Adrian T. Fung

Visual and anatomical outcomes of intravitreal aflibercept in eyes with persistent subfoveal fluid despite previous treatments with ranibizumab in patients with neovascular age-related macular degeneration.

Purpose: To assess the efficacy of intravitreal aflibercept (2.0 mg) in patients with treatment-resistant neovascular age-related macular degeneration. Methods: Retrospective analysis of eyes treated with aflibercept with persistent subretinal and/or intraretinal fluid despite previous treatments with intravitreal ranibizumab (0.5 mg). All patients were switched to intravitreal aflibercept (2.0 mg) and analyzed after 3 consecutive injections and after 6 months of treatment. Main outcome measures included change in visual acuity, central foveal thickness, and the height and diameter of the pigment epithelial detachment on the subfoveal scan on optical coherence tomography. Results: Thirty-four eyes of 33 patients were analyzed. Mean duration of symptoms and average number of previous injections with anti–vascular endothelial growth factor agents was 44.7 ± 29.8 months (interquartile range [IQR] 24–76 months) and 28.6 ± 20.1 (IQR 10–47), respectively. At the 6-month follow-up, mean visual acuity and central foveal thickness improved significantly from 20/75 (logarithm of minimum angle of resolution 0.57 ± 0.36; IQR 0.30–1.0) and 416 ± 217 &mgr;m (IQR 263–487 &mgr;m) at baseline to 20/60 (logarithm of minimum angle of resolution 0.47 ± 0.32; IQR 0.30–0.60) (P = 0.004) and 248 ± 171 &mgr;m (IQR 235–419 &mgr;m) (P < 0.001), respectively. Maximum pigment epithelial detachment height improved significantly from 260 ± 162 &mgr;m (IQR 129–368 &mgr;m) to 214 ± 142 &mgr;m (IQR 111–305 &mgr;m) (P < 0.001) and PED diameter decreased significantly from 3,265 ± 1,622 &mgr;m (IQR 2,353–4,555 &mgr;m) to 2,949 ± 1,653 &mgr;m (IQR 1,721–4,484 &mgr;m) (P = 0.04). Conclusion: Intravitreal injections of aflibercept resulted in a significant improvement in visual and anatomical outcomes in eyes with persistent subfoveal fluid despite previous treatment with ranibizumab.

Type 1 (sub-retinal pigment epithelial) neovascularization in central serous chorioretinopathy masquerading as neovascular age-related macular degeneration.

Purpose: The purpose of this study was to describe clinical and multimodal imaging features of patients with Type 1 neovascularization who lack findings of age-related macular degeneration but instead have features consistent with long-standing central serous chorioretinopathy (CSC). Methods: Nonconsecutive, retrospective, observational case series. Two groups of patients were identified and analyzed. Group 1 included patients presenting with Type 1 neovascularization who at the time of diagnosis were found to have findings more consistent with long-standing CSC than age-related macular degeneration. Group 2 included patients with a known history of CSC who developed Type 1 neovascularization over their course of follow-up. Clinical histories and multimodal imaging findings (color and red-free photography, fundus autofluorescence imaging, fluorescein angiography, indocyanine green angiography, spectral domain optical coherence tomography, and enhanced depth imaging optical coherence tomography) were analyzed. Results: Twenty-seven eyes of 22 patients were identified. Thirteen patients presented with Type 1 neovascularization thought to be secondary to CSC (Group 1), and 9 patients with CSC were observed to develop Type 1 neovascularization over their course of follow-up (Group 2). Eight patients (36%) had polypoidal neovascular structures within their Type 1 neovascular lesions, of which 4 (18% of all patients) had bilateral Type 1 neovascularization. The mean age of patients was 61 years (range, 48–76 years), and the median age was 58.5 years. Thirteen patients (59%) were men. For those patients in Group 2, the mean duration between diagnosis of CSC and detection of Type 1 neovascularization was 139 months (range, 7–365 months). The mean subfoveal choroidal thickness was 354 &mgr;m (range, 186–666 &mgr;m). Conclusion: Some patients presenting with Type 1 neovascularization may have clinical and multimodal imaging findings more consistent with long-standing CSC than with age-related macular degeneration. These patients are more likely to be younger, men, have thicker choroids, and have a higher prevalence of polypoidal neovasculopathy than those patients with Type 1 neovascularization secondary to age-related macular degeneration. Proper identification of these patients may have implications for their natural course and management.

Retinal Pigment Epithelial Cell Loss Assessed by Fundus Autofluorescence Imaging in Neovascular Age-related Macular Degeneration

PURPOSE To characterize retinal pigment epithelial (RPE) cell loss as evidenced by autofluorescence imaging in patients with neovascular age-related macular degeneration (AMD). DESIGN Retrospective cohort study. PARTICIPANTS There were 162 eyes of 116 consecutive patients with neovascular AMD examined in a retinal practice. METHODS Each patient underwent a complete examination including autofluorescence imaging. Areas of confluent absence of autofluorescence signal of at least 0.5 mm in greatest linear diameter were measured within the macular area. Patient demographic and examination data were evaluated in relation to the autofluorescence data. MAIN OUTCOME MEASURES Prevalence and progression of confluent areas of absent autofluorescence and the relationship these areas had with visual acuity. RESULTS The mean age of the patients was 82.9 years, and the mean visual acuity was 20/71 (logarithm minimum angle of resolution [logMAR], 0.55). Confluent loss of autofluorescence was seen in 58.6% of eyes at baseline, and the median area of absent autofluorescence among those was 1.57 mm(2) (interquartile range [IQR], 0.62-4.32 mm(2)). Using generalized estimation equation modeling, the significant predictors for area of confluent absent autofluorescence at baseline were duration of disease and any previous treatment with photodynamic therapy. The significant predictor of baseline visual acuity was baseline area of confluent absent autofluorescence. Follow-up was available for 124 (76.5%) eyes, with a mean follow-up of 2.9 years. By then, the mean visual acuity was 20/90 (logMAR, 0.65), and 79% of eyes had confluent areas of absent autofluorescence, the large majority of which affected the central macula. The median area of absent autofluorescence was 3.61 mm(2) (IQR, 1.16-7.11 mm(2)). The best predictor of final visual acuity was the area of absent autofluorescence at the final follow-up. CONCLUSIONS Confluent absence of autofluorescence, a measure signifying RPE loss, was a significant predictor of visual acuity both at baseline and at final follow-up. This is the first study to document the prevalence, rate of progression, and factors associated with measures of confluent RPE loss in patients with neovascular AMD. Application of strategies to limit RPE cell loss may prove useful in eyes with neovascular AMD.

Meta-analysis of randomised controlled trials comparing latanoprost with brimonidine in the treatment of open-angle glaucoma, ocular hypertension or normal-tension glaucoma

Aim: To compare the efficacy and tolerability of latanoprost versus brimonidine in the treatment of open-angle glaucoma, ocular hypertension or normal-tension glaucoma. Method: Systematic review of randomised controlled trials comparing latanoprost and brimondine, identified by searches including Medline, Embase and Cochrane Controlled Trials Register. Two reviewers independently assessed trials for eligibility and quality and extracted data. Data were synthesised (random effects model) and expressed as the absolute mean intraocular pressure (IOP) reduction difference from baseline to end point for efficacy and relative risk for adverse events. Subgroup analysis and regression were used to explore heterogeneity according to patient characteristics, trial design and quality. Results: 15 publications reporting on 14 trials (1784 participants) were included for meta-analysis. IOP reduction favoured latanoprost (weighted mean difference (WMD) = 1.10 mm Hg (95% confidence interval (CI) 0.57 to 1.63)). Significant heterogeneity was present (χ213 = 38.29, p = 0.001, I2 = 66.0%). Subgroup analysis showed greater WMD for studies where data were analysed from end points >6 months duration, cross-over design, open-angle glaucoma or ocular hypertension and monotherapy. Multiple regression showed no significant association of WMD with trial duration (t9 = 1.92, p = 0.09), trial design (t9 = 1.79, p = 0.11), trial quality (t9 = −0.46, p = 0.66), or monotherapy or adjunctive therapy (t9 = −2.14, p = 0.06). Fatigue was less commonly associated with latanoprost (RR = 0.27, 95% CI 0.08 to 0.88). Publication bias was not evident on visual inspection of a funnel plot. Conclusion: Latanoprost is more effective than brimonidine as monotherapy in lowering IOP. Brimonidine is associated with a higher rate of fatigue.

New best1 mutations in autosomal recessive bestrophinopathy.

Purpose: To report the ocular phenotype in patients with autosomal recessive bestrophinopathy and carriers, and to describe novel BEST1 mutations. Methods: Patients with clinically suspected and subsequently genetically proven autosomal recessive bestrophinopathy underwent full ophthalmic examination and investigation with fundus autofluorescence imaging, spectral domain optical coherence tomography, electroretinography, and electrooculography. Mutation analysis of the BEST1 gene was performed through direct Sanger sequencing. Results: Five affected patients from four families were identified. Mean age was 16 years (range, 6–42 years). All affected patients presented with reduced visual acuity and bilateral, hyperautofluorescent subretinal yellowish deposits within the posterior pole. Spectral domain optical coherence tomography demonstrated submacular fluid and subretinal vitelliform material in all patients. A cystoid maculopathy was seen in all but one patient. In 1 patient, the location of the vitelliform material was seen to change over a follow-up period of 3 years despite relatively stable vision. Visual acuity and fundus changes were unresponsive to topical and systemic carbonic anhydrase inhibitors and systemic steroids. Carriers had normal ocular examinations including normal fundus autofluorescence. Three novel mutations were detected. Conclusion: Three novel BEST1 mutations are described, suggesting that many deleterious variants in BEST1 resulting in haploinsufficiency are still unknown. Mutations causing autosomal recessive bestrophinopathy are mostly located outside of the exons that usually harbor vitelliform macular dystrophy–associated dominant mutations.

Meta-analysis of randomized controlled trials comparing timolol with brimonidine in the treatment of glaucoma

This paper aims to compare the efficacy and tolerability of timolol versus brimonidine in the treatment of glaucoma. Comprehensive searches were performed using Medline, Embase and the Cochrane Controlled Trials Register for randomized controlled trials comparing timolol and brimonidine. Two reviewers independently assessed trials for eligibility and quality and extracted data. A random effects model was used to combine studies. Outcome was defined as the absolute mean intraocular pressure (IOP) reduction from baseline to end‐point for efficacy, and relative risk (RR) for adverse events. Subgroup analysis and meta‐regression were used to explore heterogeneity according to trial design and quality. Ten publications reporting on eight trials with 2387 participants were included in the meta‐analysis. Two further trials were commented on qualitatively. IOP reduction was not significantly different between timolol and brimonidine. Weighted mean difference (WMD) of IOP reduction was 0.24 mmHg (favouring brimonidine) with a 95% confidence interval of −0.57 to 1.04 mmHg. There was significant heterogeneity between studies (χ213 = 73.75, P < 0.00001, I2 = 91%). Subgroup analysis showed no significant WMD for studies where data were analysed from end‐points ≥6 months or <6 months. Meta‐regression analysis showed increased WMD IOP reduction in favour of brimonidine with increased trial quality (t3 = −4.58, P = 0.01), but no significant association with trial duration (t3 = 0.73, P = 0.51) or size (t3 = −0.59, P = 0.57). The RR of ocular allergy was much lower with timolol than brimonidine (RR = 0.08, 95% confidence interval 0.01 to 0.47). Publication bias was not evident on a funnel plot, although the number of studies was small. The conclusion is that both drugs are equally effective in lowering IOP. Brimonidine is associated with a higher rate of allergy.

Multifocal choroiditis without panuveitis: clinical characteristics and progression.

Purpose: To describe the clinical characteristics and progression of patients with multifocal choroiditis lesions who had minimal or no evidence of anterior uveitis and/or vitritis. Methods: Retrospective, observational, single-center consecutive case series. Clinical histories, examination, and multimodal imaging findings were analyzed. Results: Sixty-five eyes of 41 patients were identified. The mean age at diagnosis was 38.4 years (median, 35 years; range, 15–81 years), and 70.7% of the patients were women. Involvement was bilateral in 21 patients (51.2%) at presentation. The 60-month bilateral event-free survival was 75.0% (95% confidence interval, 49.8–91.2%). The mean visual acuity was 20/46 (median, 20/25; range, 20/20 to count fingers at 2 feet) at presentation and 20/42 (median, 20/25; range, 20/20–5/400) at the last recorded visit. The 60-month “20/50 or worse” event-free survival was 100%. Between the first presentation and final follow-up (a mean duration of 92.6 months; range, 0–343 months), 46.7% of the eyes developed new or larger chorioretinal spots and 32.6% developed new or recurrent choroidal neovascularization. The 60-month choroidal neovascularization event-free survival was 68.1% (95% confidence interval, 39.2–85.4%). Conclusion: Patients with multifocal choroiditis lesions, but with minimal or no anterior uveitis or vitritis, tended to be young women. Approximately half of the patients presented with bilateral involvement, which is less than has been reported in most case series of multifocal choroiditis with panuveitis. One quarter of all unilaterally affected patients will develop bilateral involvement by 60 months.

Optical Coherence Tomographic Imaging of Sub-Retinal Pigment Epithelium Lipid

OBJECTIVE To describe an optical coherence tomographic finding of layered hyperreflective bands beneath the retinal pigment epithelium (RPE), the so-called onion sign believed to represent lipid within a vascularized pigment epithelial detachment. METHODS This retrospective observational case series involved reviewing clinical histories of patients with the onion sign. Imaging studies analyzed included spectral-domain optical coherence tomography, color and red-free photographs, near infrared reflectance, fundus autofluorescence, and blue-light fundus autofluorescence. RESULTS A total of 22 eyes of 20 patients with sub-RPE hyperreflective bands were identified. There were 15 women and 5 men with a mean patient age of 76 years (range, 60-92 years). Snellen best-corrected visual acuities ranged from 20/25 to counting fingers, with a median of 20/80. Two patients had bilateral involvement, and 3 of 17 eyes had multifocal onion signs in the same eye. All eyes had neovascular age-related macular degeneration, with type 1 (sub-RPE) neovascularization. In all patients, the onion sign correlated with areas of yellow-gray exudates seen clinically that appeared bright on red-free and near infrared reflectance imaging. No specific fundus autofluorescence or blue-light fundus autofluorescence pattern was identified. CONCLUSIONS The onion sign refers to layered hyperreflective bands in the sub-RPE space usually associated with chronic exudation from type 1 neovascularization in patients with age-related macular degeneration. With an associated bright near infrared reflectance, these bands may correspond to lipid, collagen, or fibrin. Because the onion sign colocalizes to areas of exudation that are known to consist of lipoprotein, we propose that this finding may represent layers of precipitated lipid in the sub-RPE space. To our knowledge, this is the first report of lipid detected in the sub-RPE space on clinical examination.

Central Serous Chorioretinopathy in Myopic Patients

Funding/Support: This work was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc, New York, New York, and the Jack A. and Elaine D. Klieger Professorship, Medical College of Wisconsin, Milwaukee. Online-Only Material: The video is available at http: //www.archophthalmol.com. Additional Contributions: Deb Wahlers and Adam Dubis provided technical assistance in preparing the video.

In vivo confocal microscopy and polarizing microscopy of the cornea in a patient with nephropathic cystinosis

The clinicopathological and in vivo confocal microscopic characteristics of the corneas from a patient with infantile cystinosis is reported. Crystals were demonstrated in the epithelium and stroma of this patient.