Macular Degeneration: Eter N

Meyer CH, Helb HM, Eter N. · Augenklinik, Universitätsklinikum Bonn, Ernst-Abbe-Strasse 2, 53127, Bonn, Germany. · Ophthalmologe. · Pubmed #18256841 No free full text.

Abstract: Age-related macular degeneration (AMD) is one of the most common causes of blindness in western industrialised nations. Most AMD patients suffer from the dry early form of AMD; however, wet AMD with choroidal neovascularization (CNV) is the main cause of blindness in all AMD patients. New prospects have been developed in AMD treatment using pharmacological methods available for treating all subtypes of exudative AMD. A number of inhibiting and inducing growth factors, such as vascular endothelial growth factor (VEGF), are particularly important in the pathophysiology of wet AMD. The secreted VEGF appears to play a crucial role in the pathogenesis of CNV and macular edemas as a result of its angiogenetic and permeability-enhancing effect. This recognition led to the treatment approach now used, i.e., competitive VEGF blocking through intravitreal adminsitration of anti-VEGF drugs. The anti-VEGF durgs lead to a rapid decrease in retinal thickness. Optical coherence tomography (OCT) is a valuable monitoring tool, but may only be used to assist in decision-making. Clinical follow-up of patients and further treatment recommendations must always be guided by the overall clinical picture. Visual acuity is regarded as the decisive criterion for repeat treatment.

Ladewig MS, Ziemssen F, Jaissle G, Helb HM, Scholl HP, Eter N, Bartz-Schmidt KU, Holz FG. · Augenklinik, Universität, Ernst-Abbe-Strasse 2, 53127 Bonn. · Ophthalmologe. · Pubmed #16763862 No free full text.

Abstract: The efficacy and safety of the therapeutic anti-VEGF concept has already been demonstrated for pegaptanib and ranibizumab. Bevacizumab acts as an antibody against all VEGF-A isoforms and has been developed for oncological indications with intravenous application. Initial reports on intravitreal administration in patients with neovascular age-related macular disease (AMD) have shown beneficial morphological and functional effects. In the meantime, bevacizumab has been used off-label in thousands of patients with AMD. However, data from prospective, controlled, randomized trials on both safety and efficacy are lacking. Herein recent experiences with bevacizumab are summarized and discussed. Furthermore, a web-based platform for online data registration and pooled analyses is presented.

Eter N, Krohne TU, Holz FG. · Department of Ophthalmology, University of Bonn Medical Center, Bonn, Germany. · BioDrugs. · Pubmed #16724865 No free full text.

Abstract: As a result of a better understanding of molecular mechanisms, a variety of new pharmacologic treatments have recently been developed for patients with age-related macular degeneration (AMD). Efficacy and tolerability have been demonstrated for drugs targeting vascular endothelial growth factor (VEGF), a key player in the pathogenesis of choroidal neovascularization. Both pegaptanib (anti-VEGF aptamer) and ranibizumab (anti-VEGF antibody fragment), applied at 4- to 6-week intervals into the vitreous, modified the natural course of the disease in phase III clinical studies. Corticosteroids with anti-angiogenic properties also represent a treatment option for wet AMD. Both intravitreal triamcinolone and anecortave acetate, administered juxtasclerally, are currently being pursued.The combination of different treatment strategies and potential synergistic effects offers new perspectives. While photodynamic therapy (PDT) combined with intravitreal triamcinolone is already frequently applied, other combinations (e.g. anti-VEGF drugs with PDT or antifibrotic agents) appear to be attractive alternatives. Pigment epithelium-derived factor represents another potential target, as well as inhibitors of matrix-metallo-proteinases. With the advent of gene therapy, the use of small interfering RNA (siRNA) is also on the horizon.Prophylactic measures are still limited. The combination of vitamins C and E, beta-carotene, and zinc as used in the AREDS (Age-Related Eye Disease Study) reduces risk for conversion from early- to late-stage disease in patients with high-risk features, at least to some extent. Lutein and zeaxanthin dietary supplements for improvement of macular pigment density need to be investigated in future longitudinal trials.

Eter N, Holz FG. · Universitäts-Augenklinik Bonn. · Klin Monatsbl Augenheilkd. · Pubmed #15912458 No free full text.

Abstract: It has been noted for some time that cataract surgery in the presence of retinal comorbidity such as diabetic macular edema may generate a progression of macular changes and result in a poor visual outcome. Recent findings show that adverse events may also occur in the presence of age-related macular degeneration (AMD). Therefore, when indicating cataract surgery the surgeon needs to consider the risks both for progression of early into late stages of AMD or further deterioration of late manifestations of AMD. Furthermore, in the presence of advanced atrophic or neovascular AMD the question arises whether or not the patient may benefit from cataract surgery in spite of an already existing central visual loss. Here we critically review results from recent studies.

Eter N, Bindewald A, Roth F, Holz FG. · Augenklinik, Universität, Bonn. · Ophthalmologe. · Pubmed #15459788 No free full text.

Abstract: Optical coherence tomography (OCT) represents a fast and noninvasive examination technique that generates two-dimensional sections of the posterior pole in vivo. Although this method is now widely applied in the diagnosis of various heterogeneous macular diseases, its role in patients with age-related macular degeneration (AMD) is less well established. OCT allows for quantitative as well as qualitative assessment of various AMD phenotypes. Qualitative assessment comprises the evaluation of intra- or subretinal fluid, intraretinal cystoid spaces, and retinal pigment epithelial detachments. However, together with the clinical findings and fluorescence angiography, it can provide useful additional information including monitoring of treatment effects.

Krohne TU, Eter N, Holz FG, Meyer CH. · Department of Ophthalmology, University of Bonn, Bonn, Germany. · Am J Ophthalmol. · Pubmed #18635152 No free full text.

Abstract: PURPOSE: To investigate intraocular concentrations and pharmacokinetics of bevacizumab after a single intravitreal injection in humans. DESIGN: Prospective, noncomparative, interventional case series. METHODS: We included 30 nonvitrectomized eyes of 30 patients (age range, 43 to 93 years) diagnosed with clinically significant cataract and concurrent macular edema secondary to neovascular age-related macular degeneration, diabetic retinopathy, or retinal venous occlusion in the same eye. All patients received an intravitreal injection of 1.5 mg bevacizumab. Between one and 53 days after injection, an aqueous humor sample was obtained during elective cataract surgery. Concentrations of unbound bevacizumab in these samples were quantified by enzyme-linked immunosorbent assay. RESULTS: Concentration of bevacizumab in aqueous humor peaked on the first day after injection with a mean concentration (c(max)) of 33.3 microg/ml (range, 16.6 to 42.5 microg/ml) and subsequently declined in a monoexponential fashion. Nonlinear regression analysis determined an elimination half-time (t(1/2)) of 9.82 days (R(2) = 0.81). No significant differences between diagnosis subgroups were noted. CONCLUSIONS: In human nonvitrectomized eyes, the aqueous half-life of 1.5 mg intravitreally injected bevacizumab is 9.82 days.

Meyer CH, Scholl HP, Eter N, Helb HM, Holz FG. · Department of Ophthalmology, University of Bonn, Germany. · Acta Ophthalmol. · Pubmed #18221499 No free full text.

Abstract: PURPOSE: To assess the effectiveness of consecutive intravitreal injections of recombined tissue plasminogen activator (rtPA), expansile gas and bevacizumab in eyes with acute subretinal haemorrhage (SRH). METHODS: A retrospective, non-randomized consecutive case series included 19 eyes in 19 patients with SRH related to exudative age-related macular degeneration (AMD). The initial size of the subfoveal SRH was 1-3 disc diameters. Each patient received a triple procedure using 0.05 ml rtPA (50 microg), 0.3 ml of sulphur hexafluoride (SF6) gas and 0.05 ml bevacizumab (1.25 mg). Lesion size, location of the SRH and early treatment in diabetic retinopathy study (ETDRS) visual acuity were evaluated pretreatment as well as 1 and 3 months after the procedure. RESULTS: At the initial presentation, the patients' mean age was 77 years (range 63-88 years) and the mean duration of symptoms was 9.3 days (range 4-12 days). The mean visual acuity pretreatment (20/133) improved significantly to 20/86 at 1 month and to 20/74 at 3 months. The mean ETDRS visual acuity improved from baseline by 2.1 lines at 1 month (Wilcoxon ranks test; P < 0.005) and 3.7 lines at 3 months after treatment (Wilcoxon ranks test; P < 0.005). None of our patients had reading visual acuity prior to treatment, with visual acuity below 0.3. One month after the triple procedure, 25% of our patients had reading visual acuity (> or = 0.4); at 3 months, the figure was 35%. A successful inferior displacement of the SRH was achieved in 17/19 eyes. Eyes with elevated intraocular pressure were treated immediately by a corneal paracentesis. CONCLUSION: The intravitreal application of rtPA, gas and bevacizumab appears to be beneficial and well tolerated in the treatment of SRH in the short term. The triple approach seems a logical alternative to the current combined dual approach in limiting the progression of the underlying disease and achieving better visual outcome. Further randomized evaluations are warranted.

Ladewig MS, Karl SE, Hamelmann V, Helb HM, Scholl HP, Holz FG, Eter N. · Department of Ophthalmology, University of Bonn, Ernst-Abbe-Strasse 2, 53127, Bonn, Germany. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #17701197 No free full text.

Abstract: BACKGROUND: Our aim was to evaluate the short-term safety and efficacy of combined photodynamic therapy (PDT) with verteporfin and intravitreal bevacizumab in neovascular age-related macular degeneration (AMD). METHODS: A prospective non-randomized interventional case series of 30 eyes of 30 patients with choroidal neovascularization (CNV) caused by AMD was studied. All patients were treated with PDT followed by an intravitreal injection of bevacizumab (1.5 mg) on the same day. Ophthalmic evaluations included determination of best-corrected visual acuity by using ETDRS charts. CNV lesion characteristics were determined by fluorescein angiography, and retinal morphology by optical coherence tomography. Review examinations were performed 1, 4, and 12 weeks following treatment. RESULTS: The median ETDRS letter scores increased by 3 letters after 4 weeks and 4.3 letters after 12 weeks. Median central retinal thickness decreased from the baseline by 145 microm (week 1), 205 microm (week 4), and 171 microm (week 12), respectively (P < 0.0001, for all comparisons). One patient experienced a transient moderate vision loss after 4 weeks post treatment. Leakage on fluorescein angiography was resolved in all patients at week 12. No significant ocular or systemic side-effects were observed. CONCLUSIONS: Short-term results suggest that a single PDT in combination with intravitreal bevacizumab is safe and associated with stabilization of visual acuity and decrease of intraretinal and subretinal fluid accumulation in the macula. Further evaluation of this treatment strategy for neovascular AMD appears warranted.

Bindewald A, Stuhrmann O, Roth F, Schmitz-Valckenberg S, Helb HM, Wegener A, Eter N, Holz FG. · Department of Ophthalmology, University of Bonn, Ernst-Abbe-Strasse 2, D-53127 Bonn, Germany. · Br J Ophthalmol. · Pubmed #16299141 links to  free full text

Abstract: BACKGROUND: With the advent of digital confocal scanning laser ophthalmoscopy it is possible to detect low levels of fluorescence. Here we used a novel confocal scanning laser ophthalmoscope (cSLO) to determine lower limits of dye required for fluorescein (FL) and indocyanine green (ICG) angiography. METHODS: A cSLO (Heidelberg retina angiograph 2, Heidelberg Engineering, Dossenheim, Germany) with an optically pumped solid state laser (488 nm) for FL and a diode laser (790 nm) for ICG angiography (FL/ICG-A) was used. 62 FL-As were performed in 53 patients and 45 ICG-As were performed in 39 patients with neovascular age related macular degeneration. The volume and overall dye content of bolus injections was gradually tapered (FL: 500 mg, 250 mg, 200 mg, 166 mg, 100 mg; ICG: 25 mg, 20 mg, 15 mg, 10 mg, 5 mg, 2.5 mg), while dye concentrations were kept constant at 100 mg/ml for FL and at 5 mg/ml for ICG. Images were obtained 1, 5, 15, and 30 minutes after dye injection. Image quality was evaluated by two independent readers using standardised criteria. RESULTS: For amounts down to 166 mg for FL and to 5 mg for ICG, sufficient image quality was achieved during all phases following injection. Only late phase images showed less contrast compared to typically used dye amounts, which was irrelevant for interpretation and clinical management. CONCLUSIONS: With the increased sensitivity of this novel cSLO system, amounts of injected dye during FL-A can be reduced to one third for FL and to one fifth for ICG without relevant loss of image quality or information compared to conventionally used dye levels. These amounts can be used for routine angiography and allow relevant savings for units performing FL-A.

Eter N, Spaide RF. · Department of Ophthalmology, University of Bonn Medical Center, Bonn, Germany. · Retina. · Pubmed #16141855 No free full text.

Abstract: PURPOSE: To investigate retinal morphology by means of fluorescein angiography (FA) and optical coherence tomography (OCT) in patients who had undergone photodynamic therapy (PDT) with verteporfin at their 3-month-interval examination. METHODS: Sixty patients with predominantly classic choroidal neovascularization (CNV) secondary to age-related macular degeneration were evaluated with FA and OCT 3 months after their last PDT. FA images were evaluated in a masked fashion for staining of and leakage from the lesion and also for cystoid loculation of fluorescein in the macula. OCT was used to evaluate foveal thickness and the presence of subretinal fluid or cystoid spaces within the retina, also in a masked fashion. RESULTS: The median age of the 60 patients was 78 years, and the median visual acuity of the eyes examined was 20/100. The median number of previous PDT sessions was 2. Fluorescein staining was seen in 57 eyes (95%), and fluorescein leakage was seen in 50 eyes (83%). Cystoid loculation of fluorescein was seen in 21 eyes (35%). By OCT, cystoid spaces in the macula were seen in 42 patients (70%), and subretinal fluid was seen in 15 patients (25%). Leakage seen shown by FA was correlated with the OCT finding of cystoid spaces but not with the OCT finding of subretinal fluid. Some patients had leakage during FA that did not have any observable induced OCT abnormality attributable to fluid accumulation. CONCLUSIONS: After PDT leakage from CNV seen during FA is associated with intraretinal fluid, often seen in loculated cystoid spaces, but not with subretinal fluid.

Dwinger MC, Pieper-Bodeewes I, Eter N, Holz FG. · Universitäts-Augenklinik Bonn. · Klin Monatsbl Augenheilkd. · Pubmed #16118744 No free full text.

Abstract: BACKGROUND: Intravitreal triamcinolone injection (IVT) has become a treatment option for macular edema of heterogeneous etiology and neovascular retinal diseases including AMD. Besides the risk for a steroid-induced secondary open-angle glaucoma, the acute rise in intravitreal volume induces IOP elevations immediately after injection. To decrease the intravitreal volume a paracentesis is advocated by many surgeons. The aim of this study was to determine variations in IOP at different time points immediately after IVT in order to assess the necessity for routine paracentesis. METHODS: The IOP was recorded by Goldmann applanation tonometry preoperatively, 10 minutes, 1, 3 and 24 hours after intravitreal injection of 0.1 mL (4 mg) triamcinolone. A consecutive series of 32 eyes of 32 patients with diabetic macular edema, diffuse edema after central vein occlusion or occult subfoveal choroidal neovascularization due to age-related macular degeneration was included. Statistical analysis was performed with ANOVA test and Bonferroni correction. RESULTS: Compared to baseline (15.24 +/- 0.52 mm Hg) IOP was significantly elevated 10 min postoperatively (22.28 +/- 1.4 mmHg; p < 0.05). One hour after injection IOP decreased to 15.58 +/- 0.69 mmHg (p < 0.05). Three and 24 h after injection mean IOP was not significantly different from preoperative baseline levels. Immediately after IVT light perception was tested and retinal perfusion was evaluated by indirect ophthalmoscopy. In none of the patients was a paracentesis necessary. CONCLUSION: Intravitreal injection of 0.1 mL triamcinolone led to a moderate transient rise in IOP. Based on these results, a routinely performed paracentesis immediately before or after IVT is not required. As paracentesis bears an additional risk including endophthalmitis it should only be considered if functional testing following injection indicates a relevant impairment of retinal perfusion.

Eter N, Vogel A, Inhetvin-Hutter C, Spitznas M. · Department of Ophthalmology, University of Bonn Medical Center, Bonn, Germany. · Eur J Ophthalmol. · Pubmed #14620172 No free full text.

Abstract: PURPOSE: To identify the number of primary angiographic nonresponders to photodynamic therapy (PDT) with verteporfin, to determine the rate and speed of reperfusion of choroidal neovascularization (CNV) within a short observation period of only 5 weeks, and to examine the reaction of the underlying choroidal vessels. METHODS: PDT according to the TAP regimen was carried out in 36 eyes with subfoveal classic CNV secondary to age-related macular degeneration. The response to PDT was examined 1 (T1) and 5 (T2) weeks following treatment. At all visits distant visual acuity was measured and both fluorescein and indocyanine green angiography was carried out. RESULTS: One week after treatment (T1), complete closure of classic CNV had not been achieved in 17% of eyes (primary angiographic nonresponders). At T2, 91% of eyes showed reperfusion of the CNV. In 83% of the primary angiographic nonresponders the CNV size was larger than before treatment. Choroidal shadowing was present in 82% at T1 and in 48% at T2. CONCLUSIONS: Primary angiographic PDT nonresponders are relatively rare; however, in contrast to former reports, they exist and can be identified by follow-up examination 1 week after PDT. Recurrence of leakage occurred earlier than expected and may require closer follow-up and earlier retreatment than recommended by the TAP trial.

Eter N, Vogel A, Inhetvin-Hutter C, Spitznas M. · Universitäts-Augenklinik Bonn. · Ophthalmologe. · Pubmed #12682765 No free full text.

Abstract: PURPOSE: To find out if carrying out PDT again 6 weeks after initial PDT will improve the results at 3 months. METHODS: A total of 22 eyes were treated according to the dose regimen proposed by the TAP study. RESULTS: After the first PDT, the CNV remained permanently closed in 14% of the eyes.Repeating the treatment 6 weeks later did not lead to permanent closure of more CNVs or a diminished size at 3 months. Short-term re-treatment had no substantial effect on the underlying choriocapillaries. Visual acuity did not profit or suffer from early re-treatment. CONCLUSION: Shortening of the treatment interval has no serious side-effects, but does not seem to improve the results reported in the TAP study.

Eter N, Schüller H, Spitznas M. · Department of Ophthalmology, University of Bonn Medical Center, Germany. · Int Ophthalmol. · Pubmed #11998881 No free full text.

Abstract: AIM: To evaluate the efficacy of radiotherapy in the treatment of subfoveal classic and occult choroidal neovascularization (CNV) in age-related macular degeneration (AMD) under strict fixation control. METHODS: Twenty-seven eyes of 27 patients with subfoveal CNV as a result of AMD were treated with a total dose of 20 Gy in 10 fractions (10 well-defined, 17 occult). Fixation monitoring was achieved by installing a TV camera with an attached fixation light 3 cm from the cornea of the eye being treated. Visual acuity and fluorescein angiography were obtained before and 6 months after treatment. Fifteen eyes of 15 patients served as controls (4 well-defined, 11 occult). RESULTS: After 6 months the treated group showed an average decrease in visual acuity of 27%; the control group experienced a decrease of 31%. Membrane size increased by 56% in the treated group and by 28% in the control group. There was no statistically significant difference. Within the subgroup analysis, however, patients with classic CNV suffered significantly less visual loss than in the control group. CONCLUSION: Radiation therapy under optimized treatment conditions by fixation monitoring failed to control further growth in membrane size in both classic and occult CNV. Regarding visual acuity, however, patients with classic CNV seem to benefit from radiation treatment compared to the natural course.

Eter N, Schüller H. · Department of Ophthalmology, University of Bonn Medical Center, Germany. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #11820697 No free full text.

Abstract: PURPOSE: Dry-eye symptoms have been described as possible radiation side effects after external beam radiotherapy for age-related macular degeneration. We therefore investigated tear-film function before and after treatment. METHODS: Thirty-nine patients with no apparent history of dry-eye symptoms were treated with a 6 MV linear accelerator using a 2x2 cm lateral field angled 10 degrees posteriorly. A total dose of 20 Gy, divided into 10 fractions of 2 Gy and administered 3 times a week, was delivered. Before and 1, 3, and 6 months after radiotherapy, tear secretion was measured by means of tear-film fluorophotometry. The fellow eyes served as controls. RESULTS: At baseline, mean tear secretion as measured by tear-film fluorophotometry was 7.15 microl/min in the eyes receiving radiation and 5.89 microl/min in the control eyes. No statistically significant differences were found between the two eyes at baseline (signed rank test). One month after treatment, again no significant differences could be found between the two eyes; 3 months after radiation, however, tear secretion was significantly lower in the irradiated eyes than in the fellow eyes (P=0.0017). Six months after treatment this effect could no longer be detected. CONCLUSION: External beam radiotherapy using 20 Gy in 10 fractions and a 2x2 cm lateral field causes a statistically significant difference in tear secretion 3 months after radiation. This effect seems to be transient, as it had disappeared in later follow-up examinations.

Eter N, Wegener A, Schüller H, Spitznas M. · Department of Ophthalmology, Bonn University Medical Center, Bonn, Germany. · Br J Ophthalmol. · Pubmed #10873989 links to  free full text

Abstract: AIM: Evaluation of potential side effects of photon radiotherapy on the transparency of the lens. METHODS: The anterior segments of 14 phakic eyes from patients suffering from subfoveal neovascularisation as a result of age related macular degeneration (AMD) were documented by Scheimpflug photography (Topcon SL-45, Kodak Tmax 400) before the start of radiotherapy as well as 6 and 12 months afterwards. All negatives were evaluated by microdensitometry, and peak heights for distinct layers of the lens were used for statistical comparison. External beam radiotherapy (6 MeV photons) consisted of a total dose of 20 Gy, delivered as 10 fractions of 2 Gy. RESULTS: Six and 12 months following irradiation statistical comparison of the ratios in density change of lenses from irradiated versus non-irradiated fellow eyes revealed statistically significant (p</=0.05) loss of transparency of layers 5 and 7 of the nuclear region. In layer 1 (capsuloepithelial complex) the changes were close to significance. At the 12 month examination, however, all of these significant changes had disappeared. CONCLUSION: Six months following radiotherapy for AMD, both the anterior capsuloepithelial region and the nuclear layers showed precataractous changes. As most of these significant differences had disappeared after 12 months, it is obvious that these findings reflect acute radiation damage to the lens epithelial cells and an ionising effect on the proteins of the lens nucleus. Long term studies will have to be carried out to demonstrate whether or not this acute radiation damage, which is expressed as a transient increase in light scattering of some layers of the lens, actually does lead to permanent transparency changes, thus reflecting radiation cataractogenesis, and if so, after what time interval and to what extent cataract occurs.

Meyer CH, Eter N. · No affiliation provided · Am J Ophthalmol. · Pubmed #18222195 No free full text.

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