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Recent studies deciphering the transcriptional profile of choroidal neovascularization (CNV) in body donor eyes with neovascular age-related macular degeneration are limited by the time span from death to preservation and the associated 5′-RNA degradation. This study therefore used CNV and control specimens that were formalin-fixed and paraffin-embedded immediately after surgical extraction and analyzed them by a 3′-RNA sequencing approach. Transcriptome profiles were analyzed to estimate content of immune and stromal cells and to define disease-associated gene signatures by using statistical and bioinformatics methods. This study identified 158 differentially expressed genes (DEGs) that were significantly increased in CNV compared with control tissue. Cell type enrichment analysis revealed a diverse cellular landscape with an enrichment of endothelial cells, macrophages, T cells, and natural killer T cells in the CNV. Gene ontology enrichment analysis found that DEGs contributed to blood vessel development, extracellular structure organization, response to wounding, and several immune-related terms. The S100 calcium-binding proteins A8 (S100A8) and A9 (S100A9) emerged among the top DEGs, as confirmed by immunohistochemistry on CNV tissue and protein analysis of vitreous samples. This study provides a high-resolution RNA-sequencing–based transcriptional signature of human CNV, characterizes its compositional pattern of immune and stromal cells, and reveals S100A8/A9 to be a novel biomarker and promising target for therapeutics and diagnostics directed at age-related macular degeneration.

Retinal vein occlusion (RVO) is one of the most frequently occurring retinal vascular disorders. Occlusion of either the central retinal vein or one of its branches leads to disruption of retinal blood flow and subsequent tissue hypoxia. The disease mechanisms underlying RVO are not fully understood. One seminal study by Green et al1 has found venous thrombi in postmortem eyes of patients with RVO. However, it is not fully established whether thrombus formation is the cause or rather a consequence of RVO. The main presenting symptom in patients with RVO is painless vision loss that usually develops over the course of hours to days. The vision loss perceived by patients with RVO is partially the result of central macular edema (CME) that develops secondary to the venous occlusion. Central macular edema is thought to result from a combination of increased intraluminal pressure in occluded veins and increased amounts of the permeability factor vascular endothelial growth factor (VEGF) that is expressed as a result of tissue hypoxia in retinas with impeded circulation.2 The extent to which CME affects visual acuity in patients with RVO is illustrated by numerous studies reporting a decline in CME with a concomitant rise in visual acuity after intravitreal injection of anti-VEGF antibodies.3–12 Inversely, visual acuity often deteriorates during phases of CME rebound, when intravitreal VEGF inhibition ceases to sufficiently block VEGF signaling.13 Vascular endothelial growth factor expression is known to be regulated through the hypoxia-sensitive transcription factor Hif1α.14 Erythropoietin (EPO) is similarly induced by Hif1α in a hypoxia-dependent fashion.15 In addition to its well-established hematopoietic effects, EPO has neuroprotective properties both in the retina16 and in models of ischemic brain injury17 in which EPO has been shown to limit the extent of secondary brain edema.18 With regard to retinal EPO expression in patients with RVO, the data published to date are still fragmentary. One study by Inomata et al19 found a significant 12-fold EPO increase in the vitreous of 12 patients with branch RVO. Another study by Garci-Arumi et al20 reported a fourfold increase in vitreal EPO in a cohort of nine patients with central RVO and three patients with branch RVO. However, this increase was not statistically significant. The aim of our study was to measure vitreal EPO in patients with RVO and control subjects without vascular disease and to identify parameters that correlate with vitreal EPO concentrations and could thus account for the reported differences.

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.

Purpose Bevacizumab (Avastin®) was first used clinically in 2005. Reports on the treatment of more than 600 patients with central retinal vein occlusion (CRVO) have been published to date. However, there are limited data on the long-term effects of bevacizumab in patients with CRVO. Methods We retrospectively re-evaluated 10 patients with CRVO who were initially part of one of the first published case series on the short-term effects of bevacizumab (1). The patients were invited for a follow-up visit 2 years after their initial bevacizumab injection. Study endpoints were changes in visual acuity (VA) and central macular edema (CME) compared to 1) baseline values and 2) short-term values after the initial injection. Results Short-term VA gain had been 2.9 lines 3 weeks after the first bevacizumab injection. Two years later, mean VA gain vs baseline was 1.6 lines. Low baseline VA and good response to the first injection correlated positively with higher long-term VA gains (Pearson correlation of r = 0.50 and r = 0.66). There was no correlation for injection number, occlusion time, or CME changes with long-term VA gain. Conclusions The initial short-term VA gain after bevacizumab treatment was not always maintained over a 2-year period despite repeated injections. Patients with low baseline VA and good response to the first injection seemed to benefit most from repeated bevacizumab injections.

Purpose: Endogenous endophthalmitis is a severe and potentially blinding complication caused by haematogenous spreading of microorganisms. We evaluated the causative microorganisms, disposition to and prognosis of the disease. Methods: Thirty-one eyes of 28 patients were treated between 1996 and 2006 as the result of an endogenous endophthalmitis. Results: The microorganisms responsible for infection could be identified in 94% of all eyes investigated. Candida isolates were obtained in 15, gram-positive isolates in 11, gram-negative in one and Aspergillus in two of the 29 eyes studied. The majority of patients suffered from severe general disease (immuno-deficiency, severe surgical procedures, diabetes mellitus) and one third were intravenous drug abusers. Only one patient was otherwise healthy. The prognosis depended on the causative microorganisms. Whereas none of the eyes with Candida infection became blind, all except two of the eyes with gram-positive bacteria, Nocardia or Aspergillus infection lost visual function or had to be enucleated. Conclusion: Compared to postoperative endophthalmitis, patients with endogenous endophthalmitis are more likely to have Candida isolates. Visual prognosis depends mainly on the underlying microorganisms, and is particularly poor in the case of infection with gram-positive bacteria or Aspergillus.

To evaluate the potential role of radial optic neurotomy (RON), a new surgical technique has been recently proposed for treating central retinal vein occlusion (CRVO). It is hypothesized that CRVO constitutes a neurovascular compartment syndrome at the site of the lamina cribrosa, which can be alleviated by performing a radial incision at the nasal part of the optic nerve head, relaxing the cribriform plate and the adjacent sclera. One hundred and seven patients were treated with RON for CRVO at five collaborating ophthalmologic centers. All patients were evaluated by a standardized protocol. For analysis of the angiographic and fundus findings, reference images were used. Intraoperative and postoperative complications were reviewed. On 55 right and 52 left eyes of 107 patients (55.6% male, 44.4% female) with a median age of 68 years (range 21–91 years), RON was performed. The median follow-up time was 6 months (range 1–24 months). The median preoperative visual acuity (VA) was 0.05 (logMAR 1.3), increasing to a median postoperative VA of 0.08 (logMAR 1.1). Patients with an interval of more than 90 days between RON and onset of CRVO showed no significant change in VA at the 6-month follow-up. Severe peripapillary swelling of the optic nerve head prior to RON resulted in an average increase of 4.2 lines in VA at the 6-month follow-up. Angiographic findings of shunt vessels were seen in 18/30 cases after 12 months and were accompanied by an average improvement of VA of six lines. Visual field tests showed various defects in 86.8% of all cases. In one patient an iatrogenic injury of the central retinal artery occurred (0.9%). Despite the potential risk of visual field defects, RON seems to be a quite safe procedure. The majority of patients showed rapid normalization of the morphologic fundus findings, with an improvement in VA uncommon for the natural history of CRVO. No significant change in VA was seen in patients with an interval of more than 90 days between the onset of CRVO and RON. A prospective study is warranted for further investigation.

Intravitreal application of triamcinolone acetonide has become increasingly popular for the treatment of various retinal disorders. However, dosage, mode of preparation and application differ worldwide. The aim of this study was to find a safe vehicle that would allow intravitreal injection of an exact amount of triamcinolone acetonide without potentially retinotoxic preservatives.Solutions of triamcinolone acetonide with a theoretical concentration of 4 mg/0.2 ml were prepared following one sedimentation (A) and two filtration (B, C) methods. In addition, a filtration method using carboxymethylcellulose 2% as a carrier (D) was established. During processing and after injection into an eye model, the crystals were quantified by weight and high-performance liquid chromatography (HPLC), and, hence, the rate of crystal loss during this process was determined.The initial preparation contained 93-106% of the calculated quantity. Method A, containing the entire vehicle, delivered 45%+/-7.3% of the target quantity to the eye model, whereas the vehicle-free methods B and C delivered 15%+/-6.9% and 11%+/-3.2%, respectively. Using carboxymethylcellulose 2% as a preservative-free vehicle, we found 93%+/-3.7% of the calculated amount in the eye model. The missing crystals were mainly sticking to the walls of the syringes and needles used for transfer.Common methods for preparing triamcinolone acetonide vary in the amount of drug actually injected intravitreally. Carboxymethylcellulose is an ideal carrier substance for intravitreal application of an exact dose of triamcinolone acetonide without preservatives.

Arteriovenous dissection (sheathotomy) is a new therapeutic option in patients with branch retinal vein occlusion (BRVO) and macular involvement. We present an angiographic follow-up of 22 patients who underwent arteriovenous dissection (AVD).Twenty-two patients (15 women; mean age 68.7+/-8.0 years) were examined preoperatively and 6 weeks, 3 months, 6 months, and 1 year after AVD. For assessment of retinal hemodynamics, arteriovenous passage time (AVP) of the affected and unaffected branches at first (AVPe) and at maximal (AVPmax) venous filling were measured. Changes in the foveal avascular zone (FAZ) were calculated to determine foveal structural changes. Visual acuity was assessed as functional parameter.The early AVP (AVPe) of the affected branch increased from 4.4+/-0.8 s preoperatively to 4.9+/-0.6 s 6 weeks after surgery and decreased to 2.7+/-0.4 s 1 year after surgery (p=0.05). When compared to the unaffected control branch, AVPe was significantly increased in the affected branch preoperatively (4.5+/-0.8 s versus 1.5+/-0.2 s, p0.01), 6 weeks (4.9+/-0.6 s versus 2.1+/-0.3 s, p0.01), 3 months (2.7+/-0.4 s versus 1.5+/-0.2 s, p0.01), and 6 months (3.1+/-0.4 s versus 2.2+/-0.3 s, p=0.02) after AVD. After 1 year, AVPe no longer differed between the affected and the control branch (2.7+/-0.4 s versus 2.6+/- 0.3 s). AVPmax was significantly increased in the affected branch preoperatively (11.8+/-0.8 s versus 7.7+/-1.0 s, p0.05). The AVPmax in the affected branch with the exception of 3 months after surgery (10.2+/-1.1 s, p0.01) was no longer elevated when compared to preoperative values. The area of the FAZ did not change significantly but showed a trend for enlargement.AVD for decompression of BRVO leads to a significant decrease of AVP and may ameliorate retinal perfusion in the affected branch.

JC virus (JCV) is a human polyomavirus that exists in at least eight different genotypes as a result of coevolution with different human populations all over the world. Well adapted to its host, it usually persists in the kidneys and possibly the brain. If the host becomes immunodeficient, JCV can cause the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). There is increasing evidence that JCV is transactivated by cytomegalovirus (CMV) and the human immunodeficiency virus (HIV). Both CMV and HIV can infect the retina of acquired immunodeficiency syndrome (AIDS) patients, causing severe necrosis in the case of CMV retinitis or a mild HIV-associated vasculopathy, with bleeding and cotton wool spots. The authors therefore investigated by polymerase chain reaction (PCR) whether DNA of these three viruses was detectable in paraffin-embedded eyes of AIDS patients with a clinical history of CMV retinitis. From a total of 65 eyes, JCV was detected in 21 (32%). Thirty-six (55%) were positive for CMV and 6 (9%) for proviral DNA of HIV. JCV and CMV were found in 13 eyes, JCV and HIV in 3 eyes, CMV and HIV in 1 eye, and DNA from all three viruses in 1 eye. The JCV genotypes were types 1A, 2A, 2E, 3, and 4. In 21 eyes of patients without AIDS, only one sample was JCV positive. In conclusion, JCV DNA can be detected in ocular tissue of AIDS patients at a significantly higher level than in eyes of nonimmunosuppressed patients. Further investigations will help to decide if JCV contributes to the retinopathy caused by CMV and HIV.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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. peerReviewed

· Background: To correlate the retinal ganglion cell pattern to visual acuity and visual field data in a patient with bilateral optic disc drusen, a quantitative clinicopathological study was carried out. · Methods: Both retinae of a patient with optic drusen were whole-mounted. Retinal ganglion cell counts were made using a sampling scheme covering the whole retina and compared to the findings in 10 normal retinae. Relative ganglion cell reduction in the drusen retinae was correlated to clinical data. · Results: The total retinal ganglion cell count was reduced from 1244858±98736 in normal retinae to 305319 on the right and 527571 on the left eye with optic disc drusen. Large ganglion cells had a better chance of survival. Parafoveal ganglion cell loss was 57% for the right and 36% for the left eye, while visual acuity was 0.8 and 1.0 respectively. The mean light sensitivity loss increased from the centre (6.2 dB) to paracentral (9.9 dB), mid-peripheral (13.7 dB) and outer peripheral (15.0 dB) retina, while ganglion cell losses were smallest in outer peripheral retina (21.9%), followed by central (53.0%), mid-peripheral (70.9%) and paracentral retina (87.7%). · Conclusion: These data validate Frisen’s theory on central retinal resolution and provide the structural basis for the clinical rule that low visual acuity should not be attributed to disc drusen. Automated light sense perimetry gives an inadequate picture of retinal damage caused by optic disc drusen.

Aim To conduct a systematic review in order to compare adverse effects (AE) and the reporting of harm in randomised controlled trials (RCTs) and non-RCTs evaluating intravitreal ranibizumab and bevacizumab in age-related macular degeneration. Methods Medline, Embase and the Cochrane Library were searched with no limitations of language and year of publication. Studies which compared bevacizumab or ranibizumab as monotherapy with any other control group were included. Case series were included if they met predefined quality standards. Results The 2 year results of phase III trials evaluating ranibizumab show that the rates of serious ocular AE were low (≤2.1%) but indicate major safety concerns (RR 3.13, 95% CI 1.10 to 8.92). A possible signal with regard to thromboembolic events (RR 1.35, 95% CI 0.66 to 2.77) and a significant increase in non-ocular haemorrhage (RR 1.62, 95% CI 1.03 to 2.55) were also noted. In contrast to ranibizumab trials, the RCTs evaluating bevacizumab are of limited value. The main shortcomings are small sample sizes and an apparent lack of rigorous monitoring for AE. A critical assessment of the large number of published case series evaluating bevacizumab also shows that no reliable conclusions on safety can be drawn using this study design. Therefore, any perception that intravitreal bevacizumab injections are not associated with major ocular or systemic AE are not supported by reliable data. Conclusion The bevacizumab studies show too many methodological limitations to rule out any major safety concerns. Higher evidence from ranibizumab trials suggests signals for an increased ocular and systemic vascular and haemorrhagic risk which warrants further investigation.

Purpose To determine the concentration of the pro-angiogenic vascular endothelial growth factor VEGF 165 (VEGF) and the anti-angiogenic VEGF 165b in vitreous samples of patients with branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO) in comparison to patients without retinal occlusive disease. Design Experimental laboratory investigation. Methods Vitreous samples were collected from patients undergoing surgery for arteriovenous dissection after BRVO, radial optic neurotomy after CRVO in the occlusion group, or macular pucker or macular hole in the control group. Concentrations of VEGF and VEGF 165b were determined by ELISA and an ELISA-type antibody microarray. Results Average vitreal concentration of VEGF was 8.6 ng/mL in the CRVO group and 2.0 ng/mL in the BRVO group as compared to 0.26 ng/mL in the control group. Average vitreal concentration of VEGF 165b was 27 pg/mL in the CRVO group, 42 pg/mL in the BRVO group, and 49 pg/mL in the control group. In patients with CRVO and BRVO, the angiogenic balance was shifted towards angiogenic stimulation. Conclusion The severity of RVO from BRVO to CRVO correlates with an increase of VEGF and the decrease of VEGF 165b , indicating a pro-angiogenic shift. Altering the ratio of VEGF 165b /VEGF 165 might be a feasible approach for treating retinal occlusive diseases.

Purpose of review We conducted a systematic review to evaluate whether the existing evidence justifies the intravitreal use of bevacizumab in comparison to ranibizumab in age-related macular degeneration. Recent findings Compared with photodynamic therapy, bevacizumab shows a relative improvement in visual acuity that is of similar size as in the comparison of ranibizumab with photodynamic therapy (relative improvement from 30 to 35%). However, this finding is based on one randomized controlled trial including less than 50 patients treated with bevacizumab. Also, nothing is known about long-term (>12 months) improvements in visual acuity and optimal treatment intervals for bevacizumab.Regarding safety, the published literature indicates that ocular and systemic adverse effects are less frequent under bevacizumab than ranibizumab treatment. But the validity of this finding is strongly limited by inadequate reporting, an unsystematic evaluation of adverse effects and short follow-up times in studies evaluating bevacizumab. Summary Given the lack of controlled data, the widespread off-label use of bevacizumab is not justified in clinical practice. On the other hand, a major challenge in the management of patients who require repeated antivascular endothelial growth factor injections is the high cost of ranibizumab. This dilemma underlines the need for head-to-head studies comparing both vascular endothelial growth factor antibodies, or, at least, well conducted randomized controlled trials evaluating intravitreal bevacizumab.

Acta Ophthalmol. 2011: 89: 82–90 Abstract. Purpose: To investigate whether EphrinB2 (EfnB2) or EphB4 influence retinal angiogenesis under physiological or pathological conditions. Methods: Using the mouse model of oxygen-induced proliferative retinopathy (OIR), the expression of EfnB2, EphB4, vascular endothelial growth factor (VEGF), VEGFR1 and VEGFR2 was quantified by quantitative polymerase chain reaction (qPCR) and localized in EfnB2- and EphB4-lacZ mice. Angioproliferative retinopathy was manipulated by intravitreal injection of dimeric EfnB2 and monomeric or dimeric EphB4. Results: Dimeric EphB4 (EphB4-Fc) and EfnB2 (EfnB2-Fc) enhanced hypoxia-induced angioproliferative retinopathy but not physiological angiogenesis. Monomeric EphB4 (sEphB4) reduced angiogenesis. The messenger RNA (mRNA) level of EfnB2 increased significantly in the hyperoxic phase (P7–P12), while EphB4, VEGF, VEGFR1 and VEGFR2 showed a significant – up to fivefold – increased expression at P14, the start of morphologically visible vasoproliferation caused by relative hypoxia. Conclusion: The ephrin/Eph system is involved in angioproliferative retinopathy. Stimulation of EphB4 and EfnB2 signalling using EfnB2-Fc and EphB4-Fc, respectively, enhanced hypoxia-induced angiogenesis. In contrast, sEphB4 inhibited hypoxia-induced angiogenesis. Therefore, angiogenesis is enhanced by signalling through both EphB4 (forward) and EfnB2 (reverse). The distinction in the expression kinetics of EphB4 and EfnB2 indicates that they govern two different signalling pathways and are regulated in diverse ways. sEphB4 might be a useful drug for antiangiogenic therapy.

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. 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. 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. 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.

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; p0.01 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.

PURPOSE: To evaluate the safety and efficacy of the COX-2 inhibitor valdecoxib in treating macular edema after cataract surgery. SETTING: University Eye Clinic, Freiburg, Germany and Reis Medical Institution, Liechtenstein. METHODS: The COX-2 inhibitor valdecoxib (Bextra) was administered systemically to patients with significant visual loss resulting from macular edema in a prospective clinical trial. RESULTS: Ten patients were enrolled. Valdecoxib was tolerated well and led to a significant visual improvement within 10 days of therapy in all patients. CONCLUSION: The fast and persistent control of macular edema with valdecoxib warrants further investigation.

Retinal endovascular lysis is a new therapeutic option for patients with central retinal vein occlusion (CRVO). In this procedure, a fibrinolytic agent is injected directly into a cannulated retinal vein after pars plana vitrectomy.Prospective interventional case series.Thirteen strictly defined patients with ischemic CRVO.Patients with a decimal visual acuity (VA) of 0.2 or worse were scheduled for surgery within the first 5 months after onset of CRVO. A full ocular examination, determination of VA (Early Treatment Diabetic Retinopathy Study charts), and fluorescein angiography were done preoperatively and 6, 12, 26, and 52 weeks postoperatively.Visual acuity 1 year after retinal endovascular lysis. Secondary study end points were (1) correlation of VA and successful recombinant tissue plasminogen activator injection into a retinal vein, (2) complication rate, and (3) number of additional surgical procedures within the first year after retinal endovascular lysis.All patients had an ischemic CRVO and completed the 1-year follow-up visit. Preoperative decimal VA was 0.063 +0.025/-0.018 (VA range, light perception [LP]-0.2); 6-week postoperative VA, 0.049 +0.024/-0.016 (LP-0.4); 3-month postoperative VA, 0.043 +0.019/-0.014 (LP-0.3); 6-month postoperative VA, 0.035 +0.022/-0.013 (blindness-0.4); and 12-month postoperative VA, 0.04 +0.026/-0.016 (blindness-0.4). Visual acuity changed 1 year after retinal endovascular lysis by -1.923+/-1.619 lines (+6 to -16 lines; P = 0.258). We considered the retinal endovascular lysis procedure to have been technically successful in 10 eyes. Visual changes did not depend on successful lysis. Six eyes developed neovascular glaucoma, of which 2 globes ended up with painful phthisis and had to be removed. Retinal detachment was found in 3 eyes and cataract in 4. Together, the 13 eyes needed 22 additional surgical procedures. Preoperative and postoperative angiographic examinations showed no significant changes.Ischemic CRVO patients did not profit from retinal endovascular lysis in this pilot study. Visual results and the risk of developing iris neovascularization and neovascular glaucoma took the natural course. Although these results may be due to the overall bad prognosis of these particular ischemic eyes, the number of postoperative complications is unacceptably high.

Purpose The visual acuity (VA) of patients with very low vision is classified using the semiquantitative scale "counting fingers" (CF), "hand motion" (HM), "light perception" (LP), and "no light perception." More quantitative measures would be desirable, especially for clinical studies. The results of clinical VA measurements, Early Treatment Diabetic Retinopathy Study (ETDRS) charts, and the Freiburg Visual Acuity Test (FrACT) were compared. The FrACT is a computerized visual acuity test that can present very large Landolt C optotypes when necessary. Methods Examined were 100 eyes of 100 patients with various eye diseases (e.g., diabetic retinopathy, ARMD), covering a range of VAs from LP to decimal 0.32. The FrACT optotypes were presented on a 17-inch LCD monitor with random orientation. After extensive training, two ETDRS and FrACT measurements were obtained. The testing distance was 50 or 100 cm. Results ETDRS and FrACT coincided closely for VA > or = 0.02 (n = 80). ETDRS measures were successfully obtainable down to CF (at 30 cm; test-retest averaged over all patients, coefficient of variation [CV](ETDRS) = 9% +/- 8%), and FrACT provided reproducible measurements down to HM (test-retest CV(FrACT) =12% +/- 11%). For CF (n = 6), both ETDRS and FrACT resulted in a mean VA of 0.014 +/- 0.003 (range, 0.01-0.02). The VA results of FrACT for HM (n = 12) were 0.005 +/- 0.002 (range, 0.003-0.009); the individual values were highly reproducible. No results were obtainable for LP (n = 2). Conclusions The three acuity procedures concur above a VA of 0.02. The results suggest that the category CF at 30 cm can be replaced by 0.014, using ETDRS or FrACT. Using FrACT, one can even reproducibly quantify VA in the HM-range, yielding a mean VA of 0.005.

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.

A 39-year-old obese woman presented with bilateral blurred vision worsening over 2 days. She also complained of lower back pain for the previous 3 weeks. Her ocular history revealed no abnormalities. Her medical history was significant for HELLP (Haemolysis, Elevated Liver enzyme levels, Low Platelet count) syndrome 12 years ago during her first pregnancy. On examination, best-corrected visual acuity (BCVA) was 20/100 in the right and 20/400 in the left eye. Intraocular pressure, motility and anterior segments of both eyes were normal. Ophthalmoscopy revealed bilateral central serous retinal detachment and several cotton wool spots (figure 1). On general examination, blood pressure (BP) was 230/150 mmHg. Laboratory tests showed leucocytosis (19 700/µl), anaemia (3.77 Mio RBC/µl), thrombocytopenia (57 000/µl), elevated liver enzymes (GOT 58 U/I, GPT 52 U/I, alkaline phosphatase 170 U/I) and impaired renal function (creatinine 1.24 mg/dl). Figure 1 Fundus photography taken on the day of admission, composite image; (A) right eye, (B) left eye; both eyes showed a pronounced central serous retinal detachment on the day of admission. 1. How will you approach a patient presenting with secondary retinal detachment in both eyes of acute origin. What further investigations will you do? 2. How do you manage such a case? 3. Describe the spectral domain optical coherence tomography (OCT) findings (figure 2). Figure 2 Spectral domain optical coherence tomography (OCT), pictures on the left show infrared photography with selected scan, on the right corresponding scan. (A) Right eye: —top, OCT at first presentation; …

Introduction. Exudative diabetic retinopathy is difficult to treat. We describe a patient in whom we believe extracorporeal LDL-precipitation (HELP) improved visual acuity. Methods. HELP is a variant of extracorporeal dialysis which reduces low-density lipoprotein and fibrinogen levels. Case report. A heavily overweight patient with massive exudative diabetic retinopathy was administered HELP. Four months after starting HELP, and after vitrectomy and panretinal photocoagulation, the massive exudation was drastically lower. Visual acuity improved from 0.03 (0.02) OD (0S) to 0.25 (0.13) OD (OS). Discussion. The role of vitrectomy and panretinal photocoagulation is discussed. HELP seems to be the most probable explanation for our patient's gain in visual acuity.

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.

A method is described for cultivating retinal pigment epithelial cells from choroidal neovascular membrane (CNV) specimens that were surgically removed in patients with age-related macular degeneration (AMD). CNV specimens of 43 patients were available for cultivation. They were incubated in supplemented DMEM/Ham's F12 cell culture medium on microporous semipermeable filter membranes. Thirty-four specimens gave rise to cell cultures, 28 of which could be subcultivated for up to 15 passages. The membrane type as classified by fluorescence angiography was compared with cellular growth in vitro. Immunocytochemistry revealed a uniform expression of cytokeratin 18 and vimentin, while factor 8, glial fibrillary acidic protein and alpha smooth muscle actin were absent in all 21 cultures stained. The expression of RPE markers cellular retinaldehyde binding protein (CRALBP) and RPE65 was detected by RT-PCR in all cultures tested. An epithelial character of the cultures was supported by the presence of apical microvilli as determined by electron microscopical studies. Therefore, the cell cultures from CNV in AMD bear characteristics of retinal pigment epithelial cells. For the first time, this cell culture system holds the potential to study human RPE cells in the context of neovascular AMD in vitro.

BACKGROUND: The utility of cytomegalovirus (CMV) urine cultures was checked in patients with HIV (a) to identify those at risk for CMV retinitis and (b) to guide clinical decisions on treatment and prophylaxis of CMV retinitis. METHODS: HIV infected patients were tested for CMVuria by shell vial cell cultures. The prevalence of CMVuria was related to CD4 count, HIV risk group, and time before and after diagnosis of CMV retinitis. RESULTS: A total of 639 shell vial cell cultures were obtained from 266 HIV infected ophthalmic patients. Only 4% of all patients with a CD4 count > 400 x 10(6)/l shed CMV in their urine compared with 42% with a CD4 count < or = 50 x 10(6)/l. Twenty three of 25 patients with CMV retinitis had a CD4 count < or = 50 x 10(6)/l. Among 130 patients with a CD4 count < or = 50 x 10(6)/l (a) those who were CMVuric had a nearly sevenfold risk (p < 0.0001) of developing CMV retinitis (35%) compared with those who did not shed CMV in their urine (5%), and (b) CMVuria and CMV retinitis were more frequent in homosexuals (58%/25%) than in intravenous drug users (23%/15%). More than 1 year before diagnosis of CMV retinitis 18% of patients were CMVuric compared with 83% of patients who were CMV culture positive in the last 3 months. CMVuria under virustatic maintenance therapy is associated with worsening of retinitis in two thirds of cases. CONCLUSION: Ophthalmic screening of patients with HIV should include those with a CD4 count < or = 50 x 10(6)/l and focus on the subgroup with additional CMVuria. Screening of other patients can be dropped without undue risk in order to spare AIDS patients unnecessary hospital visits. CMVuria as a single finding, however, does not justify antiviral prophylaxis of CMV retinitis.

Anti-VEGF treatment has become accepted first-line treatment for choroidal neovascularisation (CNV) in age-related macular degeneration. However, VEGF-inhibition does not always lead to sustained CNV-reduction. In this study, the effect of rapamycin was superior to VEGF-inhibition in a co-culture assay of endothelial cells (ECs) and retinal pigment epithelium (RPE). Rapamycin reduced EC sprouting in groups that did not respond to anti-VEGF treatment. Rapamycin did not induce EC apoptosis, but reduced both VEGF-production in RPE and the responsiveness of ECs to stimulation. Rapamycin might therefore be a therapeutic option for CNV patients that do not respond sufficiently to the established anti-VEGF treatments.