[Cost Comparison of Licensed Intravitreal Therapies for Insufficiently Anti-VEGF Responding Fovea Involving Diabetic Macular Edema in Germany]. / Kostenvergleich zugelassener intravitrealer Therapien bei nicht ausreichend auf primäre Therapie ansprechendem diabetischem Makulaödem mit fovealer Beteiligung in Deutschland.

BACKGROUND: In the treatment of center-involving diabetic macular edema, despite initial therapy with an anti-VEGF compound, an insufficient response may occur. Further therapy options include a switch of anti-VEGF products or to corticosteroid implants, such as Fluocinolone acetonide or Dexamethasone. OBJECTIVES: Firstly, to investigate systematically which evidence-based study data are available describing the efficacy of in-label treatments after primary anti-VEGF treatment, secondly, to investigate which costs go along for the healthcare provider. METHODS: A systematic literature review (SLR) for randomized controlled trials (RCT) was performed in Medline and Embase. A short-term cost-cost model was built in MS Excel with a 3 year time horizon to compare in-label intravitreal options Ranibizumab (Lucentis®), Aflibercept (Eylea®), Fluocinolone acetonide implant (Iluvien®), and Dexamethasone implant (Ozurdex®). Cost components comprised of drug and injection costs, optical coherence tomography (OCT) procedures, and adverse events such as endophthalmitis, IOP-lowering drugs and surgery and cataract surgery. RESULTS: A total of 42 publications of 20 RCTs were identified. No study had a clearly defined population after first line anti-VEGF treatment, thus no direct efficacy comparison was possible. In the short-term cost-cost model total costs were 17,542 € for Ranibizumab, 15,896 € for Aflibercept, 10,826 € for Fluocinolone acetonide implant and 12,365 € for Dexamethasone implant. For all treatment regimens, drug costs were the predominant cost component, followed by injection costs (with variations dependent on the specific drug) and OCT costs. In the uni- and multivariate sensitivity analyses, the results obtained were robust to changes of model inputs. CONCLUSIONS: In summary, the short-term cost-cost comparison demonstrates that steroid implants can provide significant cost savings versus in-label anti-VEGF treatment for center-involving diabetic macular edema. Single application of the long-lasting Fluocinolone acetonide implant is the most cost-efficient in-label treatment option.

Central serous chorioretinopathy.

The pathogenesis of central serous chorioretinopathy (CSC) is still not fully understood. The involvement of corticosteroids is undisputed, although their exact role has not been clarified; other parts of the underlying mechanism of CSC have been mainly elucidated by imaging techniques such as fluorescein and indocyanine green angiography. Even though most cases of CSC are self-limiting, severe as well as recurrent courses exist, and for these patients only a limited number of treatment options are available: laser photocoagulation, with a risk of scotoma and choroidal neovascularization, and photodynamic therapy. In this review article, we give an overview of its epidemiology, the current understanding of its pathogenesis as well as systemic and ocular risk factors. We illuminate modern diagnostic tools as well as current treatment options in the context of CSC, particularly in the light of a better understanding of corticosteroids and their receptors involved in its pathogenesis.

Nonmydriatic ultra-wide-field scanning laser ophthalmoscopy (Optomap) versus two-field fundus photography in diabetic retinopathy.

The purpose of this study was to investigate the diagnostic properties of a 2-laser wavelength nonmydriatic 200° ultra-wide-field scanning laser ophthalmoscope (SLO) versus mydriatic 2-field 45° color fundus photography (EURODIAB standard) for assessing diabetic retinopathy (DR). A total of 143 consecutive eyes of patients with different levels of DR were graded regarding DR level and macular edema based on 2-field color photographs or 1 Optomap Panoramic 200 SLO image. All SLO images were nonmydriatic and all photographs mydriatic. Grading was performed masked to patient and clinical data. Based on photography, 20 eyes had no DR, 44 had mild, 18 moderate and 42 severe nonproliferative DR, and 19 eyes had proliferative DR. Overall correlation for grading DR level compared to Optomap SLO was moderate with kappa 0.54 (p < 0.001), fair-to-moderate in macular edema grading with kappa 0.39 (p < 0.001), and substantial for grading clinically significant macular edema (kappa 0.77). The wide-field SLO offers a wider field of view and can potentially better differentiate lesions by applying the 2 laser wavelengths. However, these advantages over 2-field fundus photography need to be confirmed in further studies.

Axitinib modulates hypoxia-induced blood-retina barrier permeability and expression of growth factors.

This study investigates the effects of the multikinase inhibitor axitinib on the expression of vascular endothelial growth factor (VEGF) receptors 1/2 (VEGFR-1/2) and platelet-derived growth factor (PDGF) receptor beta (PDGFR-ß), hypoxia-induced increased tissue permeability, occludin, zonula occludens protein 1 (ZO-1), VEGF-A, and PDGF expression of human retinal pigment epithelial (RPE) cells and human umbilical vein endothelial cells (HUVECs). Primary human RPE cells and HUVECs were exposed to hypoxia and axitinib. Viability of cells, tissue permeability, and expression of occludin, ZO-1, VEGF, PDGF, VEGFR-1/2 and PDGFR-ß, and their mRNAs, were investigated by reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, and immunohistochemistry. Treatment with axitinib reduced expression of VEGFR-1/2 and PDGFR-ß. Hypoxia decreased cell viability, occludin, and ZO-1 expression and increased tissue permeability, expression, and secretion of VEGF and PDGF. Axitinib significantly reduced hypoxia-induced effects on HUVEC and RPE cells. Our in vitro results suggest that axitinib may have promising properties as a potential treatment for diabetic macular edema.

Inhibitory activity of ranibizumab, sorafenib, and pazopanib on light-induced overexpression of platelet-derived growth factor and vascular endothelial growth factor A and the vascular endothelial growth factor A receptors 1 and 2 and neuropilin 1 and 2.

BACKGROUND: Cumulative light exposure is significantly associated with progression of age-related macular degeneration. Growth factors and growth factor receptor signaling are known to have a substantial impact on the development of age-related macular degeneration. This study explored the effects of ranibizumab, sorafenib, and pazopanib on vascular endothelial growth factor A (VEGF) receptors 1 and 2 and neuropilin 1 and 2 expression in human retinal pigment epithelial cells. In addition, their effects on light-induced overexpression of VEGF and platelet-derived growth factor were investigated. METHODS: Primary human retinal pigment epithelial cells were exposed to white light and then treated with ranibizumab (0.125 mg/mL), sorafenib (1 µg/mL), or pazopanib (1 µg/mL). Viability of cells, expression of VEGF receptors 1 and 2 and neuropilin 1 and 2 and their mRNA, and secretion of VEGF and platelet-derived growth factor were investigated by reverse transcription-polymerase chain reactions, immunohistochemistry, and enzyme-linked immunosorbent assays. RESULTS: Treatment with sorafenib or pazopanib reduced the expression of VEGF receptors 1 and 2 and neuropilin 1, and sorafenib also reduced neuropilin 2. Light exposure decreased cell viability and increased expression and secretion of VEGF and platelet-derived growth factor. Sorafenib and pazopanib significantly reduced light-induced overexpression and secretion of VEGF and platelet-derived growth factor. Ranibizumab reduced secreted VEGF in cell culture supernatants only. CONCLUSION: Our in vitro results suggest that multikinase inhibitors have promising properties as a potential antiangiogenic treatment for age-related macular degeneration.

Filtering blue light reduces light-induced oxidative stress, senescence and accumulation of extracellular matrix proteins in human retinal pigment epithelium cells.

BACKGROUND: Cumulative light exposure is significantly associated with ageing and the progression of age-related macular degeneration. To prevent the retina from blue-light damage in pseudophakia, blue light-absorbing intraocular lenses have been developed. This study compares the possible protective effects of a blue light-absorbing intraocular lens to an untinted ultraviolet-absorbing intraocular lens with regard to light-induced oxidative stress and senescence of human retinal pigment epithelium. METHODS: As primary human retinal pigment epithelium cells were exposed to white light, either an ultraviolet- and blue light-absorbing intraocular lens or ultraviolet-absorbing intraocular lens was placed in the light beam. After 60 min of irradiation, cells were investigated by electron microscopy for viability, induction of intracellular reactive oxygen species, and senescence-associated ß-galactosidase activity. Expression and secretion of matrix metalloproteinases 1 and 3 and their mRNA were determined by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. RESULTS: Light exposure induced structural damage, decreased retinal pigment epithelium cell viability, and increased reactive oxygen species, senescence-associated ß-galactosidase activity and matrix metalloproteinases 1 and 3 expression and secretion. Although both types of intraocular lens significantly reduced these effects, the protective effects of the ultraviolet- and blue light-absorbing intraocular lens were significantly stronger than those of the ultraviolet-absorbing intraocular lens. CONCLUSIONS: The ultraviolet- and blue light-absorbing intraocular lens demonstrated significantly better protection against light-induced oxidative stress, senescence and structural damage than the ultraviolet-absorbing intraocular lens. These in vitro findings support the hypothesis that the ultraviolet- and blue light-absorbing intraocular lens may prevent retinal damage in clinical use.

Alpha-lipoic acid for the prevention of diabetic macular edema.

INTRODUCTION: To evaluate the effect of α-lipoic acid (ALA) on the occurrence of diabetic macular edema. METHODS: Randomized, double-blind, placebo-controlled, multicenter, multinational study. Patients were randomized to the treatment group with 600 mg ALA per day or the placebo group. Every 6 months stereo fundus photographs, HbA1c levels, and an ophthalmological examination were documented. The primary endpoint was the occurrence of clinically significant macular edema (CSME) within a follow-up period of 2 years. RESULTS: We randomized 235 patients with type II diabetes mellitus into the treatment group (mean age 58.0 years) and 232 into the placebo group (mean age 57.9 years). Mean HbA1c level was 8.1, with no significant differences between the treatment (mean 8.2, SD ± 1.35) and placebo groups (mean 8.1, SD ± 1.29). HbA1c values remained constant over time. In the treatment and placebo groups, 84 and 86 patients (35.7 and 37.1%) had insulin-dependent diabetes mellitus (IDDM) with a median duration of diabetes of 9.3 versus 9.0 years in the placebo group. Visual acuity remained unchanged during the entire trial. Concerning the primary endpoint, the study provided a negative result, i.e. 26/235 patients in the treatment group and 30/232 patients in the placebo group developed CSME. Confirmatory intention-to-treat analysis of the primary endpoint revealed no statistically significant difference between groups (log-rank test, p = 0.7108, HR = 0.9057 with CI = 0.5355-1.5317). Median follow-up was identical (2.00 years). CONCLUSIONS: A daily dosage of 600 mg ALA does not prevent the occurrence of CSME in IDDM patients.

Effect of calcium dobesilate on occurrence of diabetic macular oedema (CALDIRET study): randomised, double-blind, placebo-controlled, multicentre trial.

BACKGROUND: Medical treatment for diabetic retinopathy could have an important role in prevention of complications such as visual loss. We aimed to assess the effect of calcium dobesilate on occurrence of diabetic macular oedema. METHODS: We undertook a randomised, double-blind, placebo-controlled, multicentre study in 40 centres in 11 countries. We enrolled outpatients with adult-onset type 2 diabetes and mild-to-moderate non-proliferative diabetic retinopathy, and randomly allocated them via sealed envelopes either calcium dobesilate (1500 mg per day) or placebo. The primary endpoint was development of clinically significant macular oedema (CSME) within a follow-up period of 5 years. Patients who dropped out of the study early were censored. Analysis was by intention to treat. FINDINGS: We enrolled 635 patients. 324 were randomly allocated calcium dobesilate and 311 were assigned placebo. In the calcium dobesilate group, 86 patients developed CSME compared with 69 in the placebo group. Accounting for censored cases, estimated cumulative 5-year CSME probability was 35% and 28%, respectively (hazard ratio 1.32, 95% CI 0.96-1.81; p=0.0844). Adverse events did not differ between treatment groups (78 [24%] on calcium dobesilate and 90 [29%] with placebo). No relevant drug-related complications were noted. Nine patients (3%) died in the calcium dobesilate group and eight (3%) deaths were recorded on placebo. INTERPRETATION: Calcium dobesilate did not reduce the risk of development of CSME.

Comparison of intravitreal bevacizumab versus triamcinolone for the treatment of diffuse diabetic macular edema.

BACKGROUND: Our purpose was to compare the effect of triamcinolone and bevacizumab (Avastin) on the retinal thickness and functional outcome in patients with diabetic macular edema. METHODS AND MATERIALS: A collective of 32 patients, who had been treated by a single 4.0-mg intravitreal triamcinolone injection (group 1), was matched to 32 patients ('matched pairs'), who had received 3 injections of 1.25 mg of bevacizumab within 3 months in 4-week intervals (group 2). The outcome variables were changes in best corrected visual acuity (VA) and central retinal thickness 3 months after therapy. RESULTS: Both groups did not differ regarding preoperative VA and central retinal thickness measured by optical coherence tomography. The baseline mean VA was 0.72 +/- 0.39 logMAR in group 1 and 0.73 +/- 0.39 logMAR in group 2 (p = 0.709). The mean central retinal thickness measured by optical coherence tomography was 548 +/- 185 mum in group 1 and 507 +/- 192 mum in group 2. While the patients in group 1 experienced a slight increase in VA of on average 0.7 lines following a single triamcinolone injection to a mean of 0.64 +/- 0.40 logMAR (p = 0.066) after 3 months, the patients in group 2 showed almost no effect on VA with an average increase of 0.2 lines to a mean VA of 0.72 +/- 0.30 logMAR (p = 0.948) following 3 intravitreal injections of bevacizumab. Comparing the effect on VA between both groups no statistically significant difference (p = 0.115) was noted. Concerning decrease in central retinal thickness both therapies were highly effective (p < 0.001 each), again, without statistically significant difference between the groups (p < 0.128). CONCLUSION: Our data suggest that a single triamcinolone injection may be as effective as a 3 times repeated intravitreal administration of bevacizumab for the treatment of diabetic macular edema. Further prospective trials should be performed.

In vitro safety of intravitreal moxifloxacin for endophthalmitis treatment.

PURPOSE: To investigate the safety of moxifloxacin for intravitreal application in a cell culture model. SETTING: Department of Ophthalmology, Ludwig-Maximilians-Universität, Munich, Germany. METHODS: Primary human retinal pigment epithelium (RPE) cells, ARPE19 cells, and primary optic nerve head astrocyte (ONHA) cells were treated with concentrations of moxifloxacin ranging from 10 to 750 microg/mL. Possible toxic effects and median inhibitory concentration were evaluated after 24 hours as well as under conditions of oxidative stress. After treating the RPE and ONHA cell lines with tumor necrosis factor-alpha (TNF-alpha; 10 microg/mL), lipopolysaccharides (LPS; 20 microg/mL), and interleukin-6 (IL-6; 20 microg/mL), the effects of moxifloxacin on cellular viability under conditions of inflammation were investigated. Toxicity was evaluated by measuring the inhibition of RPE cell proliferation with the tetrazolium dye-reduction assay (MTT; 3-[4,5-dimethylthiazol- 2-yl]-2,5-diphenyl tetrazolium bromide). Cell viability was quantified by a microscopic live/dead assay. RESULTS: At concentrations higher than 150 microg/mL, moxifloxacin had adverse effects on primary RPE, ARPE19, and ONHA cell proliferation and viability. Lower concentrations did not affect RPE or ONHA cell proliferation and viability when administered for 24 hours. No significant decrease in proliferation and viability was observed after preincubation with TNF-alpha, LPS, and IL-6 for 24 hours and subsequent treatment with moxifloxacin concentrations of 10 to 150 microg/mL for 24 hours. Hydrogen peroxide exposure did not increase cellular toxicity. CONCLUSIONS: No significant toxicity of moxifloxacin was seen on primary RPE cells, ARPE19 cells, or ONHA cells at concentrations up to 150 microg/mL. Intravitreal use of moxifloxacin up to this concentration may be safe and effective for the treatment of endophthalmitis.

Epi-LASIK using the Amadeus II microkeratome: evaluation of cut quality using light and electron microscopy.

PURPOSE: To investigate the cut quality and surface characteristics of the epithelial flap and underlying Bowman's membrane created by the Amadeus II (AMO) microkeratome on human corneas using light and electron microscopy. SETTING: Center for Refractive Therapy, Department of Ophthalmology, Ludwig-Maximilians University, Munich, Germany. METHODS: Using a 9.0 mm type II suction ring and settings, as recommended by the manufacturer, epithelial laser in situ keratomileusis (epi-LASIK) was performed in 2 fresh human eyes of 1 donor. Ocular pathology and previous ocular surgery were ruled out. Tissues for light microscopy were examined using hematoxylin-eosin and periodic acid-Schiff reaction staining. Further tissue samples were examined using scanning electron microscopy and transmission electron microscopy. RESULTS: Light microscopy showed a thoroughly separated epithelial sheet with no evident anatomical abnormalities. Stratification of the separated epithelium layer and cell shape was conserved. The cleavage plane was located at Bowman's membrane. Scanning electron microscopy showed a consistent transition from adherent epithelium to the denuded area. Bowman's layer showed a very smooth surface without remains of basal lamina. Transmission electron microscopy examination showed interruptions of the basement membrane at high magnification. CONCLUSIONS: This in vitro study found a high cut quality using the epi-LASIK separator of the Amadeus II microkeratome. The resulting cleavage plane at Bowman's membrane was well suited for the subsequent laser ablation.

Tele-screening for diabetic retinopathy with the retinal thickness analyzer.

OBJECTIVE: To compare the effectiveness of tele-screening using a novel enhanced retinal thickness analyzer (RTA) with onsite routine ophthalmologic examination for diabetic retinopathy. RESEARCH DESIGN AND METHODS: A consecutive series of 31 eyes from diabetic patients were included. All underwent ophthalmologic examination, including stereoscopic dilated funduscopy and scanning with the RTA. The RTA reports consisted of a wide-angle, red-free fundus photograph and a macular-region retinal thickness map. Reports were graded by three independent graders in a masked manner. The diagnoses of proliferative retinopathy, macular edema, and treatment decisions made by the RTA graders and the clinical examiner were compared. RESULTS: On clinical examination 5 of 31 eyes were diagnosed with proliferative diabetic retinopathy (PDR). All five were referred for treatment by two graders and four eyes by one grader. All eyes with PDR and 12 of the 26 eyes with nonproliferative diabetic retinopathy showed severe macular edema. Seven of the 12 eyes with macular edema were clinically eligible for focal laser treatment, and all of them were detected by all RTA graders. Macular thickening was detected in eight eyes by RTA where no treatment was necessary, as judged by clinical examination. Thus, sensitivity was 93% (mean) for detecting PDR and 100% for detecting macular edema, with a specificity of 58-96% depending on the grader. The RTA did not allow valid assessment due to poor image quality in only one case. CONCLUSIONS: Screening for diabetic retinopathy with a combination of wide-angle fundus photography and macular thickness mapping by an objective method, such as optical coherence tomography or the RTA, offers the prerequisites for establishing a successful tele-screening program.

Diabetic retinopathy - ocular complications of diabetes mellitus.

In industrialized nations diabetic retinopathy is the most frequent microvascular complication of diabetes mellitus and the most common cause of blindness in the working-age population. In the next 15 years, the number of patients suffering from diabetes mellitus is expected to increase significantly. By the year 2030, about 440 million people in the age-group 20-79 years are estimated to be suffering from diabetes mellitus worldwide (prevalence 7.7%), while in 2010 there were 285 million people with diabetes mellitus (prevalence 6.4%). This accounts for an increase in patients with diabetes in industrialized nations by 20% and in developing countries by 69% until the year 2030. Due to the expected rise in diabetic patients, the need for ophthalmic care of patients (i.e., exams and treatments) will also increase and represents a challenge for eye-care providers. Development of optimized screening programs, which respect available resources of the ophthalmic infrastructure, will become even more important. Main reasons for loss of vision in patients with diabetes mellitus are diabetic macular edema and proliferative diabetic retinopathy. Incidence or progression of these potentially blinding complications can be greatly reduced by adequate control of blood glucose and blood pressure levels. Additionally, regular ophthalmic exams are mandatory for detecting ocular complications and initiating treatments such as laser photocoagulation in case of clinical significant diabetic macular edema or early proliferative diabetic retinopathy. In this way, the risk of blindness can considerably be reduced. In advanced stages of diabetic retinopathy, pars-plana vitrectomy is performed to treat vitreous hemorrhage and tractional retinal detachment. In recent years, the advent of intravitreal medication has improved therapeutic options for patients with advanced diabetic macular edema.

Scanning laser ophthalmoscope findings in acute macular neuroretinopathy.

PURPOSE: The typical reddish-brown retinal lesions of acute macular neuroretinopathy are difficult to detect. We demonstrate a role for scanning laser ophthalmoscopy in the diagnosis of acute macular neuroretinopathy. METHODS: Observational case report. We used scanning laser ophthalmoscopy in a 23-year-old woman with acute macular neuroretinopathy. RESULTS: In contrast to biomicroscopy, color fundus photography, and red-free fundus photography, scanning laser ophthalmoscopy precisely disclosed the size of the lesions within the macula. Microperimetry showed absolute scotomata corresponding to the macular lesions. CONCLUSION: Scanning laser ophthalmoscopy enhances the visibility of the retinal lesions in acute macular neuroretinopathy. The lesion size can be determined more precisely, and follow-up of patients is more accurate compared with conventional techniques.

Long-term follow-up after macular hole surgery with internal limiting membrane peeling.

PURPOSE: To report long-term anatomical and functional results after pars plana vitrectomy with peeling of the internal limiting membrane (ILM) for idiopathic macular hole. DESIGN: Prospective, nonrandomized, consecutive series. METHODS: Ninety-nine patients with a follow-up of at least 12 months were included. The surgical technique consisted of a standard pars plana vitrectomy, removal of the ILM, and an intraocular gas tamponade (15% hexafluoroethane [C(2)F(6)] gas mixture) followed by head-down positioning for at least 5 days. Follow-up examinations included a clinical examination, Goldmann perimetry, optical coherence tomography, and static microperimetry using a Rodenstock scanning laser ophthalmoscope (SLO-105). Stimulus size was 0.2 degrees (Goldmann II), intensities employed were 0 and 12 dB. Twenty-degree fields were used for all tests. RESULTS: Mean period of review was 32 months (median 34). Anatomic closure was achieved in 86 (87%) of 99 patients by one surgical procedure. Nine patients underwent a successful second operation with an improvement of visual acuity in 7 patients. The closure rate after two surgical interventions was 96%. Best-corrected visual acuity improved from a median of 20/100 preoperatively to a median of 20/40 postoperatively (P <.001). An improvement of visual acuity was achieved in 94% of patients. In 13 of 99 patients (13%) a combined vitrectomy and cataract surgery with intraocular lens implant was performed; 72 patients (73%) underwent cataract surgery later. Ninety of 99 patients (91%) were pseudophakic on last presentation. Paracentral scotomata did not change in size, density, or shape over time. Its incidence was not correlated with the stage of the macular hole. No postoperative epiretinal membrane formation or late reopening of the macular hole was observed. One patient presented with a peripheral visual field defect after vitrectomy. CONCLUSIONS: Macular hole surgery with peeling of the ILM without the use of adjuvants or ILM staining leads to good functional long-term results. Paracentral scotomata remained subclinical in most cases and may be due to a mechanical trauma of the nerve fiber layer.

Indocyanine green-assisted peeling of the internal limiting membrane in macular hole surgery affects visual outcome: a clinicopathologic correlation.

PURPOSE: To report the ultrastructure of the internal limiting membrane (ILM) after macular hole surgery with indocyanine green (ICG) staining and to investigate an association with the postoperative functional outcome. DESIGN: Retrospective, noncomparative analysis of a consecutive case series. METHODS: Twenty eyes of 20 patients after macular hole surgery with ICG staining were included. Visual acuity and Goldmann perimetry were obtained before and after surgery. The ILM was obtained during three-port pars plana vitrectomy for idiopathic macular hole. Twenty-five milligrams of sterile ICG powder was dissolved in 5 ml of sterile water as recommended by the manufacturer and then diluted in balanced salt solution. The ultrastructure of the ILM was analyzed using light and transmission electron microscopy. Osmolarity and pH of the ICG solution were measured preoperatively. RESULTS: There was no statistically significant improvement of postoperative visual acuity after ICG-assisted peeling (P =.755). In seven patients, postoperative visual field defects occurred. Indocyanine green-stained specimens revealed cellular elements resembling the plasma membrane of Müller cells and other undetermined retinal structures adherent to the retinal side of the ILM. Histologic findings disclosed no difference between patients with and without visual field defects after the use of ICG. The osmolarity of the ICG solution applied was 275 mOsm; pH was 7.5. CONCLUSIONS: Intravitreal application of ICG may cause retinal damage by altering the cleavage plane to the innermost retinal layers. That may result in less improvement of visual acuity and unexpected visual field defects. The underlying mechanisms of action remain unclear and are the subject of ongoing investigations.

The effect of indocyanine-green on functional outcome of macular pucker surgery.

PURPOSE: To compare functional results after surgery for macular pucker either with or without indocyanine-green staining of the internal limiting membrane (ILM) and to evaluate the ultrastructure of the tissue removed. DESIGN: Retrospective analysis of two successive, consecutive, interventional case series. METHODS: Functional outcome (visual acuity, Goldmann perimetry) of 48 eyes of 48 consecutive patients with (group 1, n = 20) or without (group 2, n = 28) intraoperative use of indocyanine-green (ICG) was retrospectively analyzed. For statistical analysis, best-corrected visual acuity measured at the last presentation was considered. Only patients with an idiopathic macular pucker were included. Surgery consisted of three-port pars plana vitrectomy, and removal of epiretinal tissue and the ILM in a second step. Commercially available ICG with a concentration of.05% and an osmolarity of 275 mOsm was used to stain the ILM. The surgical technique used for both groups was identical, except the use of ICG. Epiretinal tissue of all eyes was harvested and prepared for ultrastructural analysis using light and electron microscopy. RESULTS: Follow-up time was 8.5 months in group 1 and 5.4 months in group 2. Whereas patients operated on without ICG experienced a significant improvement of median best-corrected visual acuity from 20/63 (range, 20/400 to 20/32) preoperatively to 20/40 (range, 20/200 to 20/25) postoperatively (P < .001), median best-corrected visual acuity remained 20/63 before (range, 20/200 to 20/63) and after (range, 20/400 to 20/20) (P > .9) ICG-assisted peeling. There was a statistically significant difference (P = .013) in best-corrected postoperative visual acuity of patients with and without the use of ICG. An improvement of vision was noted in 86% of patients without and 55% of patients with ICG-assisted surgery. Thirty-five percent of patients after ICG application presented with a deterioration of visual acuity. Furthermore, we observed large visual field defects in 7 of 20 patients after ILM staining. No visual field defects were noted after conventional peeling. Histologic analysis revealed clear differences between the two groups concerning the amount of cellular elements adjacent to the retinal surface of the ILM: There was more cellular debris visible in specimens after ICG application during surgery. Additionally, in contrast to surgery without ILM staining, epiretinal cells had ruptured and lost their cellular integrity after ICG-assisted vitrectomy. CONCLUSIONS: Indocyanine green-assisted surgery for macular pucker might have an adverse effect on functional outcome. Although there were obvious differences in the ultrastructure of tissue removed during surgery, our observations cannot be explained by histologic analysis alone. Other, so far unknown mechanisms of action must be considered.

Comparative evaluation of combined navigated laser photocoagulation and intravitreal ranibizumab in the treatment of diabetic macular edema.

OBJECTIVE: To evaluate if a standardized combination therapy regimen, utilizing 3 monthly ranibizumab injections followed by navigated laser photocoagulation, reduces the number of total ranibizumab injections required for treatment of diabetic macular edema (DME). RESEARCH DESIGN AND METHODS: A 12-month, prospective comparison of 66 patients with center-involving DME: 34 patients with combination therapy were compared to 32 patients treated with ranibizumab monotherapy. All patients initially received 3 monthly ranibizumab injections (loading phase) and additional injections pro re nata (PRN). Combination therapy patients additionally received navigated laser photocoagulation after the loading phase. Main outcome measures were mean number of injections after the loading phase and change in BCVA from baseline to month 12. RESULTS: Navigated laser combination therapy and ranibizumab monotherapy similarly improved mean BCVA letter score (+8.41 vs. +6.31 letters, p = 0.258). In the combination group significantly less injections were required after the 3 injection loading phase (0.88 ± 1.23 vs. 3.88 ± 2.32, p< = 0.001). By month 12, 84% of patients in the monotherapy group had required additional ranibizumab injections as compared to 35% in the combination group (p< = 0.001). CONCLUSIONS: Navigated laser combination therapy demonstrated significant visual gains in most patients. Retreatment rate and number of injections were significantly lower compared to ranibizumab monotherapy and compared to the results of conventional laser combination therapy previously reported in pivotal anti-VEGF studies.