Half-dose photodynamic therapy versus 577 nm subthreshold pulse laser therapy in treatment-naive patients with central serous chorioretinopathy.

BACKGROUND: To compare real-life anatomical and functional outcomes of half-dose photodynamic therapy (HD-PDT) and 577 nm subthreshold pulse laser therapy (SPL) in treatment-naïve patients with central serous chorioretinopathy (CSC). METHODS: We retrospectively reviewed consecutive treatment-naïve CSC patients with non-resolving subretinal fluid (SRF) for more than 2 months who received either HD-PDT or SPL treatment. One repetition of the same treatment was allowed in patients with persistent SRF after first treatment. Functional and anatomical outcomes were assessed after first treatment and at final visit. RESULTS: We included 95 patients (HD-PDT group, n = 49; SPL group, n = 46). Complete resolution of SRF after a single treatment was observed in 42.9% of HD-PDT-treated patients (n = 21; median time to resolution 7.1 weeks) and in 41.3% of SPL-treated patients (n = 19; median time to resolution 7.0 weeks). In the HD-PDT-group, 44.9% of patients (n = 22) and in the SPL-group, 43.5% (n = 20) of patients, received a second treatment due to persistent SRF, while 12.2% (n = 6) and 15.2% (n = 7), respectively, opted against a second treatment despite persistent SRF. After the final treatment, complete SRF resolution was observed in 61.2% of all HD-PDT-treated patients (n = 30; median time to resolution 8.8 weeks) and 60.9% of all SPL-treated patients (n = 28; median time to resolution 13.7 weeks, p = 0.876). In the final visit, both groups showed significant improvement of BCVA in comparison to baseline (p < 0.001 for all). The change in BCVA from baseline to final visit was similar for the two groups (HD-PDT, median BCVA change 0.10 logMAR (IQR: 0.0-0.2); in SPL group, median BCVA change 0.10 logMAR (IQR: 0.0-0.2), P = 0.344). The CSC subclassification (simple versus complex) had no influence on the anatomical or functional outcome. CONCLUSIONS: High-density 577 nm SPL resulted in as good anatomical and functional treatment as HD-PDT and may thus represent a treatment alternative to HD-PDT in CSC.

Ocular and Systemic Complement Activation during Anti-Vascular Endothelial Growth Factor Treatment and Age-Related Eye Disease Study 2 Dietary Supplementation in Neovascular Age-Related Macular Degeneration.

PURPOSE: The aim of this study was to investigate the influence of dietary supplementation using Age-Related Eye Disease Study 2 (AREDS2) on complement activation in patients with neovascular age-related macular degeneration (nAMD) under ongoing treatment. METHODS: In this prospective, single-center, controlled, open-label investigator-initiated trial, eligible nAMD patients were randomized at a ratio of 1:1 in 2 groups: those with and without dietary AREDS2 supplementation for 4 weeks. Zinc, plasma, and aqueous humor (AH) complement levels were quantified via enzyme-linked immunosorbent assays. RESULTS: Fifty of 62 enrolled patients completed the trial (AREDS2 n = 27, controls n = 23). Systemic zinc and complement levels were not different at baseline between the 2 groups (p > 0.1). At the final visit, systemic zinc levels were significantly higher in the AREDS2 group (10.16 ± 2.08 µmol/L; 8.66 ± 1.17 µmol/L; p = 0.007), whereas systemic and AH complement levels were not different (p > 0.1). In both groups, no significant change was observed in systemic levels of C3, C3a, FH, FI, and sC5b-9 (p > 0.1). Only systemic complement component Ba showed an increase from baseline to the end visit (p = 0.01). This increase was higher in the control group (p = 0.02) than in the AREDS2 group (p = 0.23). CONCLUSIONS: Short-term dietary AREDS2 supplementation leads to a significant increase in systemic zinc levels without any influence on complement activation levels.

SALIVARY ALPHA-AMYLASE LEVELS MAY CORRELATE WITH CENTRAL SEROUS CHORIORETINOPATHY ACTIVITY.

PURPOSE: To investigate and compare the salivary alpha-amylase (sAA) activity as an indicator of the sympathetic activity and stress response in patients with central serous chorioretinopathy (CSC) and healthy control subjects. METHODS: Prospective multicenter case series, including 80 CSC patients and 88 healthy control subjects. Central serous chorioretinopathy status was classified as either active or inactive, depending on the presence of subretinal fluid on optical coherence tomography. Salivary samples were collected in the morning from patients and control subjects of the main cohort and at midnight for the additional cohort. Salivary alpha-amylase activity was determined in all patients and control subjects. RESULTS: Morning sAA activity was significantly higher in patients with active CSC compared with inactive CSC (P = 0.049) and to healthy control subjects (P = 0.012). There was no significant difference in sAA activity between patients with inactive CSC and control subjects (P = 1.0). Nocturnal sAA activity did not show any significant difference between patients with active CSC and either inactive CSC or control subjects (P = 0.139). CONCLUSION: Morning sAA activity is increased in patients with active CSC, although diurnal rhythmicity is preserved. Measurement of sAA is easy to perform and might be an eligible tool to further investigate the relation between stress and CSC.

Association of imaging biomarkers and local activation of complement in aqueous humor of patients with early forms of age-related macular degeneration.

PURPOSE: To investigate a possible correlation between established imaging biomarkers for age-related macular degeneration and local complement system activation, measured in aqueous humor (AH) of patients with early stages of age-related macular degeneration (AMD) and controls. METHODS: This analysis included prospectively acquired AH samples of 106 eyes (35 with early/intermediate AMD, 71 controls). The levels of complement protein 3 (C3), 4 (C4), 5 (C5); activation products of complement factor 3a (C3a) and Ba, C3b/iC3b; complement factors B, D, H, I (CFB, CFD, CFH, CFI); and total protein concentration were analyzed. Quantitative levels of complement factors were correlated to the presence of reticular pseudodrusen (RPD), the presence of hyperreflective foci (HRF), and total drusen volume (DV) graded on imaging by spectral-domain optical coherence tomography and using Spearman's rank correlation test. RESULTS: DV correlated with C3b/iC3b (r = 0.285; P = 0.034), C3a (r = 0.200; P = 0.047), Ba (r = 0.262; P = 0.009), and C5 (r = 430; P = 0.005), and showed a tendency towards correlation with C3a (r = 0.198; P = 0.057). HRF correlated significantly with C5 (r = 0.388; P = 0.011) and RPD showed a tendency towards correlation with CFB (r = 0.196; P = 0.050). CONCLUSION: In patients with early AMD, HRF and drusen parameters but not RPD show low to fair levels of correlation with local complement activation in patients' AH. Better understanding of complement activation could provide some insights into the pathogenesis of AMD. Imaging biomarkers could be useful to identify suitable patients for future clinical trials with complement-modulating therapies.

Major Predictive Factors for Progression of Early to Late Age-Related Macular Degeneration.

INTRODUCTION: We present a prediction model for progression from early/intermediate to advanced age-related macular degeneration (AMD) within 5.9 years. OBJECTIVES: To evaluate the combined role of genetic, nongenetic, and phenotypic risk factors for conversion from early to late AMD over ≥5 years. METHODS: Baseline phenotypic characteristics were evaluated based on color fundus photography, spectral-domain optical coherence tomography, and infrared images. Genotyping for 36 single-nucleotide polymorphisms as well as systemic lipid and complement measurements were performed. Multivariable backward logistic regression resulted in a final prediction model. RESULTS AND CONCLUSIONS: During a mean of 5.9 years of follow-up, 22.4% (n = 52) of the patients (n = 232) showed progression to late AMD. The multivariable prediction model included age, CFH variant rs1061170, pigment abnormalities, drusenoid pigment epithelial detachment (DPED), and hyperreflective foci (HRF). The model showed an area under the curve of 0.969 (95% confidence interval 0.948-0.990) and adequate calibration (Hosmer-Lemeshow test, p = 0.797). In addition to advanced age and carrying a CFH variant, pigment abnormalities, DPED, and HRF are relevant imaging biomarkers for conversion to late AMD. In clinical routine, an intensified monitoring of patients with a high-risk phenotypic profile may be suitable for the early detection of conversion to late AMD.

Elevated Steroid Hormone Levels in Active Chronic Central Serous Chorioretinopathy.

Purpose: Chronic central serous chorioretinopathy (cCSC) is characterized by fluid accumulation between photoreceptors and the retinal pigment epithelium of which the cause is unknown. Associations with steroid use, stress, pregnancy, and the male sex suggest a role for the steroid hormone system in the disease. Here, we performed a comprehensive analysis of the steroid hormone system in active cCSC. Methods: Serum hormone levels of 17 steroid hormones were measured in 46 male Caucasian patients with active cCSC and 46 male Caucasian age-matched controls using the AbsoluteIDQ stero17 kit. Results: Elevated levels of androsterone, estrone, etiocholanolone, and androstenedione were observed in cCSC patients compared with controls. Median hormone levels in cCSC patients versus controls, respectively, were as follows: androsterone, 0.84 ng/mL (interquartile range [IQR] = 0.61-1.06) versus 0.69 ng/mL (IQR = 0.48-0.96, P = 0.031); estrone, 0.12 ng/mL (IQR = 0.10-0.15) versus 0.10 ng/mL (IQR = 0.08-0.11; P = 0.0048); etiocholanolone, 0.19 ng/mL (IQR = 0.15-0.29) versus 0.13 ng/mL (IQR = 0.099-0.20, P = 0.0061). Mean levels of androstenedione were 3.10 ng/ml (SD = 1.03) versus 2.55 ng/mL (SD = 0.95), in cCSC patients versus controls, respectively. Additionally, Spearman's correlations between aldosterone and 11-deoxycortisol, androsterone, DHEA, DHEAS, and E1 differed between cCSC patients and controls, as well as between andosterone and E1, and between DHT and 17OHP. Conclusions: We present a comprehensive overview of the status of the steroid hormone system in active cCSC. Levels of four hormones were elevated in cCSC patients compared with controls, and the relationships between steroid hormones was altered, indicating that the balance in the steroid hormone system is altered in cCSC patients.

COMPARISON OF RESOLUTION OF VITREOMACULAR TRACTION AFTER OCRIPLASMIN TREATMENT OR VITRECTOMY.

PURPOSE: To compare the functional and morphologic outcome of patients with vitreomacular traction (VMT) treated with either ocriplasmin treatment or vitrectomy. METHODS: Retrospective case series of patients treated with ocriplasmin or vitrectomy for VMT. OUTCOME MEASURES: resolution of VMT, change in outer retinal thickness, integrity of ellipsoid zone, subretinal fluid formation, and best-corrected visual acuity 2 weeks and 4 months after treatment. RESULTS: Fourteen eyes received ocriplasmin (Group 1). Vitreomacular traction resolved in 50% (Group 1a), and in 50%, it did not (Group 1b). Ten eyes underwent vitrectomy (Group 2). Vitreomacular traction resolved in 100%. Outer retinal thickness decreased significantly 2 weeks after treatment in Group 1 (P = 0.003) and in 1a (P = 0.018). Two weeks after treatment, Group 1a showed a disruption of the ellipsoid zone (P = 0.001) and subretinal fluid formation (P = 0.01) more often than 1b. Neither was observed 4 months after treatment. Best-corrected visual acuity decreased significantly in Groups 1 (P = 0.034) and 1a (P = 0.026). CONCLUSION: Most patients treated with ocriplasmin for VMT showed a transient reduction of best-corrected visual acuity, accumulation of subretinal fluid, and a loss of the ellipsoid zone after the resolution of VMT. Patients with surgical resolution of VMT did not show these findings. The advantage of a less-invasive intravitreal injection of ocriplasmin must be weighed against the lower success rate, the (transient) morphologic changes, and the uncertain visual benefit.

Onset of Retinal Pigment Epithelium Atrophy Subsequent to Anti-VEGF Therapy in Patients with Neovascular Age-Related Macular Degeneration.

PURPOSE: The aim of this study was to evaluate risk factors for the development of retinal pigment epithelium (RPE) atrophy in patients with neovascular age-related macular degeneration (nAMD). PROCEDURES: This post hoc analysis of the prospective RESPONSE study includes 52 therapy-naive nAMD patients without baseline RPE atrophy, who were treated with ≥9 anti-vascular endothelial growth factor (VEGF) injections for ≥3 years. RPE atrophy was assessed via multimodal imaging. Baseline aqueous VEGF and serum complement levels (C3d/C3) were measured. Risk factors for atrophy development were evaluated via logistic regression analysis. RESULTS: Atrophy onset was significantly associated with the duration of nAMD (mean 5.34 years; odds ratio = 1.83, p = 0.012). Anti-VEGF injection number, age, C3d/C3 ratio, baseline intraocular VEGF, or delay to the first treatment had no influence on RPE atrophy. CONCLUSIONS: The duration of treatment-requiring nAMD was identified as primary risk factor for the onset of concomitant RPE atrophy after commencing therapy. Targeting concomitant atrophy in nAMD patients might improve the long-term prognosis of the disease.

Early Changes of Retinal Morphology in Therapy of Neovascular Age-Related Macular Degeneration with Three Commonly Used Anti-VEGF Agents.

PURPOSE: To compare changes of retinal morphology in the first weeks following injection of anti-VEGF agents for neovascular age-related macular degeneration (nAMD). PROCEDURES: In a prospective study 50 patients with active choroidal neovascularization secondary to nAMD were monitored weekly by spectral-domain optical coherence tomography for 3 weeks after treatment. Twenty-two patients received bevacizumab, 15 ranibizumab, and 13 aflibercept. Morphological parameters of retinal compartments were compared. RESULTS: Mean central retinal thickness (391.22 ± 123.41 µm) was reduced by -26.15 µm (p < 0.001) after 1 week, by -12.54 µm (p < 0.001) after 2 weeks, and by -3.52 µm (p = 0.09) after 3 weeks. Mean intraretinal layer thickness changed only significantly between baseline and week 1 (p < 0.001). Mean subretinal thickness also decreased between weeks 1 and 2 (p = 0.01). CONCLUSIONS: Early morphological changes occur primarily in the first 14 days after treatment. This information could be clinically helpful to evaluate early non-response.

Retinal Nerve Fiber Loss in Anti-VEGF Therapy for Age-Related Macular Degeneration Can Be Decreased by Anterior Chamber Paracentesis.

PURPOSE: To analyze peripapillary retinal nerve fiber layer thickness (RNFLT) change after long-term intravitreal anti-VEGF therapy. Patients with regular anterior chamber paracentesis (ACP) prior to intravitreal injections (IVIs) were compared to those without ACP. METHODS: Neovascular age-related macular degeneration (nAMD) was treated in a pro re nata regimen with a minimum of 9 IVIs. RNFLT change was determined in spectral domain optical coherence tomography. RESULTS: In 32 patients without ACP, mean RNFLT loss (-2.16 ± 3.60 µm) was significantly higher than in 44 patients with regular ACP (0.16 ± 3.60; p = 0.029). Both groups were comparable in age (75.0 vs. 76.8 years; p = 0.35), number of IVIs (16.2 vs. 16.6; p = 0.98), and observational time (30.0 vs. 32.3 months; p = 0.32). In patients without ACP, RNFLT loss was higher compared to IVI-naive fellow eyes (p = 0.005), whereas in ACP patients, no difference was detected (p = 0.5). CONCLUSIONS: A moderate RNFLT loss is found in nonglaucomatous patients after injection therapy for nAMD. As it is decreased with regular ACP, tight management of intraocular pressure seems advisable.

Fibrovascular pigment epithelial detachment is a risk factor for long-term visual decay in neovascular age-related macular degeneretion.

BACKGROUND: The individual outcome of anti-vascular endothelial growth factor treatment in neovascular age-related macular degeneration is variable. To investigate the prognostic value of spectral domain optical coherence tomography structures for best-corrected visual acuity (BCVA) outcome, volumetric analysis of spectral domain optical coherence tomography structures was performed in neovascular age-related macular degeneration correlated with BCVA after 24 months. METHODS: At the Department of Ophthalmology, University of Cologne, Germany, 75 patients with neovascular age-related macular degeneration were analyzed prospectively over 24 months. Patients received three initial consecutive monthly intravitreal ranibizumab injections followed by monthly spectral domain optical coherence tomography controls. Therapy was continued as a pro re nata regimen. Volumetric analysis of spectral domain optical coherence tomography images was performed using commercially available software (3D-Doctor). RESULTS: Subretinal tissue, subretinal fluid, serous pigment epithelial detachment, and fibrovascular pigment epithelial detachment (FPED) were identified. By contrast to all other structures, FPED did not respond to ranibizumab therapy. Volume of FPED at baseline and after the loading phase correlated most with impaired BCVA after 24 months (r = -0.0215, P = 0.9263 [subretinal tissue]; r = -0.3120, P = 0.0216 [subretinal fluid]; r = -0.0757, P = 0.6470 [serous pigment epithelial detachment]; r = -0.4182, P = 0.0111 (FPED baseline); r = -0.4768; P = 0.0002 [FPED after loading phase]). CONCLUSION: Of all identified structures, FPED was most deleterious for BCVA after 24 months. The knowledge about possible BCVA course can influence the decision for more intense treatment regimens.