Gabriele E. Lang

The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema.

OBJECTIVE To demonstrate superiority of ranibizumab 0.5 mg monotherapy or combined with laser over laser alone based on mean average change in best-corrected visual acuity (BCVA) over 12 months in diabetic macular edema (DME). DESIGN A 12-month, randomized, double-masked, multicenter, laser-controlled phase III study. PARTICIPANTS We included 345 patients aged ≥18 years, with type 1 or 2 diabetes mellitus and visual impairment due to DME. METHODS Patients were randomized to ranibizumab + sham laser (n = 116), ranibizumab + laser (n = 118), or sham injections + laser (n = 111). Ranibizumab/sham was given for 3 months then pro re nata (PRN); laser/sham laser was given at baseline then PRN (patients had scheduled monthly visits). MAIN OUTCOME MEASURES Mean average change in BCVA from baseline to month 1 through 12 and safety. RESULTS Ranibizumab alone and combined with laser were superior to laser monotherapy in improving mean average change in BCVA letter score from baseline to month 1 through 12 (+6.1 and +5.9 vs +0.8; both P<0.0001). At month 12, a significantly greater proportion of patients had a BCVA letter score ≥15 and BCVA letter score level >73 (20/40 Snellen equivalent) with ranibizumab (22.6% and 53%, respectively) and ranibizumab + laser (22.9% and 44.9%) versus laser (8.2% and 23.6%). The mean central retinal thickness was significantly reduced from baseline with ranibizumab (-118.7 μm) and ranibizumab + laser (-128.3 μm) versus laser (-61.3 μm; both P<0.001). Health-related quality of life, assessed through National Eye Institute Visual Function Questionnaire (NEI VFQ-25), improved significantly from baseline with ranibizumab alone and combined with laser (P<0.05 for composite score and vision-related subscales) versus laser. Patients received ∼7 (mean) ranibizumab/sham injections over 12 months. No endophthalmitis cases occurred. Increased intraocular pressure was reported for 1 patient each in the ranibizumab arms. Ranibizumab monotherapy or combined with laser was not associated with an increased risk of cardiovascular or cerebrovascular events in this study. CONCLUSIONS Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with visual impairment due to DME. Visual acuity gains were associated with significant gains in VFQ-25 scores. At 1 year, no differences were detected between the ranibizumab and ranibizumab + laser arms. Ranibizumab monotherapy and combined with laser had a safety profile in DME similar to that in age-related macular degeneration.

Histologic and Morphometric Analysis of the Choroid, Bruch's Membrane, and Retinal Pigment Epithelium in Postmortem Eyes With Age-Related Macular Degeneration and Histologic Examination of Surgically Excised Choroidal Neovascular Membranes

OBJECTIVE Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in industrialized countries. Different risk factors have been associated with AMD. We performed a histopathologic and morphometric study to compare eyes with different stages of AMD to age-matched eyes. This study aimed to investigate the correlation among morphometric characteristics of choroidal vessels, the retinal pigment epithelium, and Bruchs membrane, to study the association between these characteristics and the presence and type of AMD, and to identify morphologic risk factors for exudative AMD. Furthermore, we histologically analyzed surgically removed choroidal neovascular membranes secondary to underlying diseases other than AMD to discern whether the cellular and extracellular components of the membranes of eyes with AMD are similar to those with diseases other than AMD. METHODS We analyzed 51 eye bank eyes (Georgia Eye Bank, Atlanta, GA) from 40 donors with different stages of AMD and compared them with 40 age-matched controls. The eyes were processed for light microscopy. The degree of calcification of Bruchs membrane, fragmentation of Bruchs membrane, number and types of drusen, basal laminar deposit, and seven morphometric variables of the choroid were assessed in the macular and extramacular regions. Surgically excised subfoveal membranes were processed and evaluated by light and transmission electron microscopy. RESULTS There were no statistically significant differences observed between eyes with neovascular and non-neovascular AMD. The single most important difference between eyes with and without AMD was the amount of basal laminar deposit (P < 0.001). Eyes with AMD displayed fewer large choroidal vessels in the submacular choroid than eyes without AMD (mean density values of all choroidal vessels [arteries and veins] were 3.5 +/- 1.5 mm(-1) and 5.7 +/- 1.6 mm(-1), P < 0.001, respectively). The submacular choriocapillaris density was higher in eyes with AMD (mean density, 0.62 +/- 0.06) than in eyes without AMD (mean density, 0.51 +/- 0.08 [P < 0.001]). The diameter of the larger choroidal vessels in the peripheral choroid was higher in eyes with AMD (mean diameter, 30 +/- 8 microm) than in eyes without AMD (mean diameter, 21.4 +/- 6.2 microm [P < 0.001]). The peripheral choriocapillaris density displayed the same pattern as the macular region in eyes with and without AMD. There was a statistically significant difference observed in the degree of calcification and fragmentation of Bruchs membrane in eyes with exudative AMD (mean degree of calcification, 1.6; median number of breaks in Bruchs membrane, five) as compared with controls (mean degree of calcification, 0.8; median number of breaks in Bruchs membrane, zero). The difference for these two variables between eyes with nonexudative AMD (mean degree of calcification, 0.8; median number of breaks in Bruchs membrane, one) and controls (mean degree of calcification, 0.8; median number of breaks in Bruchs membrane, zero) failed to reach statistical significance. Eyes with AMD displayed significantly more soft, diffuse, and large drusen, as well as basal laminar deposit, in the macular area than controls. CONCLUSION Combining our data with data from the literature, we conclude that AMD can be interpreted as a dynamic process with early proliferation and subsequent atrophy of capillaries of the choriocapillaris. Calcification and fragmentation of Bruchs membrane; soft, diffuse, and large drusen; and basal laminar deposit, but not hard drusen, strongly correlate with the histologic presence of AMD. The degree of calcification and fragmentation of Bruchs membrane is prominent in eyes with exudative AMD. The formation of choroidal neovascular membranes represents a stereotypic, nonspecific wound repair response independent of the underlying disease.

Two-Year Safety and Efficacy of Ranibizumab 0.5 mg in Diabetic Macular Edema: Interim Analysis of the RESTORE Extension Study

OBJECTIVE To evaluate the 2-year safety and efficacy of ranibizumab 0.5 mg in diabetic macular edema (DME). DESIGN Twenty-four-month, open-label, multicenter, Phase IIIb extension study. PARTICIPANTS Two hundred forty of 303 patients with visual impairment due to DME who completed the RESTORE core study and entered the extension. METHODS All patients were eligible to receive ranibizumab 0.5 mg pro re nata (PRN) from month 12 (end of core study) to month 36 based on best-corrected visual acuity (BCVA) stability and disease progression retreatment criteria. Patients were also eligible to receive laser PRN according to Early Treatment Diabetic Retinopathy Study guidelines. A preplanned interim analysis was performed at month 24, stratifying by treatment groups as in the RESTORE core study and referred to as prior ranibizumab, ranibizumab plus laser, or laser groups in the extension. MAIN OUTCOME MEASURES Incidence of ocular and nonocular adverse events (AEs) and mean change in BCVA. RESULTS Two hundred twenty patients (92%) completed the month 24 visit. Over 2 years, the most frequent ocular serious AE (SAE) and AE were cataract (2.1%) and eye pain (14.6%), respectively. The main nonocular AEs were nasopharyngitis (18.8%) and hypertension (10.4%). There were no cases of endophthalmitis, and the incidences of nonocular SAEs were low. Of the patients entering the extension, 4 deaths were reported in the second year, none of which were related to study drug or procedure. Mean BCVA gain, central retinal thickness (CRT) decrease, and National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) composite score observed at month 12 were maintained at month 24 (prior ranibizumab: +7.9 letters, -140.6 μm, and 5.6, respectively; prior ranibizumab plus laser: +6.7 letters, -133.0 μm, and 5.8, respectively), with an average of 3.9 (prior ranibizumab) and 3.5 ranibizumab injections (prior ranibizumab plus laser). In patients treated with laser alone in the core study, the mean BCVA, CRT, and NEI VFQ-25 composite score improved from month 12 to month 24 (+5.4 letters, -126.6 μm, and 4.3, respectively), with an average of 4.1 ranibizumab injections. CONCLUSIONS Ranibizumab 0.5 mg administered according to prespecified visual stability and disease progression criteria was well tolerated, with no new safety concerns identified over 2 years. Overall, an average of 3.8 ranibizumab injections was sufficient to maintain (prior ranibizumab) or improve (prior laser) BCVA, CRT, and NEI VFQ-25 outcomes through the second year. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Morphometric changes of the choriocapillaris and the choroidal vasculature in eyes with advanced glaucomatous changes.

PURPOSE In addition to an elevated intraocular pressure a compromise of the ocular blood supply have been implicated in the pathogenesis of primary open-angle glaucoma. The purpose of this study was to quantify morphologic changes in the choroid including choriocapillaris thickness and density and diameter of large choroidal vessels in post mortem eyes with advanced primary open-angle glaucoma. METHODS We analyzed 20 eye bank eyes (provided from the Georgia Eye Bank in Atlanta) with end stage primary open-angle glaucoma and compared them with 20 age-matched control eye bank eyes. The eyes were processed for light microscopy and following variables were measured with a digital filar micrometer: density and diameter of large choroidal vessels in the macular and equatorial choroid; thickness of the choroid in the macular and equatorial region; density and thickness of choriocapillaris in the macular, peripapillary, and equatorial choroid; and peripapillary capillary-free area nasal and temporal to the optic disk. RESULTS Eyes with glaucoma displayed a lower density of the capillaries of the choriocapillaris as compared to control eyes in the macular, temporal peripapillary, and equatorial choroid with 0.50-0.55 (p=0.018), 0.46-0.51 (p=0.016), and 0.50-0.55 (p=0.038), respectively. There was no significant difference for the choriocapillaris density in the nasal peripapillary choroid, the thickness of the capillaries of the choriocapillaris in all assessed locations, and the nasal and temporal peripapillary capillary-free zone of the choriocapillaris between eyes with glaucomatous damage and controls. Assessment of large choroidal vessels in the macular choroid showed that eyes with glaucoma had a decreased density of veins (11.7-38.9 mm(-2); p<0.001) and arteries (7.7-12.4 mm(-2); p=0.005) and arteries with a higher diameter (45.6-28.2 microm; p<0.001) as compared to control eyes. The large vessels in the equatorial choroid displayed no significant difference in diameter but a lower density (21.2-44.1 mm(-2); p=0.017) in eyes with glaucomatous damage as compared to controls. CONCLUSION Eyes with advanced glaucomatous damage after long standing primary open-angle glaucoma exhibit several changes including decreased density of capillaries of the choriocapillaris and decreased density of large choroidal vessels. We cannot conclude from our study whether the observed vascular changes in the choroid are primary pathogenic factors or secondary phenomena.

Reproducibility of measurements with a new slit lamp-mounted ocular blood flow tonograph

Abstract · Purpose: To assess the reliability of measurements of intraocular pressure (IOP), pulse amplitude (PA), and pulsatile ocular blood flow (POBF) and the validity of measurements of IOP with a new ocular blood flow tonograph. · Methods: Intraocular pressure pulse was assessed with pneumatic tonometry. In this study, we used the OBF Labs ocular blood flow tonograph with two different pneumatic probes, a modified Langham probe and a newly developed probe. One ophthalmologist compared two machines, first with the modified Langham probe and secondly with the newly developed probe (40 volunteers). Additionally, two ophthalmologists performed measurements on different days and in different sequence (34 volunteers). Furthermore, results of IOP measurements performed with this tonograph were compared to those of Goldmann applanation tonometry (213 volunteers). · Results: Using the modified Langham probe, POBF and PA were associated with the machine used for the test. However, using the newly developed pobe, no relevant or statistically significant differences were found for any variables, and reliability coefficients were between 0.70 and 0.90. Linear regression analysis of the Goldmann applanation tonometer on the measurements of IOP with the tonograph showed a regression coefficient of 0.765. · Conclusions: Results of measurements performed with this ocular blood flow tonograph and the newly developed probe are expected to be reliable and comparable.

Effect of Growth Factors on Bovine Retinal Pigment Epithelial Cell Migration and Proliferation

Background: To examine the effects of platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), and transforming growth factor beta 2 (TGFβ2) on bovine retinal pigment epithelial (RPE) cell migration and proliferation. Materials and Methods: Cultured bovine RPE cells were treated with 10 ng/ml PDGF, bFGF, aFGF, IGF-1, EGF, or TGFβ2. RPE cell migration studies were performed in multiwell plates confluently covered with RPE cells. After inhibition of proliferation and denudation of half of each well, cells were incubated with various growth factors. Migration was measured as the number of cells that had entered the denuded area after 20 h. RPE cell proliferation was determined by [3H]thymidine incorporation after growth factor stimulation for 24 h. Results: RPE cell migration was significantly enhanced after incubation with PDGF (stimulation of 213% compared to the negative control, p = 0.002), bFGF (206%, p = 0.003), aFGF (175%, p = 0.003), IGF-1 (150%, p = 0.003), and EGF (144%, p = 0.003). RPE cell proliferation was stimulated by bFGF (322% compared to the negative control, p < 0.005), PDGF (119%, p < 0.005), aFGF (121%, p < 0.005), and EGF (94%, p < 0.005). IGF-1 showed no significant effect on RPE cell proliferation; TGFβ2 displayed no effect on RPE cell migration nor on proliferation. Conclusions: The peptide growth factors PDGF, bFGF, aFGF, IGF-1, and EGF play an important role in initiating RPE cell migration. Basic FGF, PDGF, aFGF, and EGF stimulate RPE cell DNA synthesis.

Changes of retinal capillary blood flow in age-related maculopathy

Abstract  Background: To investigate retinal capillary blood flow characteristics in patients with age-related maculopathy (ARM). Methods: Retinal capillary blood volume (VOL), blood flow (FLOW), and velocity (VEL) were measured in four macular sectors (I, II, III, IV) and in two areas beyond the temporal superior and inferior major vessel arcades (V and VI) in: 10 eyes with early ARM (drusen ≥63 µm and/or atrophy of the retinal pigment epithelium, RPE, <175 µm and/or proliferation of RPE), 13 with late ARM (exudative), 10 with late ARM (fibrotic), 14 normal eyes of 14 children of patients with ARM, and in 4 age- and sex-matched control groups using the Heidelberg retinal flowmeter (HRF). Statistical analysis was performed with the exact Wilcoxon test using an additional adjustment procedure by Bonferroni-Holm. Results: As compared to the control group, there was no significant change of VOL, FLOW, and VEL in patients with early ARM. In patients with late ARM (exudative), there was a significant higher FLOW in sectors I, II, and IV and a higher VOL and VEL in sectors III and IV. The group with late ARM (fibrotic) showed a reduction of VOL and FLOW in sectors I–IV and of VEL in sectors II and IV. In children of ARM patients, VOL, FLOW, and VEL of sectors I–VI did not differ from the control group. Conclusion: HRF measurements in patients with ARM indicate an increased macular retinal capillary blood flow in patients with the exudative form of late ARM and a decreased macular perfusion in those with the fibrotic form.

Clinical, fluorescein angiographic and demographic aspects in central serous chorioretinopathy

SummaryThe purpose of this retrospective study was to analyze the demographic characteristics of central serous chorioretinopathy (CSC). Methods: Findings of 100 consecutive subjects with CSC were evaluated. Clinical and fluorescein angiographic findings, demographic characteristics, and visual acuity were analyzed. Results: The age of the patients ranged from 28 to 68 years with a mean of 43 years. No significant sex differences were found concerning age and other parameters. The highest age peak was in the group of women. The male to female ratio was 5 : 1. Patients with chronic CSC were significantly older (P = 0.015) than patients with the other angiographic findings. Median visual acuity was 0.5. In 40 % bilateral characteristics of CSC were found. Clinical and fluorescein angiographic findings showed no significant correlation with visual acuity. Conclusion: The range of age distribution in CSC is wide. In older patients distinguishing CSC from age-related macular degeneration can be difficult.ZusammenfassungZiel dieser retrospektiven Studie war die Charakterisierung demographischer Aspekte der Chorioretinopathia centralis serosa (CCS). Patienten und Methode: Hundert konsekutive Patienten mit CCS wurden hinsichtlich klinischer, fluoreszeinangiographischer, demographischer Aspekte und des Visus untersucht. Ergebnisse: Das Alter der Patienten lag zwischen 28 und 68 Jahren mit einem Mittelwert von 43 Jahren. Hinsichtlich der Befunde und der Altersverteilung konnten keine geschlechtsspezifischen Unterschiede beobachtet werden. Jedoch lagen die Altersgipfel bei den Frauen in einem höheren Lebensalter. Das Verhältnis Männer zu Frauen betrug 5 : 1. Patienten mit einer chronischen CCS waren signifikant älter (p =0,015) als die übrigen Patienten. Der Visus betrug im Median 0,5. Insgesamt fanden sich bei 40 % der untersuchten Patienten bilaterale Veränderungen einer CCS. Weder die klinischen noch die floreszeinangiographischen Befunde zeigten Zusammenhänge zum Visus. Schlußfolgerung: Die Spannweite in der Altersverteilung bei der CCS ist sehr groß. Gerade in einem höheren Lebensalter kann die Abgrenzung der CCS zur altersbezogenen Makuladegeneration Probleme bereiten.

Retinal Pigment Epithelial Changes Associated with Systemic Corticosteroid Treatment: Report of Cases and Review of the Literature

Purpose: The aim of our study was to describe two different manifestations of retinal pigment epithelial changes associated with systemic corticosteroid treatment. Methods: We report 4 patients who developed maculopathy during treatment with systemic corticosteroids. Additionally, the literature was reviewed for similar cases. Results: Two patients showed diffuse retinal pigment epitheliopathy. Two patients developed central serous chorioretinopathy with localized changes in the retinal pigment epithelium. A review of the literature revealed 51 patients with similar changes during treatment with corticosteroids. Conclusion: These 4 patients provide further evidence that systemic treatment with corticosteroids may cause central serous chorioretinopathy or diffuse retinal pigment epitheliopathy. Ophthalmologic examination is recommended on a regular basis for patients treated with systemic corticosteroids.

High-altitude retinopathy

PURPOSE To report a patient with high-altitude retinopathy. METHODS A 30-year-old man with high-altitude retinopathy was examined and treated. RESULTS After spending 2 weeks at an altitude of 7,000 meters and then descending to sea level, the patients visual acuity was RE, 20/20 and LE, 20/50. Intraretinal hemorrhages in both eyes and a scotoma in the left eye were found. Blood cell count was normal, but hematocrit had increased to 53%. The patient was treated with isovolemic hemodilution, pentoxifylline, and aspirin, which reduced hematocrit to 41%. Visual acuity and visual field returned to normal, and intraretinal hemorrhages resolved. CONCLUSIONS High-altitude hemoconcentration should be treated in patients with high-altitude retinopathy.