Clinical experience with pegaptanib sodium

Pegaptanib sodium (Macugen®) blocks the extracellular vascular endothelial growth factor (VEGF) isoform VEGF165, whose elevated levels are associated with the development of choroidal neovascularization (CNV). This selective inhibition prevents binding to the VEGF receptors and the development of the increased vascular permeability and the CNV associated with neovascular age-related degeneration (AMD). The VEGF Inhibition Study In Ocular Neovascularization (VISION) demonstrated that pegaptanib sodium confers clinically meaningful benefit in the treatment of all angiographic subtypes of neovascular AMD. It also has a favorable safety profile after 1 and 2 years of continuous treatment, and recent data suggest that the agent has a disease-modifying effect. Post hoc analysis of VISION suggests that treatment benefit may be greatest in patients with early lesions, in whom 80% achieved the primary endpoint of <15 letters lost, 47% maintained visual acuity (VA), and 20% gained ≥15 letters of vision. Similarly, our own clinical experience indicates that pegaptanib sodium achieves better outcomes in early lesions than in established lesions, particularly in patients with previously untreated minimally classic and occult lesions in whom VA improvement and lesion size stabilization has been recorded. Observations indicate that pegaptanib sodium has a slower mode of action than unselective VEGF inhibitors, resulting in an average of 3–4 injections being required to stabilize VA and lesion size. Pegaptanib sodium has good efficacy and safety profiles and represents a good treatment option for patients with early CNV membranes associated with neovascular AMD

In vivo diffuse correlation spectroscopy investigation of the ocular fundus

Diffuse correlation spectroscopy (DCS) measurements in vivo recorded from rabbits' ocular fundus are presented. Despite the complexity of these ocular tissues, we provide a clear and simple demonstration of the DCS abilities to analyze variations in physiological quantities of clinical interest. Indeed, the reported experimental activities demonstrate that DCS can reveal both choroidal-flow and temperature variations and detect nano- and microaggregates in ocular fundus circulation. Such abilities can be of great interest both in fundamental research and practical clinical applications. The proposed measuring system can be useful in: (a) monitoring choroidal blood flow variations, (b) determining the end-point for photo-dynamic therapy and transpupillary thermo therapy and, (c) managing the dye injection and determining an end-point for dye-enhanced photothrombosis. Moreover, it could allow both diagnoses when the presence of nano- and micro-aggregates is related to specific diseases and verifying the effects of nanoparticle injection in nanomedicine. Even though the reported results demonstrate the applicability of DCS to investigate ocular fundus, a detailed and accurate investigation of the limits of detection is beyond the scope of this article. \uc2\ua9 2013 Society of Photo-Optical Instrumentation Engineers

The dark atrophy with indocyanine green angiography

PURPOSE. To evaluate differences in fluorescein angiography (FA) and indocyanine green angiography (ICGA), findings between subjects affected by Stargardt disease (STGD) and atrophic AMD. METHODS. This was a consecutive, cross-sectional case series. A total of 24 eyes of 12 patients with STGD and 23 eyes of 14 patients with atrophic AMD were enrolled in the study. Patients underwent dynamic simultaneous FA and ICGA using a dual beam confocal scanning system. Images were recorded from the initial filling of choroidal and retinal vessels throughout all the phases of the angiogram. Spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence were also executed. FA and ICGA findings in the two groups were evaluated. RESULTS. In 92% (22/24) of eyes affected by STGD, ICGA showed hypocyanescence from the areas of atrophy, more evident in the late phases. This finding, defined as ICGA-imaged &apos;&apos;dark atrophy,&apos;&apos; was present in only 13% (3/23) of the eyes affected by atrophic AMD. The remaining eyes in both groups showed iso-or mild hypercyanescence from the areas of atrophy. Eyes with ICGA-imaged dark atrophy, both in STGD and in atrophic AMD groups, did not show early obscuration of the choroidal vessels by FA. SD-OCT revealed morphologically intact choroid in STGD patients with ICGA-imaged dark atrophy. In atrophic AMD eyes with ICGA-imaged dark atrophy, SD-OCT revealed a severely thinned choroid. CONCLUSIONS. Hypocyanescence by ICGA from the areas of atrophy was more frequent in STGD compared with atrophic AMD. This finding, along with SD-OCT evidence of intact choroid, suggests a possible selective damage of the choriocapillaris in STGD. (Invest Ophthalmol Vis Sci. 2012;53:3999-4004) DOI:10.1167/iovs.11-9258 R ecessive Stargardt disease (STGD) and age-related macular degeneration (AMD) lead to progressive and severe visual acuity loss. STGD is one of the most common inherited retinal dystrophies, while AMD is the most important cause of central visual acuity loss in western countries. STGD typically appears before age 20. It exhibits simple Mendelian transmission and is caused by mutations in the ABCA4 gene. A reduction in ABCA4 activity in the photoreceptors results in the increased production and accumulation of A2E and related bisretinoids within RPE cells. 1,2 These compounds cannot be readily metabolized and have negative effects on RPE cell function and viability. 3,4 RPE cell loss might originate from several mechanisms, including photooxidative stress, 5 vascular alterations, 6,7 and deposition of toxic lipofuscin material under RPE. Fluorescein angiography (FA) and indocyanine green angiography (ICGA) are important tools for diagnostic and pathogenetic evaluation of the two diseases. In STGD, FA is helpful because it allows for the identification of the dark choroid. This finding is characterized by the absence of normal background fluorescence mainly due to the presence of RPE lipofuscin that absorbs the blue excitatory light. 8 Also, ICGA may provide useful information, in particular about the alterations of the choroid and the choriocapillaris. 10 In addition, partial absorption by retinal pigment epithelial melanin occurs. In contrast, indocyanine green absorbs and emits light in the near-infrared spectrum, and allows better penetration. Furthermore, indocyanine green is predominantly bound to plasma protein (98% compared with 60%-80% for fluorescein), and this limits its diffusion through the fenestrations of the choriocapillaris. 11 Moreover, AMD may be characterized by a presumed macular choroidal watershed filling. 12 ICGA showed diminished choroidal arterial perfusion of the macula and enlargement of choroidal veins in the pathogenesis of AMD. 13 The combination of FA and ICGA facilitates interpretation of the exam and provides more information than either FA or ICGA alone. 10 Therefore, in this study, simultaneous FA and ICGA were used to evaluate possible differences in the pathogenesis of the two clinical entities. METHODS Twenty-six consecutive patients affected by STGD and atrophic AMD

Confocal Blue Reflectance Imaging in Type 2 Idiopathic Macular Telangiectasia

PURPOSE. To report the characteristics of confocal blue reflectance imaging in type 2 idiopathic macular telangiectasia (type 2 IMT). METHODS. In a prospective observational cross-sectional study, both eyes of 33 patients with type 2 IMT were examined by means of fundus biomicroscopy, fundus photography, fluorescein angiography, and optical coherence tomography (OCT). Confocal blue reflectance (CBR) imaging was performed using a confocal scanning laser ophthalmoscope (HRA2; Heidelberg Engineering, Heidelberg, Germany). To compare the results derived from different imaging modalities, an analysis was performed using image analysis software (Heidelberg Eye Explorer; Heidelberg Engineering). RESULTS. CBR imaging revealed a parafoveal area of increased reflectance that was slightly larger than the area of hyperfluorescence in late-phase fluorescein angiography. The area usually encompassed an oval parafoveal area, but sectors could be spared. A parafoveal area of increased CBR was detected in 98% of eyes that showed angiographic evidence for type 2 IMT. CONCLUSIONS. CBR imaging is a new, noninvasive, and sensitive method that may contribute to differentiate type 2 IMT from other diseases. Abnormalities of macular pigment distribution and Miiller cell pathology may contribute to the phenomenon of increased CBR and thus the pathophysiology of type 2 IMT

Effect of Baseline Subretinal Fluid on Treatment Outcomes in VIVID-DME and VISTA-DME Studies

Purpose To evaluate the effect of baseline subretinal fluid (SRF) on treatment outcomes with intravitreal aflibercept injection (IAI) versus laser treatment in patients with diabetic macular edema (DME) in the VIVID and VISTA studies. Design Post hoc analysis of 2 randomized controlled trials. Participants Eight hundred seventy-two patients with DME. Methods We randomized patients to receive IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or laser. Main Outcome Measures Effect of presence or absence of baseline SRF on visual outcomes in the integrated dataset at weeks 52 and 100. Results Mean best-corrected visual acuity (BCVA) gains in the 2q4, 2q8, and laser arms at week 52 were +14.5, +11.0, and –2.3 letters, respectively, (those with baseline SRF) and +10.3, +10.6, and +2.5 letters, respectively, (those without). At week 100, mean gains were +13.5, +10.9, and −2.3 letters (those with baseline SRF) and +10.6, +10.0, and +2.7 letters (those without). The treatment effect for IAI versus laser from baseline to week 52 of 100 was greater for patients with baseline SRF versus those without (nominal P Conclusions This post hoc analysis demonstrated the visual outcome benefits of IAI over laser, regardless of baseline SRF status. A greater treatment effect of IAI was observed in patients with baseline SRF versus those without; however, no meaningful impact of baseline SRF status on treatment outcomes with IAI was demonstrated, indicating that the differential effects of laser might have been the driving force behind the different treatment outcomes in both groups

Optical coherence tomography-based consensus definition for lamellar macular hole.

BackgroundA consensus on an optical coherence tomography definition of lamellar macular hole (LMH) and similar conditions is needed.MethodsThe panel reviewed relevant peer-reviewed literature to reach an accord on LMH definition and to differentiate LMH from other similar conditions.ResultsThe panel reached a consensus on the definition of three clinical entities: LMH, epiretinal membrane (ERM) foveoschisis and macular pseudohole (MPH). LMH definition is based on three mandatory criteria and three optional anatomical features. The three mandatory criteria are the presence of irregular foveal contour, the presence of a foveal cavity with undermined edges and the apparent loss of foveal tissue. Optional anatomical features include the presence of epiretinal proliferation, the presence of a central foveal bump and the disruption of the ellipsoid zone. ERM foveoschisis definition is based on two mandatory criteria: the presence of ERM and the presence of schisis at the level of Henle's fibre layer. Three optional anatomical features can also be present: the presence of microcystoid spaces in the inner nuclear layer (INL), an increase of retinal thickness and the presence of retinal wrinkling. MPH definition is based on three mandatory criteria and two optional anatomical features. Mandatory criteria include the presence of a foveal sparing ERM, the presence of a steepened foveal profile and an increased central retinal thickness. Optional anatomical features are the presence of microcystoid spaces in the INL and a normal retinal thickness.ConclusionsThe use of the proposed definitions may provide uniform language for clinicians and future research

A consensus definition for lamellar macular hole

Background: A consensus on an optical coherence tomography (OCT) definition of lamellar macular hole (LMH) and similar conditions is needed. Methods: The panel reviewed relevant peer-reviewed literature to reach a consensus on LMH definition and to differentiate LMH from other similar conditions. Results: The panel reached a consensus on the definition of 3 clinical entities: LMH, epiretinal membrane (ERM) foveoschisis and macular pseudohole (MPH). LMH definition is based on 3 mandatory criteria and 3 optional anatomical features. The 3 mandatory criteria are the presence of irregular foveal contour, the presence of a foveal cavity with undermined edges, and the apparent loss of foveal tissue. Optional anatomical features include the presence of epiretinal proliferation, the presence of a foveal bump and the disruption of the ellipsoid line. ERM foveoschisis definition is based on 2 mandatory criteria: the presence of ERM and the presence of schisis at the level of Henle’s fiber layer. Three optional anatomical features can also be present: the presence of microcystoid spaces in the inner nuclear layer (INL), an increase of retinal thickness, and the presence of retinal wrinkling. MPH definition is based on 3 mandatory criteria and 2 optional anatomical features. Mandatory criteria include the presence of a foveal sparing ERM, the presence of a steepened foveal profile and an increased central retinal thickness. Optional anatomical features are the presence of microcystoid spaces in the INL and a normal retinal thickness. Conclusions: The use of the proposed definitions may provide uniform language for clinicians and future research

Randomized Trial to Evaluate Tandospirone in Geographic Atrophy Secondary to Age-Related Macular Degeneration: The GATE Study

Purpose To determine the safety and efficacy of AL-8309B (tandospirone) in the management of patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) and obtain standardized data on GA lesion growth progression. Design Prospective, controlled, double-masked, randomized, multicenter phase 3 clinical trial. Methods setting: Forty-eight clinical sites. patients: Patients with GA associated with AMD were enrolled. All patients were followed for a minimum of 30 months, and up to 36 months. intervention procedures: Patients were randomized (1:1:1) to receive AL-8309B ophthalmic solution 1.0%, 1.75%, or vehicle, administered as a twice-daily topical ocular drop. main outcome measures: The primary efficacy endpoint was mean annualized lesion enlargement from baseline as assessed with fundus autofluorescence (FAF) imaging. Results A total of 768 eyes of 768 patients were enrolled and treated with AL-8309B 1.0% (n = 250), AL-8309B 1.75% (n = 258), or vehicle (n = 260). An increase in mean lesion size was observed in both the AL-8309B and vehicle treatment groups, and growth rates were similar in all treatment groups. Annualized lesion growth rates were 1.73, 1.76, and 1.71 mm 2 for AL-8309B 1.0%, AL-8309B 1.75%, and vehicle, respectively. Conclusions AL-8309B 1.0% and 1.75% did not affect lesion growth in eyes with GA secondary to AMD. There were no clinically relevant safety issues identified for AL-8309B. The large natural history dataset from this study is a valuable repository for future comparisons

The Relationship Between Blue-Fundus Autofluorescence and Optical Coherence Tomography in Eyes With Lamellar Macular Holes

PURPOSE. The purpose of this study was to evaluate the relationship between blue-fundus autofluorescence (B-FAF) and optical coherence tomography (OCT) in eyes with lamellar macular holes (LMHs). METHODS. this was a multicenter, observational case series. Ninety-two eyes with LMH associated with the standard epiretinal membrane (ERM) or lamellar hole-associated epiretinal proliferation (LHEP) were evaluated. The eyes must also present an area of increased autofluorescence on B-FAF. RESULTS. The ERM-alone group and the LHEP group differed with respect to the following variables: logarithm of the minimum angle of resolution best-corrected visual acuity (0.13 +/- 0.13 vs. 0.25 +/- 0.17;P < 0.001), central foveal thickness (218.74 +/- 52.4 mu m vs. 187.28 +/- 50.29 mu m;P = 0.008), FAF diameter (400.78 +/- 189.36 mu m vs. 503.37 +/- 214.25 mu m;P = 0.014), outer plexiform layer (OPL) diameter (382.10 +/- 157.34 mu m vs. 550.79 +/- 228.05 mu m;P = 0.0001), and disruption of external limiting membrane and ellipsoid zone, which was noted in only 1 and 3 eyes with ERM alone, respectively, and in 18 and 23 eyes with LHEP, respectively (P < 0.0001 for both observations). No difference was found for diameters measured at the level of the inner limiting membrane and schisis/cavitation. In both the ERM-alone group and the LHEP group, a strong correlation was found between the diameters measured on B-FAF and diameters measured at the OPL level on OCT images (P < 0.0001 for both groups). CONCLUSIONS. In eyes with LMHs, a strong correlation exists between the diameters of the holes measured with B-FAF and those measured at the OPL level with OCT. This may indicate that the loss or displacement of retinal cells containing macular pigment at the OPL level, specifically photoreceptors and/or Muller cells, is involved in this vitreomaculopathy

Choroidal Structural Changes Correlate With Neovascular Activity in Neovascular Age Related Macular Degeneration.

Purpose To correlate changes in choroidal thickness and vascularity index with disease activity in patients with neovascular age-related macular degeneration (nAMD). Methods Eyes diagnosed with AMD that had two sequential visits within 12 months and that had no choroidal neovascularization (CNV) or had inactive CNV at the first visit were included. Those that had active CNV at follow-up were enrolled as cases. Eyes that did not developed a CNV or that were still inactive at the second visit were enrolled as controls. Disease activity was based on optical coherence tomography (OCT) and fluorescein angiography findings. Subfoveal choroidal thickness (SCT), mean choroidal thickness (MCT), and choroidal vascularity index (CVI) were assessed on enhanced depth imaging OCT and compared between the baseline and follow-up visit. Subgroup analysis accounting for lesion type and previous treatment, if any, were performed. Results Sixty-five eyes from 60 patients (35 females) and 50 age- and sex-matched controls were included. At the active visit, cases had an increase from 164 ± 67 μm to 175 ± 70 μm in mean ± SD SCT and from 144 ± 45 μm to 152 ± 45 μm in MCT (both P < 0.0001). The mean CVI also increased at from 54.5% ± 3.3% to 55.4% ± 3.8% (P = 0.04). Controls did not show significant changes in choroidal measurements between the two visits. Mean SCT, MCT, and CVI values were similar for previously treated and treatment-naive eyes. Conclusions Choroidal thickness and CVI significantly increased with active disease in nAMD eyes. Changes in choroidal thickness may predict CNV development or recurrence before they are otherwise evident clinically