Johann Roider

Origin of retinal pigment epithelium cell damage by pulsed laser irradiance in the nanosecond to microsecond time regimen

Selective photodamage of the retinal pigment epithelium (RPE) is a new technique to treat a variety of retinal diseases without causing adverse effects to surrounding tissues such as the neural retina including the photoreceptors and the choroid. In this study, the mechanism of cell damage after laser irradiation was investigated.

Comparison of Bevacizumab, Ranibizumab, and Pegaptanib In Vitro: Efficiency and Possible Additional Pathways

PURPOSE Vascular endothelial growth factor (VEGF) antagonists are the therapy of choice for age-related macular degeneration. Ranibizumab and pegaptanib have been approved by the United States Food and Drug Administration, whereas bevacizumab is used off label. In this study, the authors compare these VEGF inhibitors directly regarding their efficiency to neutralize VEGF in a quantifiable in vitro system. METHODS Porcine retina-retinal pigment epithelium-choroid organ culture and RPE cell culture were prepared from fresh eyes, cultivated in a perfusion chamber, and treated with clinically relevant concentrations of bevacizumab, ranibizumab and pegaptanib. VEGF content of the supernatant was analyzed with ELISA. Additionally, the influence of bevacizumab and ranibizumab on intracellular VEGF was analyzed with Western blot. RESULTS At clinically significant doses, bevacizumab (0.25 mg/mL) and ranibizumab (0.125 mg/mL) neutralized VEGF completely for 6 hours, whereas pegaptanib (0.08 mg/mL) showed no effect. Bevacizumab and ranibizumab neutralized VEGF significantly up to 16 hours. When diluted, bevacizumab lost its inhibiting properties at a concentration of 975 ng/mL, and ranibizumab neutralized VEGF up to a concentration of 120 ng/mL. Both substances significantly diminished VEGF expression in Western blot. CONCLUSIONS At clinical doses, bevacizumab and ranibizumab are equally potent in neutralizing VEGF. To neutralize VEGF completely in this system, a fraction of the clinical dose is needed. Ranibizumab is more efficient at neutralizing VEGF when diluted. Pegaptanib showed no effect in this system, which might help explain the clinical experience regarding this drug. A direct effect of ranibizumab and bevacizumab on VEGF protein expression indicates additional pathways of VEGF inhibitors.

Subthreshold (retinal pigment epithelium) photocoagulation in macular diseases: a pilot study

BACKGROUND Subthreshold (retinal pigment epithelium) photocoagulation is a new photocoagulation method, which treats the retinal pigment epithelium (RPE) and avoids damage to the neural retina. The initial results in this prospective pilot study on various macular diseases are presented. METHODS 12 patients with diabetic maculopathy (group I), 10 with soft drusen (group II), and four with central serous retinopathy (CSR) (group III) were treated and followed up for 1 year. Treatment was achieved using a train of repetitive short laser pulses (1.7 μs) of a green Nd:YLF laser (parameters: 527 nm, 100 and 500 pulses, repetition rate: 500 Hz, spot size: 160 μm, energies: 70–100 μJ). Laser energy was based on the visibility of test lesions on fluorescein angiography (50–130 μJ). Patients were examined at various times by ophthalmoscopy, fluorescein and ICG angiography, and infrared imaging. RESULTS After 6 months hard exudates disappeared in six out of nine patients in group I and leakage disappeared in six out of 12 diabetic patients. In group II drusen were less in seven out of 10 patients. In group III serous detachment disappeared in three out of four cases. Visual acuity was stable in all cases. None of the laser lesions was clinically visible immediately. After 1 day most lesions were visible as yellowish RPE depigmentation. After 3 months some of the lesions were visible as hyperpigmented areas but most were not. Fluorescein angiography showed leakage only in the first week. Infrared imaging showed that most lesions can be visualised in groups I and II after a period longer than 1 week as hyperreflective areas. CONCLUSION This study showed that subthreshold (RPE) photocoagulation is effective in some cases of diabetic maculopathy, drusens, and in CSR. Visibility of laser burns is not always necessary in the treatment of macular diseases presented here. Infrared imaging is an effective and non-invasive way of visualising subthreshold (RPE) laser burns.

VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study

Aim To evaluate intravitreal VEGF Trap-Eye (VTE) in patients with macular oedema secondary to central retinal vein occlusion (CRVO). Methods In this double-masked study, 177 patients were randomised (3:2 ratio) to intravitreal injections of VTE 2 mg or sham procedure every 4 weeks for 24 weeks. Best-corrected visual acuity was evaluated using the Early Treatment Diabetic Retinopathy Study chart. Central retinal thickness (CRT) was measured with optical coherence tomography. Results From baseline until week 24, more patients receiving VTE (60.2%) gained ≥15 letters compared with those receiving sham injections (22.1%) (p<0.0001). VTE patients gained a mean of 18.0 letters compared with 3.3 letters with sham injections (p<0.0001). Mean CRT decreased by 448.6 and 169.3 µm in the VTE and sham groups (p<0.0001). The most frequent ocular adverse events in the VTE arm were typically associated with the injection procedure or the underlying disease, and included eye pain (11.5%), increased intraocular pressure (9.6%) and conjunctival haemorrhage (8.7%). Conclusions VTE 2 mg every 4 weeks was efficacious in CRVO with an acceptable safety profile. Vision gains with VTE were significantly higher than with observation/panretinal photocoagulation if needed. Based on these data, VTE may provide a new treatment option for CRVO.

Acute Retinal Necrosis: Clinical Features, Early Vitrectomy, and Outcomes

OBJECTIVE To determine the viral diagnosis and the outcome of eyes with acute retinal necrosis (ARN) treated with intravenous acyclovir and oral prednisolone alone or combined with early vitrectomy and intravitreal acyclovir lavage. DESIGN Nonrandomized, retrospective, interventional, comparative, consecutive series. PARTICIPANTS A cohort of 27 human immunodeficiency virus-negative patients with ARN comprising 24 unilateral and 3 bilateral cases. INTERVENTION Vitreous biopsy for viral diagnosis. Twenty eyes were treated with intravenous acyclovir in combination with oral prednisolone (group A). Ten eyes were treated additionally with early vitrectomy, intravitreal acyclovir lavage, laser demarcation of necrotic retinal areas when feasible-with or without scleral buckling, and gas or silicone oil tamponade (group B). Vitrectomy was performed in all cases of secondary rhegmatogenous retinal detachment (RD). MAIN OUTCOME MEASURES Results of vitreous biopsy, rate of RD, rate of phthisis bulbi, and course of best-corrected visual acuity (BCVA). RESULTS Varicella zoster virus (VZV) was detected in 26 eyes, followed by herpes simplex virus (5 eyes), and Epstein-Barr virus (2 eyes, in conjunction with VZV). An RD developed in more eyes in group A (18 of 20 eyes) than in group B (4 of 10 eyes; P = 0.007). In 2 of 20 eyes in group A and in 0 of 10 eyes in group B, phthisis bulbi developed without a significant difference between groups A and B. Mean BCVA (logarithm of the minimum angle of resolution) at first visit was 1.09 (standard deviation [SD], 0.83), and mean final BCVA was 1.46 (SD, 0.88) without significant difference between groups A and B. CONCLUSIONS Varicella zoster virus is the leading cause of ARN. Visual prognosis is guarded. Early vitrectomy with intravitreal acyclovir lavage was associated with a lower incidence of secondary RD; however, it did not improve mean final visual acuity.

Pars plana vitrectomy, phacoemulsification and intraocular lens implantation. Comparison of clinical complications in a combined versus two-step surgical approach.

PurposeTo report intra-and postoperative complications in pars plana vitrectomy, phacoemulsification and intraocular lens implantation. A comparison of the combined versus two step surgical approach is given.MethodMedical records and operative notes of 111 eyes with combined surgery and 50 eyes with sequential surgery were retrospectively analysed. Subgroup analysis was performed to evaluate differences in disease groups, the use of endotamponading or endolaser and cryocoagulation. Postoperative follow-up time was between 3 and 18 months.ResultsCombined surgery: 64 eyes (57.5%) showed no complications. 17 eyes (15.3%) showed transient intraocular pressure rise, 17 eyes (15.3%) fibrinous exudation in the anterior chamber. Posterior capsule tears occurred in 7 eyes (6,3%), formation of posterior synechia was observed in 7 eyes (6.3%). IOL dislocation was seen in 3 eyes (2.7%), heavy covering of macrophages in 3 eyes (2,7%). Rare complications included silicon oil efflux into the anterior chamber (1.8%), anterior chamber hemorrhage (1,8%) and iris incarceration into the corneoscleral incision (0,9%). One eye needed explantation of the IOL during the follow-up. Sequential surgery: 31 eyes (62%) showed no complication. Transient intraocular pressure rise occurred in 14 eyes (28%), fibrinous exudation in 2 eyes (4%). Formation of posterior synechia was observed in 1 eye (2%), posterior capsule tears occurred in 4 eyes (8%). Dislocation of the IOL was seen in 1 eye (2%). Subgroup analysis revealed fibrinous exudation in the anterior chamber to be significantly more frequent after combined surgery, particularly in cases of proliferative diabetic retinopathy.ConclusionCombined pars plana vitrectomy, phacoemulsification and intraocular lens implantation as well as the two-step procedure are safe and effective. Sequential surgery could be advantageous to minimize the postoperative anterior chamber inflammatory response.

Autofluorescence imaging after selective RPE laser treatment in macular diseases and clinical outcome: a pilot study

Aim: Selective retinal pigment epithelium (RPE) laser treatment is a new technique which selectively damages the RPE while sparing the neural retina. One difficulty is the inability to visualise the laser lesions. The aim of the study was to investigate whether fundus autofluorescence (AF) is changed because of the RPE damage, and thus might be used for treatment control. Additionally, the clinical course of patients with various macular diseases was evaluated. Methods: 26 patients with macular diseases (diabetic maculopathy (DMP), soft drusen maculopathy (AMD), and central serous retinopathy (CSR)) were treated and followed up for at least 6 months. Treatment was performed with a train of repetitive short laser pulses (800 ns) of a frequency doubled Nd:YAG laser (parameters: 532 nm, 50 and 500 pulses at 100 and 500 Hz, retinal spot diameter 200 μm, pulse energies 75–175 μJ). AF was excited by 488 nm and detected by a barrier filter at 500 nm (HRA, Heidelberg Engineering, Germany). Patients were examined by ophthalmoscopy, fluorescein angiography, and autofluorescence measurements at various times after treatment (10 minutes, 1 hour, 1 and 6 weeks, 3, 6, and 12 months). Results: Fluorescein angiography showed leakage from the irradiated areas for about 1 week after treatment. None of the laser lesions was ophthalmoscopically visible during treatment. Identification of the lesions was possible by AF imaging showing an intensity decay in the irradiated area in 22 out of 26 patients, predominantly in patients with CSR and AMD. Lesions could be identified 10 minutes after treatment as hypoautofluorescent spots, which were more pronounced 1 hour later. During follow up the laser spots became hyperautofluorescent. In patients with DMP some AF images were less helpful because of diffuse oedema and larger retinal thickness. In these cases ICG angiography was able to confirm therapeutic success very well. Most of the patients have had benefit from the treatment, with best results obtained for CSR patients. Conclusion: Imaging of non-visible selective RPE laser effects can be achieved by AF measurements predominantly in patients without retinal oedema. Therefore, AF may replace invasive fluorescein angiography in many cases to verify therapeutic laser success. Selective laser treatment has the potential to improve the prognosis of macular diseases without the risk of laser scotomas.

Intravitreal Aflibercept for Macular Edema Secondary to Central Retinal Vein Occlusion: 18-Month Results of the Phase 3 GALILEO Study

PURPOSE To evaluate intravitreal aflibercept for treatment of macular edema secondary to central retinal vein occlusion (CRVO). DESIGN Randomized, double-masked, phase 3 study. METHODS A total of 177 patients with macular edema secondary to CRVO were randomized to receive 2 mg intravitreal aflibercept (n = 106) or sham (n = 71) every 4 weeks for 20 weeks. From weeks 24 to 48, patients were monitored every 4 weeks; the former group received intravitreal aflibercept as needed (PRN), and the sham group received sham. From weeks 52 to 76, patients were monitored every 8 weeks, and both groups received intravitreal aflibercept PRN. The primary endpoint (proportion of patients who gained ≥15 letters) was at week 24. This study reports exploratory outcomes at week 76. RESULTS The proportion of patients who gained ≥15 letters in the intravitreal aflibercept and sham groups was 60.2% vs 22.1% at week 24 (patients discontinued before week 24 were considered nonresponders; P < .0001), 60.2% vs 32.4% at week 52 (last observation carried forward, P < .001), and 57.3% vs 29.4% at week 76 (last observation carried forward; P < .001). Mean μm change from baseline central retinal thickness was -448.6 vs -169.3 at week 24 (P < .0001), -423.5 vs -219.3 at week 52 (P < .0001), and -389.4 vs -306.4 at week 76 (P = .1122). Over 76 weeks, the most common ocular serious adverse event in the intravitreal aflibercept group was macular edema (3.8%). CONCLUSIONS The visual and anatomic improvements seen after fixed, monthly dosing at week 24 were largely maintained when treatment intervals were extended. Patients with macular edema following CRVO benefited from early treatment with intravitreal aflibercept.

Macular function and morphology after peeling of idiopathic epiretinal membrane with and without the assistance of indocyanine green

Aim: To investigate macular function and morphology after surgical removal of idiopathic epiretinal membrane (IEM) with and without assistance of indocyanine green (ICG). Methods: A retrospective study as a consecutive case series, of 39 patients with IEM. 39 patients, 23 female, 16 male, mean age 67 years, underwent standard three port pars plana vitrectomy with removal of epiretinal membrane. Two groups of patients were consecutively operated: in 20 patients ICG 0.1% in glucose 5% was used to stain the epiretinal membrane. 19 patients underwent the identical procedure but without use of ICG. Postoperative follow up was 1–92 months (mean 15.5 months). Functional outcome was assessed with subjective improvement, best corrected visual acuity (BCVA), Amsler grid test, 10° and 30° automated perimetry (Heidelberg visual field analyser) (HFA), and Goldmann kinetic perimetry. Macular morphology was assessed with stereoscopic biomicroscopy and optical coherence tomography (OCT). The main outcome measures were macular function as determined by BCVA, presence of visual field defects, and metamorphopsia as determined by Amsler grid test, macular morphology as determined by slit lamp biomicroscopy, and OCT. Results: BCVA improved in 28 patients, remained unchanged in eight patients, and decreased in three patients. Improvement of BCVA was statistically significant in both groups (p = 0.003). Mean BCVA in patients operated with ICG improved from 0.33 preoperatively to 0.53 postoperatively. Mean BCVA in patients operated without ICG improved from 0.32 preoperatively to 0.54 postoperatively. Reduction of macular oedema as measured by OCT was statistically significant in both groups (p<0.01). There was no statistically significant difference in postoperative BCVA, macular oedema as measured by OCT, postoperative Amsler grid test, and subjective improvement between the two groups. The incidence of residual or recurrent epiretinal membrane was greater in the group operated without ICG (p = 0.014). Visual field defects were detected in one patient operated with ICG and in three patients operated without ICG. Conclusions: Removal of epiretinal tissue with or without assistance of ICG improved visual function and reduced macular oedema in most patients. Adverse effects clearly attributable to the use of ICG were not observed but further investigation is warranted.

Noninvasive optoacoustic temperature determination at the fundus of the eye during laser irradiation

In all fundus laser treatments of the eye, the temperature increase is not exactly known. In order to optimize treatments, an online temperature determination is preferable. We investigated a noninvasive optoacoustic method to monitor the fundus temperature during pulsed laser irradiation. When laser pulses are applied to the fundus, thermoelastic pressure waves are emitted, due to thermal expansion of the heated tissue. Using a constant pulse energy, the amplitude of the pressure wave increases linearly with an increase in the base temperature of between 30 and 80 degrees C. This method was evaluated in vitro on porcine retinal pigment epithelium (RPE) cell samples and clinically during selective RPE treatment with repetitive microsecond laser pulses. During the irradiation of porcine RPE with a neodymium-doped yttrium (Nd:YLF) laser (527 nm, 1.7 micros, 500 Hz repetition rate, 160 mJ/cm(2)) an increase in the base temperature of 30+/-4 degrees C after 100 pulses was found. During patient treatments, a temperature increase of 60+/-11 degrees C after 100 pulses with a 500-Hz repetition rate and 7+/-1 degrees C after 30 pulses with 100 Hz at 520 mJ/cm(2) was found. All measured data were in good agreement with heat diffusion calculations. Optoacoustic methods can be used to noninvasively determine retinal temperatures during pulsed laser treatment of the eye. This technique can also be adapted to continuous-wave photocoagulation, photodynamic therapy and transpupillary thermotherapy, or other fields of laser-heated tissue.