Retinal Vasculitis and Intraocular Inflammation after Intravitreal Injection of Brolucizumab.

PURPOSE: To evaluate features and outcomes of eyes with retinal vasculitis and intraocular inflammation (IOI) after intravitreal injection (IVI) of brolucizumab 6 mg/0.05 ml for treatment of neovascular age-related macular degeneration. DESIGN: Retrospective case series. PARTICIPANTS: Fifteen eyes from 12 patients identified from 10 United States centers. METHODS: Review of patient demographics, ophthalmologic examination results, and retinal imaging findings. MAIN OUTCOME MEASURES: Baseline and follow-up visual acuity (VA), prior anti-vascular endothelial growth factor (VEGF) injections, clinical presentation, retinal findings, fluorescein angiography results, and treatment strategies. RESULTS: The number of previous anti-VEGF IVIs ranged between 2 and 80 in the affected eye before switching to brolucizumab. Retinal vasculitis and IOI were diagnosed at a mean of 30 days after brolucizumab IVI. Mean VA before brolucizumab IVI was 0.426 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, 20/53) and VA at diagnosis of retinal vasculitis was 0.981 logMAR (Snellen equivalent, 20/191; range, 20/25-20/1600; P = 0.008). All affected eyes showed IOI with variable combinations of focal or elongated segmental sheathing and discontinuity of small and large retinal arteries, sclerotic arteries, regions of vascular nonperfusion, cotton-wool spots, Kyrieleis plaques, irregular venous caliber with dilated and sclerotic segments, perivenular hemorrhages, and foci of phlebitis. Fluorescein angiography revealed delayed retinal arterial filling, retinal vascular nonperfusion, and variable dye leakage from affected vessels and the optic nerve. Systemic evaluation for embolic causes was unrevealing in 2 patients, and 3 patients showed negative laboratory assessment for uveitis. Treatment consisted of various combinations of corticosteroids (systemic, intravitreal, and topical), and 2 eyes underwent vitrectomy without improvement in vision. After a mean follow-up of 25 days, mean VA was 0.833 logMAR (Snellen equivalent, 20/136), which was reduced compared with baseline (P = 0.033). CONCLUSIONS: Retinal vasculitis and IOI after brolucizumab IVI are characterized by variable occlusion of large or small retinal arteries, or both, and perivenular abnormalities. It may span from peripheral vasculitis to occlusion of large retinal arteries around the optic nerve or macula with severe vision loss. A high index of suspicion is required because vitreous cells may obscure visualization of retinal details.

Cytokines and Effector/Regulatory Cells Characterization in the Physiopathology of Cutaneous Lupus Erythematous: A Cross-Sectional Study.

We compared the presence of diverse cytokines and regulatory T and B cells in skin biopsies of discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE). We included 19 patients with DLE, 13 with SCLE, 8 healthy controls, and 5 patients with hypertrophic scars. We assessed the CLASI activity score. To determine IL-22-producing cells and the subpopulation of CD4(+)/IL-17A(+)-, CD4(+)/IL-4(+)-, and CD4(+)/IFN-γ (+)-expressing T cells, CD123(+)/IDO(+) pDCs, CD25(+)/Foxp3(+) Tregs, and CD20(+)/IL-10(+)-producing B cells, an immunostaining procedure was performed. Also intracellular IL-22, IL-17, IL-4, IFN-γ, and Foxp3 in CD4 T cells, IL-10 in B cells, and IDO in pDCs were analyzed by flow cytometry in peripheral blood. The main cellular participation in both lupus groups was IL-17- and IL-22-producing cell responses both at skin and at peripheral blood but prevailed in DLE. The CLASI activity scores negatively correlated with Th22 subpopulation and positively correlated with CD25(+)/Foxp3(+) Treg cells. In conclusion a proinflammatory and regulatory imbalance coexists in cutaneous lupus, both responses being more intense in DLE.

Late Vitreoretinal Complications of Regressed Retinopathy of Prematurity: Retinal Break, Vitreous Hemorrhage, and Retinal Detachment.

PURPOSE: To investigate late vitreoretinal complications and visual outcomes in patients with regressed retinopathy of prematurity (ROP) with or without prior treatment. DESIGN: International, multicenter, noncomparative retrospective case series. PARTICIPANTS: We analyzed 264 eyes of 238 patients from 13 centers worldwide who developed vitreoretinal complications (retinal detachment [RD], vitreous hemorrhage [VH], or retinal break) ≥ 2 years after resolution of acute ROP. METHODS: Each participant was assigned to 1 of 3 groups (the RD, VH, and retinal break groups) according to their primary diagnosis. The average age at presentation, visual acuities, refractive error, axial length, gestational age, birth weight, acute ROP classification, prior treatments for acute ROP, postoperative visual acuity (VA), and concomitant eye conditions in the 3 groups were documented and compared. MAIN OUTCOME MEASURES: Clinical features and visual outcomes of late vitreoretinal complications in patients with regressed ROP. RESULTS: A total of 264 eyes of 238 patients were included. The prior acute ROP status was comparable among the 3 groups, except that the VH group had a higher proportion of patients with type 1 ROP (P = 0.03) and prior treatment (P < 0.001) than the other groups. The average age at presentation was earlier in the RD (20.3 ± 15.5 years) and VH (21.4 ± 18.9 years) groups than in the retinal break group (31.9 ± 18.2 years; P < 0.001). The retinal break group had the best presenting best-corrected VA, followed by the RD and VH groups (P < 0.001). Surgical intervention improved VA in both the RD and VH groups (both P < 0.05). The overall trend of VA was the most favorable in the retinal break group, followed by that in the VH and RD groups. Cicatricial changes in the fellow retina were observed in > 90% of patients with unilateral involvement. CONCLUSIONS: Infants with acute ROP remain at a high risk of vision-threatening complications throughout childhood and adulthood. Continual follow-up of patients with ROP is important. When severe complications, such as RD or VH, are detected, timely surgical intervention is necessary to ensure favorable visual outcomes in these patients.

Early Experience With Brolucizumab Treatment of Neovascular Age-Related Macular Degeneration.

IMPORTANCE: Outcome data are limited regarding early experience with brolucizumab, the most recently approved anti-vascular endothelial growth factor (VEGF) agent for the treatment of neovascular age-related macular degeneration (nAMD). OBJECTIVE: To report clinical outcomes after intravitreous injection (IVI) of brolucizumab, 6 mg, for nAMD. DESIGN, SETTING, AND PARTICIPANTS: This retrospective case series conducted at 15 private or academic ophthalmological centers in the United States included all consecutive patients with eyes treated with brolucizumab by 6 retina specialists between October 17, 2019, and April 1, 2020. EXPOSURES: Treatment with brolucizumab IVI, 6 mg. MAIN OUTCOMES AND MEASURES: Change in mean visual acuity (VA) and optical coherence tomography parameters, including mean central subfield thickness and presence or absence of subretinal and/or intraretinal fluid. Secondary outcomes included ocular and systemic safety. RESULTS: A total of 172 eyes from 152 patients (87 women [57.2%]; mean [SD] age, 80.0 [8.0] years) were included. Most eyes (166 [96.5%]) were not treatment naive, and 65.7% of these eyes (109 of 166) were switched from the prior anti-VEGF agent because of persistent fluid detected on optical coherence tomography scans. Study eyes received a mean (SD) of 1.46 (0.62) brolucizumab IVIs. The mean (SD) VA prior to starting brolucizumab was a 64.1 (15.9) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score (Snellen equivalent, 20/50) and was a 63.3 (17.2) ETDRS letter score (Snellen equivalent, 20/63) at the last study evaluation (mean difference, 0.8; 95% CI, -2.7 to 4.3; P = .65). When analyzed by number of brolucizumab IVIs, the presence or absence of fluid prior to starting brolucizumab, or the presence or absence of intraocular inflammation after receiving brolucizumab, there was no difference in mean VA prior to starting brolucizumab compared with after brolucizumab IVIs or at the final study evaluation. The mean (SD) central subfield thickness in all eyes prior to starting brolucizumab was 296.7 (88.0) µm and was 269.8 (66.5) µm at the last study examination (mean difference, 26.9 µm; 95% CI, 9.0-44.7 µm; P = .003). Intraocular inflammation was reported in 14 eyes (8.1%) and was self-limited and resolved without treatment in almost half those eyes (n = 6). One previously reported eye (0.6%) had occlusive retinal vasculitis and severe loss of vision. CONCLUSIONS AND RELEVANCE: In this analysis of brolucizumab IVI for nAMD, VA remained stable, with a reduction in central subfield thickness. Intraocular inflammation events ranged from mild with spontaneous resolution to severe occlusive retinal vasculitis in 1 eye.

Platelet senescence and phosphatidylserine exposure.

BACKGROUND: The exposure of phosphatidylserine occurs during platelet (PLT) activation and during in vitro storage. Phosphatidylserine exposure also occurs during apoptosis after the release of mitochondrial cytochrome c. We have examined the role of cytochrome c release, mitochondrial membrane potential (ΔΨm), and cyclophilin D (CypD) in phosphatidylserine exposure due to activation and storage. STUDY DESIGN AND METHODS: The exposure of phosphatidylserine and the loss of ΔΨm were determined in a flow cytometer using fluorescein isothiocyanate-lactadherin and JC-1, a lipophilic cationic reporter dye. The role of CypD was determined with cyclosporin A and CypD-deficient murine PLTs. Cytochrome c-induced caspase-3 and Rho-associated kinase I (ROCK1) activation were determined by immunoblotting and using their inhibitors. RESULTS: Collagen- and thrombin-induced exposure of phosphatidylserine was accompanied by a decrease in ΔΨm. Cyclosporin A inhibited the phosphatidylserine exposure and the loss of ΔΨm. CypD(-/-) mice had decreased loss of ΔΨm and impaired phosphatidylserine exposure. Collagen and thrombin did not induce the release of cytochrome c nor the activation of caspase-3 and ROCK1. In contrast, in PLTs stored for more than 5 days, the phosphatidylserine exposure was associated with cytochrome c-induced caspase-3 and ROCK1 activation. ABT737, a BH3 mimetic that induces mitochondrial pathway of apoptosis, induced cytochrome c release and activation of caspase-3 and ROCK1 and phosphatidylserine exposure independent of CypD. CONCLUSION: These results show that in stored PLTs cytochrome c release and the subsequent activation of caspase-3 and ROCK1 mediate phosphatidylserine exposure and it is distinct from activation-induced phosphatidylserine exposure.

Update on Anti-Vascular Endothelial Growth Factor Safety for Retinopathy of Prematurity.

Retinopathy of prematurity (ROP) is a neovascular retinal disorder that occurs in infants born prematurely. Nowadays, ROP constitutes a leading cause of childhood blindness worldwide and for decades the standard of care has involved peripheral retinal ablation. However, this type of treatment requires the use of specialized equipment by well-trained physicians, has been associated with poor structural and visual outcomes in some preterm infants, and despite its adequate application, some cases of ROP may continue to progress. Therefore, the need for simpler and more efficient strategies made anti-vascular endothelial growth factor (anti-VEGF) medications an appealing option for treatment. Recently, the use of anti-VEGF agents for ROP has increased worldwide; nevertheless, this practice remains off-label, and there is a lack of information regarding its safety profile and the possibility of unfavorable long-term outcomes causes the utmost concern. This review updates the recent evidence regarding the systemic and ocular safety of anti-VEGF treatment for ROP.

Unilateral Orbital Emphysema Secondary to Vitreoretinal Surgery.

PURPOSE: To describe preoperative, intraoperative, and postoperative characteristics, imaging findings, and clinical evolution of patients who developed orbital emphysema after vitreoretinal surgery. DESIGN: Retrospective, descriptive, observational case series. PARTICIPANTS: Patients with orbital emphysema after vitreoretinal surgery who were diagnosed and treated between January 2006 and October 2018 at a single ophthalmology referral center. METHODS: Medical records and orbital computed tomography images were reviewed and analyzed. A minimum follow-up of 3 months was required. MAIN OUTCOME MEASURES: Final best-corrected visual acuity (BCVA). RESULTS: This study included 16 patients with a mean age of 47.9 ± 14.7 years, 50% were women, and 25% had a history of previous ocular trauma. A diagnosis of rhegmatogenous retinal detachment was established in 75% of patients. Twenty-five percent of patients underwent pars plana vitrectomy (PPV), 50% underwent encircling scleral buckling plus PPV, 18.8% underwent repeat PPV, and 6.2% underwent scleral buckling plus repeat PPV. Additionally, 62.5% received silicone oil endotamponade. The median time between vitreoretinal surgery and orbital emphysema was 8 days (interquartile range [IQR] 5-15 days). Mean proptosis was 6.7 ± 4.6 mm. Orbital cellulitis was considered as a differential diagnosis in 31.2% of patients, and tomographic evidence of fracture was observed in 25% of patients. Treatment with compressive patching was prescribed for 87.5% of patients, transpalpebral drainage was prescribed for 75% of patients, hyperbaric oxygen therapy was prescribed for 43.8% of patients, and surgical management was prescribed for 31.2% of patients. The comparison between BCVA before vitreoretinal surgery (median, 1.8 logarithm of the minimum angle of resolution [logMAR]; IQR, 1.33-2.3 logMAR) and at the last follow-up (median, 2.3 logMAR; IQR, 1.42-2.8 logMAR) was not statistically significant (P = 0.125, Wilcoxon matched-pairs signed-rank test). No association was found between surgeon experience and lower final BCVA (P = 0.604, Fisher exact test); however, development of ocular hypertension was associated with worse final BCVA (P = 0.0101; relative risk, 7; 95% confidence interval, 1.01-44.63). CONCLUSIONS: Although orbital emphysema constitutes a very unusual complication of vitreoretinal surgery, it is important to identify this condition promptly and treat patients efficiently to avoid potential vision loss.

Multimodal imaging in choroidal osteoma.

PURPOSE: To describe characteristics of choroidal osteomas (CO), using ocular ultrasound, fluorescein angiography, ultra-widefield retinal imaging, ultra-widefield autofluorescence, optical coherence tomography, enhanced-depth-imaging OCT, and OCT angiography (OCT-A). METHODS: Retrospective, observational case series study. Clinical records from patients with diagnosis of CO who underwent complete imaging evaluation were analyzed. RESULTS: Sixteen eyes from 11 patients were included. Mean patient age was 33.4 years (range 20-61), 72.7% were female, 100% were Hispanic, and 54.5% had unilateral CO. Median visual acuity was 20/150 (range 20/20-2000). CO was completely calcified in 25%, partially decalcified in 50%, and decalcified in 25%. Other features included choroidal neovascularization (18.75%), focal choroidal excavation (12.5%), choroidal depression associated to decalcification (18.75%), thinning of outer retina and photoreceptor layers over decalcified tumor (75%). Decreased fluorescence on FAF was observed in decalcified regions while relatively preserved fluorescence was observed in calcified regions. CONCLUSIONS: Nowadays, diagnostic tests provide important information about each stage of choroidal osteoma. Progressive decalcification of the tumor might have a common pathogenic role for development of FCE or choroidal depression. OCT-A/FA proved to be valuable tools for detection of CNV in patients with CO.