Marc Biarnés

Update on geographic atrophy in age-related macular degeneration.

Age-related macular degeneration (AMD) is the main cause of legal blindness in older patients in developed countries, and geographic atrophy (GA) represents the advanced form of dry AMD. Although it accounts for one third of the cases of late AMD and is responsible for 20% of the cases of severe visual loss due to the disorder. GA currently lacks effective treatment, whereas antiangiogenic therapies have been shown to be successful in managing choroidal neovascularization, the other form of late AMD. Recent advances in GA epidemiology, etiology, genetics, and imaging techniques have renewed the interest in this entity, which is a cause of progressive visual loss even in treated patients with neovascular AMD. This knowledge has triggered many clinical trials targeting different molecules shown to be associated with the disease, and it is hoped that this research will translate into effective drugs for GA in the near future.

Corneal shape changes induced by first and second generation silicone hydrogel contact lenses in daily wear

PURPOSE To compare the corneal topographical changes induced by two first and second generation silicone-hydrogel (SiH) contact lenses after 3 months of daily wear (DW). METHODS Prospective, consecutive case-series in which patients wore one of 3 different contact lenses (either the first generation SiH Focus Night & Day, the second generation SiH Acuvue Oasys or the monthly disposable Soflens 38 hydrogel lens as control group) on a DW basis for 3 months. Over-refraction, visual acuity, mean keratometry, corneal astigmatism, corneal eccentricity, superficial regularity and superficial asymmetry indices were monitored over the 3-month period. RESULTS Nineteen eyes of 10 patients completed the study. Seven Focus Night & Day, 7 Acuvue Oasys and 5 Soflens 38 contact lenses were fitted. There were no significant changes between any of the parameters measured at the 3-month visit in any of the SiH groups (non-parametric Wilcoxon test, p>0.05). However, the control group (Soflens 38) showed statistically significant changes regarding mean keratometry, corneal astigmatism and corneal eccentricity (p<0.05). Three patients wearing the first generation SiH showed adverse events of different degree related to their high modulus of elasticity. CONCLUSIONS After 3 months of DW, wearers of first and second generation SiH lenses showed greater corneal stability than hydrogel monthly disposable contact lenses users regarding commonly used topographic corneal shape indices. However, complications related to the mechanical properties of first generation SiH were seen in three patients in the follow-up time.

Increased fundus autofluorescence and progression of geographic atrophy secondary to age-related macular degeneration. The GAIN study.

PURPOSE To define the role of increased fundus autofluorescence (FAF), a surrogate for lipofuscin content, as a risk factor for progression of geographic atrophy (GA). DESIGN Prospective natural history cohort study, the GAIN (Characterization of geographic atrophy progression in patients with age-related macular degeneration). METHODS setting: Single-center study conducted in Barcelona, Spain. PATIENTS After screening of 211 patients, 109 eyes of 82 patients with GA secondary to age-related macular degeneration and a minimum follow-up of 6 months were included. OBSERVATION PROCEDURES Lipofuscin content was classified independently by 2 masked observers according to FAF patterns described previously. Bivariate, stratified, and multivariable analyses were used to explore the associations between GA growth and independent variables. Mediation analysis was used to evaluate the contribution of FAF patterns to GA progression. MAIN OUTCOME Progression of GA in mm(2)/year as measured with FAF. RESULTS Median follow-up was 18 months (range, 6-42). Median GA growth was 1.61 mm(2)/year. FAF, baseline area of atrophy, and time of follow-up were independently associated with GA progression (P < .004). FAF patterns and baseline area of atrophy were strongly associated (P < .0001), suggesting potential confounding. Mediation analysis suggested that most of the effect of FAF patterns on GA growth was actually caused by baseline area of atrophy. CONCLUSIONS FAF patterns, baseline area of atrophy, and time of follow-up were associated with GA progression. However, FAF patterns seem to be a consequence (not a cause) of enlarging atrophy and their effect on GA progression seems mostly driven by baseline area of atrophy.

Hyporeflective Wedge-Shaped Band in Geographic Atrophy Secondary to Age-related Macular Degeneration: An Underreported Finding

OBJECTIVE To describe and interpret the frequently observed spectral-domain optical coherence tomography (SD-OCT) finding of a marked hyporeflective wedge-shaped structure at the boundaries of the areas of atrophy. DESIGN A prospective, longitudinal follow-up study. PARTICIPANTS Consecutive patients (n = 71) 50 years of age and older with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) were examined between January 2010 and June 2011. METHODS Patients were evaluated with the use of imaging techniques that included 35° fundus photography, infrared, fundus autofluorescence (FAF), and SD-OCT. Visualization of the fundus with FAF was done simultaneously with OCT. Two acquisition protocols were followed: a macular cube for coverage (19 horizontal B-scans centered on the fovea) and high-resolution horizontal B-scan for qualitative foveal detail. MAIN OUTCOMES MEASURES Estimation of the prevalence of a hyporeflective wedge-shaped band among patients with GA. RESULTS A marked hyporeflective wedge-shaped structure, with its base on Bruchs membrane and its apex pointing toward the inner limit of the outer plexiform layer (OPL) adjacent to the margin between the atrophied area and the preserved retina, was observed in 72.9% of eyes (70/96; 95% confidence interval, 63.9-82.0). This hyporeflective band appeared to be within the OPL. Using eccentric SD-OCT acquisition, the boundaries between the outer nuclear layer (ONL) and Henles fiber layer (HFL) were well defined, showing that the ONL ends before the margin of atrophy of the retinal pigment epithelium (RPE). A narrow hyperreflective band separated the margin of the ONL and RPE from the hyporeflective band, already within the atrophic area. CONCLUSIONS A hyporeflective wedge-shaped structure appears frequently within the boundaries of the OPL in patients with GA secondary to AMD, corresponding to an increase in the width of the HFL, presumably because of axonal swelling or interaxonal edema. This finding may improve the interpretation of SD-OCT images of the outer layers, may help in understanding better the interactions between photoreceptor cells and the RPE, and may help in the development of monitoring techniques and therapies for GA secondary to AMD.

As-needed treatment with ranibizumab 0.5 mg in patients with neovascular age-related macular degeneration

Purpose TO describe the results obtained in patients with neovascular age-related macular degeneration treated with ranibizumab 0.5 mg on an as-needed basis from the start after 1 year of follow-up. Methods Retrospective, consecutive interventional case series of patients with all angiographic types of neovascular age-related macular degeneration (mean baseline size, 3.4 disk areas) in a tertiary retinal center (Institut de la Màcula i la Retina; Barcelona, Spain). Main outcome was mean vision change; secondary outcomes were center retinal thickness change, number of injections, adverse events, and independent covariates associated with a good response. Results Mean visual acuity change was an increase of 1.3 letters (95% confidence interval −2.7 to +5.3), and difference between angiographic patterns did not reach statistical significance (p=0.30). A decrease in retinal thickness of 44.6 μm was identified (p<0.001), with a median of 3 injections. Absence of baseline arterial hypertension, lower visual acuity, and lesions located outside the fovea were associated with a better response to therapy. Conclusions As-needed treatment from the start achieved stabilization of visual acuity and a moderate decrease of retinal thickness with a low number of injections, but did not achieve the same efficacy as regular monthly injections.

A Swine Model of Selective Geographic Atrophy of Outer Retinal Layers Mimicking Atrophic AMD: A Phase I Escalating Dose of Subretinal Sodium Iodate

PURPOSE To establish the dose of subretinal sodium iodate (NaIO3) in order to create a toxin-induced large animal model of selective circumscribed atrophy of outer retinal layers, the retinal pigment epithelium (RPE), and photoreceptors, by spectral-domain optical coherence tomography (SD-OCT) and immunocytochemistry. METHODS Fifteen male and female healthy Yorkshire pigs received unilateral subretinal escalating doses of NaIO3 under general anesthesia. In all the animals, volumes of 0.1 to 0.2 mL NaIO3 were injected into the subretinal space of the area centralis through a 23/38-gauge subretinal cannula. Control SD-OCTs were performed 1 and 2 months after the surgery, at which time pigs were euthanized and eyes enucleated. Globes were routinely processed for histologic and immunohistochemical evaluation. RESULTS Spectral-domain OCT and immunohistochemistry revealed circumscribed and well-demarcated funduscopic lesions, limited to the outer retinal layers in pigs treated with 0.01 mg/mL subretinal sodium iodate. CONCLUSIONS The swine model of a controlled area of circumscribed retinal damage, with well-delimited borders, and selectively of the outer layers of the retina presented herein shows several clinical and histologic features of geographic atrophy in AMD. Therefore, it may represent a valuable tool in the investigation of new emerging regenerative therapies that aim to restore visual function, such as stem cell transplantation or optogenetics.

Optical coherence tomography assessment of apparent foveal swelling in patients with foveal sparing secondary to geographic atrophy.

OBJECTIVE To determine whether foveal swelling exists in patients with foveal sparing and geographic atrophy (GA) secondary to dry age-related macular degeneration (AMD) and to establish the contribution of different foveal layers to this condition by use of spectral-domain optical coherence tomography (SD-OCT). DESIGN Prospective comparative case series. PARTICIPANTS We assessed patients from a longitudinal study with foveal sparing and GA secondary to AMD. Of an initial sample of 108 patients, 13 eyes of 10 patients complied with the inclusion criteria to study eyes in which apparent swelling would not be questionable. We used a control group of 13 healthy patients to compare the outcome measurements. METHODS We acquired high-resolution SD-OCT horizontal and oblique B-scans centered at the umbo. Two retinal specialists (J.M., F.T.) independently classified the SD-OCT images. MAIN OUTCOME MEASURES Difference in foveal center thickness, apparent outer nuclear layer (ONL) thickness, ONL thickness without Henles fiber layer (HFL), sub-ONL thickness, and retinal thickness at 1000 μm and 3500 μm from the foveal center. RESULTS The thickness at the foveal center was similar between patients with apparent foveal swelling (cases) and controls without AMD (226 vs. 227 μm; P = 0.56), but the apparent ONL was thicker in cases than in controls (125 vs. 114 μm; P = 0.02). However, when HFL was excluded from the measurements, there was little difference in the results (74 vs. 73 μm; P = 0.82). CONCLUSIONS We found neither foveal nor ONL swelling in this study. We observed HFL thickening in foveal sparing secondary to GA, which might be related to swelling of the axons of the photoreceptors, or Müllers cells. We also observed thinning of the retina below the external limiting membrane. The clinical significance of these findings should be addressed by longitudinal studies and may have specific therapeutic implications.

Reappraisal of Geographic Atrophy Patterns Seen on Fundus Autofluorescence Using a Latent Class Analysis Approach

PURPOSE To reappraise fundus autofluorescence (FAF) patterns in patients with geographic atrophy (GA) with the aim of simplifying the existing classification and to evaluate their stability with time using a data-driven approach, latent class analysis (LCA). METHODS One hundred seventy-one patients in the prospective, natural history study on GA (GAIN, NCT01694095) with a minimum follow-up of 12 months were screened. Five experienced observers independently evaluated FAF patterns according to the original classification, and LCA was used to determine the new, emerging categories (classes). A set of prespecified FAF features was then used to characterize each resulting class. RESULTS Seventy-five eyes of 59 subjects with a median follow-up of 19 months were included. The optimal LCA model resulted in five classes, which showed an association with GA size, among others. The classes did not change in a given individual during the study period, but the time frame may have been too short to evaluate hypothetical transitions. CONCLUSIONS The original description of FAF patterns, which is based exclusively on distribution of hyperautofluorescence around GA, ultimately classifies patients according to area of atrophy. These results suggest that FAF patterns are not true phenotypes and that they rather represent different stages of the disease. This may have implications regarding the role of lipofuscin on disease pathogenesis.

Geographic atrophy phenotype identification by cluster analysis

Background/aims To identify ocular phenotypes in patients with geographic atrophy secondary to age-related macular degeneration (GA) using a data-driven cluster analysis. Methods This was a retrospective analysis of data from a prospective, natural history study of patients with GA who were followed for ≥6 months. Cluster analysis was used to identify subgroups within the population based on the presence of several phenotypic features: soft drusen, reticular pseudodrusen (RPD), primary foveal atrophy, increased fundus autofluorescence (FAF), greyish FAF appearance and subfoveal choroidal thickness (SFCT). A comparison of features between the subgroups was conducted, and a qualitative description of the new phenotypes was proposed. The atrophy growth rate between phenotypes was then compared. Results Data were analysed from 77 eyes of 77 patients with GA. Cluster analysis identified three groups: phenotype 1 was characterised by high soft drusen load, foveal atrophy and slow growth; phenotype 3 showed high RPD load, extrafoveal and greyish FAF appearance and thin SFCT; the characteristics of phenotype 2 were midway between phenotypes 1 and 3. Phenotypes differed in all measured features (p≤0.013), with decreases in the presence of soft drusen, foveal atrophy and SFCT seen from phenotypes 1 to 3 and corresponding increases in high RPD load, high FAF and greyish FAF appearance. Atrophy growth rate differed between phenotypes 1, 2 and 3 (0.63, 1.91 and 1.73 mm2/year, respectively, p=0.0005). Conclusion Cluster analysis identified three distinct phenotypes in GA. One of them showed a particularly slow growth pattern.

Bimonthly half-dose ranibizumab in large pigment epithelial detachment and retinal angiomatous proliferation with high risk of retinal pigment epithelium tear: a case report.

Introduction The management of large pigment epithelial detachments (PEDs) associated with retinal angiomatous proliferation (RAP) remains a challenge due to the high risk of retinal pigment epithelial (RPE) tear. We describe the successful progressive anatomical result and the maintenance of visual acuity to bimonthly, half-dose ranibizumab in a patient with this condition. Purpose To describe the management of a large PED secondary to RAP with bimonthly, half-dose ranibizumab. Method Case report. Patient A 71-year-old woman presented with visual symptoms due to an enlarged PED, compared with previous visits, secondary to a RAP lesion, with a visual acuity of 20/32. To reduce the risk of an RPE tear and a significant decrease in vision, we discussed with the patient the possibility of treating the lesion in a progressive manner, with more frequent but smaller doses of ranibizumab. The patient was treated biweekly with 0.25 mg of ranibizumab until fattening of the PED. Results The large PED fattened progressively, and visual acuity was preserved with no adverse events. Discussion The use of half-dose antiangiogenic therapy may be useful in managing large vascularized PED associated with RAP, in an attempt to reduce the risk of RPE tear.