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Central retinal vein occlusion (CRVO) is a common disease characterized by a disrupted retinal blood supply and a high risk of subsequent vision loss due to retinal edema and neovascular disease. This study was designed to assess the concentrations of selected signaling proteins in the vitreous and blood of patients with ischemic CRVO. Vitreous and blood samples were collected from patients undergoing surgery for ischemic CRVO (radial optic neurotomy (RON), n = 13), epiretinal gliosis or macular hole (control group, n = 13). Concentrations of 40 different proteins were determined by an ELISA-type antibody microarray. Expression of proteins enriched in the vitreous (CCL2, IGFBP2, MMP10, HGF, TNFRSF11B (OPG)) was localized by immunohistochemistry in eyes of patients with severe ischemic CRVO followed by secondary glaucoma. Vitreal expression levels were higher in CRVO patients than in the control group (CRVO / control; p < 0.05) for ADIPOQ (13.6), ANGPT2 (20.5), CCL2 (MCP1) (3.2), HGF (4.7), IFNG (13.9), IGFBP1 (14.7), IGFBP2 (1.8), IGFBP3 (4.1), IGFBP4 (1.7), IL6 (10.8), LEP (3.4), MMP3 (4.3), MMP9 (3.6), MMP10 (5.4), PPBP (CXCL7 or NAP2) (11.8), TIMP4 (3.8), and VEGFA (85.3). In CRVO patients, vitreal levels of CCL2 (4.2), HGF (23.3), IGFBP2 (1.23), MMP10 (2.47), TNFRSF11B (2.96), and VEGFA (29.2) were higher than the blood levels (vitreous / blood, p < 0.05). Expression of CCL2, IGFBP2, MMP10, HGF, and TNFRSF11B was preferentially localized to the retina and the retinal pigment epithelium (RPE). Proteins related to hypoxia, angiogenesis, and inflammation were significantly elevated in the vitreous of CRVO patients. Moreover, some markers known to indicate atherosclerosis may be related to a basic vascular disease underlying RVO. This would imply that local therapeutic targeting might not be sufficient for a long term therapy in a systemic disease but hypothetically reduce local changes as an initial therapeutic approach.

Macular edema is the main reason for decreased visual acuity (VA) in early retinal vein occlusion (RVO). Bevacizumab (Avastin, Genentech) is an anti-VEGF substance to treat macular edema triggered by hypoxia-induced expression of vascular endothelial growth factor (VEGF). Initial reports showed a significant reduction of central retinal thickness and improved visual acuity (VA) after bevacizumab injection. To date, only retrospective studies and case reports have been published on bevacizumab treatment of RVO. In this prospective interventional case series, we evaluated the response to a single bevacizumab treatment in 21 RVO patients (14 CRVO, 7 BRVO). Study endpoints were visual acuity (VA) using ETDRS charts and central macular edema (CME) over 9 weeks. Mean VA from all 21 patients increased by more than 2 lines (2.4+/-0.4 lines; p<0.01 compared to baseline). The improvement of VA after bevacizumab injection was concordant with a decrease in central retinal thickness. Peak VA was reached between 3 and 6 weeks after injection. Between week 6 and 9 a decrease in VA was observed. This VA decrease was precipitated by an increase in CME between week 3 and 6. In subgroup analyses, patients receiving bevacizumab injection within the first 3 months after RVO showed an average VA gain of 4 lines (range 2-7 lines) compared to an average gain of 1.8 (range 1-3) and 2.5 (range 1-7) in patients receiving bevacizumab between 4-6 months and after more than 6 months, respectively. Bevacizumab injection is able to improve CME and VA in RVO patients within the first 3 to 9 weeks. We did not observe any short-term adverse effects during our study. As the decrease in VA was anticipated by an increase in central retinal thickness, regular OCT examinations between week 3 and 6 may be helpful for judging the appropriate timing for re-injection in order to maintain patients within the initially reached range of VA until a new balance between inflow and outflow in the retinal circulation is reached.

OBJECTIVE: The expression of vascular endothelial growth factor (VEGF) is elevated in diabetic macular edema (DME). Ranibizumab binds to and inhibits multiple VEGF variants. We investigated the safety and efficacy of ranibizumab in DME involving the foveal center. RESEARCH DESIGN AND METHODS: This was a 12-month, multicenter, sham-controlled, double-masked study with eyes (age >18 years, type 1 or 2 diabetes, central retinal thickness [CRT] ≥300 μm, and best corrected visual acuity [BCVA] of 73-39 ETDRS letters [Early Treatment Diabetic Retinopathy Study]) randomly assigned to intravitreal ranibizumab (0.3 or 0.5 mg; n = 51 each) or sham (n = 49). The treatment schedule comprised three monthly injections, after which treatment could be stopped/reinitiated with an opportunity for rescue laser photocoagulation (protocol-defined criteria). After month 1, dose-doubling was permitted (protocol-defined criteria, injection volume increased from 0.05 to 0.1 ml and remained at 0.1 ml thereafter). Efficacy (BCVA and CRT) and safety were compared between pooled ranibizumab and sham arms using the full analysis set (n = 151, patients receiving ≥1 injection). RESULTS: At month 12, mean ± SD BCVA improved from baseline by 10.3 ± 9.1 letters with ranibizumab and declined by 1.4 ± 14.2 letters with sham (P < 0.0001). Mean CRT reduction was 194.2 ± 135.1 μm with ranibizumab and 48.4 ± 153.4 μm with sham (P < 0.0001). Gain of ≥10 letters BCVA from baseline occurred in 60.8% of ranibizumab and 18.4% of sham eyes (P < 0.0001). Safety data were consistent with previous studies of intravitreal ranibizumab. CONCLUSIONS: Ranibizumab is effective in improving BCVA and is well tolerated in DME. Future clinical trials are required to confirm its long-term efficacy and safety.

Background Choroidal neovascularisation (CNV) as a feature of exudative age-related macular degeneration (AMD) is partially regulated by retinal pigment epithelium (RPE). In this study, the effect of combinatory anti-angiogenic treatment was evaluated using a novel in vitro assay of RPE-induced angiogenesis. Methods RPE isolated from surgically excised CNV-membranes (CNV-RPE) was used to stimulate sprouting of endothelial cell (EC) spheroids in a 3D collagen matrix. The anti-angiogenic effect of solitary anti-VEGF antibodies (bevacizumab) was compared to a combinatory treatment with anti-VEGF and anti-FGF2 antibodies. Results Anti-VEGF treatment inactivated all RPE-derived VEGF but was unable to fully inhibit EC sprouting induced by CNV-RPE. Combined anti-VEGF/anti-FGF treatment inactivated both growth factors and reduced EC sprouting significantly. Conclusions RPE from CNV patients expresses angiogenic growth factors that act in part independently of VEGF. Targeted combinatory therapy can be superior to solitary anti-VEGF therapy. One possible candidate for combinatory therapy is FGF2.

Choroidal neovascularization (CNV) causes loss of vision in age-related macular degeneration (AMD). In CNV, choroidal capillaries penetrate Bruch's membrane and the retinal pigment epithelium (RPE). Angiogenic factors produced by RPE cells are suspected as major contributors to CNV development. We therefore studied the differential expression of angioregulatory factors in normal and CNV-derived RPE. Cultures of normal (ARPE-19) and CNV-derived RPE (CNV-RPE) were compared by quantitative PCR. Differential expression was verified on the protein level by immunohistochemistry in tissue samples. The angioregulatory factors VEGF-A, VEGF-B, VEGF-C, Angiopoietin-1 (Ang-1) and Angiopoietin-2, Semaphorin-3A, PEDF, HIF-1, FGF-2, and the receptors VEGF-R2, Neuropilin-1 and Neuropilin-2 were detected in both, ARPE-19 and CNV-RPE. Transcription of PEDF, FGF-2, Neuropilin-2, Ang-1 and Ang-2 was significantly upregulated in CNV-RPE. EphA7, VEGF-R1 and leptin were transcribed exclusively in CNV-RPE and Eph-A7 and VEGF-R1 proteins were present exclusively in CNV specimens. A set of common factors controlling angiogenesis was detected in both, ARPE-19 cells and CNV-RPE cells. Surprisingly, PEDF and other factors inhibiting angiogenesis are strongly upregulated in CNV-RPE; thus, at least in later stages, the RPE has a potential to control angiogenesis in age-related macular degeneration.

Retinal neovascularisation occurs under the influence of angiogenic factors that are induced by hypoxia, like vascular endothelial growth factor (VEGF), which is one of the major mediators. PTK/ZK inhibits VEGF signal transduction by blocking the tyrosine kinase of all three VEGF receptors. PTK/ZK is currently being evaluated in clinical trials for angioinhibitory therapy in tumour patients. To avoid potential systemic side effects, local application would be desirable for the treatment of ischemic retinopathies in humans. We therefore investigated the effect of intravitreally applied PTK/ZK in a mouse model for ischemia-induced retinopathy. C57BL/6J mice were placed in 75% oxygen on postnatal day 7. On day 12, they were treated with an intravitreal injection of PTK/ZK (5 microM or 40 microM) in one eye and buffer solution in the fellow eye. Afterwards, the animals were kept in room air until intracardial perfusion with fluorescein-dextran on day 17. Retinal whole mounts were prepared and ischemic retinopathy was evaluated using a standardised retinopathy score. A single intravitreal injection of 40 microM PTK/ZK reduced angioproliferative changes compared to the control eye of each animal (n=37). The difference in retinopathy scores was highly significant (P=0.002, Wilcoxon signed-rank test). Injection of 5 microM PTK/ZK did not show a significant antiangiogenic effect. Tyrosine kinase inhibitors are promising substances not only in cancer therapy, but also in the treatment of ischemic retinopathies that are mediated by VEGF. We showed that in a mouse model for ischemia-induced retinopathy a single intravitreal injection of 40 microM PTK/ZK is capable of significantly reducing angioproliferative retinopathy. The local application of PTK/ZK could be a new way to treat ischemic ocular diseases such as diabetic retinopathy in humans.

From a histological postmortem study of eyes with central retinal vein occlusion (CRVO), it is still questionable whether an older thrombus can be dissolved using recombinant tissue plasminogen activator (rt-PA). After a standard vitrectomy with detachment of the posterior hyaloid, the vessel wall was pierced with a glass cannula (Micron Ophthalmic, Margate, Florida, USA) as described by Weiss et al,).

The rationale for this pilot study was to add arterio-venous dissection (AVD) after unsuccessful medical treatment in a well-defined group of patients with branch retinal vein occlusion (BRVO). In this prospective, interventional case series 35 consecutive patients with a visual acuity (VA) of 0.4 (logMar) or worse were scheduled for surgery within the first 3 months of the onset of BRVO. The study endpoint was VA 1 year after AVD. Secondary study endpoints were: correlation of VA and successful vessel dissection; complication rate; and number of additional surgical procedures within the first year of AVD. Preoperative VA (logMar) was 0.82+/-0.05 (range 0.2-1.6). VA 6 weeks postoperatively was 0.54+/-0.06 (range 0-1.6), 3 months postoperatively 0.61+/-0.07 (0-1.56), 6 months postoperatively 0.74+/-0.08 (range 0-2) and 12 months postoperatively 0.55+/-0.07 (range 0.1-1.5). VA improved 1 year after AVD (p=0.0004). An improvement in VA did not depend on successful separation of the artery and the vein. Four patients had a retinal detachment, 19 patients needed cataract surgery within the first year of AVD. A total of 24 additional surgical procedures were needed. Patients with BRVO may profit from AVD compared with a historical control group. Visual improvement was found irrespective of the successful dissection of vessels. The cataract formation rate and additional surgery was a shortcoming of the AVD procedure.

Purpose : To present a case of macular dystrophy with early changes in fundus autofluorescence. Methods : A 20-year-old woman with a recent loss of visual acuity and onset of photophobia was examined. Color vision and visual field testing, fluorescein angiography, full-field and multifocal electroretinograms as well as fundus autofluorescence were performed. Results : Best-corrected visual acuity was 20/100 (right eye) and 20/60 (left eye). There was a red-green color vision defect and a relative central scotoma in both eyes. Ophthalmoscopy and fluorescein angiography were essentially normal, the presence of a dark choroid was debatable. Full-field ERG responses were normal, but the multifocal ERG showed severely reduced responses in the macular region. Both eyes showed a slight circular parafoveolar increase of fundus autofluorescence. Conclusion : Besides multifocal ERG, fundus autofluorescence aids to objectively assess the manifestation of macular dystrophies but does not discern between different types in early stages.