G. Soubrane

Evolving European guidance on the medical management of neovascular age related macular degeneration

Background: Until recently, only two options were available for the treatment of choroidal neovascularisation (CNV) associated with age related macular degeneration (AMD)—thermal laser photocoagulation and photodynamic therapy with verteporfin (PDT-V). However, new treatments for CNV are in development, and data from phase III clinical trials of some of these pharmacological interventions are now available. In light of these new data, expert guidance is required to enable retina specialists with expertise in the management of AMD to select and use the most appropriate therapies for the treatment of neovascular AMD. Methods: Consensus from a round table of European retina specialists was obtained based on best available scientific data. Data rated at evidence levels 1 and 2 were evaluated for laser photocoagulation, PDT-V, pegaptanib sodium, and ranibizumab. Other treatments discussed are anecortave acetate, triamcinolone acetonide, bevacizumab, rostaporfin (SnET2), squalamine, and transpupillary thermotherapy. Results: PDT-V is currently recommended for subfoveal lesions with predominantly classic CNV, or with occult with no classic CNV with evidence of recent disease progression and a lesion size ⩽4 Macular Photocoagulation Study (MPS) disc areas (DA). The new classes of anti-angiogenic agents—namely, pegaptanib sodium and ranibizumab (the latter when peer reviewed phase III data become available) are recommended for subfoveal lesions with any proportion of classic CNV or occult with no classic CNV. For juxtafoveal classic CNV, PDT-V or anti-angiogenic therapy should be considered if the new vessels are so close to the fovea that laser photocoagulation would almost certainly extend under the centre of the foveal avascular zone. For all other well demarcated juxtafoveal lesions and for extrafoveal classic lesions, laser photocoagulation remains the standard treatment. Therapy should be undertaken within 1 week of the fluorescein angiogram on which the clinical decision to treat is based. At each follow up, fluorescein angiography should be performed and best corrected visual acuity measured as a minimum requirement. Conclusions: These recommendations provide evidence based guidance for the choice and use of non-surgical therapies for the management of neovascular AMD. Revisions of the recommendations may be required as new data become available.

Clinical features of drusenoid pigment epithelial detachment in age related macular degeneration

Aim: To analyse clinical features of drusenoid pigment epithelium detachment (PED) in age related macular degeneration. Methods: 61 eyes of 32 patients with untreated drusenoid PED were followed for an average of 4.6 years (range 1–17 years). Drusenoid PED was defined as ½ disc diameter (DD) of confluent soft drusen under the centre of the macula. All patients underwent visual acuity measurement, biomicroscopic fundus examination, stereoscopic colour photograph, and fluorescein and indocyanine green angiography. Optical coherence tomography was performed in selected cases at the last examination. Kaplan Meier survival analysis was performed to estimate the probability of complications. Results: Three different natural outcomes were identified: persistence of drusenoid PED (38%), development of geographic atrophy (49%), and choroidal neovascularisation (CNV) (13%). Based on Kaplan Meier survival analysis, drusenoid PED had a 50% of chance of developing geographic atrophy after 7 years. If the drusenoid PED was greater than 2 DD or was associated with metamorphopsia at initial presentation, progression to atrophy or ingrowth of CNV occurred after 2 years (p<0.01). Indocyanine green angiography confirmed fluorescein angiographic features or ascertained the presence of CNV when fluorescein angiography was equivocal. Optical coherence tomography was helpful in distinguishing coalescent soft drusen from drusenoid PED and disclosed the accumulation of sub or intraretinal fluid in eyes with CNV. Conclusion: Drusenoid PED size greater than 2 DD and metamorphopsia were risk factors identified at presentation which affected prognosis. The evaluation of the eyes at risk requires the use of all imaging means in order to ascertain the diagnosis of CNV. At long term (over 10 years), geographic atrophy and CNV had occurred in 75% and 25% respectively, with a poor visual outcome.

High-resolution spectral domain optical coherence tomography features in adult onset foveomacular vitelliform dystrophy

Purpose To describe the different morphological features in adult onset foveomacular vittelliform dystrophy (AOFVD) using high-resolution spectral domain optical coherence tomography (OCT). Design Prospective observational case series. Methods Complete ophthalmologic examination, including spectral domain OCT, was performed in 49 consecutive AOFVD patients (60 eyes). Results In 28/60 eyes, spectral domain OCT showed hyper-reflective clumps within the outer plexiform and outer nuclear layers. In 9/60 eyes, the photoreceptor inner segment/outer segment (IS/OS) interface appeared highly reflective like a shell all around the vitelliform material, and appeared irregular and discontinued in 27/60 eyes. The Verhoeff membrane was clearly visible at the border of the lesion, disappeared over the vitelliform lesion in 20/60 eyes, became thickened and less defined on the outer aspect of the lesion in 11/60 eyes, appeared without noticeable alterations in 10/60 eyes and not well defined in 19/60 eyes. The vitelliform material appeared as a highly reflective dome-shaped lesion (homogeneous in 14/60 eyes and heterogeneous in 36/60 eyes) located between the photoreceptor layer and the retinal pigment epithelium (RPE). In 10/60 eyes, the macular lesion appeared as hypo/a-reflective. The RPE appeared irregular in 14/60 eyes, with hyper-reflective mottling on its inner aspect. We observed discrete RPE detachments in 29/60 eyes. Conclusions We hypothesise that early changes involve the layer between RPE and the IS/OS interface, first with vitelliform material accumulation beneath the sensory retina, and then with IS/OS alterations, pigments migration towards inner layers and fluid accumulation. These changes come with RPE alterations such as hypertrophy or sub-RPE deposits.

Analysis of retinal flecks in fundus flavimaculatus using optical coherence tomography

Background/aim: Retinal flecks are commonly observed in both Stargardt disease and fundus flavimaculatus (FFM). The aim was to determine the precise localisation of these flecks within the retinal layers using Stratus optical coherence tomography (OCT). Methods: A prospective observational case series. A complete ophthalmological examination, including autofluorescence, fluorescein angiography (FA), and Stratus OCT (Carl Zeiss) was performed in 49 eyes of 26 consecutive patients with FFM. Six to 12 Stratus OCT linear scans focused on the retinal flecks were performed in each eye. Results: The age at presentation ranged from 23 years to 71 years and visual acuity ranged from 20/20 to 20/400. Hyper-reflective deposits classified into two types were observed on Stratus OCT: type 1 lesions (94% of eyes) presented as dome-shaped deposits located in the inner part of the retinal pigment epithelium (RPE) layer and type 2 lesions (86% of eyes) presented as small linear deposits located at the level of the outer nuclear layer and clearly separated from the RPE layer. Conclusions: Stratus OCT is a non-invasive instrument that provides new information on the location of flecks in FFM. The location of type 2 lesions is quite unusual among macular dystrophies; OCT may therefore be useful in the diagnosis of retinal flecks in some cases of FFM.

Association of diabetes with age-related macular degeneration in the EUREYE study

Objective: To examine the association between self-reported diabetes history and early or late age-related macular degeneration (AMD) in the European population. Methods: Participants aged 65 years and over in the cross-sectional population-based EUREYE study underwent an eye examination including digital retinal photography. The images were graded at a single centre. A structured questionnaire was administered by trained field workers for putative risk factors for AMD including history of diabetes mellitus. Logistic regression models were used to examine the association between diabetes and stages of AMD, taking account of potential demographic, behavioural, dietary and medical (history of cardiovascular disease) confounders. Main outcome measures: Photographic images were graded according to the modified International Classification System for AMD and stratified into five exclusive stages from no signs of AMD (AMD stage 0), early AMD (Stages 1–3) and late AMD (Stage 4). Late AMD was subdivided in neovascular AMD (NV-AMD) or geographic atrophy (GA). Results: Data on diabetes history and potential confounders were available in 2117 control subjects without AMD, 2182 with early AMD, 49 with GA and 101 with NV-AMD. Of all participants, 13.1% reported a history of diabetes. After adjusting for potential confounders, subjects with neovascular AMD compared with controls had increased odds for diabetes (odds ratio 1.81; 95% confidence interval, 1.10 to 2.98, p = 0.02). Subjects with AMD grades 1 to 3 or GA had no increased odds for diabetes compared with those without AMD. Conclusions: In the EUREYE study, after multiple adjustments, positive association of diabetes mellitus with neovascular AMD was found. The hypothesis that diabetes is associated with neovascular AMD but not with geographic atrophy may suggest a different pathogenesis of the two advanced forms of the disease and needs to be further evaluated.

Eligibility for treatment and angiographic features at the early stage of exudative age related macular degeneration.

Aims: To determine the eligibility for laser photocoagulation treatment or for photodynamic therapy (PDT) with verteporfin in eyes at the earliest stage (first month of symptoms) of exudative age related macular degeneration (AMD) based on fluorescein angiographic (FA) features; to evaluate the potential contribution of indocyanine green angiography (ICG-A) for occult choroidal neovascularisation (CNV) at this stage. Methods: Retrospective review of 252 consecutive patients (269 eyes) examined within the first month of symptoms of exudative AMD. Results: On FA, 97 eyes (36%) had classic CNV alone. Occult CNV associated with fibrovascular retinal pigment epithelium detachments (PEDs) was observed in 71 eyes (26%) and without fibrovascular PED in 101 eyes (38%). 91 eyes (34%) met the Macular Photocoagulation Study criteria for laser photocoagulation. 53 eyes (20%) met the Verteporfin In PDT (VIP) or Treatment of AMD with PDT (TAP) studies criteria. By ICG-A, occult CNV was visualised as focal spots in 49% of eyes examined within 15 days v 32% of eyes examined between 16 and 30 days after the onset of symptoms (p=0.07). 8.5% of late staining plaques disclosed in eyes examined within 15 days were combined with focal spots v 36% in eyes examined between 16 and 30 days (p<0.01). Conclusions: Early examination of eyes with exudative AMD would allow the treatment of 47% of eyes. 60% of eyes with subfoveal CNV would be eligible for PDT with verteporfin. Up to half of eyes with occult CNV would be converted by ICG-A into well delineated focal spots.

Two novel missense mutations in the peripherin/RDS gene in two unrelated French patients with autosomal dominant retinitis pigmentosa

Purpose To report the identification of two novel RDS mutations in the peripherin/RDS gene of two unrelated French patients affected by autosomal dominant retinitis pigmentosa (ADRP). Methods Fifty-eight unrelated patients affected by ADRP were analyzed. Our diagnostic criteria for RP were bilateral fundus involvement, concentric depression of the visual field and severe involvement on electroretinogram. Transmission of the trait was unambiguous. Our strategy was to analyze the coding sequence of the gene using a combination of single-strand conformation polymorphism (SSCP) and direct sequence analysis of the exons of the gene. Exons that displayed conformational polymorphisms were sequenced on an automated DNA sequencer. Results The sequence analyses revealed two previously unreported missense mutations: Cys165Tyr and Phe211Leu in exons 1 and 2, respectively. None of the 70 controls analyzed carried these base changes. Cosegregation of the base substitution with the disease could be tested in both families presenting the Cys165Tyr and Phe211Leu mutations. Conclusions Several lines of evidence support the idea that these base substitutions are disease-causing mutations. To the best of our knowledge, no peripherin/RDS gene analysis has been previously reported in ADRP in France.

Association Between Myopia, Ultraviolet B Radiation Exposure, Serum Vitamin D Concentrations, and Genetic Polymorphisms in Vitamin D Metabolic Pathways in a Multicountry European Study

Importance Myopia is becoming increasingly common globally and is associated with potentially sight-threatening complications. Spending time outdoors is protective, but the mechanism underlying this association is poorly understood. Objective To examine the association of myopia with ultraviolet B radiation (UVB; directly associated with time outdoors and sunlight exposure), serum vitamin D concentrations, and vitamin D pathway genetic variants, adjusting for years in education. Design, Setting, and Participants A cross-sectional, population-based random sample of participants 65 years and older was chosen from 6 study centers from the European Eye Study between November 6, 2000, to November 15, 2002. Of 4187 participants, 4166 attended an eye examination including refraction, gave a blood sample, and were interviewed by trained fieldworkers using a structured questionnaire. Myopia was defined as a mean spherical equivalent of −0.75 diopters or less. Exclusion criteria included aphakia, pseudophakia, late age-related macular degeneration, and vision impairment due to cataract, resulting in 371 participants with myopia and 2797 without. Exposures Exposure to UVB estimated by combining meteorological and questionnaire data at different ages, single-nucleotide polymorphisms in vitamin D metabolic pathway genes, serum vitamin D3 concentrations, and years of education. Main Outcomes and Measures Odds ratios (ORs) of UVB, serum vitamin D3 concentrations, vitamin D single-nucleotide polymorphisms, and myopia estimated from logistic regression. Result Of the included 3168 participants, the mean (SD) age was 72.4 (5) years, and 1456 (46.0%) were male. An SD increase in UVB exposure at age 14 to 19 years (OR, 0.81; 95% CI, 0.71-0.92) and 20 to 39 years (OR, 0.7; 95% CI, 0.62-0.93) was associated with a reduced adjusted OR of myopia; those in the highest tertile of years of education had twice the OR of myopia (OR, 2.08; 95% CI, 1.41-3.06). No independent associations between myopia and serum vitamin D3 concentrations nor variants in genes associated with vitamin D metabolism were found. An unexpected finding was that the highest quintile of plasma lutein concentrations was associated with a reduced OR of myopia (OR, 0.57; 95% CI, 0.46-0.72). Conclusions and Relevance Increased UVB exposure was associated with reduced myopia, particularly in adolescence and young adulthood. The association was not altered by adjusting for education. We found no convincing evidence for a direct role of vitamin D in myopia risk. The relationship between high plasma lutein concentrations and a lower risk of myopia requires replication.

Indocyanine green angiography features of malattia leventinese

Background/aim: Malattia leventinese (ML) is an inherited macular degeneration characterised by the presence of small radial drusen. Despite extensive descriptions of this study of the fundus, angiographic features of ML have been inadequately described. The aim is to describe the indocyanine green angiography (ICG) features observed in ML. Methods: 10 eyes from five consecutive ML patients (aged 27–44 years) were prospectively included. A complete ophthalmological examination including colour fundus photographs, autofluorescence, fluorescein angiography (FA), and ICG was performed. Results: ICG differentiated two types of drusen. Large round aggregated drusen were consistently hypofluorescent in the early phases and presented as hyperfluorescent spots surrounded by halos of hypofluorescence in the late phases. Conversely, small radial drusen were mostly hyperfluorescent in the early phases with decreased fluorescence in the late phases of the ICG sequence. FA also showed differences in staining between the two types of drusen. Conclusions: ICG angiography revealed marked differences between the large round and small radial drusen observed in ML. The large central drusen presented with an unusual pustuliform feature on the late phases of the ICG sequence. This distinct feature may be useful in the diagnosis of late stage disease when drusen consolidation could obscure the radial drusen.

Occurrence of macular hematoma after ranibizumab treatment for age-related macular degeneration.

Purpose To report the occurrence and study the characteristics of macular hematoma after ranibizumab (anti-VEGF) intravitreal injection for subfoveal choroidal neovascularization in age-related macular degeneration (AMD). Methods The charts of 6000 patients treated with ranibizumab (0.5 mg) for exudative AMD were reviewed. Inclusion criteria were a minimum follow-up of 1 year after the first injection and the occurrence of a large macular hematoma involving the fovea in patients with macular lesions considered stabilized or still active. All patients had a complete ophthalmologic assessment including Early Treatment of Diabetic Retinopathy Study visual acuity (VA) measurement, fundus photography, fundus fluorescein angiography, scanning laser ophthalmoscopy–infracyanine green angiography, and spectral-domain optical coherence tomography. Results Of the 6000 eyes, 24 (0.4%) developed macular hematoma during follow-up. There were 8 men (33.3%) and 16 women (66.7%). The mean age at the time of initial presentation was 76.7 ± 3.8 years (range 61-81 years). The mean time to occurrence of macular hematoma after the last injection was 4.8 months. Spectral-domain optical coherence tomography showed the presence of a retinal pigment epithelium (RPE) tear in 19 eyes (79.1%). Vitreomacular traction (VMT) was only present in 4 eyes (17%). Final VA after macular hematoma resorption was <20/50 in 17 cases (70.9%) and ≥20/50 in 7 cases (29.1%). Conclusions Macular hematoma may follow intravitreal anti-VEGF injection for exudative AMD with large occult neovascularization, especially if a large RPE tear is found. The occurrence does not seem to be linked to anticoagulation treatment or the presence of VMT.