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Purpose: To study age- and sex-adjusted heritability of small hard drusen and early age-related macular degeneration (AMD) in a population-based twin cohort. Methods: This was a single-centre, cross-sectional, classical twin study with ophthalmic examination including refraction, biometry, best-corrected visual acuity assessment, colour and autofluorescence fundus photography, and fundus optical coherence tomography. Grading and categorization of drusen was by diameter and location. Results: The study enrolled 176 same-sex pairs of twins of mean (SD) age 58.6 (9.9) years. The prevalence of the four phenotypes ≥20 small hard macular drusen (largest diameter < 63 μm), ≥20 small hard extramacular drusen, intermediate drusen (63–125 μm) anywhere, and large drusen (>125 μm) anywhere was 12.4%, 36.4%, 5.8%, and 8.4%, respectively, and the respective heritabilities, adjusted for age and sex, were 78.2% [73.5–82.9], 69.1% [62.3–75.9], 30.1% [4.1–56.1], and 65.6% [26.4–100]. Age trajectory analysis supported a gradual transition to larger numbers of small hard drusen with increasing age. The heritability of ≥20 small hard drusen was markedly lower than the 99% found in the 40% overlapping twin cohort that was seen 20 years earlier. Conclusion: Numerous (≥20) small hard drusen and larger drusen that fit the definition of dry AMD were highly heritable. Small hard drusen counts increased with age. Decreasing heritability with increasing age suggests that the impact of behavioural and environmental factors on the development of small hard drusen increases with age.

PURPOSE To determine the fundus autofluorescence (FAF) lifetimes and spectral characteristics of individual drusen and hyperpigmentation independent of those with retinal pigment epithelium (RPE) in geographic atrophy (GA) areas in late-stage age-related macular degeneration (AMD). METHODS Three consecutive patients with complete RPE and outer retinal atrophy (cRORA) exhibiting drusen that were calcified or associated with hyperpigmentation were investigated with multimodal non-invasive ophthalmic imaging including colour fundus photography (CFP), optical coherence tomography (OCT), near-infrared reflectance (NIR), blue FAF and fluorescence lifetime imaging ophthalmoscopy (FLIO). Fluorescence lifetimes were measured in two spectral channels (short-wavelength spectral channel (SSC): 500-560 nm and long-wavelength spectral channel (LSC): 560-720 nm). RESULTS Drusen lacking RPE coverage, as confirmed by CFP and OCT, had longer FAF lifetimes than surrounding cRORA by 127 ± 66 ps (SSC) and 113 ± 48 ps (LSC, both p = 0.008 in Wilcoxon test, N = 9) and by 209 ± 100 ps (SSC) and 121 ± 56 ps (LSC, p

Age-related macular degeneration (AMD) is aetiologically linked to immunological ageing and dysfunction. One aspect of this is the altered neutrophil-to-lymphocyte ratio (NLR), which in other domains have been associated with inflammation and angiogenesis, and therefore investigated in patients with AMD in several papers. In this systematic review and meta-analysis, we summarize findings in patients with AMD in relation to NLR, both qualitatively and quantitatively. We searched PubMed/MEDLINE, EMBASE, Web of Science, and the Cochrane Central and identified six studies from where we extracted data on 1178 individuals (777 patients with AMD and 401 healthy controls). Patients with AMD had a higher NLR (weighted mean difference: 0.37, CI 95% 0.08 to 0.66, p = 0.013) when compared to healthy controls. In subgroup analyses, we did not find a significant difference between patients with dry AMD and healthy controls (weighted mean difference: 0.34, CI 95% -0.03 to 0.69, p = 0.068), but did find a strong significant difference between patients with neovascular AMD and healthy controls (weighted mean difference: 0.54, CI 95% 0.23 to 0.86, p = 0.00068). Hence, we find that the association between AMD and elevated NLR may have stronger relevance to the neovascular subtype of AMD. However, the clinical value of measuring the NLR remains unclear.

PURPOSE To investigate choriocapillaris (CC) perfusion, by evaluating flow voids (FV), in eyes with intermediate age-related macular degeneration (iAMD) using swept-source optical coherence tomography angiography (SS-OCT-A). METHODS Patients with bilateral or unilateral iAMD and normal controls underwent SS-OCT and OCT-A examination. Choriocapillaris (CC) FVs were quantitatively assessed on OCT-A images using matlab (version 2017b; MathWorks, Natick, MA, USA), after a preprocessing aimed at compensating for CC attenuation artefacts. Three different thresholds [1 standard deviation (SD), 1.25 SD and 1.5 SD] were applied. Final FV percentage (FV%) was calculated as the ratio between area with absent flow and total scanned area. RESULTS Of 41 patients with iAMD and 16 normal subjects enrolled in the study, 39 eyes (39 patients) with iAMD and all 16 normal eyes (16 control subjects) were included in the final analysis. Mean FV% (1 SD) was 13.45 ± 0.66 in controls, 14.19 ± 1.23 in bilateral iAMD and 14.21 ± 0.99 in unilateral iAMD (p = 0.03, for difference between controls and bilateral iAMD). Mean FV% (1.25 SD) was 6.55 ± 0.65 in controls, 7.33 ± 1.4 in bilateral iAMD and 7.06 ± 1.4 in unilateral iAMD (p = 0.048, for difference between controls and bilateral iAMD). Mean FV% (1.5 SD) was 2.71 ± 0.82 in controls, 2.55 ± 1.12 in bilateral iAMD and 3.25 ± 1.17 in unilateral iAMD (p = 0.038, for difference between bilateral and unilateral iAMD). CONCLUSION A significantly higher FV% was found in patients with iAMD versus controls. A higher trend in FV% was found in unilateral iAMD (with neovascular AMD in the fellow eye) versus bilateral iAMD, when applying the lowest threshold. Further, larger and longitudinal studies are needed to confirm this data.

PURPOSE Quantification of fundus autofluorescence has only recently become available. We report our findings on the evaluation of the repeatability and reliability of quantitative fundus autofluorescence (qAF) measurements in patients with early and intermediate age-related macular degeneration (AMD), using the first approved and commercially available instrument. METHODS A total of 43 eyes of 22 patients (aged between 52 and 84 years) diagnosed with early and intermediate AMD were included. All eyes were imaged at day 1, 3 months and 6 months using a modified scanning laser ophthalmoscope, equipped with an internal fluorescent reference. Mean qAF values were calculated for the fovea and for each concentric ring of the Delori pattern. Repeatability and reliability were calculated using Bland-Altman analysis and intraclass correlation (ICC). RESULTS The mean patient age was 73.5 ± 7.9 years. Sixteen patients (73%) were female. qAF repeatability of the eight segments in the middle ring of the Delori pattern (qAFM8 ) for between sessions was ±8.2%. Agreement at 3- and 6-month follow-up in eyes without retinal changes was ±8.3% and ±9.8%, respectively. Reliability of qAFM8 was high for all images acquired [ICC = 0.98 (CI: 0.96-0.99), 0.97 (0.93-0.99) and 0.98 (0.92-0.99)]. Agreement at 3- and 6-month follow-up in eyes with retinal changes was ±18.1% and ±20.2%, respectively. Intraclass correlation (ICC) was slightly lower in eyes with retinal changes at 0.93 (0.84-0.97) and 0.96 (0.91-0.98), respectively. CONCLUSIONS Quantitative autofluorescence shows excellent repeatability and reliability as well as follow-up agreement in patients with early and intermediate AMD without retinal changes. This is relevant when conducting longitudinal studies using qAF.

Purpose To evaluate the efficacy of photobiomodulation (PBM) treatment for patients with dry age‐related macular degeneration (AMD). Methods Assessments on 42 eyes with dry AMD (age related eye disease study (AREDS) 2–4) were conducted. Multiwavelength light emitting diode (LED) light comprising of yellow (590 nm), red (670 nm) and near‐infrared (790 nm) bandwidths was applied to subjects’ eyes for a treatment course of 3 weeks. Outcome measures were changes in best‐corrected visual acuity (BCVA), contrast sensitivity (CS), drusen volume and central drusen thickness. Results Significant improvement in mean BCVA of 5.90 letters (p

Purpose Fluorescence Lifetime Imaging Ophthalmoscopy (FLIO) allows non-invasive in vivo measurement of fluorescence lifetimes of natural fluorophores of the retina upon excitation with a laser light. FLIO in different retinal diseases showed that the technique is useful to detect early metabolic changes and can differentiate between retinal deposits. The aim of this study was to characterize fluorescence lifetimes in retinal drusen due to age-related macular degeneration (AMD). Methods FLIO imaging was performed using a Fluorescence Lifetime Imaging Ophthalmoscope (Heidelberg Engineering, Germany). Autofluorescence was elicited with a 473 nm laser and decay times were measured in a short (498–560 nm) and in a long (560–720 nm) spectral channel. Fluorescence lifetime data was compared with autofluorescence intensity images, optical coherence tomography (OCT) and color fundus images. Soft drusen and reticular pseudodrusen were analysed and compared to an age matched control group. Results 64 eyes from 64 patients with AMD and retinal drusen (age: mean ± SD 78 ± 8.5 years) were investigated and compared to 20 age matched healthy controls. Mean fluorescence lifetime in patients with AMD was significantly prolonged compared to the healthy control eyes (mean ± SEM; SSC 486 ± 18 ps vs 332 ± 11 ps, p > 0.0001; LSC: 493 ± 9 ps vs 382 ± 17 ps, p > 0.0001). Areas of drusen featured a broader range of fluorescence lifetime values. Long lifetimes were identified in areas of atrophy and intraretinal hyperreflective deposits. Areas of short lifetime corresponded to deposits within the photoreceptor outer segment band. Conclusions Mean retinal autofluorescence lifetimes in AMD were significantly prolonged compared to healthy control eyes. Intraretinal deposits caused prolonged lifetimes whereas deposits in the area of the outer photoreceptor segments lead to short fluorescence lifetimes.

Purpose: To evaluate the association between telomere length and age-related macular degeneration (AMD). Methods: Circulating leucocyte telomere length and the proportion of telomeres

Age-related macular degeneration (AMD) is attributed to a complex interaction of genetic and environmental factors. It is characterized by degeneration involving the retinal photoreceptors, retinal pigment epithelium (RPE) and Bruch's membrane, as well as alterations in choroidal capillaries. AMD pathogenesis is strongly associated with chronic oxidative stress and inflammation that ultimately lead to protein damage, aggregation and degeneration of RPE. Specific degenerative findings for AMD are accumulation of intracellular lysosomal lipofuscin and extracellular drusens. In this review, we discuss thoroughly RPE-derived mechanisms in AMD pathology.

Purpose: The Nidek F-10 is a scanning laser ophthalmoscope that is capable of a novel fundus imaging technique, so-called ‘retro-mode’ imaging. The standard method of imaging drusen in age-related macular degeneration (AMD) is by fundus photography. The aim of the study was to assess drusen quantification using retro-mode imaging. Methods: Stereoscopic fundus photographs and retro-mode images were captured in 31 eyes of 20 patients with varying stages of AMD. Two experienced masked retinal graders independently assessed images for the number and size of drusen, using purpose-designed software. Drusen were further assessed in a subset of eight patients using optical coherence tomography (OCT) imaging. Results: Drusen observed by fundus photography (mean 33.5) were significantly fewer in number than subretinal deposits seen in retro-mode (mean 81.6; p < 0.001). The predominant deposit diameter was on average 5 μm smaller in retro-mode imaging than in fundus photography (p = 0.004). Agreement between graders for both types of imaging was substantial for number of deposits (weighted κ = 0.69) and moderate for size of deposits (weighted κ = 0.42). Retro-mode deposits corresponded to drusen on OCT imaging in all eight patients. Conclusion: The subretinal deposits detected by retro-mode imaging were consistent with the appearance of drusen on OCT imaging; however, a larger longitudinal study would be required to confirm this finding. Retro-mode imaging detected significantly more deposits than conventional colour fundus photography. Retro-mode imaging provides a rapid non-invasive technique, useful in monitoring subtle changes and progression of AMD, which may be useful in monitoring the response of drusen to future therapeutic interventions.

Purpose: To evaluate the influence of haemorheopheresis on anatomical and functional findings in patients with soft-drusen maculopathy. Methods: We investigated 29 eyes (16 patients) and randomized 25 eyes (16 controls) with soft-drusen maculopathy [soft, confluent and reticular drusen, drusenoid retinal pigment epithelium detachment (RPED)]. Each patient received a series of eight haemorheophereses (cascade filtration of 1.5 plasma volume) within 10 weeks. The patients were followed up using Early Treatment Diabetic Retinopathy Study (ETDRS) charts, optical coherence tomography, fluorescein angiography, electroretinography and measurements of pulsed ocular blood flow. Results: After the procedures, there was a substantial reduction in rheologically active substances [lipoproteins, α2-macroglobulin, immunoglobulin M (IgM), fibrinogen], plasma and blood viscosity. At the 1.5-year follow-up, we noticed soft drusen absorption; reattachment of drusenoid RPED and stabilization or improvement of visual acuity occurred in 72% of patients in comparison to only 39% of patients in the control group. Full-field electroretinograms showed significantly higher scotopic activity of treated patients in comparison with the control group, and mainly insignificant differences in photopic activity between both groups. Despite the significant increase of activity in the paramacular retina in treated patients, the differences in amplitudes of multifocal electroretinography (mfERG) average responses were insignificant between groups. Conclusion: Haemorheopheresis seems to be capable of changing the activity of promoters of the natural course of soft-drusen maculopathy, its development and progression. Visual acuity and electrical activity of the retina can be stabilized or even improved. The therapy has been shown to be effective and safe.

An analysis of visual field findings in the material of 200 patients with pseudopapilloedema with and without verified optic disc drusen was performed. Goldmann and/or Friedmann visual fields were examined in 383 eyes. Visual field defects were found in 38.9% of the pseudopapilloedema eyes without verified drusen, but in 73.4% of the drusen eyes. The strongest field defects were found only in the eyes with drusen seen by oblique illumination or with superficial drusen. The eyes with superficial drusen showed visual field defects in 85.8%. Only 7 patients complained of visual field defects. A progression of visual field defects could be documented in 22% of 118 patients with visual field examinations 2 or more times.

Using Littmann's method for correcting the magnification of central fundus photographs, we determined the absolute size of 35 unselected optic discs with pseudopapilledema. The optic disc area (1.95 +/- 0.33 mm2 (mean and SD)) was significantly (P less than 0.001, Student's t-test ) smaller than standard values of normal unselected optic nerve heads (2.73 +/- 0.76 mm2). There was no cupping in the discs with pseudopapilledema. Coefficients of variation for intraobserver re-evaluation were 0.045, and for interobserver re-evaluation 0.08. The markedly reduced optic disc size coincide with an abnormally small optic nerve scleral canal may inhibit the intraaxoplasmatic flow with secondary swelling of the juxtapapillary optic nerve fibers. This may lead t o prominence and indistinct borders of the optic disc. Pseudopapilledema might be related to optic nerve head drusen, which are also associated with abnormally small optic discs.

A prospective fluorescein angiographic study of 45 patients with unilateral age-related exudative maculopathy revealed at the 4-year follow-up that 14 (31%) had developed neovascular membranes in the fellow eyes. Age, drusen size and confluence, as well as pigmentary changes of these 14 were compared with the corresponding characteristics of the 31 eyes that remained non-exudative (atrophic). No significant differences were found. Among the 14 eyes that developed exudative maculopathy, visual acuity (Snellen) deteriorated 3-4 steps in 6 eyes (43%), 5-6 steps in 4 eyes (28.5%), and 7-8 steps or more in 4 eyes (28.5%). Among the 31 eyes that remained non-exudative, visual acuity was unchanged in 20 eyes (64%), deteriorated 1-2 steps in 7 eyes (23%), 3-4 steps in 3 eyes (10%), and 5-6 steps in 1 eye (3%). Social blindness (6/60 or less in the better eye) was found among 79% of the patients who had developed exudative maculopathy, whereas the figure was 19% among patients who still had atrophic macular degeneration.

Previously, small defects in the retinal pigment epithelium appearing as depigmented spots in the fundus photographs have been observed in a high proportion of adult diabetic patients. In order to evaluate whether these changes already occur in children we examined the black-and-white and colour fundus photographs of 206 diabetic children aged 4.6-19.6 years (median 12.6), with the median duration of diabetes of 4.7 years (range 0.0-14.2). Early signs of retinopathy were observed in 27 (13.1%) of them. The control group was composed of 45 healthy children aged 8.1-16.6 years (median 11.8). One or more tiny white spots in the fundus of one or both eyes were observed in 97 diabetics (47.1%), more often in those with retinopathy than in those without (66.7% vs. 44.1%, p less than 0.001). In the control group similar spots were observed in 24 children (53.5%). Only in a small proportion of children (4.4% of both diabetic and control patients) were the spots numerous. In children most of the white spots in the fundus may represent drusen type deposits rather than defects in the pigment epithelium.

As a part of more comprehensive examination of 180 patients with optic disc drusen, fundus photographs of 159 cases were evaluated. There were 70 patients whose optic discs were photographed two or more times during the years from 1967 to 1981. Four patients were selected to present the changes which can take place in optic discs with drusen and the alterations are demonstrated by autofluorescence pictures, stereophotographs, and electronic subtraction method.

Computerized image processing was used to analyze color fundus photographs of 11 patients (22 eyes) with macular drusen who were followed for more than 2 years (mean follow-up, 4.7 years). Significant changes over time (more than +/- 20% of baseline area) were measured in the surface area of macular drusen in 18 of 22 (82%) eyes. An increase in the drusen area was associated significantly with eyes with mostly hard drusen and an initially smaller drusen area; but a decrease was associated with eyes with mostly soft drusen and an initially larger drusen area (P less than 0.01). The mean absolute rate of change in the drusen area was more than twice as great in eyes with mostly soft drusen compared with those with mostly hard drusen (P less than 0.05). All eye pairs studied showed a concomitant increase or decrease in the drusen area.

As part of an examination of 180 patients with optic disc drusen, auto-fluorescence pictures had been taken in 116 patients and fluorescein angiograms in 67 patients. The superficial optic disc drusen often show a very bright nodular autofluorescence, but more important is the diffuse, not so intensive autofluorescence that the buried drusen may show. Thus, a diagnosis of hidden drusen can also be made if autofluorescence can be demonstrated. Fluorescein angiography may also reveal the buried drusen that do not show autofluorescence, and it may be of help in the differential diagnosis of pseudopapilloedema from true papilloedema. It may also indicate anomalous vascular patterns that may be associated with optic disc drusen.

In a family consisting of 8 surviving siblings, pseudoxanthoma elasticum was diagnosed in 4 sisters. One of them had a severe visual handicap, and another a slight decrease of the visual acuity because of the ocular lesions. The other 2 sisters also had fundal lesions, but they were visually symptom-free. Great variation was also found in the appearance of the ocular lesions in the affected siblings. In addition to the angioid streaks, the fundal findings in the probands affected included changes of the retinal pigment epithelium, exudative maculopathy, optic disc drusen and 'fire-work'-pattern of drusen of the Bruch's membrane. A similar variety of alterations was also found in the histopathology of the skin.

Purpose To ascertain the association between fundus drusens and biological parameters in a colony of 1174 monkeys. Methods Presence or absence of drusens was determined through the assessment of fundus photos taken during 2011 – 2013 from 1,174 Macaca fascicularis at Tsukuba Primate Research Center. Biological data from these monkeys including blood test result, age, sex, and body weight were tested for an association between the presence of drusens by applying t-test and logistic regression analysis. Results We identified 387 and 787 monkeys with and without drusens, respectively. Among them, 317 and 628 monkeys with and without drusens that had a complete biological data set were further studied. After comparing each parameter in monkeys with and without drusens, 13 factors with a significance of P

Age-related macular degeneration (AMD), the most common cause of visual loss after the age of 65, displays a degeneration of the retinal pigment epithelial (RPE) cells and photoreceptors in the retinal centre (macula). The central macula (fovea) that contains mostly cone photoreceptors mediates the high visual acuity. Drusen maculopathy may lead to visual deterioration. Drusen are extracellular deposits of debris that accumulate on Bruch's membrane. Drusen attract inflammatory, immunological and vasoactive stimuli. RPE and photoreceptor cells overlying drusen exhibit biochemical and morphological signs of degeneration. Strong and intermittent light exposure (photons) induces the formation of free radicals in the very high oxygen tension milieu of the retina. The negative effects of irradiation stimulate accumulation of lipofuscin in RPE and photoreceptor cells leading to mitochondrial dysfunction and apoptotic cell death. A hydrophobic barrier is built up in Bruch's membrane reducing diffusion to the choroid. Hereditary and inflammatory factors modify the risk for AMD. There is a genetic dysregulation of the complement system leading to inappropriate complement activation. The genetic polymorphism of complement factor H (CFH) and age-related maculopathy susceptibilty 2 (ARMS2) increase the risk of progression to advanced AMD. The photoelectric effect creates free radicals, resulting in a continuous increase of lipofuscin formation and impairing mitochondrial activity. In addition, inflammation and complement dysregulation contribute to the formation of drusen and vasoproliferative reactions with neovascularization. Antioxidants neutralize reactive oxygen species and reduce lipofuscin accumulation in RPE and photoreceptor cells. For prophylactic treatment of drusen maculopathy, high doses of antioxidants such as vitamins C and E, lutein, zeaxanthine and zinc are used according to the Age-Related Eye Disease Study 2 (AREDS 2). The risk of developing advanced AMD was reduced by 27% at 10 years follow-up. No adverse events were noted.

Purpose The differential diagnosis of small pigmented choroidal tumors is based on the evaluation of the tumor diameter, thickness, retinal detachment, pigment epithelium changes, and possible associated symptoms. Methods The diagnostic contribution of color fundus photography, fluorescein angiography (FA), indocyanine green angiography (ICGA), fundus autofluorescence (FAF) and optical coherence tomography (OCT), was analyzed in 85 eyes with a small pigmented choroidal tumors, measuring 2-10 mm in diameter and 0.8-2.5 mm in thickness. The presumed diagnosis was a large choroidal nevus in 60 cases (71%), and a small choroidal melanoma in 25 cases (29%). The identification of the tumor border, the presence of any retinal detachment on the tumor surface or outside the tumor borders, the presence of orange pigment, drusen, pigment epithelium changes and/or pin points were analyzed on each imaging technique. Results The highest identification score for the tumor margins was reached by color fundus photography. An associated retinal detachment was best identified on OCT. Orange pigment was best detected on fundus color photography and then by FAF. Drusen identification reached the same score on fundus color photography and FA. The appearance of pin points was exclusively seen on FA. Pigment epithelium changes showed the best score on FAF. Conclusion The majority of the investigated ocular imaging techniques played an important role in the identification of diagnostic elements that contribute to the distinction between a small choroidal melanoma and a large nevus. Multimodal imaging techniques have to be used in order to obtain a higher efficacy in differentiating small pigmented choroidal tumors.

Purpose Evaluation of influence of the drusen on optic nerve function. Comparison of various diagnostic methods. Methods 27 patients (54 eyes) with optic nerve drusen (average age: 33 years) and 15 healthy patients (30 eyes; average age: 32 years) have been examined. By all patients full ophthalmological examination, static perimetry (Octopus 301, Zeiss), contrast sensitivity with the sine wave contrast test (SWCT) as well as pattern electroretinography (PERG) and pattern visual evoked potentials (PVEP; Reti-Port, Roland Consult) were conducted. Statistical analysis was based on Mann-Whitney U Test and Spearman Test. Results Best Corrected Visual Acuity in all eyes amounted to 0.0 logMAR. In PVEP examination, the eyes with optic nerve drusen have revealed a statistically significantly lower P100 wave amplitude at 1 check size (p = 0,0004) and at 15’ (p = 0,046) as well as longer P100 wave latency at 15’ check size (p = 0,046) than healthy eyes. In PERG the amplitude of N95 wave was statistically significantly lower for eyes with optic nerve drusen than for healthy eyes. Statistically significant, negative correlation between the amplitude of N95 wave PERG and the value of MD factor of static visual field (r = - 0,1003) has been found. No significant differences in degrees of contrast sensitivity have been identified. Conclusion Presence of drusen disturbs optic nerve function. Electrophysiological examinations are a sensitive test in identifying visual neuropathy.

To suggest a clinical distinction between idiopathic typical polypoidal choroidal vasculopathy (PCV) and secondary polyps associated with late AMD and its therapeutic application.Retrospective case series of 30 eyes of 30 consecutive patients (xx females and xx males) with PCV. Initial diagnosis was based on SLO-ICGA, associated with FA and EDI SD-OCT, which allowed a clinical distinction between two subtypes of polyps. This multimodal imaging and visual acuity testing were repeated then at regular follow-up visits. The central macular and choroidal thickness, presence and number of hyper-reflective dots in retina and in choroid were also evaluated.The two groups were clinically different, based on demographic and ethnical characteristics, imaging findings and topography of lesions, presence of drusen, of true CNV, and changes in choroidal thickness. Therapeutic response was different in the two groups. After treatment, hyper-reflective dots decreased significantly but choroidal morphology did not change significantly. Functional and anatomical changes after treatment are analyzed and discussed.The clinical distinction between idiopathic typical PCV and secondary polyps associated with late AMD and results of treatment, sugges

Purpose Age-related Macular Degeneration (AMD) is the leading cause of blindness in people older than 50 in developed countries, and is associated with formation of subretinal deposits (drusen) and damage to Bruch’s membrane (BM) basal to the retinal pigment epithelium (RPE). It has been reported that activities of the ubiquitin-proteasome pathway (UPP) in retinal pigment epithelium decrease upon aging. Previous studies demonstrated that expression of ubiquitin in which lysine 6 is replaced by tryptophan (K6W-Ub) impairs the function of UPP. The main objective of this work was to investigate the hypothesis that chronically impairment of UPP in RPE contributes to some of the cardinal features of AMD, including drusens. Methods To address this question ARPE-19 cells were infected with empty vector, K6W Ubiquitin mutant and Wild Type Ubiquitin. The drusen formation and accumulation in basal matrix was evaluated by confocal microscopy, using specific drusen markers such as APOE, while exosome realease was determined by western blot (such as CD63 and Tsg101) and flow cytometry following exosomes isolation by ultracentrifugation. Results The results obtained showed that expression of K6W mutant Ub leads to an impairment of proteasome activity and an increased amount of exosomes release and drusen accumulation. Conclusion In this study the data might provide a vaulable tool to eluciadte the biological determinats of age-related proteolytic stress and its impacts on proteostasis in the retina.

Purpose Choroidal neovascular membranes are a rare cause of decreased vision in children with optic disc drusen. It can cause central vision loss by subfoveal progression of the choroidal neovascularization, serous macular detachment, or submacular hemorrhage. Methods We report two cases of optic nerve head drusen in childhood. A 6 year-old girl and a 12 year-old boy were both refered to our hospital for optic disc edema with unilateral visual loss Results Fundus examination showed pseudopapillary edema in the two cases. A pediatric check-up with neurologic and cardiovascular exams and CT scan were performed. B-Scan ultrasonography showed the presence of the optic nerve head drusen in both eyes but wasn’t identified on CT scan in the two cases. In our cases, optic disc drusen causes peripapillary haemorrhages proceeding from the same mechanism with a juxtapapillary choroidal neovascularization. Because of the location of the hemorrhage only monitoring was recommended. Partial spontaneous visual acuity improvement in 6 months was observed with regression of haemorrhage. Conclusion Optic nerve head drusen are calcified deposits arising from the prelaminar portion of the optic nerve, they have a reported prevalence of 0.4% in children. Although usually benign, their presence can sometimes be associated with serious ocular conditions and cause amblyopia. They have been reported to cause myriad local vascular complications, including central retinal artery and vein occlusion and peripapillary choroidal neovascularization.

In phagocytic cells, the endolysosomal system is a crucial regulator of both phagocytosis and autophagy, thereby helping to maintain cellular homeostasis. Prime examples of this are retinal pigmented epithelial (RPE) cells, which are not only among the most actively phagocytic cells, continuously phagocytosing shed photoreceptor outer segments (OS), but also are post-mitotic cells having high metabolic activity and a high rate of autophagy. For proper RPE function, and to ensure the functional integrity of the neural retina, both phagocytosis and autophagy need to be in balance. We show that in the RPE, bA3/A1-crystallin is required for normal lysosomal-mediated waste removal. Our studies suggest that bA3/A1-crystallin acts via the AMPK-mTORC1 signaling pathway. Based on our findings, we postulate that loss of bA3/A1-crystallin inhibits these signaling pathways, leading to a defect in the V-ATPase-mediated acidification of the lysosomal machinery. Since bA3/A1-crystallin has been reported to be present in human drusen and a possible role for lysosomes in age-related macular degeneration (AMD) has been suggested, it is possible that perturbation of normal phagocytosis/autophagy in RPE could cause some manifestations of AMD.

Purpose The objective of this study is to examine long-term effects of low-level laser therapy (LLLT) in patients with age-related macular degeneration (AMD). Methods The research was implemented for a period of two years. For LLLT, a He-Ne Laser with continuous emission at 633 nm (01 mW/cm2) was used in patients with AMD of all stages (dry to wet exudative forms were included). In total, 54 patients (25 men and 29 women - 108 eyes) with AMD of various stages and a mean age of 67.5 ±5.2 years were included in the study. Progressive, exudative AMD was diagnosed in 33 eyes. 75 eyes had drusen or were depigmented. Laser radiation was applied transpupillary 6 times for 3 min once in two days to the macula. 20 patients with AMD (40 eyes) were randomly selected to receive mock treatment (control group 9 men and 11 women with a mean age of 68.5± 4.2 years). Visual acuity was followed for a 2-year period. The perimetry and Amsler test was used to screen central scotomas. Fluorescein angiogram of AMD and control groups was examined. Results Visual acuity remained unchanged in all patients in the control group. There was a statistically significant increase in visual acuity (p

Purpose To investigate the distribution and expression of macrophage phenotypes and the complement activation protein, C3d, in human choroid/retina in young, aged and AMD eyes. Methods Paraffin sections of central and peripheral choroid/retina from young ( 70 years, n=4) and AMD (>70 years, n=8) human post-mortem eyes were co-immunolabelled with antibodies to leukocyte and macrophage markers (CD68, CD163, Iba1 & CD45) and complement activation component, C3d. Localisation and distribution of antibodies was assessed using confocal microscopy. Counts of macrophage sub-populations were compared in central and peripheral choroid for each group. Results Heterogeneous populations of macrophages were found in the choroid/retina of all groups. Iba1+ and CD45+ retinal microglia and macrophages, and choroidal macrophages were observed in all eyes. In AMD eyes, Iba1+ and CD45+ cells were seen in the subretinal space amongst photoreceptors, as well as in inner retina. Compared to young eyes, aged and AMD specimens showed increased numbers of CD163+ macrophages (M2, proangiogenic) in choroid, and in central vs peripheral retina. Fewer CD68+ cells were seen in all specimens, regardless of age or location. C3d was expressed in young, aged and AMD eyes, localised to Bruch’s membrane and choriocapillaris, with more extensive immunostaining in aged and AMD eyes. C3d was also seen in drusen in aged and AMD eyes, and more peripherally, compared to young eyes. Conclusion Age-related changes in macrophage phenotypes and in complement pathway activation at the choroidal/retinal interface may play a role in development and progression of AMD. Supported by Sydney Foundation for Medical Research.

Purpose To summarize salient characetristics of suspicious uveal naevi and guidelines for their management. Methods Review of literature and personal experience. Results The differential diagnosis of uveal naevi and melanoma is based on clinical examination with the slit lamp and indirect ophthalmoscope together with ultrasonography of the eye. Large to medium-sized melanomas are reliably differentiated from naevi using these methods. The challenge lies in early detection of small melanomas which are more difficult to tell from presumed naevi. A useful mnemonic 'To Find Small Ocular Melanomas' reminds the general ophthalmologist to look for tumour Thickness of more than 2 mm, subretinal Fluid, visual Symptoms, Orange pigment and location of the tumour Margin at the optic disc. Optical coherence tomography and fundus autofluorescence imaging help in identifying subretinal fluid and orange pigment and in measuring the thickness of thin choroidal naevi and melanomas. Each of the risk characteristics roughly doubles the likelihood of growth so that the risk for growth is about 30 times higher when all five characteristics are present as compared to their absence. In addition, a low acoustic profile, the absence of a halo around the tumour and the absence of drusen over it increase the likelihood of growth. The trend is toward taking a biopsy of suspicious small choroidal tumours as an alternative to documenting growth before treating them as melanomas. Conclusion Patients with a choroidal melanocytic tumour with at least one risk characteristic benefit from referral to an ocular oncologist. The rest of the patients can be made aware of their presumed naevus and that they should be observed periodically. The patients should be told to return immediately if they develop new visual symptoms.

Purpose To evaluate the impact of AMD on Alzheimer disease and their in-between visionary correlation. Methods 285 patients, 95 men, 190 women, with AMD.3 Groups A,B,C: A, 90 patients with first stage AMD (drusen, drusenoid PED, pigment, small atrophic areas);B:80 patients with predominant atrophic areas;C,115 patients with Neovascular AMD. AMD evaluation included ETDRS visual acuity (VA), complete ophthalmic examination, autofluorescence imaging (FAF), optical coherence tomography (OCT) and fluorescein (FA) angiography, and ICG when neovascular complication.AD was diagnosed and valuated by general practice doctors and /or neurologists. Results 20% patients in group A , 25% in group B, 30% in group C have mild cognitive impairment (MCI). 25% in group B, 35% in group C have early stage AD. 20% in group C have symptomatic AD. AMD ophthalmologic signs are predictive and precursor for AD. Fundus examination and even more (FAF , OCT) are useful and needed to enhance AD screening and follow-up. Conclusion The AMD-AD correlation allows us to improve detection, follow-up, screening of both AMD and AD pathologies and furthermore progress in etiopathogenic knowledge and therapeutic prospects.

Age-related macular degeneration (AMD) shares several pathological and epidemiological similarities with systemic atherosclerosis (AS). First, an association between AS and AMD is apparent from the analyses of the histological and biochemical structure of atherosclerotic plaques in the vascular walls and retinal drusen, the hallmark of AMD. Second, there is considerable evidence implicating endothelial dysfunction in the pathogenesis of both disorders, and cellular oxidative stress appears to be a common denominator underlying this process. Moreover, there are observations that the complement system (CS) triggering inflammatory response contributes to the onset and advancement of both diseases. The CS plays a role in the generation of drusen and neovascularization in AMD as well as in vascular endothelium activation, cell damage and ultimately atherosclerotic plaque formation in the course of systemic arteriosclerosis. It is widely recognized that both AMD and AS are not only related to local stimulation of the CS, but also result in its systemic activation. In addition, a specific Y402H polymorphism of the complement inhibitor factor H has been found to be associated with the incidence of both AMD and AS. Here, we propose a linking hypothesis between CS activation, endothelial dysfunction and the pathogenesis of two common and age-related pathological processes, AS and AMD. We also discuss the potential therapeutic value of pharmacological modulation of CS activation in these disorders.

Purpose To document cases of drusen and age-related geographic atrophy(GA) at the microscopic scale using adaptive optics(AO). Methods Four cases of age-related drusens, 2 cases of familial drusen and 7 patients of GA underwent en face retinal imaging by AO retinal camera(rtx1, Imagine Eyes, Orsay, France). AO images were confronted to high-resolution spectral-domain optical coherence tomography(OCT) and scanning laser ophthalmoscopy(SLO) examinations. Results In AO images, most drusen appeared as doughnut-shaped highly reflective zones, and were better delineated than by color fundus photograph. The overlying cone mosaic could be detected over most of them, including their top. Between drusen, the cone photoreceptor mosaic appeared normal. In GA cases, AO images revealed irregular patches of multiple cone-like bright spots as well as larger dark disks in atrophic areas. Conclusion AO provided images of microscopic structures in various types of AMD, including GA. Local losses in cone contrast at the drusen slopes confirmed a strong relation between cone visibility and their orientation. There was no evidence of cone loss in association to drusen. In GA patients, our findings suggest that photoreceptors with shortened outer segments may survive within atrophic areas, which may lead to the development of novel therapeutic strategies aimed at restoring the function of surviving cones. These results demonstrate that AO retinal camera can detect isolated residual photoreceptors, and hence that it will be a powerful tool for quantifying spontaneous or therapeutic changes in AMD patients. Supported by ANR through Tecsan Program (project iPhot n° ANR-09-TECS-009)

Purpose To distinguish fluorophores at the human ocular fundus by their different emission spectra. Methods Autofluorescence images were taken from 62 eyes (78.3±6.3 years) with age-related macular degeneration (AMD), 65 eyes (71.2±8.4 years) with diabetic retinopathy (RD), and 19 eyes (60.7±18.3 years) without any ophthalmic or systemic pathology (control group) by a fundus camera. All eyes were pseudophacic. A 3-chip color CCD camera was used as detector, recording the fluorescence in two separate spectral bands: Upon excitation at 475-515 nm, fluorescence was observed at 530-570 nm and 570-675 nm. For a global estimation of the fluorescence characteristics, the ratio of the green vs. the red emission (g/r) was calculated in a 70 by 70 pixel area temporal to the macula and apart from pathologic lesions and retinal vessels. Local changes of fluorescence emission spectra were assessed. Results An orange fluorescence was found in the control group. Compared to that group (g/r=0.869±0.073), the global fundus fluorescence of AMD-patients (g/r=0.906±0.105) and diabetics (g/r=0.974±0.119) was green-shifted. This shift was statistically significant (t-test, p=0.001) for the RD and the control group. The optic disc, hypo-fluorescent atrophic areas (geographic atrophy, laser scars), hyper-fluorescent drusen, and lipid exudates appeared greenish. Conclusion The ocular fundus autofluorescence is dominated by the orange fluorescence of lipofuscin. The green-shift of the fluorescence in AMD and RD may indicate protein glycation since advanced glycation end products show green fluorescence. Greenish fluorescence of drusen and exudates reveal non-lipofuscin fluorescence which needs further clarification. Color autofluorescence visualizes different fluorophores and, thus, may be of diagnostic merit.

Purpose To review the important aspects of the history and fundus examination that serve as clues toward diagnosis Methods didactic lecture Results In the patient with unilateral disc swelling, it is important to discern if the patient has noted accompanying visual loss and / or pain. If visual dysfunction is noted, is it unilateral or bilateral, acute or subacute? If pain is an accompanying feature, is it localized pain or diffuse headache, is it associated with eye movements or constant? The examination should first affirm that the swollen disc appearance is not due to a congenital anomaly like buried drusen, hamartoma or hypoplasia. In the event of true, acquired optic disc swelling, certain features such as segmental edema, pallid swelling or the presence of retinociliary shunt vessels point strongly to specific diagnoses. Conclusion History and careful examination are the first steps to diagnosis in the patient with unilateral disc swelling. Commercial interest

Purpose To recall that fluorescein angiography (FA) is not only the basis of our knowledge but also mandatory to improve our understanding. Methods Macular disciform lesions have been described and drawed since about 150 years. It is only in 1977 with the advent of fluorescein that the connection with choroidal new vessels (CNV) was performed. The identification of drusen as precursors of CNV was the following stage. With time a number of precursors and clinical forms of macular degeneration were described. Results Currently, the precursors (Age-Related Maculopathy) are distinguished from the neovasdcular or atrophic complications (Age-Related Macular Degeneration). The precursors presenting an early hyperfuorescence can be either hard drusen or RPE atrophy distinguished from each other on the late phase of FA.The late hyperfluorescence of soft drusen particularly when confluent requires a careful analysis of the complete FA sequence to ensure the diagnosis. The neovascular stage presents mainly as sub epithelial occult lesions of which the other types develop that display different angiographic behaviours. Specific aspects have been described gradually based on their FA features. The atrophic stage of the disease seems to behave in a stereotyped way but sub goups are presently identified. Conclusion The fluorescein features of the different component of AMD remain the reference for all other more recent imaging technics and helps to understand and differentiate the various aspects of the disease.

Purpose Two different systems, adaptive optics scanning laser ophthalmoscope (AOSLO), and Spectral Domain Ophtalmoloscopy (SD-OCT) were used to visualize cones in the outer neurosensory retina overlying soft macular drusen and the surrounding retinal areas. Methods High resolution images were obtained with Adaptive Optics (AO) in addition to complete ophthalmic examination including BCVA on ETDRS chart, biomicroscopic examination, autofluorescence imaging, fluorescein and indocyanine angiographies (HRA2 Heidelberg ,Germany) and SD-OCT. The AO image are then compared with conventional infrared and SD-OCT. Soft macular drusen from 50 patients (age between 65 and 85) visible on the scanning laser ophthalmoscope(SLO) examination were evaluated included in the study Results The soft drusen were visible in AO images as generally round areas delimited by a peripheral low-reflectance line. The highly reflective photoreceptor inner/outer segment junction (IS/OS) can be used as a pattern of photoreceptors integrity in SD-OCT images. In areas where the IS/OS junction is absent on SD-OCT, no cones are visualized in registered AOSLO images. In the inner area of many drusen, hyper reflective spots of a size between 2 and 15 µm were sometimes isolated, sometimes grouped into tight aggregates of 2 to 40 components. Cone photoreceptors were visible in areas between drusen in most AO images, however the mosaic image sharpness was significantly less uniform in these elderly patients than previously observed in younger, healthy retinas. Conclusion This study shows the synergistic nature of these two high-resolution retinal imaging systems The microscopic characteristics of soft drusen on AO imaging suggest some analogy with the anatomopathologic characteristics. AO technology will be a powerful tool to refine their clinical classification

Purpose To summarise signs and symptoms useful in diagnosing adult ophthalmic tumours. Methods Personal experience of the author as a member of the European Ophthalmic Oncology Group. Results According to studies from the United Kingdom, Finland and United States, 28-42% of adult patients with intraocular tumours may experience delays because the lesion is either misdiagnosed (e.g. as macular degeneration, naevus, rhegmatogenous retinal detachment) or missed at the initial visit. Of these patients, 72-87% have symptoms attributable to the tumour such as blurred vision, photopsia, floaters, metamorphopsia, and visual field loss. These symptoms can also be caused by many benign conditions (e.g. vitreous detachment) but should not be interpreted as innocent without thorough clinical examination. Signs specific for iris and ciliary body tumours include a tumour mass, sentinel vessels, acquired astigmatism, and cataracts. Choroidal tumours may induce serous retinal detachments, subretinal and vitreous bleedings and, sometimes, lipid exudation. Finally, orange subretinal pigment suggests the diagnosis of a uveal melanoma whereas many drusen point to a long-standing naevus. Conclusion Signs and symptoms of ophthalmic tumours are mostly nonspecific, necessitating an appropriately high level of suspicion and a systematic approach to clinical examination to avoid delayed or missed diagnoses. Earlier diagnosis could be achieved especially if dilated fundus examinations were performed without exception and if all suspicious naevi were referred for a second opinion.