Normal Variation of Photoreceptor Outer Segment Volume With Age, Gender, Refractive Error, and Vitreomacular Adhesion.

BACKGROUND AND OBJECTIVE: Thickness and volume changes of the photoreceptor outer segment (PROS) layer on spectral-domain optical coherence tomography (SD-OCT) images are associated with various disease states. However, there are limited data on normal anatomical variation. This study evaluates the correlation of PROS volume with age, gender, refractive error, and presence of vitreomacular adhesion (VMA) in healthy subjects. PATIENTS AND METHODS: SD-OCT scans of 68 normal eyes were analyzed. The ellipsoid zone and the apical retinal pigment epithelium boundary were segmented using an automated algorithm. The PROS volume was calculated as the region bounded by these two layers within a 6-mm diameter circle centered at the fovea. A general linear model was used for statistical analysis. RESULTS: PROS volume increased with age to a significant degree (P = .013). Gender, refractive error, and presence of VMA were insignificant factors. CONCLUSION: PROS volume, as measured on routine SD-OCT, increases with age in healthy subjects, after adjusting for gender, refractive error, and VMA. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:523-527.].

Aqueous Humor Cytokine Levels and Anatomic Response to Intravitreal Ranibizumab in Diabetic Macular Edema.

Importance: Variability in response to anti-vascular endothelial growth factor (VEGF) treatment in diabetic macular edema (DME) remains a significant clinical challenge. Biomarkers could help anticipate responses to anti-VEGF therapy. Objectives: To investigate aqueous humor cytokine level changes in response to intravitreal ranibizumab therapy for the management of DME, and to determine the association between baseline aqueous levels and anatomic response. Design, Setting, and Participants: In this prospective multicenter cohort study, 49 participants with diabetes mellitus complicated by center-involving DME, with a central subfield thickness of 310 µm or greater on spectral-domain optical coherence tomography (SD-OCT), were recruited from December 22, 2011, to June 13, 2013 and statistical analysis were performed from March 1, 2017, to June 1, 2017. A total of 48 participants proceeded to follow-up. Interventions: Participants received monthly injections of ranibizumab, 0.5 mg, for 3 months. Aqueous fluid for cytokine analysis was obtained at baseline and repeated at the 2-month visit. Multiplex immunoassay was carried out in duplicate for VEGF, placental growth factor, transforming growth factor beta 2, intercellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), IL-8, IL-10, vascular intercellular adhesion molecule, and monocyte chemoattractant protein 1. Main Outcomes and Measures: Baseline and 2-month change in aqueous cytokine levels, 3-month change in SD-OCT central subfield thickness and macular volume (MV), and the statistical association between baseline aqueous cytokine levels and these measures of anatomic response to ranibizumab in center-involving DME. Results: Among the 48 participants, the mean (SD) age was 61.9 (7.1) years and 36 participants (75.0%) were men. The following cytokines were lower at month 2 vs baseline: ICAM-1 (median change, -190.88; interquartile range [IQR], -634.20 to -26.54; P < .001), VEGF (median change, -639.45; IQR, -1040.61 to -502.61; P < .001), placental growth factor (median change, -1.31; IQR, -5.99 to -0.01; P < .001), IL-6 (median change, -38.61; IQR, -166.72 to -2.80; P < .001), and monocyte chemoattractant protein 1 (median change, -90.13; IQR, -382.74 to 109.47; P = .01). When controlling for age, foveal avascular zone size, and severity of retinopathy, multiple linear regression determined that increasing baseline aqueous ICAM-1 was associated with a favorable anatomic response, in terms of reduced SD-OCT MV at 3 months (every additional 100 pg/mL of baseline ICAM-1 was associated with a reduction of 0.0379 mm3; P = .01). Conversely, increasing baseline aqueous VEGF was associated with a less favorable SD-OCT MV response at 3 months (every additional 100 pg/mL of baseline VEGF was associated with an increase of 0.0731 mm3; P = .02) and was associated with lower odds of being a central subfield thickness responder (odds ratio, 0.868; 95% CI, 0.755-0.998). Conclusions and Relevance: Elevated aqueous ICAM-1 and reduced VEGF levels at baseline are associated with a favorable anatomic response to ranibizumab in DME, although there is not always direct correlation between anatomic and visual acuity response.

Comparison of endophthalmitis rates following intravitreal injection of compounded bevacizumab, ranibizumab, and aflibercept.

OBJECTIVE: Whereas the incidence of endophthalmitis after compounded intravitreal bevacizumab is known to be low, the rates of endophthalmitis after intravitreal injection of compounded ranibizumab and aflibercept are not known. The purpose of this study was to determine the incidence of endophthalmitis after treatment with compounded intravitreal ranibizumab and aflibercept and to compare this to the incidence with compounded intravitreal bevacizumab. DESIGN: Retrospective chart review. PARTICIPANTS: All patients with post-injection endophthalmitis who were seen over a 6.5-year period at a tertiary retina referral practice. METHODS: We identified all cases of endophthalmitis by searching for patients who received intravitreal antibiotics and had antecedent intravitreal injection of bevacizumab, ranibizumab, or aflibercept. RESULTS: A total of 54,101 injections of bevacizumab, 5,614 injections of ranibizumab, and 3,468 injections of aflibercept were performed. The incidence of suspected endophthalmitis was 0.041% (95% CI: 0.026-0.062) for bevacizumab, 0.036% (95% CI: 0.0043-0.13) for ranibizumab, and 0.06% (95% CI: 0.007-0.2) for aflibercept. For culture-positive cases, the incidence was 0.017% (95% CI: 0.0076-0.032) for bevacizumab, 0.02% (95% CI: 0.0005-0.1) for ranibizumab, and 0.03% (95% CI: 0.0007-0.2) for aflibercept. There was no statistically significant difference in endophthalmitis rate between the 3 different compounded drugs with respect to both overall suspected endophthalmitis rate and culture-positive endophthalmitis rate (p = 0.87). CONCLUSION: Compounding of ranibizumab and aflibercept for intravitreal use appears to be safe because the endophthalmitis rate does not appear to be different from that of intravitreal bevacizumab.

Antigen-specificity of antiretinal antibodies in patients with noninfectious uveitis.

OBJECTIVE: Antiretinal antibodies (ARAs) have previously been described in noninfectious uveitis. However, the antigen specificity of these ARAs has not been investigated. The purpose of this study was to identify antigen-specific ARAs in noninfectious uveitis. METHODS: A total of 18 patients with noninfectious uveitis were enrolled. Surface plasmon resonance was used to measure binding responses of patient and control sera against several uveitogenic proteins: recoverin, S-antigen, interphotoreceptor retinoid binding (IRBP), retinal-pigment-epithelium-specific 65-kDa protein (RPE65), tyrosinase-related protein 1 (TRYP1), and tyrosinase-related protein 2 (TRYP2). RESULTS: The frequency of ARA positivity against S-antigen, IRBP, RPE65, TYRP1, and TYRP2 in patients with uveitis did not differ significantly from that of normal controls. However, ARA positivity for recoverin was more frequently observed in patients with uveitis (p = 0.002). A total of 10 patients in the uveitis cohort had birdshot chorioretinopathy, and all 10 were positive for anti-recoverin ARAs. CONCLUSIONS: Patients with noninfectious uveitis have increased frequency of ARA positivity against recoverin. This ARA deserves further investigations as a potential biomarker and pathogenic agent in noninfectious uveitis, especially in birdshot chorioretinopathy.

Long-term in vitro functional stability of compounded ranibizumab and aflibercept.

OBJECTIVE: To determine the long-term in vitro functional stability of compounded ranibizumab and aflibercept. DESIGN: Laboratory study. METHODS: Ranibizumab and aflibercept were compounded into plastic syringes and stored under refrigerated conditions for up to 4 weeks. Half maximal inhibitory concentrations (IC50) from dose-response curves generated by using drugs and their respective targets in enzyme-linked immunosorbent assays were calculated. The functional activity of the drugs stored under these conditions was then compared with that of drug from a fresh glass vial obtained from the manufacturer. RESULTS: There was no statistically significant change in IC50 between ranibizumab stored in plastic syringes for 4 weeks compared with drug obtained from a fresh glass vial (p = 0.4883). Similarly, there was no statistically significant change in IC50 between aflibercept stored in plastic syringes for 4 weeks compared with drug obtained from a fresh glass vial (p = 0.6202). CONCLUSION: Compounding of ranibizumab and aflibercept in plastic syringes with storage for up to 4 weeks does not appear to have a detrimental effect on the in vitro functional activity of these medications. Because the cost of these medications can be prohibitive, compounding may be considered as a method of reducing cost.

AQUEOUS HUMOR CYTOKINE LEVELS AS BIOMARKERS OF DISEASE SEVERITY IN DIABETIC MACULAR EDEMA.

PURPOSE: To determine whether aqueous cytokine levels correlate with disease severity in diabetic macular edema. METHODS: A prospective cross-sectional study of 49 adults with diabetes mellitus, centre-involving diabetic macular edema and central subfield macular thickness ≥310 µm on spectral domain optical coherence tomography. Clinical examination and aqueous sampling were carried out before an initial injection of ranibizumab. Multiplex immunoassay of sample was carried out for vascular endothelial growth factor, placental growth factor, transforming growth factor beta, intercellular adhesion molecule-1, interleukin (IL)-2, IL-3, IL-6, IL-8, IL-10, IL-17, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, and epidermal growth factor. Multivariate robust regression models were constructed, and adjusted for age, lens status, or severity of retinopathy, and size of foveal avascular zone. RESULTS: Spectral domain optical coherence tomography macular volume was an excellent measure of disease severity, correlating strongly with central subfield macular thickness (P < 0.001), best-corrected Snellen visual acuity (P < 0.001), and baseline diabetic retinopathy severity (P = 0.01). Elevated aqueous intercellular adhesion molecule-1 correlated with greater macular volume (P = 0.002). No aqueous cytokine, including VEGF, correlated with central subfield macular thickness. There was an association between IL-10 levels and best-corrected Snellen visual acuity (P = 0.03). CONCLUSION: Aqueous intercellular adhesion molecule-1 correlates with disease severity as measured by macular volume on spectral domain optical coherence tomography, and IL-10 is associated with BCVA. Intercellular adhesion molecule-1 may be a clinically useful biomarker for diabetic macular edema severity.

Choroidal Neovascularization Associated With Birdshot Chorioretinopathy.

BACKGROUND AND OBJECTIVE: Patients with birdshot chorioretinopathy (BCR) may develop visual compromise due to choroidal neovascularization (CNV), and few series address management strategies in the anti-vascular endothelial growth factor (VEGF) era. The purpose of this study was to describe the clinical outcomes of combination anti-VEGF and immunosuppressive therapy for CNV associated with BCR. PATIENTS AND METHODS: Retrospective, interventional case series. Patients with BCR from two tertiary uveitis and retina practices were reviewed. Patients with CNV in association with BCR were identified and reviewed in detail. Clinical features, treatments utilized (ie, anti-VEGF injections, immunosuppressive therapy), and functional and structural outcomes over long-term follow-up were recorded. Outcomes measured included Snellen visual acuity, spectral-domain optical coherence tomography macular thickness during treatment, number and type of anti-VEGF injections, the need for initiation or escalation of immunosuppression, and incidence of CNV in macula-involved versus macula-sparing BCR. RESULTS: Four of 36 BCR patients were diagnosed with choroidal neovascularization (11%). Identification of CNV in all patients prompted treatment with intravitreal anti-VEGF injections and an increase or initiation of local or systemic immunosuppression. Mean Snellen visual acuity improved from 20/60 to 20/30 at final follow-up (P = .02). Mean central subfield thickness improved from 443 µ to 254 µ (P = .04). CNV in association with BCR occurred at a rate of 0.11 events per patient-year (95% CI, 0.02-0.31) in macula-involved BCR versus zero events/patient-year in macula-spared BCR (95% CI, 0-0.058; P = .009). CONCLUSION: Anti-VEGF therapy was effective for the treatment of CNV in BCR patients. A combination of systemic or local immunosuppression and anti-VEGF therapy may be useful in the management of CNV associated with BCR. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:450-457.].

Alterations in intraocular cytokine levels following intravitreal ranibizumab.

OBJECTIVE: Our previous work has shown that, after intravitreal bevacizumab (IVB) administration, decreases in the levels of vascular endothelial growth factor (VEGF)-A and placental growth factor (PlGF), along with increases in the levels of interleukin (IL)-8 and transforming growth factor (TGF)-ß2, can be observed. It is not yet known if similar changes occur after intravitreal ranibizumab (IVR). The purpose of this study was to examine intraocular cytokine changes after IVR. DESIGN: Prospective clinical study. PARTICIPANTS: Subjects with proliferative diabetic retinopathy requiring pars plana vitrectomy (PPV) were recruited. METHODS: Participants received IVR as pre-treatment before PPV. Aqueous humour levels of IL-8, VEGF-A, PlGF, and TGF-ß2 were measured at time of pre-treatment and PPV. Results were analyzed using univariate statistical models. RESULTS: A total of 14 participants were recruited. After IVR administration, we observed a decrease in the levels of VEGF-A and PlGF, and an increase in the levels of IL-8 and TGF-ß2. These results were statistically significant only for VEGF-A (p = 0.0001) and IL-8 (p = 0.0002). CONCLUSIONS: The changes in cytokine levels after IVR mirror the changes seen after IVB. Further studies are warranted in order to determine if there are any differences between IVB and IVR in this regard.

Topical difluprednate monotherapy for uveitic macular edema.

OBJECTIVE: To describe the use of topical difluprednate for the treatment of uveitic macular edema. DESIGN: Retrospective review of 3 consecutive cases of uveitic macular edema. METHODS: Patients were treated with topical difluprednate monotherapy. RESULTS: All patients experienced complete resolution of uveitic macular edema within 2-4 weeks. We observed a statistically significant improvement in central subfield macular thickness (p = 0.04). There was an overall improvement in visual acuity, but this result was not statistically significant (p = 0.33). CONCLUSIONS: Topical difluprednate can be effective for uveitic macular edema. Further investigation of this therapy in prospective randomized controlled trials is warranted.

DEVELOPMENT OF EPSTEIN-BARR VIRUS UVEITIS AFTER REMISSION OF PRIMARY VITREORETINAL LYMPHOMA.

PURPOSE: To describe a case of Epstein-Barr virus (EBV) uveitis that occurred after the treatment and remission of primary vitreoretinal lymphoma (PVRL). METHODS: Descriptive case report. Complete ophthalmologic evaluation, cytology, polymerase chain reaction, cytokine analysis of aqueous humor, and diagnostic vitrectomy were performed. RESULTS: A 66-year-old Caucasian woman developed uveitis in the same eye 20 months after remission of PVRL. Empiric chemotherapy failed to treat the suspected PVRL recurrence, and aqueous humor cytology showed an absence of malignant cells. Qualitative polymerase chain reaction of aqueous humor confirmed the presence of EBV. Treatment for EBV resulted in remission of the uveitis. CONCLUSION: The authors describe a rare case of EBV uveitis that was preceded by PVRL. It is important to consider EBV in cases where suspected recurrence of PVRL does not respond to appropriate treatment.

VOLUMETRIC ASSESSMENT OF THE RESPONSIVENESS OF PIGMENT EPITHELIAL DETACHMENTS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION TO INTRAVITREAL BEVACIZUMAB.

PURPOSE: To determine baseline factors that can predict the response of pigment epithelial detachments (PEDs) in neovascular age-related macular degeneration to treatment with intravitreal bevacizumab (IVB). METHODS: Patients with newly diagnosed neovascular age-related macular degeneration and PED who were treated exclusively with IVB were included. Response to treatment was defined by change in PED volume (determined using spectral-domain optical coherence tomography). PEDs were classified as either predominantly serous or fibrovascular. Multivariable regression and receiver operating characteristic analyses were performed. RESULTS: A total of 48 eyes were identified (mean follow-up time 73 weeks). Overall, the response to the first IVB treatment was predictive of the response to treatment at the final visit (P = 0.015). Serous PEDs had a greater decrease in volume at the final visit (P = 0.008). With respect to both PED types, a decrease in PED volume of 21% after the first IVB treatment was predictive of an overall decrease in volume of 30% at the final visit (sensitivity 83%, specificity 76%). CONCLUSION: In neovascular age-related macular degeneration, serous PEDs respond more favorably to IVB than fibrovascular PEDs. Overall, for both types of PED, the response to the first treatment is predictive of the final response to treatment. Taken together, the results would suggest that if there is less than 21% reduction in PED volume after the first IVB treatment, and/or the PED is predominantly fibrovascular, then switching to another antivascular endothelial growth factor agent should be considered.

Quantitative Assessment of Retinal Degeneration in Birdshot Chorioretinopathy Using Optical Coherence Tomography.

BACKGROUND AND OBJECTIVE: Retinal degeneration in birdshot chorioretinopathy (BSCR) has been assessed qualitatively using spectral-domain optical coherence tomography (SD-OCT). The purpose of this study was to determine whether these changes could be quantified. PATIENTS AND METHODS: The charts of 22 eyes of 11 patients with BSCR and 22 eyes of 22 controls were reviewed. SD-OCT was used to determine the photoreceptor outer segment (PROS) volume and choroidal thickness. RESULTS: PROS volume in patients with BSCR was lower than in controls (P < .003). Furthermore, the PROS volume in BSCR patients with abnormalities on electroretinography (ERG) was lower than the PROS volume in BSCR patients with normal ERGs (P < .02). There was no correlation between PROS volume and choroidal thickness (r = 0.27; P = .22). CONCLUSION: SD-OCT can be used to quantitate retinal degeneration in BSCR. The retinal and choroidal degeneration in BSCR are not correlated, suggesting that the inflammatory pathophysiology affecting these two structures may be different.

Serous Index of Pigment Epithelial Detachments in Neovascular Age-Related Macular Degeneration Predicts Response to Anti-Vascular Endothelial Growth Factor Treatment.

BACKGROUND AND OBJECTIVE: To determine whether optical density measurements of pigment epithelial detachments (PEDs) in neovascular age-related macular degeneration (AMD) can predict the response to treatment with anti-VEGF therapy. PATIENTS AND METHODS: Retrospective review of SD-OCT scans of 21 eyes of 21 patients with neovascular AMD and PED. Response to treatment was determined using SD-OCT volumetric analysis. The authors used optical density measurements of PED lesions on SD-OCT images to calculate the serous index, which is a measure of the serous component of PEDs. RESULTS: The serous index was found to correlate with the response to anti-VEGF treatment (r = .69, P = .0005), and to be predictive of the response to treatment (P = .007). CONCLUSION: The serous index of PEDs can help predict the response to anti-VEGF treatment. This measure may be useful in decisions regarding switching anti-VEGF agents in the clinical care of patients with neovascular AMD and PED.

Uveitic crystalline maculopathy.

BACKGROUND: The purpose of this case report is to present a novel cause of crystalline maculopathy. FINDINGS: A 52-year-old Japanese female presented with a 4-month history of decreased vision in the left eye. Best corrected visual acuity in the left eye was 20/40. Dilated fundus examination of the right eye was unremarkable, but that of the left eye demonstrated foveal yellow-green intraretinal crystals and mild vitritis. Optical coherence tomography of the left eye revealed small intraretinal fluid cysts and intraretinal crystals. Ultra-widefield fluorescein angiography was normal in the right eye, but that of the left eye demonstrated features of intermediate uveitis. There was no history or findings to suggest any cause for the crystals other than the uveitis. CONCLUSIONS: We propose that this may represent a novel category of crystalline retinopathy, termed uveitic crystalline maculopathy. We hypothesize that breakdown of the blood-retinal barrier as seen in uveitis may contribute to the deposition of crystals in the macula, although the precise composition of the crystals is unknown.

A randomized study comparing the efficacy of bevacizumab and ranibizumab as pre-treatment for pars plana vitrectomy in proliferative diabetic retinopathy.

BACKGROUND AND OBJECTIVE: To compare intravitreal bevacizumab versus ranibizumab as adjuvant treatment prior to pars plana vitrectomy (PPV) in proliferative diabetic retinopathy (PDR) with respect to parameters of surgical complexity. PATIENTS AND METHODS: Prospective, randomized, double-masked pilot study of patients requiring PPV for nonclearing vitreous hemorrhage or tractional retinal detachment (TRD) secondary to PDR. Patients were randomized to receive either intravitreal bevacizumab or ranibizumab at standard doses 1 week preoperatively. Measured parameters included total surgical time, presence of TRD, intraoperative bleeding, iatrogenic retinal breaks, and use of endolaser and endodiathermy or silicone oil. RESULTS: A total of 29 patients were recruited. For surgical parameters, there were no statistically significant differences between the groups in the univariate analyses. Multivariable analysis showed no statistically significant difference for total surgical time. CONCLUSION: This pilot study suggests that intravitreal bevacizumab and ranibizumab are equivalent as surgical adjuvants when used as pre-treatment in patients with PDR undergoing PPV.

Vitelliform focal choroidal excavation.

Focal choroidal excavations (FCE) are characterized by foveal or perifoveal choroid excavations seen on optical coherence tomography (OCT). The authors report a case of FCE associated with a vitelliform lesion within the excavation. A case of FCE associated with a small vitelliform lesion has been described previously, but the larger extent of the vitelliform lesion observed in the current case has not been previously reported. This may represent a novel category of FCE, vitelliform focal choroidal excavation, in which deposition of vitelliform material is associated with its development.

Exacerbation of choroidal and retinal pigment epithelial atrophy after anti-vascular endothelial growth factor treatment in neovascular age-related macular degeneration.

PURPOSE: To study the progression of retinal pigment epithelium (RPE) and choroidal atrophy in patients with neovascular age-related macular degeneration (AMD) and to assess for a possible association with the number and type of anti-vascular endothelial growth factor treatments. METHODS: Patients with neovascular AMD and a minimum of 1-year follow-up were reviewed. Fellow eyes with nonneovascular AMD were used as control eyes. Retinal pigment epithelial atrophy area and choroidal thickness were determined using spectral-domain optical coherence tomography. Multivariable regression models were used for statistical analyses. RESULTS: A total of 415 eyes were included in the study, with a mean follow-up of 2.2 years. Eyes with neovascular AMD had greater progression of RPE atrophy and choroidal atrophy compared with those with nonneovascular AMD (P < 0.001). Progression of RPE atrophy and choroidal atrophy was independently associated with the total number of injections of bevacizumab and ranibizumab (all P values ≤ 0.001). In the subgroup of 84 eyes with neovascular AMD and without RPE atrophy at baseline, only bevacizumab was associated with the progression of RPE atrophy (P = 0.003). This study likely lacked statistical power to detect an association with ranibizumab in this subgroup. CONCLUSION: Retinal pigment epithelial atrophy and choroidal atrophy in neovascular AMD seem to be exacerbated by anti-vascular endothelial growth factor treatment. Possible differences between bevacizumab and ranibizumab require further investigation.