Marcela Marsiglia

Visual and anatomical outcomes of intravitreal aflibercept in eyes with persistent subfoveal fluid despite previous treatments with ranibizumab in patients with neovascular age-related macular degeneration.

Purpose: To assess the efficacy of intravitreal aflibercept (2.0 mg) in patients with treatment-resistant neovascular age-related macular degeneration. Methods: Retrospective analysis of eyes treated with aflibercept with persistent subretinal and/or intraretinal fluid despite previous treatments with intravitreal ranibizumab (0.5 mg). All patients were switched to intravitreal aflibercept (2.0 mg) and analyzed after 3 consecutive injections and after 6 months of treatment. Main outcome measures included change in visual acuity, central foveal thickness, and the height and diameter of the pigment epithelial detachment on the subfoveal scan on optical coherence tomography. Results: Thirty-four eyes of 33 patients were analyzed. Mean duration of symptoms and average number of previous injections with anti–vascular endothelial growth factor agents was 44.7 ± 29.8 months (interquartile range [IQR] 24–76 months) and 28.6 ± 20.1 (IQR 10–47), respectively. At the 6-month follow-up, mean visual acuity and central foveal thickness improved significantly from 20/75 (logarithm of minimum angle of resolution 0.57 ± 0.36; IQR 0.30–1.0) and 416 ± 217 &mgr;m (IQR 263–487 &mgr;m) at baseline to 20/60 (logarithm of minimum angle of resolution 0.47 ± 0.32; IQR 0.30–0.60) (P = 0.004) and 248 ± 171 &mgr;m (IQR 235–419 &mgr;m) (P < 0.001), respectively. Maximum pigment epithelial detachment height improved significantly from 260 ± 162 &mgr;m (IQR 129–368 &mgr;m) to 214 ± 142 &mgr;m (IQR 111–305 &mgr;m) (P < 0.001) and PED diameter decreased significantly from 3,265 ± 1,622 &mgr;m (IQR 2,353–4,555 &mgr;m) to 2,949 ± 1,653 &mgr;m (IQR 1,721–4,484 &mgr;m) (P = 0.04). Conclusion: Intravitreal injections of aflibercept resulted in a significant improvement in visual and anatomical outcomes in eyes with persistent subfoveal fluid despite previous treatment with ranibizumab.

Association Between Geographic Atrophy Progression and Reticular Pseudodrusen in Eyes With Dry Age-Related Macular Degeneration

PURPOSE To evaluate geographic atrophy (GA) progression in eyes with dry AMD and to determine factors related to GA expansion, notably reticular pseudodrusen (RPD), also known as subretinal drusenoid deposits (SDD) or reticular macular disease (RMD). METHODS This was a retrospective cohort study of patients with dry AMD who were diagnosed with GA in at least one eye and were imaged with sequential fundus autofluorescence (FAF) and/or near infrared reflectance (NIR-R) imaging. Images were analyzed for the presence of GA within the macular region. Geographic atrophy progression was measured in the fields of a modified Wisconsin grid and spatially correlated with RPD. Factors also evaluated for association with GA progression included initial GA size and pattern. RESULTS The study sample included 126 eyes of 92 patients, with an average follow up of 20.4 months (SD = 11.7). At baseline, 93.6% of eyes had RPD, and the average GA area was 2.8 mm(2) (SD = 2.9). The average GA progression rate was 0.8 mm(2)/y (SD = 0.6), with a statistically significant difference between the unilobular and multilobular phenotype groups (0.3 mm(2)/y vs. 0.9 mm(2)/y, P = 0.02). Patients in the lower 50th percentile of initial GA area had a lower progression rate than patients in the upper 50th percentile (0.6 mm(2)/y vs. 1.1 mm(2)/y, P < 0.001). Geographic atrophy progression was more frequent in fields with RPD than in those without RPD (74.2% vs. 41.7%, P < 0.001). CONCLUSIONS The high correlation between the presence of RPD (also known as SDD or RMD) and the presence of GA, and the expansion of GA into areas with these lesions suggest that they are an early manifestation of the process leading to GA.

Retinal Pigment Epithelial Cell Loss Assessed by Fundus Autofluorescence Imaging in Neovascular Age-related Macular Degeneration

PURPOSE To characterize retinal pigment epithelial (RPE) cell loss as evidenced by autofluorescence imaging in patients with neovascular age-related macular degeneration (AMD). DESIGN Retrospective cohort study. PARTICIPANTS There were 162 eyes of 116 consecutive patients with neovascular AMD examined in a retinal practice. METHODS Each patient underwent a complete examination including autofluorescence imaging. Areas of confluent absence of autofluorescence signal of at least 0.5 mm in greatest linear diameter were measured within the macular area. Patient demographic and examination data were evaluated in relation to the autofluorescence data. MAIN OUTCOME MEASURES Prevalence and progression of confluent areas of absent autofluorescence and the relationship these areas had with visual acuity. RESULTS The mean age of the patients was 82.9 years, and the mean visual acuity was 20/71 (logarithm minimum angle of resolution [logMAR], 0.55). Confluent loss of autofluorescence was seen in 58.6% of eyes at baseline, and the median area of absent autofluorescence among those was 1.57 mm(2) (interquartile range [IQR], 0.62-4.32 mm(2)). Using generalized estimation equation modeling, the significant predictors for area of confluent absent autofluorescence at baseline were duration of disease and any previous treatment with photodynamic therapy. The significant predictor of baseline visual acuity was baseline area of confluent absent autofluorescence. Follow-up was available for 124 (76.5%) eyes, with a mean follow-up of 2.9 years. By then, the mean visual acuity was 20/90 (logMAR, 0.65), and 79% of eyes had confluent areas of absent autofluorescence, the large majority of which affected the central macula. The median area of absent autofluorescence was 3.61 mm(2) (IQR, 1.16-7.11 mm(2)). The best predictor of final visual acuity was the area of absent autofluorescence at the final follow-up. CONCLUSIONS Confluent absence of autofluorescence, a measure signifying RPE loss, was a significant predictor of visual acuity both at baseline and at final follow-up. This is the first study to document the prevalence, rate of progression, and factors associated with measures of confluent RPE loss in patients with neovascular AMD. Application of strategies to limit RPE cell loss may prove useful in eyes with neovascular AMD.

Flecks in Recessive Stargardt Disease: Short-Wavelength Autofluorescence, Near-Infrared Autofluorescence, and Optical Coherence Tomography.

PURPOSE We evaluated the incongruous observation whereby flecks in recessive Stargardt disease (STGD1) can exhibit increased short-wavelength autofluorescence (SW-AF) that originates from retinal pigment epithelium (RPE) lipofuscin, while near-infrared AF (NIR-AF), emitted primarily from RPE melanin, is usually reduced or absent at fleck positions. METHODS Flecks in SW- and NIR-AF images and spectral-domain optical coherence tomography (SD-OCT) scans were studied in 19 STGD1 patients carrying disease-causing ABCA4 mutations. Fleck spatial distribution and progression were recorded in serial AF images. RESULTS Flecks observed in SW-AF images typically colocalized with darkened foci in NIR-AF images; the NIR-AF profiles were larger. The decreased NIR-AF signal from flecks preceded apparent changes in SW-AF. Spatiotemporal changes in fleck distribution usually progressed centrifugally, but in one case centripetal expansion was observed. Flecks in SW-AF images corresponded to hyperreflective deposits that progressively traversed photoreceptor-attributable bands in SD-OCT images. Outer nuclear layer (ONL) thickness negatively correlated with expansion of flecks from outer to inner retina. CONCLUSIONS In the healthy retina, RPE lipofuscin fluorophores form in photoreceptor cells but are transferred to RPE; thus the SW-AF signal from photoreceptor cells is negligible. In STGD1, NIR-AF imaging reveals that flecks are predominantly hypofluorescent and larger and that NIR-AF darkening occurs prior to heightened SW-AF signal. These observations indicate that RPE cells associated with flecks in STGD1 are considerably changed or lost. Spectral-domain OCT findings are indicative of ongoing photoreceptor cell degeneration. The bright SW-AF signal of flecks likely originates from augmented lipofuscin formation in degenerating photoreceptor cells impaired by the failure of RPE.

Correlations Among Near-Infrared and Short-Wavelength Autofluorescence and Spectral-Domain Optical Coherence Tomography in Recessive Stargardt Disease

PURPOSE Short-wavelength (SW) fundus autofluorescence (AF) is considered to originate from lipofuscin in retinal pigment epithelium (RPE) and near-infrared (NIR) AF from melanin. In patients with recessive Stargardt disease (STGD1), we correlated SW-AF and NIR-AF with structural information obtained by spectral-domain optical coherence tomography (SD-OCT). METHODS Twenty-four STGD1 patients (45 eyes; age 8 to 61 years) carrying confirmed disease-associated ABCA4 mutations were studied prospectively. Short-wavelength AF, NIR-AF, and SD-OCT images were acquired. RESULTS Five phenotypes were identified according to features of the central lesion and extent of fundus change. Central zones of reduced NIR-AF were typically larger than areas of diminished SW-AF and reduced NIR-AF usually approximated areas of ellipsoid zone (EZ) loss identified by SD-OCT (group 1; r, 0.93, P < 0.0001). In patients having a central lesion with overlapping parafoveal rings of increased NIR-AF and SW-AF (group 3), the extent of EZ loss was strongly correlated with the inner diameter of the NIR-AF ring (r, 0.89, P < 0.0001) and the eccentricity of the outer border of the NIR-AF ring was greater than that of the SW-AF ring. CONCLUSIONS Lesion areas were more completely delineated in NIR-AF images than with SW-AF. In most cases, EZ loss was observed only at locations where NIR-AF was reduced or absent, indicating that RPE cell atrophy occurs in advance of photoreceptor cell degeneration. Because SW-AF was often increased within the central area of EZ disruption, degenerating photoreceptor cells may produce lipofuscin at accelerated levels. Consideration is given to mechanisms underlying hyper-NIR-AF in conjunction with increased SW-AF.

Long-Term Visual Outcomes for a Treat and Extend Anti-Vascular Endothelial Growth Factor Regimen in Eyes with Neovascular Age-Related Macular Degeneration

With the advent of anti-vascular endothelial growth factor (VEGF) therapy, clinicians are now focused on various treatment strategies to better control neovascular age-related macular degeneration (NVAMD), a leading cause of irreversible blindness. Herein, we retrospectively reviewed consecutive patients with treatment-naïve NVAMD initially classified based on fluorescein angiography (FA) alone or with an anatomic classification utilizing both FA and optical coherence tomography (OCT) and correlated long-term visual outcomes of these patients treated with an anti-VEGF Treat-and-Extend Regimen (TER) with baseline characteristics including neovascular phenotype. Overall, 185 patients (210 eyes) were followed over an average of 3.5 years (range 1–6.6) with a retention rate of 62.9%, and visual acuity significantly improved with a TER that required a mean number of 8.3 (±1.6) (± standard deviation) intravitreal anti-VEGF injections/year (range 4–13). The number of injections and the anatomic classification were independent predictors of visual acuity at 6 months, 1, 2, 3 and 4 years. Patients with Type 1 neovascularization had better visual outcomes and received more injections than the other neovascular subtypes. There were no serious adverse events. A TER provided sustained long-term visual gains. Eyes with Type 1 neovascularization had better visual outcomes than those with other neovascular subtypes.

Correlation between neovascular lesion type and clinical characteristics of nonneovascular fellow eyes in patients with unilateral, neovascular age-related macular degeneration.

Purpose: To investigate the association between the type of neovascularization (NV) and the clinical characteristics of nonneovascular fellow eyes in patients with unilateral, neovascular age-related macular degeneration. Methods: Eighty-three patients with treatment-naive, unilateral, neovascular age-related macular degeneration were retrospectively analyzed. Neovascular lesions were classified using both fluorescein angiography and optical coherence tomography as Type 1 (subretinal pigment epithelium), 2 (subretinal), 3 (intraretinal), or mixed NV. The associations between NV lesion type and baseline clinical and imaging characteristics of the fellow eye, including central geographic atrophy, noncentral geographic atrophy, pigmentary changes, soft drusen, cuticular drusen, reticular pseudodrusen, and subfoveal choroidal thickness, were examined. Subfoveal choroidal thickness was defined as thin if thickness was <120 &mgr;m. Results: In the fellow eyes of patients with treatment-naive, unilateral, neovascular age-related macular degeneration, Type 3 NV had an increased adjusted odds ratio of reticular pseudodrusen (15.361, P < 0.001) and thin subfoveal choroidal thickness (21.537, P < 0.001) as well as a tendency toward an increased adjusted odds ratio of central geographic atrophy (4.775, P = 0.028). Fellow eyes of patients with Type 1 NV showed a decreased adjusted odds ratio of reticular pseudodrusen (0.233, P = 0.007) and thin subfoveal choroidal thickness (0.080, P = 0.005). Conclusion: In patients with unilateral, neovascular age-related macular degeneration, certain nonneovascular features of the fellow eye correlate with the NV lesion composition based on type, as anatomically classified utilizing both fluorescein angiography and optical coherence tomography. Patients with Type 3 NV were more likely to have reticular pseudodrusen and/or thin subfoveal choroidal thickness in the fellow eye compared with those with Type 1 NV. Patients with Type 3 NV also showed a trend toward increased central geographic atrophy in the fellow eye.

Baseline Predictors for Good Versus Poor Visual Outcomes in the Treatment of Neovascular Age-Related Macular Degeneration With Intravitreal Anti-VEGF Therapy.

PURPOSE To examine the baseline factors associated with good (20/60 or better) versus poor (20/200 or worse) visual outcomes in eyes with treatment-naïve neovascular age-related macular degeneration (AMD) receiving intravitreal antivascular endothelial growth factor (VEGF) on a treat-and-extend regimen (TER). METHODS An observational, retrospective series of patients managed with a TER, identified as having either good or poor visual outcomes, was examined. A multivariate regression analysis of baseline characteristics identified factors associated with good and poor vision at 2, 3, and 4 years. Neovascular subtypes were identified using fluorescein angiography (FA) alone and the anatomic classification system with FA and optical coherence tomography (OCT). RESULTS One hundred thirty-eight patients (154 eyes) fit the inclusion criteria at 2 years, 106 patients (113 eyes) at 3 years, and 72 patients (74 eyes) at 4 years. In the multivariate analysis, type 1 lesions, according to anatomic classification, had better vision at 24 months (95% CI: [3.1, 82.7], P = 0.01), 36 months (95% CI: [1.97, 24.17], P = 0.003), and 48 months (95% CI: [2.01, 65.47], P = 0.006). Clopidogrel use was associated with poor vision at 24 months (95% CI: [0.03, 0.68], P = 0.013). Vision at 3 months was the best predictor of vision at year 4 (β = -4.277, P = 0.002). CONCLUSIONS Eyes with neovascular AMD managed with a TER of anti-VEGF therapy having type 1 neovascularization at baseline were more likely to maintain good vision over 4 years, whereas clopidogrel use predicted poor vision at 2 years. Vision at 3 months was the best predictor for favorable long-term vision.

Expanded clinical spectrum of multiple evanescent white dot syndrome with multimodal imaging

Purpose: To evaluate and characterize multiple evanescent white dot syndrome abnormalities with modern multimodal imaging modalities. Methods: This retrospective cohort study evaluated fundus photography, fluorescein angiography, indocyanine green angiography, optical coherence tomography, enhanced depth imaging optical coherence tomography, short-wavelength autofluorescence, and near-infrared autofluorescence. Results: Thirty-four multiple evanescent white dot syndrome patients with mean age of 28.7 years were studied (range, 14–49 years). Twenty-six patients were women, and eight were men. Initial mean visual acuity was 0.41 logMAR. Final mean visual acuity was 0.03 logMAR. Fluorescein angiography shows a variable number of mid retinal early fluorescent dots distributed in a wreathlike pattern, which correlate to fundus photography, fundus autofluorescence, and indocyanine green angiography. Indocyanine green angiography imaging shows the dots and also hypofluorescent, deeper, and larger spots, which are occasionally confluent, demonstrating a large plaque of deep retinal hypofluorescence. Optical coherence tomography imaging shows multifocal debris centered at and around the ellipsoid layer, corresponding to the location of spots seen with photography, indocyanine green angiography, and fluorescein angiography. Protrusions of the hyperreflectant material from the ellipsoid layer toward the outer nuclear layer correspond to the location of dots seen with photography, indocyanine green angiography, and fluorescein angiography. Conclusion: Multimodal imaging analysis of the retina in patients with multiple evanescent white dot syndrome shows additional features that may help in the diagnosis of the disease and in further understanding its etiology. Multiple evanescent white dot syndrome is predominantly a disease of the outer retina, centered at the ellipsoid zone, but also involving the interdigitation zone and the outer nuclear layer.

Evaluation of multimodal imaging in carriers of X-linked retinitis pigmentosa

The aim of this study was to investigate visualization of the tapetal-like reflex using current imaging modalities and evaluate SD-OCT changes in known carriers of X-linked retinitis pigmentosa (XLRP); the objective being the development of an optimal protocol for clinicians to identify carriers. Ten XLRP carriers (19 eyes) were examined using color fundus photography, 488 nm reflectance (488-R), near-infrared reflectance (NIR-R), autofluorescence (AF) and spectral domain optical coherence tomography (SD-OCT) imaging (Spectralis SLO-OCT, Heidelberg). Horizontal line scans through the fovea were acquired in all subjects and in a group of 10 age-similar controls. Peripheral SD-OCT scans (extending to 27.5° eccentricity) were also acquired in both eyes of 7 carriers. MP-1 microperimetery (10-2 pattern; Nidek) was performed in one eye of each carrier. For the XLRP carriers, a tapetal reflex was observed with all imaging modalities in 8 of 19 eyes. It had the same retinal location on color fundus, 488-R and NIR-R imaging but a different location on AF. The tapetal reflex was most easily detected in 488-R images. The horizontal foveal SD-OCT scans were qualitatively normal, but measurements showed significant outer retinal layer thinning in all eyes. Additionally, the 14 eyes with peripheral SD-OCTs demonstrated patchy loss of the inner segment ellipsoid band. Microperimetry exhibited patchy visual sensitivity loss in 9 eyes. Full field ERGs were variable, ranging from normal to severely abnormal rod and cone responses. Our findings suggest that an optimal protocol for identifying carriers of XLRP should include 488-R imaging in a multimodal approach. Peripheral SD-OCT imaging and central retinal layer quantification revealed significant structural abnormalities.