Matus Rehak

Branch Retinal Vein Occlusion: Pathogenesis, Visual Prognosis, and Treatment Modalities

In branch retinal vein occlusion (BRVO), abnormal arteriovenous crossing with vein compression, degenerative changes of the vessel wall and abnormal hematological factors constitute the primary mechanism of vessel occlusion. In general, BRVO has a good prognosis: 50–60% of eyes are reported to have a final visual acuity (VA) of 20/40 or better even without treatment. One important prognostic factor for final VA appears to be the initial VA. Grid laser photocoagulation is an established treatment for macular edema in a particular group of patients with BRVO, while promising results for this condition are shown by intravitreal application of steroids or new vascular endothelial growth factor inhibitors. Vitrectomy with or without arteriovenous sheathotomy combined with removal of the internal limiting membrane may improve vision in eyes with macular edema which are unresponsive to or ineligible for laser treatment.

Retinal gene expression and Müller cell responses after branch retinal vein occlusion in the rat.

PURPOSE In a rat model of branch retinal vein occlusion (BRVO), changes in gene expression of factors implicated in the development of retinal edema and alterations in the properties of Müller cells were determined. METHODS In adult Long-Evans rats, BRVO was induced by laser photocoagulation of retinal veins; untreated eyes served as controls. The mRNA levels of after factors were determined with real-time RT-PCR in the neural retina and retinal pigment epithelium after 1 and 3 days of BRVO: VEGF-A, pigment epithelium-derived factor (PEDF), tissue factor, prothrombin, the potassium channel Kir4.1, and aquaporins 1 and 4. Potassium currents were recorded in isolated Müller cells, and cellular swelling was assessed in retinal slices. RESULTS In the neural retina, the expression of VEGF was upregulated within 1 day of BRVO and returned to the control level after 3 days. PEDF was upregulated in the neuroretina and retinal pigment epithelium after 3 days of BRVO. Prothrombin, Kir4.1, and both aquaporins were downregulated in the neuroretina. After BRVO, Müller cells displayed a decrease in their potassium currents and an altered distribution of Kir4.1 protein, an increase in the size of their somata, and cellular swelling under hypoosmotic stress that was not observed in control tissues. CONCLUSIONS BRVO results in a rapid transient increase in the expression of VEGF and a delayed increase in the expression of PEDF. The downregulation of Kir4.1 and aquaporins, the mislocation of Kir4.1 protein, and the osmotic swelling of Müller cells may contribute to the development of edema and neuronal degeneration.

The prevalence of activated protein C (APC) resistance and factor V Leiden is significantly higher in patients with retinal vein occlusion without general risk factors - Case-control study and meta-analysis

Several small case-control studies have investigated whether factor V Leiden (FVL) is a risk factor for retinal vein occlusion (RVO) and generated conflicting data. To clarify this question we performed a large two-centre case-control study and a meta-analysis of published studies. Two hundred seven consecutive patients with RVO and a control group of 150 subjects were screened between 1996 and 2006. A systematic meta-analysis was done combining our study with further 17 published European case-control studies. APC resistance was detected in 16 out of 207 (7.7%) patients and eight out of 150 (5.3%) controls. The odds ratio (OR) estimated was 1.49 with a (non-significant) 95% confidence interval (CI) of 0.62-3.57. The meta-analysis including 18 studies with a total of 1,748 patients and 2,716 controls showed a significantly higher prevalence of FVL in patients with RVO compared to healthy controls (combined OR 1.66; 95% CI 1.19-2.32). All single studies combined in the meta-analysis were too small to reliably detect the effect individually. This explains the seemingly contradictory data in the literature. In conclusion, the prevalence of APC resistance (and FVL) is increased in patients with RVO compared to controls, but the effect is only moderate. Therefore, there is no indication for general screening of factor V mutation in all patients with RVO. We recommend this test to be performed in patients older than 50 years with an additional history of thromboembolic event and in younger patients without general risk factors like hypertension.

The role of thrombophilia in patients with retinal vein occlusion and no systemic risk factors

OBJECTIVE The role of thrombophilia in the etiology of retinal vein occlusion (rVO) has not been adequately clarified. The aim of this study was to examine the prevalence of thrombophilia among RVO patients with and without systemic risk factors and among patients younger and older than 50 years. DESIGN Prospective case-control study. PARTICIPANTS One hundred and twenty one patients with RVO, including 92 with acquired risk factors (hypertension, hyperlipidemia, and diabetes mellitus) and 29 without these factors. The control group included 60 persons matched for age, sex, and risk factors. METHODS All participants were screened for Leiden mutation (FV Leiden), hyperprothrombinemia (20210 G/A mutation) and deficiency of protein C, S, and antithrombin. RESULTS The prevalence of FV Leiden was significantly higher among RVO patients without risk factors (24.1%) than among controls without risk factors (0%; p = 0.034) and among RVO patients with acquired disorders (4.3%; p = 0.001). No significant differences were found in the prevalence of the other investigated thrombophilic factors. In all, 37.9% patients without acquired risk factors were positive for at least 1 thrombophilic factor compared with 7.6% RVO patients with acquired risk factors (p < 0.001) and 8.3% of the controls (p < 0.001). There was no significant difference in the prevalence of thrombophilic disorders among RVO patients according to age. CONCLUSIONS FV Leiden is significantly more frequent among RVO patients without acquired risk factors. Thrombophilia plays a much more important role in the pathogenesis of RVO in patients without acquired risk factors. Screening for thrombophilia is thus indicated only for patients in whom these factors have been excluded.

Does ocriplasmin affect the RPE–photoreceptor adhesion in macular holes?

Background To evaluate the anatomical outcome of patients after vitrectomy due to persisting symptomatic vitreomacular traction (VMT), including full-thickness macular holes (FTMHs) of less than 400 µm, after ocriplasmin treatment. Methods Retrospective, single centre, consecutive interventional case series. Patients were treated with a single intravitreal injection of ocriplasmin (Jetrea, Thrombogenics Inc, USA, Alcon/Novartis EU). Main outcome measures: resolution of VMT, closure of FTMH and anatomical outcome of vitrectomy after unsuccessful treatment with ocriplasmin. Results Five patients were treated with ocriplasmin injection. VMT persisted in all but one case. Four patients underwent pars-plana vitrectomy (PPV) for treatment of persistent VMT and FTMH (n=2, size of macular hole <400 µm) in spectral-domain optical coherence tomography (SD-OCT). FTMHs were closed in both cases within the first week postoperatively. After PPV, in three eyes newly developed subretinal fluid was detected, which persisted up to several months postoperatively. Conclusions Data on ocriplasmin remain controversial. We report on four cases with resolution of VMT following PPV after unsuccessful ocriplasmin treatment. Newly developed subretinal fluid has been described after ocriplasmin treatment, predominantly in cases with resolution of VMT. We also detected this newly developed subretinal fluid after vitrectomy, which persisted for several weeks up to 7 months in two cases with FTMHs. This may be attributable to loosening of the photoreceptor complex due to enzyme activity of ocriplasmin. Long-term effects of ocriplasmin are still to be evaluated using SD-OCT.

Transcriptional Regulation of Aquaporins in the Ischemic Rat Retina: Upregulation of Aquaporin-9

Purpose/aim: To determine the transcriptional regulation of retinal aquaporins (AQPs) in rat models of transient and permanent retinal ischemia, and to prove the effects of chemical hypoxia, oxidative stress, glucose, and osmotic alterations on the expression of AQP9 in cultured human retinal pigment epithelium (RPE) cells. Materials and methods: Transient retinal ischemia-reperfusion in rats was induced by elevation of the intraocular pressure for 1 hour. Permanent retinal ischemia was induced by argon laser-induced retinal vein occlusion. The mRNA levels were determined one day after ischemia. Results: Transient and permanent ischemia of the rat retina resulted in downregulation of AQPs 1, 3, 4, 5, 6, 8, and 11 in the RPE and/or neural retina. Pressure-induced transient retinal ischemia-induced upregulation of AQP9 in the neuroretina and RPE, and of AQ12 in the neuroretina. Retinal vein occlusion induced upregulation of AQP0 in the neuroretina and RPE, and of AQP9 and AQP12 in the neuroretina. In cultured human RPE cells, transcriptional expression of AQP9 was stimulated by chemical hypoxia, oxidative stress, VEGF, and high glucose. Conclusions: The data may suggest that the expression of retinal AQP9 is regulated by metabolic and oxidative stress. Upregulation of AQP9 in RPE cells may prevent lactic acidosis and subretinal edema under ischemic and oxidative stress conditions.

Initial Visual Acuity Is an Important Prognostic Factor in Patients with Branch Retinal Vein Occlusion

Purpose: To evaluate the role of initial visual acuity (VA) as a potential prognostic factor for final VA in patients with branch retinal vein occlusion (BRVO). Methods: A retrospective data analysis involving 163 patients with macular edema secondary to BRVO treated according to the recommendations of the Branch Vein Occlusion Study Group was performed using univariate and multivariate logistic regression models, and receiver-operating characteristics analysis. The analyses take factors into account that can potentially influence final visual result: sex, age, type of occlusion (major temporal or macular), grid photocoagulation and ischemia. Results: The final VA ≤0.1 was statistically significantly related to initial VA ≤0.16 and age >70 years. Sex, type of occlusion, grid photocoagulation and ischemia did not significantly influence the prediction of final VA based on age and initial VA. Conclusions: The analysis shows that initial VA and age >70 years significantly influence the prognosis for final visual results in patients with BRVO.

Local Recurrence After Primary Proton Beam Therapy in Uveal Melanoma: Risk Factors, Retreatment Approaches, and Outcome

PURPOSE To evaluate the risk factors, recurrence rates, retreatments, and long-term patient outcomes following proton beam therapy for uveal melanoma. DESIGN Retrospective interventional case series. METHODS All patients treated with primary proton beam therapy for uveal melanoma at the oncology service at Charité-Berlin and Helmholtz-Zentrum-Berlin between May 1998 and December 2008 were reviewed for local recurrence. Of 982 patients, 982 eyes matched the inclusion criteria. The data were obtained from electronic health records, operative reports, discharge letters, and radiation planning. Comparisons of fundus photographs and ultrasound measurements were performed to assess the growth pattern of the tumor and to determine the success of retreatment, in the case that a globe-retaining therapy was undertaken. RESULTS Of 982 patients, 35 patients (3.6%) developed local recurrence. The median follow-up was 60.7 months (6.0-170.4 months). Local control rate was 96.4% and the overall eye retention rate was 95.0% in this cohort. Local recurrence was correlated with a higher risk for metastasis and reduced survival. Largest tumor diameter was identified as the sole statistically significant risk factor for local recurrence (P = .00001). All globe-retaining retreatment approaches for local recurrence, including proton beam therapy, brachytherapy, and transpupillary thermotherapy used for recurrences at the tumor margins, showed good local tumor control and similar metastasis-free survivals. CONCLUSIONS This study showed that each globe-retaining retreatment approach can result in satisfying local tumor control. In case of early detection of local recurrence, preservation of the globe can be warranted. Therefore, regularly performed follow-ups should be ensured.

Antiphospholipidsyndrom und retinale venöse Verschlüsse

The role of antiphospholipid syndrome (APS) in the pathogenesis of retinal vein occlusion has been discussed for several years. Conflicting results of the published studies are caused by small numbers of investigated patients and lack of control groups. We performed a meta-analysis of all case-control studies published up to July 2007 that investigated the prevalence of APS according to current diagnostic criteria for this syndrome.The results of meta-analysis show a significantly higher prevalence of APS in patients with retinal vein occlusion compared with controls. Patients with APS are treated with anticoagulants to reduce the risk of recurrence of thrombosis. Therefore, screening for APS seems to be indicated in all patients with retinal vein occlusion, and, in the case of a positive result, initiation of anticoagulation. For patients with retinal vein occlusion with APS, no data are currently available regarding the recurrence of thrombosis. To give a clear recommendation, a prospective randomized study is required to investigate the benefit of anticoagulation.ZusammenfassungDer Anteil des Antiphospholipidsyndroms (APS) an der Pathogenese von retinalen venösen Verschlüssen wird seit Jahren diskutiert. Einzelne Studien hierzu erbrachten oft widersprüchliche Ergebnisse, weil die meisten Studien kein kontrolliertes Design hatten und die Fallzahlen klein waren. In der vorliegenden Arbeit führten wir eine Metaanalyse durch, die alle bis jetzt publizierten Studien einschließt, welche den diagnostischen Kriterien für APS entsprechen. Hierzu wurde eine Literaturrecherche bis einschließlich Juli 2007 durchgeführt. Die Ergebnisse der Metaanalyse zeigen, dass die Prävalenz des APS bei Patienten mit retinalen venösen Verschlüssen im Vergleich zur Kontrollgruppe signifikant höher ist. Die Patienten mit einem APS werden wegen des deutlich erhöhten Risikos eines Thromboserezidivs antikoaguliert. Daher scheint nach jetzigem Wissen ein APS-Screening für alle Patienten mit retinalen venösen Verschlüssen und im Falle einer APS-Positivität die Durchführung einer Antikoagulation sinnvoll zu sein. Für Patienten mit einem retinalen venösen Verschluss in Rahmen eines APS liegen zurzeit bezüglich der Rezidivrate einer Thrombose keine Daten vor. Deswegen muss eine prospektive randomisierte Studie durchgeführt werden, die den Nutzen der antikoagulativen Therapie bei diesen Patienten untersucht. Erst danach kann eine endgültige Empfehlung für die klinische Behandlung gegeben werden.AbstractThe role of antiphospholipid syndrome (APS) in the pathogenesis of retinal vein occlusion has been discussed for several years. Conflicting results of the published studies are caused by small numbers of investigated patients and lack of control groups. We performed a meta-analysis of all case-control studies published up to July 2007 that investigated the prevalence of APS according to current diagnostic criteria for this syndrome.The results of meta-analysis show a significantly higher prevalence of APS in patients with retinal vein occlusion compared with controls. Patients with APS are treated with anticoagulants to reduce the risk of recurrence of thrombosis. Therefore, screening for APS seems to be indicated in all patients with retinal vein occlusion, and, in the case of a positive result, initiation of anticoagulation. For patients with retinal vein occlusion with APS, no data are currently available regarding the recurrence of thrombosis. To give a clear recommendation, a prospective randomized study is required to investigate the benefit of anticoagulation.

Head-to-head comparison of ranibizumab PRN versus single-dose dexamethasone for branch retinal vein occlusion (COMRADE-B)

To compare the efficacy and safety of ranibizumab 0.5 mg versus dexamethasone 0.7 mg according to their European labels in macular oedema secondary to branch retinal vein occlusion (BRVO) in a 6‐month, phase IIIb, randomized trial.