Jennifer J. Arnold

Reticular pseudodrusen. A risk factor in age-related maculopathy.

Background: Reticular pseudodrusen refer to a yellow interlacing network 125µm to 250µm wide appearing first in the superior outer macula and then extending circumferentially and beyond. Unlike true drusen, they do not fluoresce on fluorescein or indocyanine green angiography, and are best seen in red-free light or with the He-Ne laser of the scanning laser ophthalmoscope. Methods: One hundred patients have been seen in our retinal practice with this clinical feature in the past 3 years. Results: All had some manifestation of age-related maculopathy (ARM), and 66% had or subsequently developed subretinal new vessels in one or both eyes. The appearance is attributed to changes in the choroid. Conclusions: Reticular pseudodrusen are an easily recognizable clinical sign, and may be an important risk factor for choroidal neovascularization in ARM.

Early drusen formation in the normal and aging eye and their relation to age related maculopathy: a clinicopathological study

AIM To describe the early formation of drusen and their relation to normal aging changes at the macula and to the development of age related maculopathy (ARM). METHOD Histopathological features of 353 eyes without histological evidence of ARM are described and correlated with the clinical appearance. In addition, 45 of these eyes were examined by transmission electron microscopy. RESULTS Drusen were detected histopathologically in 177 (50%) eyes but were seen clinically in only 34% of these. Drusen were mainly small hard drusen with an occasional soft distinct drusen: no soft indistinct drusen were seen. Only those drusen deposits larger than 25–30 μm in diameter were detectable clinically. Preclinical drusen in eyes with only an occasional drusen were seen on electron microscopy as entrapment sites of coated membrane bound bodies which formed adjacent to the inner collagenous zone of Bruch’s membrane. In contrast, preclinical drusen deposits in eyes with many drusen were seen as accumulations of amorphous material which appeared hyalinised by light microscopy. A distinct feature were rows of dense hyalinised microdrusen (1–2 μm in diameter), over which larger globular hyalinised drusen formed. CONCLUSION Histological and ultrastructural examination can recognise and distinguish the earliest drusen formed as a result of normal aging from those associated with ARM. In eyes without diffuse deposits, histologically all drusen were of the hard hyalinised variety or their derivatives; no soft drusen composed of membranous debris were found. These findings support and explain those of other authors who do not consider the presence of a few small hard drusen to be a risk factor for the development of ARM.

Evolution of reticular pseudodrusen

Aims To report observations relating to the clinical recognition and possible basis of reticular pseudodrusen (RPD). Methods This retrospective study reports the evolution of RPD in 166 patients who had follow-up of over 1 year using multiple imaging techniques. Mean age when first seen was 73.3 years and the mean period of observation was 4.9 years (range 1–18 years). Associated macular changes were recorded. Results RPD were first identified in the upper fundus as a reticular network, which then became less obvious, developing a diffuse yellowish appearance. RPD also faded around choroidal neovascularisation (CNV). RPD therefore could be transient but the pattern often remained visible outside the macula or nasal to the discs. Manifestations of age-related macular degeneration (AMD) were present in nearly all eyes and there was a particularly high association with CNV (52.1%). In one clinicopathological case abnormal material was found in the subretinal space. Conclusions The prevalence of RPD may be underestimated because their recognition depends upon the imaging method used, the area of fundus examined and the confusion with typical drusen. The pathology of one eye suggests that RPD may correspond to material in the subretinal space.

Effects of verteporfin therapy on contrast sensitivity: Results from the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) investigation - TAP Report No. 4

Background In the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) investigation, verteporfin therapy reduced the risk of at least moderate vision loss (defined as a loss of at least 15 letters of visual acuity) in patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (ARMD). This report presents detailed analyses of 24-month contrast sensitivity outcomes in these patients. Methods The patients included in the TAP investigation had subfoveal CNV secondary to ARMD and received verteporfin therapy (n = 402) or placebo (n = 207) at the first visit, with retreatment at each 3-month follow-up visit if angiography revealed fluorescein leakage from CNV. Contrast sensitivity was determined at each visit using a Pelli–Robson chart. Results At the month 24 examination, verteporfin-treated patients were less likely to lose at least 6 or 15 letters of contrast sensitivity than placebo-treated patients (86 [21%] versus 94 [45%], and 27 [7%] versus 24 [12%], respectively;P < 0.05 for both comparisons). The superiority of verteporfin therapy over placebo was greater in patients with predominantly classic CNV at baseline, although verteporfin-treated patients with minimally classic CNV also had better contrast sensitivity outcomes. Conclusions Consistent with visual acuity outcomes, verteporfin therapy reduced the risk of a clinically relevant loss of contrast sensitivity in the total study population, with the greatest effect in patients with predominantly classic subfoveal CNV secondary to ARMD. Verteporfin-treated patients with minimally classic CNV also had better contrast sensitivity outcomes than patients who received placebo. Given the association between contrast sensitivity and visual disability, the beneficial effects of verteporfin therapy on contrast sensitivity outcomes are expected to have a favorable impact on patients’ daily activities.

Indocyanine Green Angiography of Drusen

PURPOSE To analyze the indocyanine green angiographic findings of drusen in the early stages of age-related macular degeneration. METHODS Sixty-nine eyes of 53 consecutive patients with drusen but without exudative complications of age-related macular degeneration were studied. Drusen were classified into four groups: hard drusen, drusen derived from clusters of hard drusen (hard cluster-derived drusen and soft cluster-derived drusen), membranous drusen, and regressing drusen. An additional category was constituted by reticular pseudodrusen that could be associated with drusen of either the inner or outer macula. Results of contact lens biomicroscopy and fluorescein angiography were compared with findings on indocyanine green angiography. RESULTS Hard drusen, either isolated hard drusen or hard cluster-derived drusen, were hyperfluorescent during indocyanine green angiography; in contrast, all sizes of soft drusen derived from clusters of hard drusen were hypofluorescent throughout the angiogram. Membranous drusen, visible on biomicroscopy and fluorescein angiography, were not visible during indocyanine green angiography. Regressing drusen may have showed hyperfluorescence at the early stages of indocyanine green angiography, but associated calcium and pigmentation were hypofluorescent. Reticular pseudodrusen were visible on red-free photographs; on midphase and late-phase indocyanine green angiography using the scanning laser ophthalmoscope only, reticular pseudodrusen were seen as a pattern of hypofluorescent dots. CONCLUSION The indocyanine green angiographic findings add to and support the clinicopathologic classification of drusen. Indocyanine green angiography may help to distinguish the different types of drusen and may thus be of use in evaluating the risk of progressive age-related macular degeneration in patients with drusen.

Intravitreal Aflibercept for Macular Edema Secondary to Central Retinal Vein Occlusion: 18-Month Results of the Phase 3 GALILEO Study

PURPOSE To evaluate intravitreal aflibercept for treatment of macular edema secondary to central retinal vein occlusion (CRVO). DESIGN Randomized, double-masked, phase 3 study. METHODS A total of 177 patients with macular edema secondary to CRVO were randomized to receive 2 mg intravitreal aflibercept (n = 106) or sham (n = 71) every 4 weeks for 20 weeks. From weeks 24 to 48, patients were monitored every 4 weeks; the former group received intravitreal aflibercept as needed (PRN), and the sham group received sham. From weeks 52 to 76, patients were monitored every 8 weeks, and both groups received intravitreal aflibercept PRN. The primary endpoint (proportion of patients who gained ≥15 letters) was at week 24. This study reports exploratory outcomes at week 76. RESULTS The proportion of patients who gained ≥15 letters in the intravitreal aflibercept and sham groups was 60.2% vs 22.1% at week 24 (patients discontinued before week 24 were considered nonresponders; P < .0001), 60.2% vs 32.4% at week 52 (last observation carried forward, P < .001), and 57.3% vs 29.4% at week 76 (last observation carried forward; P < .001). Mean μm change from baseline central retinal thickness was -448.6 vs -169.3 at week 24 (P < .0001), -423.5 vs -219.3 at week 52 (P < .0001), and -389.4 vs -306.4 at week 76 (P = .1122). Over 76 weeks, the most common ocular serious adverse event in the intravitreal aflibercept group was macular edema (3.8%). CONCLUSIONS The visual and anatomic improvements seen after fixed, monthly dosing at week 24 were largely maintained when treatment intervals were extended. Patients with macular edema following CRVO benefited from early treatment with intravitreal aflibercept.

Indocyanine Green Angiographic Features of Pathologic Myopia

PURPOSE To analyze indocyanine green angiographic findings of pathologic myopia and compare them with those of fluorescein angiography, with particular reference to the usefulness of indocyanine green angiography in the management of neovascular complications. METHODS Thirty-two consecutive patients (52 eyes) with pathologic myopia underwent a complete ophthalmologic examination including fluorescein and indocyanine green angiography. RESULTS Retrobulbar arteries and veins were visualized solely on indocyanine green angiography in 33 (63%) of 52 eyes. Choroidal arteries appeared attenuated and reduced in number. In the area of staphyloma, choroidal veins were less numerous, and in all eyes an absence of the normal choroidal flush caused by the choriocapillaris filling was observed. Subretinal and retinal hemorrhages were present in 28 (54%) of 52 eyes. Choroidal neovascularization was diagnosed in 16 eyes on fluorescein angiography and in 18 eyes on indocyanine green angiography. In seven eyes, indocyanine green angiography disclosed lacquer cracks (without choroidal neovascularization), appearing in the late phases as hypofluorescent lines, as the probable cause of the subretinal and retinal hemorrhages. In only one eye did indocyanine green angiography fail to disclose choroidal neovascularization detectable on fluorescein angiography. In two eyes, neither dye could clarify the origin of the hemorrhages. CONCLUSIONS Indocyanine green angiography allows identification of retrobulbar arteries and veins, and analysis of the altered choroidal vasculature. Moreover, indocyanine green angiography is a useful diagnostic tool to differentiate lacquer cracks from choroidal neovascularization in retinal and subretinal hemorrhages.

Two-year outcomes of "treat and extend" intravitreal therapy for neovascular age-related macular degeneration.

PURPOSE To report 24-month outcomes of anti-vascular endothelial growth factor (VEGF) therapy for treatment-naïve eyes with neovascular age-related macular degeneration (nAMD) using a treat and extend treatment regimen in routine clinical practice. DESIGN Database observational study. PARTICIPANTS We included treatment-naïve eyes receiving predominantly ranibizumab for nAMD in routine clinical practice treated using a treat and extend regimen that were tracked in the Fight Retinal Blindness observational registry. METHODS A cohort of eyes treated by practitioners using exclusively a treat and extend regimen was extracted from the Fight Retinal Blindness observational registry. MAIN OUTCOME MEASURES Change in visual acuity (VA) over 2 years and number of injections and visits. RESULTS Data from 1198 eyes from 1011 patients receiving anti-VEGF therapy using a treat and extend regimen for treatment-naïve nAMD between January 2007 and December 2012 and with 24-month follow-up were included in the analysis. Mean VA increased by +5.3 logarithm of the minimum angle of resolution letters from 56.5 letters (20/80+1) at initial visit to 61.8 (20/60+2) letters at 24 months. Mean VA gains improved and number of injections increased with successive years from +2.7 letters for eyes commencing in 2007 after a mean of 9.7 injections in 2 years, to +7.8 letters for eyes commencing in 2012 after a mean of 14.2 injections over 2 years. The proportion of eyes with VA >20/40 increased from 27% when starting treatment to 45% after 24 months; the proportion with vision of <20/200 remained unchanged (13% initial, 11% at 24 months). Of the included eyes, 90.5% avoided a vision loss of ≥15 letters. There was an overall mean of 13.0 injections over the 24 months, 7.5 injections in the first year and 5.5 in the second year, with a mean of 14.8 clinic visits. CONCLUSIONS These data indicate that eyes managed in routine clinical practice with a treat and extend regimen can achieve good visual outcomes while decreasing the burden of treatments and clinic visits.

Adult vitelliform macular degeneration: a clinicopathological study.

AbstractAims/background The yellow lesions of adult vitelliform macular degeneration (AVMD) slowly fade, progressing to hyperpigmentation or atrophy. This study aims to provide further observations on the location and nature of the vitelliform material.Methods This report describes the clinicopathological correlation of four eyes with AVMD. A retrospective histopathological study of a further 526 aged eyes previously graded for the stage of age-related macular degeneration (AMD) found another 10 eyes with similar pathology.Results The predominant finding was a collection of extracellular material beneath the sensory retina at the fovea. This material was derived internally from photoreceptor outer segments and externally from the retinal pigment epithelium (RPE), the latter first undergoing hypertrophy and then disruption and attenuation. Fallout of foveal cones occurred over these lesions and the inner retina was thinned, which may explain macular hole formation in this condition. All affected eyes showed histopathological evidence of AMD.Conclusions This study confirms that the vitelliform lesions of AVMD lie beneath the sensory retina. In contrast to previous reports, however, it is proposed that the lesions comprise mainly extracellular material consisting of photoreceptor debris, possibly the result of faulty phagocytosis by the RPE, mixed with pigment liberated as the RPE undergoes disruption. The vitelliform lesions therefore are a marker for the area of maximal RPE disturbance.

Long-Term Outcomes of Treatment of Neovascular Age-Related Macular Degeneration: Data from an Observational Study

PURPOSE To analyze the long-term outcomes of eyes with neovascular age-related macular degeneration (AMD) starting treatment with vascular endothelial growth factor (VEGF) inhibitors at least 5 years earlier. DESIGN Database observational study. PARTICIPANTS Treatment-naïve eyes with neovascular AMD tracked by the Fight Retinal Blindness outcome registry that received at least 1 anti-VEGF injection. METHODS Locally weighted scatterplot smoothing curves were used to display visual acuity (VA) results. MAIN OUTCOME MEASURES Change in mean VA and number of injections and visits from baseline up to 7 years after initiating treatment. RESULTS The mean follow-up time of all 1212 identified eyes was 53.5 months, and 549 (45%) continued attending after 60 months. Mean VA improved from 55.1 to 61.4 letters after 6 months and remained above the mean presenting VA for approximately 6 years. After 7 years, mean VA was 2.6 letters lower than baseline for the 131 eyes still being followed; 40% had VA ≥70 (20/40) letters, and 18% had VA ≤35 letters (20/200). Of those with 20/40 VA before treatment, 40% had lost it after 7 years. Geographic atrophy affecting the fovea was thought to be the cause of a ≥10-letter loss after 6.5 years in 37% of a subset of such eyes that were retrospectively analyzed. A median of 6 injections and 9 visits were recorded over the first 12 months, and then 5 treatments and 7 to 9 visits per annum thereafter through 7 years. Treatment was discontinued for 663 eyes (53%) within the first 5 years. Despite initial gains in vision, the mean VA of these eyes had deteriorated to baseline or worse around the time treatment was discontinued. The rate of serious adverse events was low. CONCLUSIONS Good long-term outcomes of VEGF inhibition for neovascular AMD were found in this study. These results may be better than other reports because more injections were given to our patients, possibly associated with a greater incentive for the physician to treat. Further studies to determine how to maximize the proportion of eyes that retain the initial VA gains of anti-VEGF are warranted.