Nicolas Leveziel

Myopic choroidal neovascularisation: current concepts and update on clinical management

Choroidal neovascularisation (CNV) is a common vision-threatening complication of myopia and pathological myopia. Despite significant advances in understanding the epidemiology, pathogenesis and natural history of myopic CNV, there is no standard definition of myopic CNV and its relationship to axial length and other myopic degenerative changes. Several treatments are available to ophthalmologists, but with the advent of new therapies there is a need for further consensus and clinical management recommendations. Verteporfin photodynamic therapy has been an established treatment for subfoveal myopic CNV for many years, but this treatment does not restore visual acuity and is associated with long-term chorioretinal atrophy. More recently, clinical trials investigating the efficacy and safety of anti-vascular endothelial growth factor agents in patients with myopic CNV have demonstrated substantial visual acuity gains and quality of life increases compared with photodynamic therapy. These enhanced outcomes provide updated evidence-based clinical management guidelines of myopic CNV, and increase the need for a generally accepted definition for myopic CNV. This review critically summarises the latest myopic CNV literature in the context of clinical experience and recommends a myopic CNV treatment algorithm.

Intravitreal ranibizumab for choroidal neovascularization complicating pathologic myopia.

Purpose: The purpose of this study was to evaluate the efficacy of intravitreal injections of ranibizumab in choroidal neovascularization secondary to pathologic myopia. Methods: A prospective case series of 32 eyes of 32 patients affected with choroidal neovascularization secondary to pathologic myopia treated by intravitreal injections of ranibizumab. Best-corrected visual acuity, fundus examination, fluorescein angiography, indocyanine green angiography, and spectral domain-optical coherence tomography were performed for the diagnosis of myopic choroidal neovascularization. Best-corrected visual acuity and central retinal thickness measurement were performed monthly during the follow-up. Results: The median number of injections was 3 with a median follow-up of 17 months. The median visual acuity at baseline was 20/100 and improved to 20/50 at final examination (P < 0.0001). Best-corrected visual acuity improved by ≥3 lines in 15 of 32 eyes (46.8%). The median central thickness was 336 &mgr;m (range, 179-663 &mgr;m) at baseline and 233 &mgr;m (range, 125-465 &mgr;m) at final examination (P < 0.0001). No severe drug-related side effect was reported. Conclusion: In our series of myopic choroidal neovascularization, intravitreal injections of ranibizumab showed visual acuity improvement and retinal thickness reduction. Further prospective multicentric clinical trials are needed to evaluate the safety and the efficacy of this treatment.

ARMS2/HTRA1 Locus Can Confer Differential Susceptibility to the Advanced Subtypes of Age-Related Macular Degeneration

PURPOSE To determine if genetic variants that have been associated with age-related macular degeneration (AMD) have a differential effect on the risk of choroidal neovascularization (CNV) and geographic atrophy. DESIGN Genetic association study. METHODS SETTING Multicenter study. STUDY POPULATION Seven hundred forty-nine participants with geographic atrophy and 3209 participants with CNV were derived from 4 AMD studies with similar procedures from Tufts Medical Center, the Age-Related Eye Disease Study, University of Utah, and Hopital Intercommunal de Creteil. PROCEDURES AMD grade was assigned based on fundus photography and examination using the clinical age-related maculopathy staging system. All samples were genotyped for single nucleotide polymorphisms (SNPs) previously associated with AMD. Allele frequencies were compared between participants with CNV and geographic atrophy using PLINK within each cohort and Mantel-Haenszel meta-analysis was performed to combine odds ratios (OR). MAIN OUTCOME MEASURES Differences in allele frequencies between participants with geographic atrophy and CNV. RESULTS The frequency of the T allele of ARMS2/HTRA1 rs10490924 was significantly higher in participants with CNV than in those with geographic atrophy (OR, 1.37; 95% confidence interval, 1.21-1.54; P value = 4.2 × 10(-7)). This result remained statistically significant when excluding individuals who had geographic atrophy in 1 eye and CNV in the contralateral eye (P = 2.2 × 10(-4)). None of the other SNPs showed a significant differential effect for CNV vs geographic atrophy, including CFH, C2/CFB, C3, CFI, LIPC, and TIMP3. CONCLUSIONS Genetic variation at the ARMS2/HTRA1 locus confers a differential risk for CNV vs geographic atrophy in a well-powered sample.

rs5888 variant of SCARB1 gene is a possible susceptibility factor for age-related macular degeneration.

Major genetic factors for age-related macular degeneration (AMD) have recently been identified as susceptibility risk factors, including variants in the CFH gene and the ARMS2 LOC387715/HTRA1locus. Our purpose was to perform a case-control study in two populations among individuals who did not carry risk variants for CFHY402H and LOC387715 A69S (ARMS2), called “study” individuals, in order to identify new genetic risk factors. Based on a candidate gene approach, we analyzed SNP rs5888 of the SCARB1 gene, coding for SRBI, which is involved in the lipid and lutein pathways. This study was conducted in a French series of 1241 AMD patients and 297 controls, and in a North American series of 1257 patients with advanced AMD and 1732 controls. Among these individuals, we identified 61 French patients, 77 French controls, 85 North American patients and 338 North American controls who did not carry the CFH nor ARMS2 polymorphisms. An association between AMD and the SCARB1 gene was seen among the study subjects. The genotypic distribution of the rs5888 polymorphism was significantly different between cases and controls in the French population (p<0.006). Heterozygosity at the rs5888 SNP increased risk of AMD compared to the CC genotypes in the French study population (odds ratio (OR) = 3.5, CI95%: 1.4–8.9, p<0.01) and after pooling the 2 populations (OR = 2.9, 95% CI: 1.6–5.3, p<0.002). Subgroup analysis in exudative forms of AMD revealed a pooled OR of 3.6 for individuals heterozygous for rs5888 (95% CI: 1.7–7.6, p<0.0015). These results suggest the possible contribution of SCARB1, a new genetic factor in AMD, and implicate a role for cholesterol and antioxidant micronutrient (lutein and vitamin E) metabolism in AMD.

Endophthalmitis After Intravitreal Injections: Incidence, Presentation, Management, and Visual Outcome

PURPOSE To report the incidence and characteristics of endophthalmitis after intravitreal injections of anti-vascular endothelial growth factor agents or corticosteroids and to describe the clinical and bacteriologic characteristics, management, and outcome of these eyes with acute endophthalmitis in France. DESIGN Retrospective, nationwide multicenter case series. METHODS From January 2, 2008 to June 30, 2013, a total of 316,576 intravitreal injections from 25 French ophthalmic centers were included. For each center, the number of intravitreal injections was determined using billing codes and the injection protocol was recorded. A registry and hospital records were reviewed to identify patients treated for endophthalmitis after injection during the same time period. The main outcome measures were the incidence of clinical endophthalmitis and visual acuity of endophthalmitis cases. RESULTS During the study period, 65 cases of presumed endophthalmitis were found, giving an overall incidence of 0.021% (2.1 in 10,000 injections) (95% confidence interval [CI], 0.016%-0.026%). The median number of days from injection to presentation was 4 [1-26] days. The most common symptom was vision loss. Bacterial identification was achieved in 43.4%. The most frequent pathogens were gram-positive bacteria (91.3%), including coagulase-negative Staphylococcus in 78.3%. Neither the interval between injection and presentation for endophthalmitis nor the clinical signs differentiated culture-positive from culture-negative cases. In multivariate analysis, the use of a disposable conjunctival mould assist device and the use of prophylaxis with an antibiotic or antiseptic were significantly associated with an increased incidence of endophthalmitis (P = .001). The majority of patients had worse visual acuity after 3 months of follow-up when compared with acuity before endophthalmitis. CONCLUSIONS The incidence of presumed endophthalmitis after intravitreal injections of anti-vascular endothelial growth factors or corticosteroids was low and the prognosis poor. Prevention and management remain challenging. It remains to be determined whether the findings of this study are relevant for other countries using different techniques for intravitreal injections.

Angiographic and Optical Coherence Tomography Characteristics of Recent Myopic Choroidal Neovascularization

PURPOSE To analyze the contribution of fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD OCT) to the diagnosis of recent choroidal neovascularization (CNV) associated with high myopia. DESIGN Retrospective, observational case series. METHODS Ninety eyes of 73 highly myopic patients (refractive error ≥-6 diopters) with CNV in 1 or both eyes were included. Epidemiologic features, refractive error, fundus examination, fluorescein angiography, and SD OCT findings at onset of CNV were analyzed. RESULTS Mean age at onset of CNV was 54.4 ± 14 years. CNV was bilateral in 17 of 73 cases. Mean refractive error was -13.9 ± 5.2 diopters. Myopic CNV was associated more frequently with patchy or geographic atrophy (P = .019). CNV was associated with exudative features on fluorescein angiography in 82% of cases (64/78), and on SD OCT in 48.6% of cases (36/74). There was no agreement about signs of active CNV between these 2 imaging methods (κ = 25.7 ± 10%; P = .0044). CNV area was significantly smaller in younger patients (<55 years) than in older patients (0.57 mm(2) vs 1.21 mm(2), respectively; P = .023). CONCLUSIONS Exudative features of myopic CNV are more obvious on FA than on SD OCT, suggesting that fluorescein angiography should be performed when new-onset myopic CNV is suspected. Myopic CNV occurring in older patients (≥55 years) is larger than those seen in younger patients and resembles CNV associated with age-related macular degeneration. This suggests an overlap between myopic CNV in older patients and age-related macular degeneration.

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.

Genetic Factors for Choroidal Neovascularization Associated with High Myopia

PURPOSE Nonsyndromic high myopia, defined by a refractive error greater than -6 diopters (D), is associated with an increased risk of macular choroidal neovascularization (CNV), a vision-threatening complication. The aim of this study was to investigate whether genetic factors associated with age-related macular degeneration (AMD) are related to myopic CNV. METHODS We conducted a case-control study, including 71 cases with myopic CNV and 196 myopic controls without CNV, from Creteil and Toulouse, France, and Boston, MA. Single nucleotide polymorphisms (SNPs) from 15 genes reported to be related to AMD were selected for association testing in this study. RESULTS In univariate analysis, the rs10033900 SNP located in CFI was associated with myopic CNV (P = 0.0011), and a SNP in APOE was also related (P = 0.041). After adjustment for age, sex, and degree of myopia, SNPs in three genes were significantly associated, including CFI (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.3-3.37, P = 0.0023), COL8A1 (OR 1.88, 95% CI 1.18-2.98, P = 0.0076), and CFH (OR 1.65, 95% CI 1.02-2.66, P = 0.04). After correction for multiple testing, only CFI remained significantly related to high myopic CNV (P = 0.045). CONCLUSIONS We report the first genetic associations with choroidal neovascularization (CNV) in a high myopic Caucasian population. One SNP (rs10033900) in the CFI gene, which encodes a protein involved in the inflammatory pathway, was significantly associated with myopic CNV in multivariate analysis after correction for multiple testing. This SNP is a plausible biological marker associated with CNV outgrowth among high myopic patients. Results generate hypotheses about potential loci related to CNV in high myopia, and larger studies are needed to expand on these findings.

Genotypic Influences on Severity of Exudative Age-Related Macular Degeneration

PURPOSE Major genetic risk factors have recently been identified for age-related macular degeneration (AMD), including the ARMS2/LOC387715 and CFH at-risk polymorphisms. The study was conducted to establish correlations between the AMD genotype and both the phenotype and severity of AMD. METHODS In a prospective cohort of 1216 AMD patients, four genotypic homozygous groups were identified (n = 264): double homozygous for wild-type alleles (group 1, n = 49), homozygous for the at-risk allele of ARMS2/LOC387715 only (group 2, n = 57), homozygous for the at-risk allele of CFH only (group 3, n = 106), and double homozygous for both at-risk alleles (group 4, n = 52). The phenotypic classification of exudative AMD was based on fluorescein angiography. RESULTS Mean age at presentation was significantly lower in group 4 than in group 1 (P < 0.014). Patients in group 4 presented more often with bilateral CNV and fibrovascular scars than did patients in group 1 (P < 0.001 and < 0.0031 respectively) and with significantly lower visual acuity (VA) in the first affected eye than did patients in group 1 (P < 0.02). Patients in group 2 presented with worse VA than did patients in group 3 (P < 0.003). Classic CNV was more commonly associated with the at-risk allele of the ARMS2/LOC387715 locus than with the at-risk allele of the CFH gene (P < 0.026). CONCLUSIONS This study demonstrates an association between the at-risk allele of the ARMS2/LOC387715 locus and classic CNV, fibrovascular lesions, and poor VA. Individuals double homozygous for both at-risk alleles had a higher risk of being affected with a severe form of AMD at an earlier age.

Genetic factors associated with age-related macular degeneration.

Age-related macular degeneration (AMD) is a complex, multifactorial disease associated with environmental and genetic factors. This review emphasizes the clinical impact of the major genetic factors mainly located in the complement factor H gene and on the 10q26 locus, and their current and future implications for the management of AMD.