Thomas Benesch

Intraocular concentrations of growth factors and cytokines in retinal vein occlusion and the effect of therapy with bevacizumab.

PURPOSE To investigate concentrations of growth factors and inflammatory cytokines in eyes with central (CRVO) and branch (BRVO) retinal vein occlusion before and during therapy with bevacizumab and to identify associations with disease activity. METHODS In a prospective clinical trial, 13 eyes of patients with CRVO (n = 5) or BRVO (n = 8) were included. Bevacizumab was administered intravitreously at baseline and months 1 and 2. Retreatments were given at monthly visits if OCT showed edema or when vision loss occurred. Aqueous humor samples were taken each time injections were performed. Follow-up was 15 months. Samples from patients with cataract served as the control. Multiplex bead assays were used for measurement of 28 growth factors and cytokines. RESULTS During therapy with bevacizumab, VEGF levels were reduced to below detection in the first 2 months. Whenever criteria for retreatment were met, VEGF was measurable again. The decrease in VEGF was associated with a decrease in central retinal thickness (CRT) and improvement in visual acuity (VA). Significantly increased concentrations of VEGF, IL-6, IL-8, IP-10, MCP-1, and PDGF-AA were observed in aqueous humor samples of patients with CRVO compared with the control samples. CONCLUSIONS VEGF levels were significantly elevated in patients with CRVO compared with control subjects. Intravitreal injections of bevacizumab resulted in a substantial decrease of VEGF under physiologic levels and remained low under the loading dose of three consecutive monthly retreatments. Macular edema was related to VEGF levels in the aqueous humor.

Neovascular Age-related Macular Degeneration: Intraocular Cytokines and Growth Factors and the Influence of Therapy with Ranibizumab

PURPOSE To investigate concentrations of growth factors and inflammatory cytokines in eyes with neovascular age-related macular degeneration (AMD) before and during therapy with intravitreal ranibizumab and to identify associations with disease activity. DESIGN Prospective clinical trial. PARTICIPANTS AND CONTROLS Twenty-eight eyes of patients with neovascular AMD were compared with 28 eyes of age-matched patients with cataract as control. METHODS Ranibizumab was administered intravitreously once at baseline, and retreatments were given at monthly visits if optical coherence tomography (OCT) revealed macular edema or vision loss had occurred. Aqueous humor samples were taken each time intravitreal interventions were performed. Follow-up was 12 months. Luminex (Luminex Inc., Austin, TX) multiplex assays were used for measurement of 29 different growth factors and cytokines, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). MAIN OUTCOME MEASURES Differences in the concentrations of growth factors and inflammatory cytokines in eyes with neovascular AMD compared with control eyes and the influence of therapy with intravitreal ranibizumab. RESULTS A significantly increased expression of VEGF (P = 0.033) and a significantly decreased expression of PDGF (P = 0.038) were measured in the aqueous humor of eyes with neovascular AMD. Furthermore, a significant decrease of VEGF (P<0.001) was observed after intravitreal injection of ranibizumab along with significant changes in visual acuity and central retinal thickness (P = 0.039 and P<0.001). During follow-up with a flexible regimen, a correlation was identified between increased VEGF levels and persistent or recurrent macular edema. Changes in PDGF levels were strongly associated with alterations in VEGF concentration. CONCLUSIONS Vascular endothelial growth factor and PDGF-AA seemed to be associated with disease activity of neovascular AMD. Intravitreal anti-angiogenic treatment with ranibizumab resulted in significantly decreased intraocular VEGF expression below physiologic levels compared with controls. This effect was measurable as long as 4 weeks after each injection and was prolonged by consecutive retreatment. With recurrence after discontinuation of treatment, VEGF levels increased again.

Spectral-Domain Optical Coherence Tomography for Monitoring Epiretinal Membrane Surgery

PURPOSE To assess prognostic factors in epiretinal membrane (ERM) surgery using spectral-domain (SD) optical coherence tomography (OCT). DESIGN Prospective, interventional case series. PARTICIPANTS Forty-one patients. METHODS Patients with a diagnosis of ERM were examined with spectral-domain and time-domain (TD) OCT before and after surgery. MAIN OUTCOME MEASURES Main outcome measures were functional results and predefined OCT patterns. Cofactors analyzed were the type of ERM, the duration and grading of subjective metamorphopsia, simultaneous cataract surgery, the type of dyes used, the duration of surgery, gender, and age. A multivariate regression analysis was performed. RESULTS Thirty-nine patients (95%) showed an improved or stable best-corrected distance visual acuity (DVA) at 3 months, whereas 36 patients (88%) showed an improved or stable best-corrected near visual acuity (NVA) at 3 months. Significant correlations (P>0.4) were found between the course of central retinal thickness (CRT) assessed using SD OCT and TD OCT (P<0.02). No clinically relevant correlations (P<0.3) were seen between CRT and VA (P>0.1). Baseline DVA and NVA were found to be significant prognostic values for the postoperative decrease in CRT in both OCT systems (P<0.04) as well as for the visual outcomes (P<0.007) at 3 months. In addition, the integrity of the junction between the photoreceptor inner segment and outer segment (IS/OS) significantly influenced the visual outcomes at 3 months (P<0.038). The baseline profile of the internal limiting membrane (ILM) significantly influenced the NVA at 3 months (P<0.009), whereas the postoperative foveal contour significantly influenced the DVA at 3 months (P<0.025). The type of ERM, subjective metamorphopsia, simultaneous cataract surgery, the type of dyes used, the duration of surgery, gender, or age had no significant influence on patient outcome (P>0.05). Compared with TD OCT, SD OCT allowed for a more precise differentiation between the ERM and the retinal surface and for a better evaluation of the IS/OS line. CONCLUSIONS Besides the baseline VA, the integrity of the IS/OS line, better visualized by SD OCT, can be used to predict the functional outcomes after surgery. Additionally, analyzing the ILM profile and the foveal contour may help to understand limited visual outcomes after surgery. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Structural and serum surrogate markers of cerebrovascular disease in obstructive sleep apnea (OSA): association of mild OSA with early atherosclerosis.

AbstractThere is increasing evidence of a causal interaction between obstructive sleep apnea (OSA) and cerebrovascular disease. The aim of the study was to elucidate the relationship between the polysomnographically (PSG) measured severity of OSA and carotid atherosclerosis determined by ultrasonography and serum surrogate markers. 147 patients (102 males, 45 females) referred to our sleep laboratory for evaluation of snoring and sleep–disordered breathing were investigated. Carotid atherosclerosis was evaluated by serum analysis of high-sensitivity C–reactive protein (hs–CRP) and fibrinogen and four sonographic indices: intima–media thickness (IMT) of the common carotid artery (CCA), IMT from bulb to internal carotid artery (Bulb–ICA), combined IMT measurements from all segments and a plaque score (PlaS). Pearson correlation analysis, intergroup comparison (ANOVA), covariance analysis and a multiple regression were performed to assess the association between surrogate markers and respiratory variables. 44 patients had no OSA (apnea–hypopnea index AHI < 5/h), 27 mild (AHI 5–15), 25 moderate (AHI 15–30) and 51 severe OSA (AHI > 30). After adjusting for potential confounders, significant differences between the controls and all three OSA groups were observed in the CCA–IMT (p = 0.032) and in the PlaS between the controls and the severe group (p = 0.034). Multiple regression revealed the AHI as an independent predictor of CCA–IMT (p = 0.001) and combined IMT (p = 0.001), whereas the percentage of total sleep time with an oxygen saturation below 90 % was associated with Bulb–ICA IMT (p = 0.018) and hs–CRP (p = 0.015). OSA is associated with higher surrogate levels of cerebrovascular disease. Even mild OSA seems to predispose to early atherosclerosis.

Angiogenic and inflammatory markers in the intraocular fluid of eyes with diabetic macular edema and influence of therapy with bevacizumab.

Purpose: The purpose of this study was to determine the concentrations of angiogenic and inflammatory markers in human eyes with diffuse diabetic macular edema before and during therapy with intravitreal bevacizumab and their association with disease activity. Methods: In a prospective clinical trial, 10 eyes of 10 consecutive patients with vision loss because of diabetic macular edema were compared with 10 eyes of 10 age-matched controls. Bevacizumab was administered at baseline; retreatments were given monthly according to disease activity. During a follow-up of 6 months, aqueous humor samples were taken each time intravitreal therapy was administered. A multiplex assay was used for measurement of 12 different growth factors and cytokines. Results: Aqueous humor of eyes with diabetic macular edema demonstrated a significantly increased expression of monocyte chemoattractant protein-1 and interleukin-8 and higher, but not significant, levels of interleukin-6 and vascular endothelial growth factor. Intravitreal therapy with bevacizumab resulted in a significant decrease of vascular endothelial growth factor below physiologic levels. This change was not associated with clinical disease activity as measured by visual acuity and central retinal thickness. Conclusion: Eyes with diabetic macular edema showed a different profile of monocyte chemoattractant protein-1 and interleukin-8 as compared with controls. The intraocular vascular endothelial growth factor expression decreased significantly after the first intravitreal injection of bevacizumab; this reduction was prolonged by consecutive monthly retreatment.

Endovascular Treatment of Unruptured Intracranial Aneurysms With Guglielmi Detachable Coils Short- and Long-Term Results of a Single-Centre Series

Background and Purpose— Purpose of the present study is to evaluate the clinical outcome of endovascular treatment of unruptured intracranial aneurysms and to address the question of long-term stability and protection against future subarachnoid hemorrhage. Methods— Retrospective analysis of all patients treated in a 12-year period (173 patients: age 26 to 76 yr, mean 52.2±10.8/202 aneurysms: size 3 to 50 mm, mean 10.0±8.3). Results— The mortality was 0.5%; the overall morbidity was 3.5%. The most frequent complications were thromboembolic events (10.9%). Of these, 3.0% of patients suffered a stroke, leading to severe disability in 1 patient (0.5%). In 1 patient, the aneurysm ruptured during treatment, resulting in relevant neurological disability. Another patient suffered a fatal aneurysm rupture hours after treatment. The occlusion rate depended on aneurysm and neck size. Follow-up angiography revealed a decrease of the occlusion rate over time. This trend was obvious in all size categories and was most pronounced in giant aneurysms. In 3 patients (1.5%) with partially thrombosed giant aneurysms of the posterior circulation, embolization could not prevent later aneurysm rupture. There were no ruptures of any other aneurysms in the follow-up period (3.7±3.4 yr). Conclusion— Endovascular treatment is a highly safe procedure with low intervention-related morbidity and mortality. Long-term data for nongiant aneurysms showed good protection against rupture in the observation period. In contrast, the risk of rupture for giant aneurysms of the posterior circulation was as high as expected in observational studies.

A Systematic Correlation between Morphology and Functional Alterations in Diabetic Macular Edema

PURPOSE The aim of this study was to correlate different types of retinal morphologic alterations secondary to diabetic macular disease with their characteristic impact on retinal function. METHODS In the present cross-sectional study, 26 eyes of 26 diabetic patients with clinically significant macular edema were examined. All patients underwent complete standardized ophthalmologic examination, including SD-OCT and microperimetry. Microperimetric values were projected over the scanning laser ophthalmoscope image of the OCT device, allowing direct correlation of functional and morphologic parameters. Results over all 1066 individual areas were analyzed using a general linear model. RESULTS All the characteristic morphologic alterations demonstrated a significant effect on retinal function (P < 0.0002), except for outer nuclear layer (ONL) hyporeflectivity and small ONL cysts. Large ONL cysts (>220 μm) and serous retinal detachment had the greatest estimated negative effect on retinal sensitivity (-3.86 and -3.66 dB), followed by medium-sized ONL cysts, hard exudates associated with an extinction of the scan signal, and inner nuclear layer cysts. CONCLUSIONS In diabetic macular edema, serous retinal detachment and large ONL cysts are the two morphologic changes with the greatest negative impact on retinal function.

Morphological and functional analysis of the loading regimen with intravitreal ranibizumab in neovascular age-related macular degeneration

Aim To quantify and correlate the morphological and functional effects of the recommended loading regimen with intravitreal ranibizumab in neovascular age-related macular degeneration (AMD). Methods In a prospective, interventional clinical trial, 29 consecutive patients (29 eyes) with choroidal neovascularisation secondary to AMD received three initial monthly intravitreal injections of ranibizumab. During this loading regimen, best corrected visual acuity (BCVA) and microperimetry (MP) testing, as well as optical coherence tomography and fluorescein angiography (FA), were performed using a standardised protocol and the results correlated. Results Significant morphological and functional therapeutic effects were observed as early as 1 week following the first treatment. Throughout the loading-dose period, central retinal thickness, including intraretinal cysts and subretinal fluid, decreased fast and significantly (p<0.01); pigment epithelial detachment resolved less rapidly. The mean leakage area by FA decreased (p<0.01) and retinal function (BCVA and MP) increased significantly (both p<0.01). However, the change in morphology and function was only significant between baseline and week 1. There was no significant additional morphological or functional benefit following the second and third injection. Conclusion The initial administration of intravitreal ranibizumab in neovascular AMD induced a significant effect on intra- and subretinal fluid and visual function; subsequent injections had a less pronounced effect. It remains to be determined whether this loading regimen should be mandatory in all patients or if a single dose regimen would lead to a comparable functional and morphological retinal improvement.

Accuracy of preoperative biometry in vitrectomy combined with cataract surgery for patients with epiretinal membranes and macular holes: results of a prospective controlled clinical trial.

PURPOSE: To evaluate how adding vitrectomy to cataract surgery affects the accuracy of preoperative biometry and postoperative refractive outcomes. SETTING: Department of Ophthalmology, Ludwig Boltzmann Institute of Retinology and Biomicroscopic Lasersurgery, Rudolf Foundation Clinic, Vienna, Austria. METHODS: This study comprised 40 patients with vitreoretinal pathology and coexisting significant cataract (study group) and 40 patients with significant cataract only (control group). The main outcome measure was intraocular lens (IOL) power prediction error. Secondary outcome measures were spherical equivalent, anterior chamber depth, axial length, keratometry values, and intraocular pressure. A multivariate regression analysis was performed. RESULTS: There was a significant difference in prediction error between the study group and control group (P<.05). The addition of vitrectomy was associated with induced myopia of approximately −0.4 diopter, more so in patients who had epiretinal membrane removal than in patients with macular hole surgery (P = .04). There was no significant difference in prediction error between the 3 IOLs used (P = .2). CONCLUSION: The myopic shift was strongly dependent on the diagnosis and the need for intraocular tamponade, indicating that a slightly hyperopic IOL should be used in patients having combined surgery.

Association of Retinal Sensitivity and Morphology during Antiangiogenic Treatment of Retinal Vein Occlusion over One Year

PURPOSE Evaluation of the association between functional and anatomic retinal changes during anti-vascular endothelial growth factor (VEGF) therapy with bevacizumab (Avastin) in patients with cystoid macular edema secondary to retinal vein occlusion (RVO) using microperimetry and spectral domain optical coherence tomography (SD-OCT). DESIGN Prospective, uncontrolled study (EUDRACT NR-2005-003288-21). PARTICIPANTS Twenty-eight patients with cystoid macular edema secondary to RVO. METHODS Patients initially received 3 consecutive intravitreal injections of 1.25 mg bevacizumab at 4-week intervals. Further treatment was based on morphologic (OCT) and functional best-corrected visual acuity (BCVA) findings. During the 1-year follow-up, a rigorous standardized evaluation was performed monthly. Macular function was documented by microperimetry (Nidek, MP1 Microperimeter) and BCVA based on the Early Treatment in Diabetic Retinopathy Study (ETDRS). Morphologic parameters included central retinal thickness (CRT) as measured by conventional OCT (Stratus), and central subfield thickness (CST), mean retinal thickness (MRT), and retinal volume (RV) measured by SD-OCT. MAIN OUTCOME MEASURES Imaging of retinal morphology using OCT and SD-OCT and evaluation of retinal function assessed with microperimetry and ETDRS charts during 12 months of anti-VEGF treatment. RESULTS Within 6 months, the mean area of absolute scotoma was reduced from 21.4% of the central visual field to 6.4% and remained at this level until month 12 (7.4%). Mean BCVA improved from 51 to 66 letters on ETDRS charts. The CRT, CST, and MRT decreased significantly (P<0.002) and remained stable during the follow-up. The RV values did not improve significantly under therapy. Statistical analysis using a linear effects model revealed significant associations between the functional and morphologic outcomes, most notably between BCVA, macular sensitivity, CRT (Stratus OCT), CST, and MRT (Cirrus OCT) values. CONCLUSIONS Central retinal morphology, especially CRT and CST measured by conventional and SD-OCT, and retinal function improved significantly during treatment of RVO with a flexible dosing regimen of intravitreal bevacizumab. Functional (central visual acuity and visual field) and morphologic parameters (retinal thickness) were significantly related. These associations highlight the value of OCT imaging for assessing this disease entity.