G. Richard

Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA)

Age-related macular degeneration (AMD) is still referred to as the leading cause of severe and irreversible visual loss world-wide. The disease has a profound effect on quality of life of affected individuals and represents a major socioeconomic challenge for societies due to the exponential increase in life expectancy and environmental risks. Advances in medical research have identified vascular endothelial growth factor (VEGF) as an important pathophysiological player in neovascular AMD and intraocular inhibition of VEGF as one of the most efficient therapies in medicine. The wide introduction of anti-VEGF therapy has led to an overwhelming improvement in the prognosis of patients affected by neovascular AMD, allowing recovery and maintenance of visual function in the vast majority of patients. However, the therapeutic benefit is accompanied by significant economic investments, unresolved medicolegal debates about the use of off-label substances and overwhelming problems in large population management. The burden of disease has turned into a burden of care with a dissociation of scientific advances and real-world clinical performance. Simultaneously, ground-breaking innovations in diagnostic technologies, such as optical coherence tomography, allows unprecedented high-resolution visualisation of disease morphology and provides a promising horizon for early disease detection and efficient therapeutic follow-up. However, definite conclusions from morphologic parameters are still lacking, and valid biomarkers have yet to be identified to provide a practical base for disease management. The European Society of Retina Specialists offers expert guidance for diagnostic and therapeutic management of neovascular AMD supporting healthcare givers and doctors in providing the best state-of-the-art care to their patients. Trial registration number NCT01318941.

Retinal cells integrate into the outer nuclear layer and differentiate into mature photoreceptors after subretinal transplantation into adult mice

Vision impairment caused by degeneration of photoreceptors, termed retinitis pigmentosa, is a debilitating condition with no cure presently available. Cell-based therapeutic approaches represent one treatment option by replacing degenerating or lost photoreceptors. In this study the potential of transplanted primary retinal cells isolated from neonatal mice to integrate into the outer nuclear layer (ONL) of adult mice and to differentiate into mature photoreceptors was evaluated. Retinal cells were isolated from retinas of transgenic mice ubiquitously expressing enhanced green fluorescence protein (EGFP) at either postnatal day (P) 0, P1 or P4 and transplanted into the subretinal space of adult wild-type mice. One week to 11 months post-transplantation experimental retinas were analyzed for integration and differentiation of donor cells. Subsequent to transplantation some postnatal retinal cells integrated into the ONL of the host and differentiated into mature photoreceptors containing inner and outer segments as confirmed by immunohistochemistry and electron microscopy. Notably, the appearance of EGFP-positive photoreceptors was not the result of fusion between donor cells and endogenous photoreceptors. Retinal cells isolated at P4 showed a significant increase in their capacity to integrate into the ONL and to differentiate into mature photoreceptors when compared with cells isolated at P0 or P1. As cell suspensions isolated at P4 are enriched in cells committed towards a rod photoreceptor cell fate it is tempting to speculate that immature photoreceptors may have the highest integration and differentiation potential and thus may present a promising cell type to develop cell replacement strategies for diseases involving rod photoreceptor loss.

Glaucoma progression is associated with decreased blood flow velocities in the short posterior ciliary artery

Background: An altered perfusion of the optic nerve head has been proposed as a pathogenic factor in glaucoma. Aim: To investigate potential differences in the ocular haemodynamics of patients having glaucoma with progressive versus stable disease, as well as healthy volunteers. Methods: Peak-systolic velocity (PSV), end-diastolic velocity (EDV) and resistivity index in the short posterior ciliary artery (SPCA), central retinal artery (CRA) and ophthalmic artery were recorded in 114 consecutive patients having glaucoma with an intraocular pressure (IOP) ⩽21 mm Hg, as well as in 40 healthy volunteers, by colour Doppler imaging (CDI). Results: Of the 114 patients with glaucoma, 12 showed glaucoma progression (follow-up period: mean 295 (standard deviation (SD) (18) days). CDI measurements in these patients showed decreased PSV and EDV in the SPCA (p<0.001 and p<0.05, respectively) and decreased PSV in the CRA compared with patients with stable glaucoma and healthy controls (p<0.05). No differences in flow velocities were found for the ophthalmic artery. IOP and systemic blood pressure was similar in all the three groups. Conclusions: Progressive glaucoma is associated with decreased blood flow velocities in the small retrobulbar vessels supplying the optic nerve head. The detected difference could represent a risk factor for progression of glaucomatous optic neuropathy.

Optical coherence tomography in uveitis patients

PURPOSE To evaluate optical coherence tomography in allergy-prone uveitis patients. METHODS Thirty-four patients (43 eyes) with posterior uveitis (31 eyes) and intermediate uveitis (12 eyes) were evaluated by fluorescein angiography, indocyanine green angiography, and optical coherence tomography. Follow-up examinations used optical coherence tomography in allergy-prone patients. RESULTS Optical coherence tomography identified epiretinal membranes, which were removed surgically (three eyes); persistent cystoid macular edema, which resolved with cytotoxic treatment (12 eyes); and juxtafoveolar membranes, which were treated by diode laser (six eyes) and excision (two eyes). CONCLUSION Optical coherence tomography may provide useful information on complications developing in uveitis patients.

Optical coherence tomography for retinal thickness measurement in diabetic patients without clinically significant macular edema.

BACKGROUND AND OBJECTIVE To evaluate the potential of optical coherence tomography (OCT) as a screening method for retinal thickness measurements in diabetic patients. PATIENTS AND METHODS We used a previously described pattern of six 5 mm OCT scans through the center of fixation in 45 diabetic patients without clinically significant macular edema: 22 patients (group 1) had no diabetic retinopathy (ETDRS classification); 18 (group 2) had nonproliferative retinopathy; 5 patients with peripheral neovascularization did not enter statistical analysis; 25 normal healthy subjects were used as a control group. Retinal thickness was measured at five locations in each scan: in the fovea, at the foveal rim, and outside the macula. Measurements were identified in nonaligned images and taken from raw data A-scans. Locations were grouped into hemispheres, quadrants and rings, and mean values tested for statistically significant differences using Mann-Whitney U-Wilcoxon rank sum W test. RESULTS Differences in retinal thickness were found to be significant in the macula (controls vs group 2 P = 0.0266), at the foveal rim (controls vs group 1 and 2: P = 0.0386 and P = 0.0193), in the nasal and superior hemisphere (controls vs group 2: P = 0.0251 and P = 0.0187), and in the superior nasal quadrant (controls vs group 1 and group 1 vs group 2: P = 0.0022 and P = 0.0462). CONCLUSIONS Significant differences of retinal thickness between patients with diabetic retinopathy and normals can be detected by OCT even in the absence of clinically significant macular edema. Significant differences between diabetic patients with and without retinopathy are most likely to be found in the superior nasal quadrant.

A method and technical equipment for an acute human trial to evaluate retinal implant technology

This paper reports on methods and technical equipment to investigate the epiretinal stimulation of the retina in blind human subjects in acute trials. Current is applied to the retina through a thin, flexible microcontact film (microelectrode array) with electrode diameters ranging from 50 to 360 microm. The film is mounted in a custom-designed surgical tool that is hand-held by the surgeon during stimulation. The eventual goal of the work is the development of a chronically implantable retinal prosthesis to restore a useful level of vision to patients who are blind with outer retinal degenerations, specifically retinitis pigmentosa and macular degeneration.

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.

CST3 genotype associated with exudative age related macular degeneration

Aims: To determine whether allelic variants of the cystatin C gene CST3 are genetically associated with exudative age related macular degeneration (ARMD). Cystatin C is a cysteine protease inhibitor that regulates the activity of cathepsin S, a protease with central regulatory functions in retinal pigment epithelial cells. Methods: CST3 of 167 patients with exudative ARMD was genotyped by using polymerase chain reaction of genomic DNA and restriction enzyme digestion with KspI and compared with those of 517 control subjects. Patients and controls were white. Results: There was a significant difference in genotype counts between patients and controls (χ2 = 7.158, df = 2; Fishers exact test: p = 0.037). There was no significant difference in allele frequencies between patients and controls and between controls from Germany, Switzerland, Italy, and United States. The significant difference in genotype counts between patients and controls could be explained completely by an excess of the homozygous CST3 genotype B/B in patients with exudative ARMD (6.6%) over controls (2.3%), suggesting an odds ratio for ARMD in association with CST3 B/B of 2.97 (95% CI: 1.28–6.86). The results also suggest a stronger association of B/B with ARMD in males than in females. However, in both males and females there was a similar and significant effect of CST3 B/B on disease free survival assessed by Kaplan-Meier analysis. The mean disease free survival time in pooled males and females with genotypes A/A or A/B was 85 years (SE 1; 95% CI: 83–86) and 76 years (SE 2; 95% CI: 72–79) respectively in B/B homozygotes (log rank p = 0.0006). Conclusion: Genotyping data, the absence of a significant difference in allele frequencies between patients and controls, and survival analyses suggest an increased susceptibility for ARMD in CST3 B/B homozygotes. Therefore, CST3 B may be a recessive risk allele, significantly contributing to disease risk in up to 6.6% of German ARMD patients. Functional correlates of the allelic CST3 variants A and B remain to be investigated.

Effect of topical dorzolamide on optic nerve head blood flow

Abstract · Purpose: The topical carbonic anhydrase inhibitor dorzolamide has proven effective in lowering intraocular pressure in glaucoma patients. Because an impaired blood supply of the optic nerve has to be regarded as a major pathogenic risk factor it seems important to examine the effect of this new antiglaucomatous drug on capillary optic nerve head blood flow. · Methods: In a double-masked, randomized clinical trial, dorzolamide eye drops were applied to both eyes of 15 healthy subjects (8 female, 7 male, mean age 30.6 years) three times daily for 3 days. The control group (15 healthy volunteers, 9 female, 6 male, mean age 30.8 years) received a placebo preparation according to the same protocol. Intraocular pressure (IOP), blood pressure, heart rate, capillary optic nerve head blood flow and retinal blood flow were measured at baseline (1D0), 90 min after single instillation (1D90), and after 3 days of therapy (3D). Scanning laser Doppler flowmetry (Heidelberg Retina Flowmeter) and laser Doppler flowmetry according to Riva (Oculix 4000) were used to measure optic nerve head blood flow. · Results: IOP dropped in dorzolamide-treated subjects from 12.5 mmHg to 11.0/10.5 mmHg (1D0, 1D90, 3DO) and in the control group from 13.0 mmHg to 12.5/12.5 mmHg. Optic nerve blood flow as measured by scanning laser Doppler flowmetry showed no significant changes in dorzolamide-treated volunteers (temporal 310/329/315 AU, nasal 387/402/399 AU) or in the placebo group (temporal 238/306/276 AU, nasal 356/382/379 AU). Also as measured by laser Doppler flowmetry optic nerve head blood flow did not show significant changes in dorzolamide-treated volunteers (temporal 12.98/12.6/11.7 AU, nasal 16.6/16.9/15.7 AU) or in the placebo group (temporal 11.9/12.4/12.4 AU, nasal 16.1/15.8/17.7 AU). The systemic parameters blood pressure and heart rate remained unchanged during the treatment period. · Conclusion: The results showed the expected drop in IOP. However, capillary optic nerve head blood flow, measured by two different techniques, did not change during therapy. This may be due to the effective autoregulation in human optic nerve head circulation, which seems not to be affected by dorzolamide.

Limitations of imaging choroidal tumors in vivo by optical coherence tomography.

Abstract · Background: Optical coherence tomography (OCT) produces two-dimensional cross-sectional images with a longitudinal resolution of 10 μm. Its capacity for imaging retinal structure has been shown in a variety of diseases. There are no reports on its capacity and limitations in imaging choriocapillary and choroidal structures. · Methods: Twenty-two patients with the diagnosis of malignant melanoma of the choroid were submitted to OCT. We used a prototype and a commercial device, both with an 850-nm superluminescent diode with a bandwidth of 30 nm (reported longitudinal resolution 10 μm). The images were evaluated for retinal thickness, changes in retinal pigment epithelium, subretinal fluid accumulation and changes in choriocapillary or choroidal reflectivity. · Results: Retinal edema and detachment found on biomicroscopic examination for fluorescein angiography was detected by OCT in all such cases. In 2 of 22 cases small retinal detachments were detected only by OCT. Tumor extension through the retinal pigment epithelium was not seen in this series, either by biomicroscopy or by OCT. The pattern of choroidal or choriocapillary reflectivity was nonspecifically lower than that of normal choroid, but did not yield any additional information about tumor histology. When normal retina was present, the OCT appearance of a malignant melanoma resembled that of normal choroid. · Conclusion: OCT may provide information about the retinal structure overlying prominent tumors and the extent of adjacent retinal detachment. In its present state of development, OCT is of little value in the differential diagnosis of choroidal tumors. Its potential value for the follow-up of shallow tumors needs further investigation.