Role of vascular endothelial growth factor polymorphisms in the treatment success in patients with wet age-related macular degeneration.

PURPOSE: Along with environmental risk factors such as smoking, hypertension, and atherosclerosis, genetic susceptibility is a primary contributor to the development and progression of exudative age-related macular degeneration (AMD). Vascular endothelial growth factor (VEGF) is a central angiogenic regulator and there has been general agreement now that it is an important trigger for the progression of exudative AMD. In the present study, we tested the hypothesis that VEGF gene polymorphisms play a role in the treatment success with VEGF inhibitors in patients with exudative AMD. DESIGN: Prospective cohort study. PARTICIPANTS: We included 185 eyes of 141 patients with exudative AMD who were scheduled for their first treatment with intravitreally administered bevacizumab in this trial. METHODS: All patients were aged >50 years and had angiographically verified exudative AMD. Blood from the finger pad was collected on blood cards for genotyping for the VEGF polymorphisms rs1413711, rs3025039, rs2010963, rs833061, rs699947, rs3024997, and rs1005230. At each follow-up visit, visual acuity was reassessed and an ophthalmic examination was carried out. Visual acuity outcome, number of retreatments, and overall time of treatment were analyzed in dependence of the VEGF polymorphisms. MAIN OUTCOME MEASURES: Mean change in visual acuity at the end of the treatment period. RESULTS: The included patients were reinjected with bevacizumab 1 to 15 times, resulting in a total treatment period of 42 to 1182 days. In univariate analysis only the G/G genotypes of rs3024997 and rs2010963 compared with all other 5 single nucleotide polymorphisms (SNPs) showed a significantly lower visual acuity at the end of treatment. In multivariate analysis including parameters such as time, baseline visual acuity, and number of reinjections, none of the SNPs showed a significant correlation. CONCLUSIONS: The current study indicates that VEGF polymorphisms are not major predictors of anti-VEGF treatment success in patients with exudative AMD.

Early intravitreal bevacizumab for non-ischaemic branch retinal vein occlusion.

PURPOSE: To evaluate the effect of early intravitreal bevacizumab application in patients with macular oedema due to non-ischaemic branch retinal vein occlusion (BRVO). PROCEDURES: The study included 21 patients (21 eyes) with macular oedema due to non-ischaemic BRVO. Inclusion criteria were significant macular oedema as measured by optical coherence tomography, loss of visual acuity and leakage in fluorescence angiography. All patients received 3 intravitreal injections of 1.5 mg bevacizumab. The mean follow-up was 6.2 +/- 1.2 months (mean +/- standard deviation). The mean duration of the BRVO prior to treatment was 9.2 +/- 5.4 days. RESULTS: The visual acuity improved significantly from baseline 0.81 +/- 0.53 logMAR to 0.54 +/- 0.47 logMAR (p < 0.001) at 1 month, 0.55 +/- 0.46 (p = 0.001) at 3 months and to 0.55 +/- 0.49 (p = 0.002) at 6 months after the first injection. The mean central retinal thickness decreased significantly (p < 0.001) from 492 +/- 113 microm at baseline to 294 +/- 117 microm at 1 month after the first injection to 325 +/- 127 microm at 3 months (p < 0.001) and to 316 +/- 117 microm at 6 months (p < 0.001) after the first injection. The increase in visual acuity correlated significantly (p < 0.01) with the decrease in macular thickness. CONCLUSIONS: Early intravitreal injection of bevacizumab may decrease macular oedema and improve visual acuity in eyes with non-ischaemic BRVO.

Intravitreal bevacizumab for myopic choroidal neovascularization.

BACKGROUND AND OBJECTIVE: To evaluate the effect of intravitreal bevacizumab on visual acuity in patients with myopic choroidal neovascularization. PATIENTS AND METHODS: The retrospective case series study included 13 patients with myopic choroidal neovascularization who received three intravitreal injections of 1.5 mg of bevacizumab. RESULTS: At 1, 3, and 6 months after the first injection, mean visual acuity improved significantly from 0.63 +/- 0.41 logarithm of the minimum angle of resolution units (LogMAR) to 0.39 +/- 0.22 (P< .001), 0.47 +/- 0.49 (P= .002), and 0.52 +/- 0.49 LogMAR (P = 0.009), respectively. The increase in visual acuity was correlated with a significant decrease in central retinal thickness (P = .003) as measured by optical coherence tomography. Mean intraocular pressure did not change significantly (P> .05) during follow-up. CONCLUSION: Intravitreal injections of bevacizumab may be a therapeutic option for exudative myopic macular degeneration.

Peripapillary atrophy after acute primary angle closure.

AIM: To determine the changes in peripapillary atrophy after episodes of acute primary angle closure (APAC). METHODS: Prospective observational study of 40 eyes in 38 patients of predominantly Chinese ethnicity. The mean (SD) intraocular pressure at the time of presentation was 51.7 (12) mm Hg (median, 55 mm Hg) and the mean duration of the symptoms was 37.7 (69.4) hours. A laser iridotomy was undertaken 3.2 (8.4) days after the APAC episode, leading to normalisation of intraocular pressure in all cases. Colour optic disc photographs taken at 2 and 16 weeks after APAC were examined morphometrically. Peripapillary atrophy was divided into alpha and beta zones. RESULTS: Comparing measurements at baseline with week 16, the minimum width of the alpha zone (0.013 (0.056) v 0.016 (0.001) arbitrary units; p = 0.23), the maximum width of the alpha zone (1.11 (1.31) v 1.31 (0.79) arbitrary units; p = 0.22), the minimum width of the beta zone (0.030 (0.122) v 0.033 (0.166) arbitrary units; p = 0.93), and the maximum width of the beta zone (0.62 (0.94) v 0.73 (0.98) arbitrary units; p = 0.42) did not vary significantly. The mean cup to disc ratio increased from 0.56 (0.05) to 0.62 (0.07) (p<0.0001) at the end of follow up. CONCLUSIONS: The alpha and beta zones of peripapillary atrophy did not enlarge markedly in patients after APAC, despite an enlargement of the optic cup during a follow up of four months.

Infectious and noninfectious endophthalmitis after intravitreal bevacizumab.

AIMS: The aim of this study was to evaluate the rate of infectious and noninfectious endophthalmitis after an intravitreal injection of bevacizumab. METHODS: This clinical interventional case-series study included 1218 intravitreal injections of 1.5 mg of bevacizumab consecutively performed for 684 eyes with exudative age-related macular degeneration. Among the injections were 534 reinjections. Follow-up after each injection was at least 4 weeks. RESULTS: One (1) eye developed an infectious endophthalmitis 3 days after a second injection. In none of the other eyes, were signs of an infectious or noninfectious endophthalmitis observed with the cellular infiltration or amorphous opacification of the vitreous as marked by the Tyndall phenomenon in the anterior chamber, retinal infiltration, or pain. CONCLUSIONS: The rate of infectious endophthalmitis after an intravitreal injection of 1.5 mg bevacizumab may be approximately 1:1000, similar to injections of other drugs available thus far.

Optic nerve head change in non-arteritic anterior ischemic optic neuropathy and its influence on visual outcome.

PURPOSE: To evaluate changes in cup/disc (C/D) diameter ratios and parapapillary atrophy in patients with non-arteritic anterior ischemic optic neuropathy (NA-AION), using morphometric methods. METHODS: The clinical non-interventional study included 157 patients with unilateral or bilateral NA-AION. Optic disc photographs taken from both eyes at the end of follow-up were morphometrically examined. RESULTS: Follow-up was 86.3±70.3 months. Horizontal and vertical disc diameters (P = 0.30;P = 0.61, respectively), horizontal and vertical C/D ratios (P = 0.47;P = 0.19,resp.), and size of alpha zone and beta zone of parapapillary atrophy (P = 0.27;P = 0.32,resp.) did not differ significantly between affected eyes and contralateral normal eyes in patients with unilateral NA-AION. Similarly, horizontal and vertical disc diameters, horizontal and vertical C/D ratios, and size of alpha zone and beta zone did not vary significantly (all P>0.05) between the unaffected eyes of patients with unilateral NA-AION and the eyes of patients with bilateral NA-AION. Optic disc diameters, C/D ratios, size of alpha zone or beta zone of parapapillary atrophy were not significantly associated with final visual outcome in the eyes affected with NA-AION (all P>0.20) nor with the difference in final visual acuity between affected eyes and unaffected eyes in patients with unilateral NA-AION (all P>0.25). CONCLUSIONS: NA-AION did not affect C/D ratios nor alpha zone and beta zone of parapapillary atrophy. Optic disc size was not related to the final visual acuity outcome in NA-AION.

Bilateral intravitreal bevacizumab injection for exudative age-related macular degeneration: effect of baseline visual acuity.

PURPOSE: To assess side differences in patients undergoing bilateral intravitreal bevacizumab injections as treatment of exudative age-related macular degeneration (AMD). METHODS: The clinical interventional case series study included 48 patients (96 eyes) who consecutively and bilaterally received 3 intravitreal bevacizumab injections. The mean age was 76.5±7.5 years (range: 59-88 years). Follow-up was 6 months. Main outcome parameters were best-corrected visual acuity (BCVA) and measurements by optic coherence tomography. The eyes of the same patient were assigned to a study group 1 for the eye with the higher visual acuity at baseline, and study group 2 for the contralateral eye with the lower visual acuity at baseline. RESULTS: The increase in BCVA was significantly (P=0.02) greater in group 2 (0.07±0.25 logarithm of the minimum angle of resolution, LogMAR) than in group 1 (0.05±0.29 LogMAR). The height of a detached retinal pigment epithelium, the height of subretinal fluid, and the tissue thickness of the macula decreased significantly (P<0.05) in group 2 during follow-up, whereas these parameters did not markedly change in the eyes of group 1 (P=0.96, P=0.38, and P=0.07, respectively). The reduction in the height of a detached retinal pigment epithelium and in the height of subretinal fluid was significantly more pronounced in group 2 than in group 1 (P=0.03, P=0.04, respectively). CONCLUSIONS: After an initial set of 3 bilateral bevacizumab injections, patients with bilateral exudative AMD have a higher likelihood for an improvement in vision in the worse-seeing eye at baseline than in the better-seeing eye.

Correlation of optic disc morphology and ocular perfusion parameters in patients with primary open angle glaucoma.

PURPOSE: Little information is available about the relationship between glaucomatous visual field defects, morphological changes of the optic disc and ocular blood flow. In this study, ocular blood flow parameters were correlated with parameters of optic nerve head (ONH) morphology and visual field performance in a cross-sectional study. METHODS: A total of 103 patients with primary open angle glaucoma were included. Choroidal and ONH blood flow was assessed using laser Doppler flowmetry. Retinal blood velocities and retinal vessel diameters were measured with laser Doppler velocimetry and a Retinal Vessel Analyzer, respectively. To evaluate the ONH morphology, fundus photographs were taken and confocal laser scanning tomography was performed. RESULTS: Among all measured ocular hemodynamic parameters, the ONH blood flow was most strongly correlated to structural parameters of ONH damage and visual field loss. Reduced retinal vessel diameters were only slightly correlated with the degree of glaucomatous damage. CONCLUSION: Reduced blood flow in the ONH was associated with increasing amount of visual field defect and morphological changes of the ONH. Retinal vessel diameters were only marginally associated with glaucomatous optic nerve damage. Based on retinal vessel diameter determination alone, it is not possible to assess whether reduced retinal blood flow is causative or secondary in glaucoma.

Postoperative mycotic endophthalmitis.

UNLABELLED: We report a series of 4 patients who experienced a low-grade mycotic endophthalmitis 3 to 7 months after uneventful cataract surgery. In all patients, the capsular bag was irrigated several times and amphotericin B was instilled intraocularly as well as systemically. In the fourth patient, a pars plans vitrectomy was been performed. Microbiological examination of aqueous humor samples revealed Candida parapsilosis in 3 patients and Candida albicans in 1 patient as causative microorganisms. At follow-up examinations performed up to 12 months after the lavage, visual acuities were 0.2, 0.1, 0.1, and hand motion in the 4 patients, respectively. The main reason for the remaining reduction in visual acuity was retinal and optic nerve atrophy. The findings show that a mycotic etiology of postoperative low-grade infectious endophthalmitis should be considered. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Combined intravitreal bevacizumab and triamcinolone in exudative age-related macular degeneration.

PURPOSE: We report on the combined application of intravitreal bevacizumab and triamcinolone acetonide for treatment of exudative age-related macular degeneration (AMD). METHODS: The clinical interventional case-series study included 16 patients (16 eyes) with exudative AMD who had previously received 3.5±1.8 mono-injections of bevacizumab (1.5mg) without significant improvement in visual acuity (VA) or reduction in macular exudation. All patients underwent a combined intravitreal injection of bevacizumab (1.5mg) and triamcinolone acetonide (about 20mg). Main outcome measures were VA and macular thickness as determined by optical coherence tomography. All patients were re-examined at 2-3months after the intervention. RESULTS: Visual acuity improved significantly (p=0.03) from 0.80±0.40 logMAR prior to the combined injection to 0.65±0.42 logMAR at 3 months after the injection. An improvement of ≥1Snellen line was found in eight subjects, an increase of ≥2lines in five subjects, and an improvement of ≥3lines in two subjects. One patient lost 1line and one patient lost 3lines. Central retinal thickness decreased significantly from 272±62µm to 220±47µm (p=0.03). At the 6-month follow-up examination, central retinal thickness had increased again to 319±142µm, which was not significantly (p=0.30) different from baseline measurements. CONCLUSIONS: The combined intravitreal application of bevacizumab and triamcinolone may temporarily be helpful in the treatment of exudative AMD if previous intravitreal bevacizumab mono-injections have failed to improve vision and reduce macular oedema.

Early intravitreal bevacizumab for non-ischaemic central retinal vein occlusion.

PURPOSE: To evaluate the effect of early intravitreal bevacizumab injections for the treatment of macular oedema caused by non-ischaemic central retinal vein occlusion (CRVO). METHODS: The study included 25 patients (25 eyes) with macular oedema caused by non-ischaemic central retinal vein occlusion, who received three intravitreal injections of 1.5 mg bevacizumab with an interval of 6 weeks between the injections. Mean duration of central retinal vein occlusion prior to the first injection was 4.2 +/- 3.6 days. All patients were re-examined 1, 3 and 6 months after the first injection. The main outcome parameters were visual acuity and macular thickness, as measured by optical coherence tomography. RESULTS: Mean visual acuity improved significantly from 0.97 +/- 0.40 logMAR at baseline to 0.70 +/- 0.42 logMAR (P = 0.007) at 1 month, 0.69 +/- 0.46 (P = 0.006) 3 months and 0.69 +/- 0.52 (P = 0.015) 6 months after the first injection. Mean central retinal thickness decreased significantly from 530 +/- 152 microm at baseline to 347 +/- 127 microm (P < 0.001) at 1 month, 370 +/- 165 microm (P < 0.001) 3 months and 346 +/- 129 microm (P < 0.001) 6 months (P < 0.001) after the first injection. The increase in visual acuity correlated significantly (P < 0.01) with the decrease in macular thickness. Mean intraocular pressure was 14.2 +/- 3.2 mmHg at baseline and did not differ significantly from the measurement obtained at 1 month (P = 0.59), 3 months (P = 0.88) and 6 months after the first injection (P = 0.65). CONCLUSION: Intravitreal bevacizumab injections given shortly after onset of non-ischaemic central retinal vein occlusion may result in a significant increase in vision and a corresponding decrease in macular oedema.

Toxicity assessment of intravitreal triamcinolone and bevacizumab in a retinal explant mouse model using two-photon microscopy.

PURPOSE: Intravitreal drug administration leads to high intraocular concentrations with potentially toxic effects on ocular tissues. This study was an assessment of the toxicity of triamcinolone and bevacizumab in living retinal explants using two-photon (2P) microscopy. METHODS: Wild-type mice received intravitreal injections of triamcinolone, bevacizumab, or vehicle. Ten and 45 days after injection, wholemounted retinal explants were incubated with the fluorescent dye sulforhodamine 101 (SR101) to analyze morphology and tissue damage with 2P microscopy ex vivo. Retinas that received the same treatment were stained for apoptosis (TUNEL) and glial activation (GFAP). An intravitreal injection of NMDA (N-methyl-d-aspartate) was used as a positive control to ensure the fidelity of detection of retinal damage with ex vivo 2P microscopy. RESULTS: Overall retinal morphology was undisturbed after all procedures and time points. NMDA injection resulted in a strong increase in the number of SR101-labeled cells and increased apoptosis and glial activation when compared with sham-injected eyes. This result was in contrast to exposure to bevacizumab, which caused no appreciable damage. After triamcinolone treatment, marked damage in the inner retina was observed. However, damaged cells were restricted to sharply demarcated areas, and only mild changes in TUNEL-positive cells and GFAP activation was observed when compared to sham-injected eyes. CONCLUSIONS: 2P microscopy in combination with SR101 staining allows fast morphologic assessment of living retinal explants and can be used to evaluate adverse effects on retinal viability of test substances. Bevacizumab treatment did not cause any detectable retinal damage, whereas triamcinolone was associated with substantial, although spatially restricted, damage.

Ophthalmodynamometric measurement of central retinal vein pressure as surrogate of intracranial pressure in idiopathic intracranial hypertension.

BACKGROUND: Since a direct non-invasive measurement of the cerebrospinal fluid pressure is not available, it was the purpose of the study to describe the non-invasive determination of the central retinal vein pressure as an estimate of an elevated cerebrospinal fluid pressure. METHODS: A 28-year-old female patient with blurred vision, nuchal pain and prominent optic discs underwent modified ophthalmodynamometry to determine the central retinal vein pressure as surrogate of the intracranial pressure. A Goldmann contact lens with a pressure sensor mounted into its holding ring was placed onto the cornea. Pressure was applied to the globe by slightly pressing the contact lens until the central retinal vein started to pulsate/collapse. RESULTS: Despite an abnormally high central retinal vein pressure (OD: 17 arbitrary units; OS: 33 arbitrary units), the neurological examination including magnetic resonance imaging of the brain was unremarkable on the first day. A lumbar puncture revealed a cerebrospinal fluid pressure of 25 cm H(2)O, which was at the upper limit of the normal range. Over the next 2 days, ophthalmodynamometry showed increasing measurements of the central retinal vein pressure for both eyes, parallel to elevated cerebrospinal fluid pressure measurements by lumbar puncture, leading to the diagnosis of idiopathic intracranial hypertension. After treatment, the cerebrospinal fluid pressure returned to normal levels, parallel to a decrease in the central retinal vein pressure as determined by ophthalmodynamometry. CONCLUSIONS: Ophthalmodynamometry of the central retinal vein was helpful in the diagnosis of an elevated intracranial pressure, with direct lumbar pressure measurement running parallel to the ophthalmodynamometric measurements.

The role of the lymphatic system and its specific growth factor, vascular endothelial growth factor C, for lymphogenic metastasis in prostate cancer.

OBJECTIVE: To compare prostate carcinoma, with and with no lymph node metastasis, to benign prostatic hyperplasia (BPH) tissue for lymphatic vessel density (LVD) and the expression of the lymph-endothelial specific growth factor, vascular endothelial growth factor C (VEGF-C), to determine their role in lymphogenic metastasis. PATIENTS, MATERIALS AND METHODS: Lymphatic vessels were stained using lymphatic vessel endothelial hyaluronan receptor 1 and assessed in standard areas. The expression of VEGF-C was assessed by the number of positive epithelial cells. The data were compared with the clinical staging. RESULTS: The lowest LVD was found in tumorous areas as opposed to periphery and nontumorous tissue (P = 0.007; P < 0.001). The highest LVD was in BPH tissue (P < 0.001). There was no correlation with clinical staging. There was more VEGF-C staining in pN1 than in pN0 and in BPH specimens (P = 0.002). CONCLUSION: LVD is not a prognostic variable for the process of lymphogenic metastasis in prostate cancer. VEGF-C is up-regulated in prostate cancer and its correlation with lymph node status suggests a role for the development of lymph node metastasis, e.g. via an increased permeability of lymphatic vessels.

Lymph and blood vessel architecture in benign and malignant prostatic tissue: lack of lymphangiogenesis in prostate carcinoma assessed with novel lymphatic marker lymphatic vessel endothelial hyaluronan receptor (LYVE-1).

PURPOSE: Due to the lack of specific markers the analysis of lymphatic vessel density (LVD) has been almost impossible in the past. We report the novel specific marker for lymphatic endothelium, lymphatic vessel endothelial hyaluronan receptor (LYVE-1), in prostatic, benign prostatic hyperplasia (BPH) and prostate cancer (PCa) tissue. Normal blood vessels were additionally quantified in BPH and PCa. MATERIALS AND METHODS: LYVE-1 lymphatics (LVD) and CD34 blood vessels were assessed in 20 paraffin sections of BPH and 50 of PCa tissue by immunohistochemistry in a standardized experimental setting. The regions of PCa, periphery of the tumor and nontumorous regions of the PCa specimens, and BPH tissue were evaluated. Double staining was done (LYVE-1/CD34). Acquired data were interrelated and compared to the pathological parameters of the specimens. RESULTS: Double staining revealed numerous CD34 blood vessels but only a few LYVE-1 lymphatic vessels in BPH and PCa sections. Mean LVD +/- SD was distinctly lower (0.55 +/- 0.93) in PCa tissue than in tumor periphery (2.45 +/- 1.93) and nontumorous (3.16 +/- 2.23) tissue (p <0.0001). Maximum LVD was observed in BPH (7.17 +/- 3.61), which differed markedly from nontumorous areas of PCa specimens (p <0.001). In contrast to LVD, significantly more blood vessels were found in PCa (116.00 +/- 39.25) than in BPH (60.30 +/- 19.34) tissue (p <0.001). CONCLUSIONS: LYVE-1 is a specific lymphatic endothelial marker in benign and malignant prostate tissues. It is a useful new marker for the investigation of lymphatics. To our knowledge we report the immunohistochemical visualization and quantification of lymphatic vessels in prostatic tissue for the first time. In contrast to the stimulated angiogenesis of blood vessels in PCa, the destruction of lymphatic vessels occurs rather than lymphangiogenesis.