nomenclature Working Group, an expert consensus panel, defined ME based on clinical observations.13 The panel also recommended ancillary testing to aid in the diagnosis but did not indicate a preference between OCT and fluorescein angiography.13 The noninvasive aspect and quantitative measurements provided by OCT have made it the most common method to detect CME in research studies and in the clinical management of retinal diseases. Previous studies that looked at CME have used time domain OCT, which is not as sensitive as SD-OCT in detecting intraretinal cysts and CME.19,20 In this study, all the patients
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were evaluated with SD-OCT at each follow-up visit, which allowed for earlier detection of intraretinal cysts after treatment. However, the presence of intraretinal cysts on OCT does not always correlate with vision loss.21 In this study, the median time to retreatment was longer than the median time to recurrence of CME (300 days vs. 201 days), because treatment was delayed until there was retinal thickening and/or vision loss in addition to the appearance of intraretinal cysts. The DEX Implant seemed to be well tolerated in this study. There were no serious adverse effects, and the incidence of elevated IOP (11% with IOP . 25 mmHg) was similar to what has been reported in earlier large Phase 3 studies of the use of the DEX Implant in nonvitrectomized eyes.8–10 Importantly, all increases in IOP were effectively managed with topical medications, and no patients required surgery to lower their IOP. This was a better safety profile than was seen in the study in vitrectomized eyes treated with the DEX Implant for uveitic CME.16 In that study, 40% of eyes experienced an increase in IOP to .25 mmHg and 6% of eyes required filtering surgery to lower their IOP.16 It is possible that vitrectomized eyes are at a higher risk for steroid-induced IOP increases than nonvitrectomized eyes.22 It is difficult to compare the results of this small study with DEX Implant with the results of studies of other interventions for uveitic CME. Most of the studies are small, and the study designs, outcome measures, and definitions of CME vary widely.6 In this study, resolution of CME (as measured by SD-OCT) was 89% and 72% at 1 month and 3 months posttreatment, respectively. In comparison, in a large retrospective cohort study of 126 patients who were treated with periocular triamcinolone acetonide for uveitic CME, the clinical resolution of CME at 1 month and 3 months was 53% and 57%, respectively, after a single injection.23 It is important to note that time domain OCT was used in the majority of those cases treated with periocular triamcinolone. Intravitreal triamcinolone acetonide is also used in the treatment of uveitic CME.18 In a prospective interventional study of 29 eyes treated with intravitreal triamcinolone acetonide for uveitic CME, the percentage of eyes with resolution of CME (as measured by SD-OCT) was 72% at 1 month and 45% at 3 months posttreatment.18 The DEX Implant and other local corticosteroid therapies should be investigated in prospective, comparative clinical trials to determine relative efficacy. The main limitations of this study are the retrospective study design and the small sample size, which makes multivariate analysis difficult. The strength of this study is that it provides the first report of anatomical outcomes after DEX Implant treatment in
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eyes with persistent CME secondary to uveitis. Other strengths of this study are the inclusion of many eyes with CME that had persisted despite multiple interventions, and the use of SD-OCT to determine CME recurrence rates. In conclusion, the results of this small retrospective study suggest that the DEX Implant may be a particularly promising treatment for persistent CME secondary to uveitis, even in those cases of uveitic CME that have been unresponsive to other treatments. Further prospective studies should be done to confirm these findings and compare them with other treatments for uveitic CME. Key words: dexamethasone intravitreal implant, cystoid macular edema, Ozurdex, uveitis, epiretinal membrane, spectral domain optical coherence tomography, intraocular pressure. References 1. De Smet M, Taylor S, Bodaghi B, et al. Understanding uveitis: the impact of research on visual outcomes. Prog Retin Eye Res 2011;30:452–470. 2. Gritz DC, Wong IG. Incidence and prevalence of uveitis in northern California; the northern California Epidemiology of uveitis study. Ophthalmology 2004;111:491–500. 3. McCluskey PJ, Towler HM, Lightman S. Management of chronic uveitis. BMJ 2000;320:555–558. 4. Nussenblatt RB. The natural history of uveitis. Int Ophthalmol 1990;14:303–308. 5. Okhravi N, Lightman S. Cystoid macular edema in uveitis. Ocul Immunol Inflamm 2003;11:29–38. 6. Karim R, Sykakis E, Lightman S, Fraser-Bell S. Interventions for the treatment of uveitic macular edema: a systematic review and meta-analysis. Clin Ophthalmol 2013;7:1109–1144. 7. Robinson MR, Whitcup SM. Pharmacologic and clinical profile of dexamethasone intravitreal implant. Expert Rev Clin Pharmacol 2012;5:629–647. 8. Haller J, Bandello F, Belfort R Jr, et al. Randomized, shamcontrolled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010;117:1134–1146. 9. 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. 10. Lowder C, Belfort R Jr, Lightman S, et al. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol 2011;129:545–553. 11. 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. 12. 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. 13. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of
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14.
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the First International Workshop. Am J Ophthalmol 2005;140: 509–516. Lehpamer B, Moshier E, Pahk P, et al. Epiretinal membranes in uveitic macular edema: effect on vision and response to therapy. Am J Ophthalmol 2014;157:1048–1055. Khurana RN, Appa SN, McCannel CA, et al. Dexamethasone implant anterior chamber migration: risk factors, complications, and management strategies. Ophthalmology 2014;121:67–71. Adán A, Pelegrín L, Rey A, et al. Dexamethasone intravitreal implant for treatment of uveitic persistent cystoid macular edema in vitrectomized patients. Retina 2013;33:1435–1440. Tomkins-Netzer O, Taylor SR, Bar A, et al. Treatment with Repeat dexamethasone implants results in Long-Term Disease control in eyes with noninfectious uveitis. Ophthalmology 2014;121:1649–1654. Munk MR, Bolz M, Huf W, et al. Morphologic and functional evaluations during development, resolution, and relapse of uveitisassociated cystoid macular edema. Retina 2013;33:1673–1683.
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19. Sayanagi K, Sharma S, Yamamoto T, Kaiser PK. Comparison of spectral-domain versus time-domain optical coherence tomography in management of age-related macular degeneration with ranibizumab. Ophthalmology 2009;116:947–955. 20. Khurana RN, Dupas B, Bressler NM. Agreement of timedomain and spectral-domain optical coherence tomography with fluorescein leakage from choroidal neovascularization. Ophthalmology 2010;117:1376–1380. 21. Taylor SR, Lightman SL, Sugar EA, et al. The impact of macular edema on visual function in intermediate, posterior, and panuveitis. Ocul Immunol Inflamm 2012;20:171–181. 22. Yamashita T, Uemura A, Kita H, Sakamoto T. Intraocular pressure after intravitreal injection of triamcinolone acetonide following vitrectomy for macular edema. J Glaucoma 2007;16: 220–224. 23. Leder HA, Jabs DA, Galor A, et al. Periocular triamcinolone acetonide injections for cystoid macular edema complicating noninfectious uveitis. Am J Ophthalmol 2011;152:441–448.
