RHEOHEMAPHERESIS IN THE TREATMENT OF DRY FORM OF AMD. A CASE REPORT.

AIM: We present a case report of a patient with dry form of age-related macular degeneration (AMD) in whom we monitored the effect of rheohemapheresis (RhF) treatment over 6 years. METHODS: A 67-year-old man was examined in April 2014 at the Department of Ophthalmology at the University Hospital in Hradec Králové for metamorphopsia and decreased visual acuity of the left eye. The patient received general treatment for hypercholesterolemia with Lipfix 10 mg once a day (atorvastatin 10 mg). The cholesterol level in the blood was 3.41 mmol/l, the lipid profile was normal. The patient's previous ocular medical history was unremarkable. The patient reported ocular complaints over the course of the last year, the main symptom of which was image distortion on the Amsler grid on the left eye. Baseline best corrected visual acuity of the left eye was 6/10. Visual acuity in the right eye was 6/6. In both eyes, the findings on the anterior segment corresponded to the patient's age, with the exception of incipient cortical cataract. On the fundus of both eyes, the border of the optic nerve was demarcated, in the macula of the left eye there were a number of soft confluent drusen, in the central periphery there were no pathological changes. On the fundus of the right eye the finding was similar, but to a lesser degree. Optical coherence tomography on the macula of the left eye showed drusoid ablation of the retinal pigment epithelium (RPE), with accumulation of hyperreflectivities below the RPE. Pattern-reversal electroretinography (pERG): showed a slightly prolonged retention of the activity of the central region of the retina (p50 wave) and ganglion cells (N95 wave). Multifocal electroretinography (mfERG) in the central 30° of the retina was within normal limits. Electroretinography (ERG) demonstrated physiological photopic and scotopic rod activity. The patient was treated with 8 RhF procedures, two per week, with a 2-week interval, and the pulse was repeated 4 times. RESULTS: We noted a gradual resorption of soft drusen in the patient, with attachment to the RPE line according to OCT examination at the following sixmonthly check-ups over the next 6 years. Visual acuity of both eyes was maintained at the baseline values at the last check-up in April 2020, the area of soft drusen was significantly reduced. The function of the rod, cone system and the central region of the retina mfERG fluctuated only to an insignificant degree during the entire follow-up period, with a tendency towards a slight increase in activity after RhF treatment. CONCLUSION: We noted an improvement of the anatomical and functional findings in a patient with dry form of AMD during a 6-year follow-up period after RhF treatment. The visual acuity of the affected eye remained at the baseline values.

Progression from intermediate to neovascular age-related macular degeneration according to drusen subtypes: Bundang AMD cohort study report 3.

PURPOSE: To investigate the ophthalmic risk factors related to neovascular change and the subtype-wise incidence of progression from intermediate to neovascular age-related macular degeneration (AMD). METHODS: In this retrospective cohort study, 632 eyes with intermediate AMD from 418 patients (older than 50 years) were enrolled. The systemic factors and ophthalmic factors were statistically analysed with respect to neovascular change. RESULTS: The 5-year cumulative incidence of progression to neovascular AMD (nAMD) from intermediate AMD was 17.8% and 17.0% in eyes with soft drusen and pachydrusen (p = 0.316). Older age (p = 0.025), preexisting nAMD in the fellow eye (p < 0.001), and reticular pseudodrusen (RPD; p = 0.007) were associated with the risk of progression to nAMD. In reference to soft drusen, pachydrusen was associated with progression to polypoidal choroidal vasculopathy (PCV; p < 0.001) and not to typical nAMD (p = 0.064). CONCLUSIONS: The ophthalmic risk factors related to the progression of nAMD from intermediate AMD were found to be preexisting nAMD in the fellow eye and RPD. Pachydrusen showed a similar incidence of neovascular change with soft drusen, and was associated with the progression to PCV but not to typical nAMD.

Vascular and structural alterations of the choroid evaluated by optical coherence tomography angiography and enhanced-depth imaging optical coherence tomography in eyes with reticular pseudodrusen and soft drusen.

BACKGROUND: To assess the vascularity of choriocapillaris and structural choroidal differences in eyes with reticular pseudodrusen (RPD) and soft drusen. METHODS: 21 eyes with RPD (group 1), 17 eyes with soft drusen (group 2), and 19 eyes as a control group (group 3) were included in this study. Choriocapillaris vascular density and flow area were measured by optical coherence tomography angiography. Total choroidal area, luminal area, stromal area, and lumen/stroma ratios were measured on optical coherence tomography B-scans converted to binary images. RESULTS: Mean choriocapillaris vascular density was higher in group 3 than other groups (group 1 vs 3, p = 0.001; group 2 vs 3, p = 0.003). Mean flow area in choriocapillaris was higher in group 3 than other groups (group 1 vs 3, p = 0.001; group 2 vs 3, p = 0.001). Mean luminal, stromal, and total choroidal areas decreased in group 1 and group 2 compared to controls (p < 0.001, p < 0.001, and p < 0.001, respectively). The stroma ratio decreased in group 1 compared to group 3 (p = 0.013). The lumen ratio and lumen/stroma ratio increased in group 1 compared to group 3 (p = 0.012 and p = 0.008, respectively). CONCLUSIONS: The choroid of eyes with RPD and soft drusen was affected in both choriocapillaris and whole choroid layer.

Retinal Distribution and Extracellular Activity of Granzyme B: A Serine Protease That Degrades Retinal Pigment Epithelial Tight Junctions and Extracellular Matrix Proteins.

Granzymes are a family of serine proteases first shown to be intracellular initiators of immune-mediated cell death in target pathogenic cells. In addition to its intracellular role, Granzyme B (GzmB) has important extracellular functions in immune regulation and extracellular matrix (ECM) degradation. Verified substrates of extracellular GzmB activity include tight junctional and ECM proteins. Interestingly, little is known about the activity of GzmB in the outer human retina, a tissue in which the degradation of the tight junctional contacts of retinal pigment epithelial (RPE) cells and within the external limiting membrane, as well as remodeling of the ECM in Bruch's membrane, cause the breakdown of the blood-retinal barrier and slowing of metabolite transport between neuroretina and choroidal blood supply. Such pathological changes in outer retina signal early events in the development of age-related macular degeneration (AMD), a multifactorial, chronic inflammatory eye disease. This study is the first to focus on the distribution of GzmB in the outer retina of the healthy and diseased post-mortem human eye. Our results revealed that GzmB is present in RPE and choroidal mast cells. More immunoreactive cells are present in older (>65 years) compared to younger (<55 years) donor eyes, and choroidal immunoreactive cells are more numerous in eyes with choroidal neovascularization (CNV), while RPE immunoreactive cells are more numerous in eyes with soft drusen, an early AMD event. In vitro studies demonstrated that RPE-derived tight junctional and ECM proteins are cleaved by exogenous GzmB stimulation. These results suggest that the increased presence of GzmB immunoreactive cells in outer retina of older (healthy) eyes as well as in diseased eyes with CNV (from AMD) and eyes with soft drusen exacerbate ECM remodeling in the Bruch's membrane and degradation of the blood-retinal barrier. Currently there are no treatments that prevent remodeling of the Bruch's membrane and/or the loss of function of the outer blood-retinal barrier, known to promote early AMD changes, such as drusen deposition, RPE dysfunction and pro-inflammation. Specific inhibitors of GzmB, already in preclinical studies for non-ocular diseases, may provide new strategies to stop these early events associated with the development of AMD.

Pachydrusen in polypoidal choroidal vasculopathy in an Indian cohort.

Purpose: To report the prevalence of pachydrusen and their relationship with subfoveal choroidal thickness (SFCT) and large choroidal vessel layer thickness (SF-LCVT) in eyes with polypoidal choroidal vasculopathy (PCV) and their fellow eyes. Methods: The case records of 50 patients (99 eyes; 59 PCV and 40 fellow eyes) were retrospectively analyzed for the presence of pachydrusen and other drusen types such as soft drusen. The diagnosis was established using colour fundus photography and optical coherence tomography (OCT). SFCT and SF-LCVT were measured and correlated with the different types of drusen. Results: The mean age of the study cohort was 62.26 ± 10.67 years and included 27 males and 23 females. Pachydrusen and soft drusen were seen in 14 (PCV: 8 and fellow eyes: 6) and 8 eyes (PCV: 2 and fellow eyes: 6) respectively. The mean SFCT and SF-LCVT in the eyes with and without pachydrusen was not significanty different (280.29 ± 103.11 µ vs. 292.63 ± 87.17 µ; P = 0.63 and 180.57 ± 59.20 vs. 173.73 ± 54.86 µ; P = 0.67, respectively). The pachydrusen were most commonly located near the vascular arcades and showed scattered distribution pattern. Though SFCT and SF-LCVT was lower in the eyes with soft drusen compared to eyes with pachydrusen, it failed to reach statistical significance (SFCT, P = 0.1 and SF-LCVT, P = 0.06). Conclusion: The prevalence of pachydrusen in PCV and their fellow eyes is lower in Indian population suggestive of ethnic variations. SFCT and SF-LCVT was not noted to vary signifcantly in eyes with and without pachydrusen in this study cohort.

Longitudinal changes in outer nuclear layer thickness in soft drusen and reticular pseudodrusen.

BACKGROUND: Drusen are seen in the early and intermediate stages of age-related macular degeneration. A retrospective, two-year observational study at a tertiary centre was designed to assess outer nuclear layer thickness in different types of drusen. METHODS: Patients over 50 years of age with predominant soft drusen or reticular pseudodrusen were included in the study. Fundus photography, infrared, fundus autofluorescence and spectral domain optical coherence tomography were performed at baseline, years one and two. Outer nuclear layer thickness was measured in the nine Early Treatment Diabetic Retinopathy Study subfields, and the rate of thinning was determined using generalised estimating equations models. RESULTS: Data were analysed from 17 eyes with soft drusen and nine eyes with reticular pseudodrusen. Greater outer nuclear layer thinning was seen overall and in all subfields in reticular pseudodrusen as compared to soft drusen, with statistically significant differences found mostly in superior and nasal subfields of ring 2. The outer nuclear layer was 5-12 µm thinner in eyes with reticular pseudodrusen, and the rate of thinning was greater in eyes with reticular pseudodrusen in the outer superior subfield. CONCLUSIONS: Outer nuclear layer thickness is consistently lower in patients with reticular pseudodrusen compared with soft drusen, irrespective of subfield location. These structural findings may contribute to explain the functional abnormalities observed in patients with reticular pseudodrusen.

Pachydrusen in Indian population: A hospital-based study.

PURPOSE: To report the prevalence of pachydrusen in Indian population and their characteristics in relation to subfoveal choroidal thickness (SFCT), choroidal vascularity index (CVI) in comparison to eyes with soft drusen and subretinal drusenoid deposits (SDD) in age-related macular degeneration (AMD). METHODS: The study was a retrospective, cross-sectional study involving patients with a diagnosis of dry AMD in at least one eye. The diagnosis of soft drusen, SDD, and pachydrusen was made on the basis of color fundus photograph and optical coherence tomography (OCT). SFCT and CVI was calculated and compared among the different subtypes of drusen. RESULTS: A total of 169 eyes (143 dry and 26 wet AMD) of 85 patients with a mean age of 67.67 ± 9.57 years were included. In eyes with dry AMD, pachydrusen were seen in 12 eyes (8.4%) with a mean (±SD) SFCT of 289.66 ± 91.01 µ. The difference in SFCT was statistically significant (P = 0.001) using analysis of variance (ANOVA) test. The eyes with pachydrusen had significantly thickened choroid compared to the eyes with SDD (30 eyes; 21.0%) or combination of soft drusen and SDD (29 eyes; 20.3%) but not soft drusen (72 eyes; 50.3%). The difference of CVI in different subgroups was significant (P = 0.03). One eye in wet AMD group had concurrent pachydrusen. Comparison of SFCT and CVI in wet AMD and fellow dry AMD eyes were not significant. CONCLUSION: In Indian eyes with dry AMD, prevalence of pachydrusen (8.4%) is slightly lower compared to western literature (11.7%) and is associated with thicker choroid and higher CVI.

Directional ABCA1-mediated cholesterol efflux and apoB-lipoprotein secretion in the retinal pigment epithelium.

Cholesterol-containing soft drusen and subretinal drusenoid deposits (SDDs) occur at the basolateral and apical side of the retinal pigment epithelium (RPE), respectively, in the chorioretina and are independent risk factors for late age-related macular degeneration (AMD). Cholesterol in these deposits could originate from the RPE as nascent HDL or apoB-lipoprotein. We characterized cholesterol efflux and apoB-lipoprotein secretion in RPE cells. Human RPE cells, ARPE-19, formed nascent HDL that was similar in physicochemical properties to nascent HDL formed by other cell types. In highly polarized primary human fetal RPE (phfRPE) monolayers grown in low-lipid conditions, cholesterol efflux to HDL was moderately directional to the apical side and much stronger than ABCA1-mediated efflux to apoA-I at both sides; ABCA1-mediated efflux was weak and equivalent between the two sides. Feeding phfRPE monolayers with oxidized or acetylated LDL increased intracellular levels of free and esterified cholesterol and substantially raised ABCA1-mediated cholesterol efflux at the apical side. phfRPE monolayers secreted apoB-lipoprotein preferentially to the apical side in low-lipid and oxidized LDL-feeding conditions. These findings together with evidence from human genetics and AMD pathology suggest that RPE-generated HDL may contribute lipid to SDDs.

Geographic atrophy phenotype identification by cluster analysis.

BACKGROUND/AIMS: To identify ocular phenotypes in patients with geographic atrophy secondary to age-related macular degeneration (GA) using a data-driven cluster analysis. METHODS: This was a retrospective analysis of data from a prospective, natural history study of patients with GA who were followed for ≥6 months. Cluster analysis was used to identify subgroups within the population based on the presence of several phenotypic features: soft drusen, reticular pseudodrusen (RPD), primary foveal atrophy, increased fundus autofluorescence (FAF), greyish FAF appearance and subfoveal choroidal thickness (SFCT). A comparison of features between the subgroups was conducted, and a qualitative description of the new phenotypes was proposed. The atrophy growth rate between phenotypes was then compared. RESULTS: Data were analysed from 77 eyes of 77 patients with GA. Cluster analysis identified three groups: phenotype 1 was characterised by high soft drusen load, foveal atrophy and slow growth; phenotype 3 showed high RPD load, extrafoveal and greyish FAF appearance and thin SFCT; the characteristics of phenotype 2 were midway between phenotypes 1 and 3. Phenotypes differed in all measured features (p≤0.013), with decreases in the presence of soft drusen, foveal atrophy and SFCT seen from phenotypes 1 to 3 and corresponding increases in high RPD load, high FAF and greyish FAF appearance. Atrophy growth rate differed between phenotypes 1, 2 and 3 (0.63, 1.91 and 1.73 mm2/year, respectively, p=0.0005). CONCLUSION: Cluster analysis identified three distinct phenotypes in GA. One of them showed a particularly slow growth pattern.

Signal reduction in choriocapillaris and segmentation errors in spectral domain OCT angiography caused by soft drusen.

PURPOSE: To analyze signal reduction in choriocapillaris (CC) and segmentation errors in spectral domain optical coherence tomography angiography (OCT-A) caused by soft drusen due to age-related macular degeneration (AMD). METHODS: Twenty-four eyes of 24 patients underwent multimodal retinal imaging including central 3 × 3mm2 OCT-A (AngioVue, Optovue). Three drusen per study eye were randomly chosen and evaluated regarding drusen height, diameter, and accuracy of OCT-A layer segmentation in lesion proximity. Structural en-face OCT CC images were graded qualitatively and quantitatively regarding signal loss underneath the individual drusen area. Those drusen that showed no distinct signal loss in structural en-face OCT CC images were further evaluated in OCT-A. CC decorrelation signal index was measured within a 30-µm OCT-A CC slab in the exact area of drusen affection. Data were compared to healthy age-matched control subjects. Accuracy of layer segmentation, OCT CC data, and OCT-A CC data were correlated to morphological drusen parameters. RESULTS: Mean drusen height and diameter were 91.57 ± 19.5µm and 315.17 ± 116.7µm. OCT-A layer segmentation of the inner plexiform layer (IPL) was disturbed by more than 50 µm in proximity to 26 drusen (36.1%). In these patients, drusen height was significantly higher compared to those with accurate IPL segmentation (p = 0.0126). Sixty-six out of 72 drusen (91.7%) caused a distinct signal loss in the structural en-face OCT CC image. Drusen height and drusen diameter were significantly higher in this group compared to the six drusen with a sufficient signal (p = 0.0276, p = 0.0025). CC decorrelation signal index measured in the area of these six drusen without OCT signal loss (8.3%) was reduced compared to age-matched healthy controls (73.6 vs. 100.1; p = 0.001). CONCLUSIONS: Signal attenuation in CC slabs and segmentation errors of the IPL depend on drusen morphology. Both are frequent artifacts in OCT-A imaging in patients with soft drusen and must be considered during image analysis.

Gender Differences in the Relationship between Sex Hormone Deficiency and Soft Drusen.

PURPOSE: To investigate the association between sex hormone deficiency and soft drusen in women and men. MATERIALS AND METHODS: We retrospectively reviewed the medical records and fundus photographs of subjects who underwent a health screening for additional examination of climacterium and age-related changes including sex hormone status. In women, sex hormone deficiency was defined as cessation of menstruation that had lasted for at least 12 months and follicular stimulating hormone (FSH) levels ≥ 25 mIU/mL; in men, it was defined as testosterone levels ≤ 3.5 ng/mL. The subjects were divided into two groups-the soft drusen and control groups-based on the presence of soft drusen in the fundus photographs. The total drusen area was measured using ImageJ™ software. RESULTS: Of total 2036 subjects, 638 (271 women; 367 men) were included. Two hundred thirteen subjects (33.4%) had soft drusen (97/271 women, 116/367 men). In women, sex hormone deficiency was more common in the soft drusen group than in the control group (P < 0.001); this was not the case in men. Multivariate logistic regression analysis revealed that sex hormone deficiency was an independent risk factor for soft drusen in women (P < 0.001; odds ratio [OR] = 3.494), as was age (P < 0.001; OR = 1.092). A long post-menopausal period was a risk factor for large soft drusen (≥ 125 µm). (P < 0.001; OR = 1.220). Age was significantly associated with total drusen area in both women (P = 0.022; ß = 0.406) and men (P = 0.015; ß = 0.246). CONCLUSIONS: Sex hormone deficiency and its duration were significantly associated with the development and progression of soft drusen in women but not in men. It may be necessary to assess and manage the sex hormone deficiency in women with age-related macular degeneration.

Regression of Some High-risk Features of Age-related Macular Degeneration (AMD) in Patients Receiving Intensive Statin Treatment.

IMPORTANCE: Age-related macular degeneration (AMD) remains the leading cause of blindness in developed countries, and affects more than 150 million worldwide. Despite effective anti-angiogenic therapies for the less prevalent neovascular form of AMD, treatments are lacking for the more prevalent dry form. Similarities in risk factors and pathogenesis between AMD and atherosclerosis have led investigators to study the effects of statins on AMD incidence and progression with mixed results. A limitation of these studies has been the heterogeneity of AMD disease and the lack of standardization in statin dosage. OBJECTIVE: We were interested in studying the effects of high-dose statins, similar to those showing regression of atherosclerotic plaques, in AMD. DESIGN: Pilot multicenter open-label prospective clinical study of 26 patients with diagnosis of AMD and the presence of many large, soft drusenoid deposits. Patients received 80 mg of atorvastatin daily and were monitored at baseline and every 3 months with complete ophthalmologic exam, best corrected visual acuity (VA), fundus photographs, optical coherence tomography (OCT), and blood work (AST, ALT, CPK, total cholesterol, TSH, creatinine, as well as a pregnancy test for premenopausal women). RESULTS: Twenty-three subjects completed a minimum follow-up of 12 months. High-dose atorvastatin resulted in regression of drusen deposits associated with vision gain (+ 3.3 letters, p = 0.06) in 10 patients. No subjects progressed to advanced neovascular AMD. CONCLUSIONS: High-dose statins may result in resolution of drusenoid pigment epithelial detachments (PEDs) and improvement in VA, without atrophy or neovascularization in a high-risk subgroup of AMD patients. Confirmation from larger studies is warranted.

Intravitreal ranibizumab for symptomatic drusenoid pigment epithelial detachment without choroidal neovascularization in age-related macular degeneration.

BACKGROUND: The aim of our study was to evaluate the functional and anatomic outcomes of intravitreal ranibizumab for the treatment of symptomatic drusenoid pigment epithelial detachment without choroidal neovascularization in age-related macular degeneration. METHODS: This was a prospective, single-center, uncontrolled, interventional pilot study. Six consecutive eyes (six patients) with drusenoid pigment epithelial detachment with a visual acuity of 20/63 to 20/100 and no evidence of choroidal neovascularization in age-related macular degeneration participated. Patients were given at least one intravitreal ranibizumab injection and were followed for a mean of 66.67 ± 10.3 weeks. Main outcome measures included best-corrected visual acuity (BCVA) measured by Early Treatment Diabetic Retinopathy Study charts and optical coherence tomography, and central macular thickness measured by optical coherence tomography. RESULTS: The mean number of intravitreal ranibizumab injections was 3.0 at the end of follow-up. Regarding BCVA and optical coherence tomography, 33.3% of eyes gained between 19 and 21 letters of BCVA, with a median decrease in central macular thickness of 21 µm. There was a statistically significant difference between baseline and final BCVA (P = 0.046). There was a positive correlation between intraretinal fluid by optical coherence tomography and improved BCVA after intravitreal ranibizumab. Metamorphopsia disappeared completely after the first injection in all subjects, with no further recurrences. No patient developed choroidal neovascularization or atrophic changes. CONCLUSION: Intravitreal ranibizumab demonstrated anatomic and functional benefit in patients with symptomatic drusenoid pigment epithelial detachment without choroidal neovascularization in age-related macular degeneration. Further long-term, randomized, controlled trials should be performed to confirm our preliminary results.