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Purpose: The aim was to investigate the effect and underlying mechanism of anti-vascular endothelial growth factor (anti-VEGF) in diabetic macular edema (DME) by optical coherence tomography angiography (OCTA). Methods: Twenty-five eyes in 18 treatment-naïve patients with DME were included. All eyes were imaged by OCTA at baseline and 1 week after monthly intravitreal aflibercept injection (IAI). Visual acuity was measured as best corrected visual acuity (BCVA). Additional parameters were evaluated by OCTA, including central macular thickness (CMT), the number of hyperreflective foci (HRF), foveal avascular zone (FAZ), vessel density (VD) in the deep capillary plexus (DCP), the en-face area of cystoid edema in DCP segmentation, and subretinal fluid (SRF) height. Results: The mean time between baseline and final follow-up by OCTA was 79.24 ± 38.15 (range, 28–163) days. Compared with baseline, BCVA was increased significantly after the 3rd IAI, while CMT was decreased significantly from the 1st IAI. SRF height and the area of cystoid edema in DCP segmentation were decreased significantly after the 2nd IAI compared with baseline. The number of HRF was decreased significantly after the 1st IAI (8.87 ± 9.38) compared with baseline (11.22 ± 10.63). However, FAZ's area and perimeter as well as VD in DCP showed no significant changes post-treatment. Conclusion: Anti-VEGF is effective in treating DME, improving visual acuity and decreasing macular edema. The decreased HRF indicates anti-inflammatory effects of aflibercept to deactivate retinal microglia/macrophages. The decreased cystoid edema and SRF height indicated improved drainage function of Müller glial cells and retinal pigment epithelium after IAI. [ABSTRACT FROM AUTHOR]

Abstract Introduction The fluocinolone acetonide (FAc) intravitreal drug-delivery system implant is a recent, second-line, intravitreal drug for the management of diabetic macular edema (DME). FAc acts against DME with a major anti-inflammatory effect. Despite the already proved efficacy, a number of patients still show persistent DME and require anti-VEGF retreatment. The main aim of the present study was to assess the relationship between quantitative biomarkers of inflammation and both DME recovery and the need for additional anti-VEGF in eyes treated by FAc implant. Methods The study was designed as prospective and interventional with 1 year of follow-up. We analyzed structural optical coherence tomography (OCT) quantitative biomarkers of inflammation, namely choroidal hyperreflective foci (HF) and the choroidal vascularity index (CVI), and we assessed the relationship with other clinically relevant biomarkers and the outcome achieved after 1 year. Moreover, we stratified DME eyes in good and poor responders to FAc implant to highlight clinically relevant differences. Results Our study included 50 eyes (50 patients) treated by FAc implant. We found significant best-corrected visual acuity (BCVA) and central macular thickness (CMT) improvements after 1 year. Good responders started with worse visual acuity and higher CMT than poor responders, but gained letters significantly at the end of the follow-up, whereas poor responders showed stable BCVA values. Good responders were characterized by significantly higher choroidal HF and lower CVI than poor responders. Poor responders required significantly higher additional anti-VEGF treatments. Conclusions Quantitative structural OCT biomarkers of inflammation allowed distinguishing different inflammatory profiles of DME. The inflammatory component helped to categorize DME eyes in good and poor responders to FAc implant.

Abstract Background Fabry disease (FD) is an X-linked inherited storage disorder caused by deficiency of lysosomal alpha-Galactosidase A. Here we describe new retinal findings in patients with FD assessed by Spectral domain optical coherence tomography (SD-OCT) and their possible clinical relevance. Methods 54 eyes of 27 FD patients and 54 eyes of 27 control subjects were included. The ophthalmic examination included visual acuity testing, tonometry, slit lamp and fundus examination. SD-OCT imaging of the macula was performed in all subjects. Central retinal thickness and retinal nerve fiber layer analysis were quantified. Vessel tortuosity was obtained by a subjective scoring and mathematically calculated. Inner retinal hyperreflective foci (HRF) were quantified, clinically graded and correlated with a biomarker of Fabry disease (lyso-Gb3). Results In comparison to an age-matched control group, a significant amount of HRF was identified in macular SD-OCT images in FD patients. These HRF were localized within the inner retinal layers. Furthermore, lyso-Gb3 levels correlated significantly with the quantitative evaluation of HRF (p

Purpose: The aim was to investigate the effect and underlying mechanism of anti-vascular endothelial growth factor (anti-VEGF) in diabetic macular edema (DME) by optical coherence tomography angiography (OCTA).Methods: Twenty-five eyes in 18 treatment-naïve patients with DME were included. All eyes were imaged by OCTA at baseline and 1 week after monthly intravitreal aflibercept injection (IAI). Visual acuity was measured as best corrected visual acuity (BCVA). Additional parameters were evaluated by OCTA, including central macular thickness (CMT), the number of hyperreflective foci (HRF), foveal avascular zone (FAZ), vessel density (VD) in the deep capillary plexus (DCP), the en-face area of cystoid edema in DCP segmentation, and subretinal fluid (SRF) height.Results: The mean time between baseline and final follow-up by OCTA was 79.24 ± 38.15 (range, 28–163) days. Compared with baseline, BCVA was increased significantly after the 3rd IAI, while CMT was decreased significantly from the 1st IAI. SRF height and the area of cystoid edema in DCP segmentation were decreased significantly after the 2nd IAI compared with baseline. The number of HRF was decreased significantly after the 1st IAI (8.87 ± 9.38) compared with baseline (11.22 ± 10.63). However, FAZ’s area and perimeter as well as VD in DCP showed no significant changes post-treatment.Conclusion: Anti-VEGF is effective in treating DME, improving visual acuity and decreasing macular edema. The decreased HRF indicates anti-inflammatory effects of aflibercept to deactivate retinal microglia/macrophages. The decreased cystoid edema and SRF height indicated improved drainage function of Müller glial cells and retinal pigment epithelium after IAI.

With the advancement of retinal imaging, hyperreflective foci (HRF) on optical coherence tomography (OCT) images have gained significant attention as potential biological biomarkers for retinal neuroinflammation. However, these biomarkers, represented by HRF, present pose challenges in terms of localization, quantification, and require substantial time and resources. In recent years, the progress and utilization of artificial intelligence (AI) have provided powerful tools for the analysis of biological markers. AI technology enables use machine learning (ML), deep learning (DL) and other technologies to precise characterization of changes in biological biomarkers during disease progression and facilitates quantitative assessments. Based on ophthalmic images, AI has significant implications for early screening, diagnostic grading, treatment efficacy evaluation, treatment recommendations, and prognosis development in common ophthalmic diseases. Moreover, it will help reduce the reliance of the healthcare system on human labor, which has the potential to simplify and expedite clinical trials, enhance the reliability and professionalism of disease management, and improve the prediction of adverse events. This article offers a comprehensive review of the application of AI in combination with HRF on OCT images in ophthalmic diseases including age-related macular degeneration (AMD), diabetic macular edema (DME), retinal vein occlusion (RVO) and other retinal diseases and presents prospects for their utilization., Competing Interests: Conflicts of Interest: Ying JN, None; Li H, None; Zhang YY, None; Li WD, None; Yi QY, None., (International Journal of Ophthalmology Press.)

Purpose: The aim of this study was to analyze the factors associated with hyperreflective foci (HRF) in diabetic macular edema (DME) in treatment naïve eyes.Methods: This retrospective observational study included 131 eyes of 91 treatment naïve patients with DME. Details of ophthalmological examination with duration of vision loss and systemic parameters were noted. The spectral-domain optical coherence tomography (SD-OCT) images were analyzed for number and location of HRF and the associated imaging biomarkers.Results: Inner retinal (IR) HRF were seen in 88 eyes (67%), outer retinal (OR) in 28 (21%), and subretinal (SR) in 12 (9%). The IR had (7.1 ± 7) HRF, the OR (6.5 ± 4.8), and SR (3.9 ± 2.9). A greater proportion of eyes with HRF also had subretinal fluid (SRF), significantly higher blood pressure and lower serum triglycerides. Univariate linear regression analysis showed women (3 HRF greater vs. men, P = 0.04), eyes with cystoid spaces (2.95 more HRF vs. no cystoid spaces, P = 0.02), and SRF (2.96 more HRF vs. no SRF, P = 0.007) had more HRF, whereas higher triglycerides (1 HRF lesser per 50 mg lower TGL, P = 0.03) had lesser.Conclusion: Our study highlights the importance of HRF as an imaging biomarker in DME suggesting an inflammatory origin. Long-term observations of large cohorts with automated analysis can give more insights. [ABSTRACT FROM AUTHOR]

Abstract Purpose To investigate the dynamic changes of hyperreflective foci (HF) in diabetic macular edema (DME) patients during the intravitreal Conbercept treatment in China. Methods DME Patients receiving intravitreal Conbercept (IVC) injections during the year 2016–2017 were retrospectively investigated. Thirteen patients (26 eyes) were recruited in this study. They received IVC once a month for 3 consecutive months. The number and location of HFs, the best-corrected visual acuity (BCVA) and central macular thickness (CMT) at each visit were analyzed and compared. Results After the first injection, BCVA (LogMAR) was increased from 0.75 ± 0.48 to 0.43 ± 0.24 (p < 0.05), CMT improved from 575.9 ± 191.9 to 388.2 ± 198.5 μm (p = 0.014). However, the BCVA and CMT had no statistical difference after the second and third injection as compared with those after the first injection respectively. The baseline number of HFs was 5.39 ± 4.24, 5.15 ± 5.17 and 0.88 ± 1.90 in the inner retinal, outer retinal and subretinal layer respectively. The number of HFs in these three retinal layers decreased significantly after the first injection (p = 0.0045, p < 0.0001 and p = 0.0045, respectively). However, after the second injection, only the number of HFs in the inner retinal layer experienced a further decrease. After the third injection, no statistically significant HFs changes was observed in each retinal layers. Correlation analysis showed that there was a positive significant correlation between the baseline number of HFs in the inner retina, outer retina, subretina and final BCVA (r = 0.571, p = 0.002; r = 0.464, p = 0.017; r = 0.405, p = 0.04 respectively). There was also a significant positive correlation between outer retinal HFs reduction, total retinal HFs reduction and increase of BCVA (r = 0.40, p = 0.043 and r = 0.393, p = 0.04 respectively). There were no severe ocular adverse reactions or systemic adverse events. Conclusions Conbercept is effective and safe in the treatment of DME. HFs can act as a biomarker of poor final visual outcome.

BACKGROUND: This study aimed to know the association of visual status and hyperreflective foci in patients with diabetic macular edema (DME). MATERIAL AND METHODS: This observational cross-sectional study included patients with diabetes mellitus type 2 (DM2) with DME or non-proliferative diabetic retinopathy (NPDR). Baseline assessment included: ophthalmic examinations such as best-corrected visual acuity (LogMAR), color vision, contrast sensitivity, intraocular pressure (IOP), fundus examination by direct, indirect ophthalmoscopy, slit-lamp biomicroscopy with 90D, and spectraldomain -- optical coherence tomography (SD-OCT) [counting of hyperreflective foci (HF) were done manually]. Retina specialists performed counting and classification of HF. The correlation was calculated to establish the association between HF with visual status. p-value < 0.05 was considered statistically significant. RESULTS: In majority of the patients (46.67%), HF was < 50 followed by 51-100 (30.83%) and > 100 (17.50%). With increasing HF, there was a significantly decreasing trend of best-corrected visual acuity (BCVA) (0.2 in no HF to 0.5 in HF > 100, p = 0.001) and contrast (1.58 in no HF to 1.35 in HF > 100, p = 0.0004). HF were found to significantly increase with increasing duration of the disease (4 in no HF to 17 in HF > 100, p = 0.0001). The lab parameters such as glycated haemoglobin (HbA1c), serum urea, serum creatinine, triglycerides, very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL) showed significant derangement with increasing HF (p < 0.05). CONCLUSION: The presence of HF in patients with DME negatively affects BCVA and contrast sensitivity. The severity of HF may increase with the increasing duration of DME and altered glycemic index. [ABSTRACT FROM AUTHOR]

Aim: To analyze the relationship between optical coherence tomography (OCT) and OCT angiography (OCTA) imaging in patients with diabetic macular edema (DME) who are treated with a combination of aflibercept and triamcinolone acetonide (TA)., Methods: A total of 76 eyes newly diagnosed DME were included in this study. They were randomly assigned to receive either aflibercept or a combination of aflibercept and TA. Injections once a month for a total of three injections. Central macular thickness (CMT), number of hyperreflective foci (HRF), height of subretinal fluid (SRF), and area of foveal avascular zone (FAZ) were evaluated using OCT and OCTA at baseline and after each monthly treatment., Results: Both groups showed improvement in best corrected visual acuity (BCVA) and reduction in macular edema after treatment, and the difference in BCVA between the two groups was statistically significant after each treatment ( P <0.05). The difference in CMT between the two groups was statistically significant after the first two injections ( P <0.01), but not after the third injection ( P =0.875). The number of HRF (1mo: 7.41±8.25 vs 10.86±7.22, P =0.027; 2mo: 5.33±6.13 vs 9.12±8.61, P =0.034; 3mo: 3.58±3.00 vs 6.37±5.97, P =0.007) and height of SRF (1mo: 82.39±39.12 vs 105.77±42.26 µm, P =0.011; 2mo: 36.84±10.02 vs 83.59±37.78 µm, P <0.01; 3mo: 11.57±3.29 vs 45.43±12.60 µm, P <0.01) in combined group were statistically significant less than aflibercept group after each injection, while the area of FAZ showed no significant change before and after treatment in both groups., Conclusion: The combination therapy of aflibercept and TA shows more significant effects on DME eyes with decreased HRF and SRF. However, both aflibercept and combination therapy show no significant change in the area of FAZ., Competing Interests: Conflicts of Interest: Li DS, None; Liao HX, None; Zhang CH, None; Huang JG, None; Chen W, None; Zhang JL, None; Qin B, None., (International Journal of Ophthalmology Press.)

Introduction: The fluocinolone acetonide (FAc) intravitreal drug-delivery system implant is a recent, second-line, intravitreal drug for the management of diabetic macular edema (DME). FAc acts against DME with a major anti-inflammatory effect. Despite the already proved efficacy, a number of patients still show persistent DME and require anti-VEGF retreatment. The main aim of the present study was to assess the relationship between quantitative biomarkers of inflammation and both DME recovery and the need for additional anti-VEGF in eyes treated by FAc implant. Methods: The study was designed as prospective and interventional with 1 year of follow-up. We analyzed structural optical coherence tomography (OCT) quantitative biomarkers of inflammation, namely choroidal hyperreflective foci (HF) and the choroidal vascularity index (CVI), and we assessed the relationship with other clinically relevant biomarkers and the outcome achieved after 1 year. Moreover, we stratified DME eyes in good and poor responders to FAc implant to highlight clinically relevant differences. Results: Our study included 50 eyes (50 patients) treated by FAc implant. We found significant best-corrected visual acuity (BCVA) and central macular thickness (CMT) improvements after 1 year. Good responders started with worse visual acuity and higher CMT than poor responders, but gained letters significantly at the end of the follow-up, whereas poor responders showed stable BCVA values. Good responders were characterized by significantly higher choroidal HF and lower CVI than poor responders. Poor responders required significantly higher additional anti-VEGF treatments. Conclusions: Quantitative structural OCT biomarkers of inflammation allowed distinguishing different inflammatory profiles of DME. The inflammatory component helped to categorize DME eyes in good and poor responders to FAc implant. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the choriocapillaris (CC) flow deficit (FD) beneath drusen associated with overlying intraretinal hyperreflective foci (HRF). Methods: Patients with intermediate age-related macular degeneration (AMD) who had structural spectral-domain optical coherence tomography (SD-OCT) and OCT angiography (OCTA) using the Cirrus HD-OCT with AngioPlex software were retrospectively evaluated. A 6 × 6-mm-volume scan was used for the SD-OCT and OCTA. Post-imaging processing steps included generation of drusen map, identification of HRF, and generation of a signal-compensated CC slab prior to binarization and CC FD computation. The CC OCTA image was aligned with the drusen + HRF map to define regions of interest for CC FD measurement. The CC was quantified below drusen with and without overlying HRF and within a 150-μm-wide ring surrounding the drusen (unaffected by potential HRF-related shadowing), and across the entire 6 × 6 macular region. Results: Fifty-three eyes with intermediate AMD were included, 25 eyes with HRF, and 28 eyes with no HRF. The mean ± SD FD% over the whole 6 × 6 macular region was 41.1 ± 3.4 in eyes with HRF compared with 39.5 ± 3.5 in eyes without HRF (p = 0.001). The mean ± SD CC FD% below drusen with HRF (54.4 ± 9.3) was significantly greater than below drusen without HRF (49.6 ± 9.5; p = 0.001). There was a strong positive correlation between the quantity of HRF and the extent of the CC FD (Pearson correlation = 0.81). Conclusion: Choriocapillaris flow deficits appear to be more severe in eyes with HRF and in particular directly below HRF. As HRF are thought to represent a higher risk or more advanced feature of intermediate AMD, these findings highlight the relationship between the severity of CC FD and overall severity of AMD. [ABSTRACT FROM AUTHOR]

Background: We compared with and without enhanced depth imaging mode (EDI) in semi-automated quantification of retinal and choroidal biomarkers in optical coherence tomography (OCT) in patients with diabetic retinopathy (DR) or retinal vein occlusion (RVO) complicated by macular edema. We chose to study three OCT biomarkers: the numbers of hyperreflective foci (HF), the ellipsoid zone reflectivity ratio (EZR) and the choroidal vascularity index (CVI), all known to be correlated with visual acuity changes or treatment outcomes. Methods: In a single examination, one eye of each patient (n = 60; diabetic retinopathy: n = 27, retinal vein occlusion: n = 33) underwent macular 870 nm spectral domain-OCT (SD-OCT) B-scans without and with EDI mode. Semi-automated quantification of HF, EZR and CVI was applied according to preexisting published protocols. Paired Student’s t-test or Wilcoxon rank-sum test was used to test for differences in subgroups. Intraclass correlation coefficient (ICC) and Bland–Altman plots were applied to describe the agreement between quantification in EDI and conventional OCT mode. The effect of macular edema on semi-automated quantification was evaluated. Results: For the entire cohort, quantification of all three biomarkers was not significantly different in SD-OCT scans with and without EDI mode (p > 0.05). ICC was 0.78, 0.90 and 0.80 for HF, EZR and CVI. The presence of macular edema led to significant differences in the quantification of hyperreflective foci (without EDI: 80.00 ± 33.70, with EDI: 92.08 ± 38.11; mean difference: 12.09, p = 0.03), but not in the quantification of EZR and CVI (p > 0.05). Conclusion: Quantification of EZR and CVI was comparable whether or not EDI mode was used. In conclusion, both retinal and choroidal biomarkers can be quantified from one single 870 nm SD-OCT EDI image.

Abstract Background Hyperreflective foci have been described in OCT imaging of patients with retinal vascular diseases. It has been suggested that they may play a role as a prognostic factor of visual outcomes in these diseases. The purpose of this study is to describe the presence of hyperreflective foci in patients with non-infectious uveitic macular edema and evaluate their behavior after treatment. Methods We conducted a multicenter, prospective, observational, 12-month follow-up study. Inclusion criteria were age > 18 years and a diagnosis of non-infectious uveitic macular edema, defined as central macular thickness of > 300 μm as measured by OCT and fluid in the macula. Collected data included best corrected visual acuity, central macular thickness and the presence, number and distribution (inner or outer retinal layers) of hyperreflective foci. Evaluations were performed at baseline, and at 1, 3, 6, and 12 months after starting treatment. Results We included 24 eyes of 24 patients. The frequency of patients with ≥11 hyperreflective foci was 58.4% at baseline, falling to 20.8% at 12 months. Further, hyperreflective foci were observed in the outer retinal layers in 50% of patients at baseline and just 28.6% at 12 months. Mean LogMAR visual acuity improved from 0.55 (95% CI 0.4–0.71) at baseline to 0.22 (95% CI 0.08–0.35) at 12 months (p

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. [ABSTRACT FROM AUTHOR]

Aims: Hyperreflective foci (HF), detected in the retina of diabetic patients, suggest the presence of microglial activation and migration, while controversies still remain for the origin of HF to be precursors of hard exudates. We investigated the presence of HF and their association with dyslipidemia in serous retinal detachment (SRD)-type diabetic macular edema (DME). Methods: Forty-two eyes in 42 patients with diabetic retinopathy (DR) and 22 eyes in 22 patients with branch retinal vascular occlusion (BRVO) showing macular edema were included in this study. The medical records and OCT findings were retrospectively reviewed in patients with SRD-type DME and compared with those with BRVO. The mean number of HF, the mean choroidal thickness, and lipid profiles were analyzed and compared between groups. Results: The mean number of HF was significantly higher in DR group compared to BRVO group. Significant correlation of HF was noted with triglycerides (r = 0.523, P = 0.002). Triglycerides were significantly associated with HF by linear regression (β = 0.012, 95% CI 0.001–0.024, P = 0.034) and remained significantly associated by multiple linear regression (β = 0.014, 95% CI 0.003–0.025, P = 0.014). Conclusions: HF on OCT of DME patients could be indicative of activated microglia. HF are associated with dyslipidemia, especially high triglycerides, suggesting inflammatory reaction from dyslipidemia in diabetic retina. [ABSTRACT FROM AUTHOR]

Purpose: To describe the optical coherence tomographic findings of hyperreflective foci (HF) in neovascular age-related macular degeneration and evaluate the use of HF to predict visual outcome after antivascular endothelium growth factor (anti-VEGF) therapy. Methods: This was a post-hoc analysis of a retrospective cohort study. Hyperreflective foci were localized in the inner retina, outer retina, or subretinal fluid (SRF) layer. The treatment response of HF was recorded. The association between HF and visual outcome was analyzed. Results: We enrolled 126 eyes. Hyperreflective foci involving more than one layer were associated with poor initial visual acuity (P < 0.001). Hyperreflective foci in each layer at baseline were negatively correlated with baseline visual acuity. At 3 months posttreatment, HF in the SRF layer had decreased significantly (P = 0.003), which was faster compared with HF in other layers. Baseline HF status at each layer was not associated with final visual outcome. The eyes with reduced HF in the SRF at 3 months had better visual improvement at 12 months (P = 0.038). Conclusion: Hyperreflective foci involving multiple layers were associated with poor initial visual acuity but not with final visual outcome. With anti-VEGF treatment, HF in the SRF layer resolved faster, which may predict better visual outcome. [ABSTRACT FROM AUTHOR]

Purpose: The vitelliform stage is the typical phenotypic manifestation of Best vitelliform macular dystrophy (BVMD). As yet, no study has focused specifically on the clinical changes occurring in the vitelliform stage over the follow-up. Methods: The survey takes the form of a prospective observational study with a 5-year follow-up. Twenty-one eyes of 11 patients in the vitelliform stage were examined annually. The primary outcome was the identification of the changes in the vitelliform lesion over a 5-year follow-up. Secondary outcomes included changes in structural optical coherence tomography (OCT) parameters and the correlation with the BCVA variation over the follow-up. Results: Spectral domain OCT at baseline showed one subform characterized by solid vitelliform deposition, in 81% of eyes, and another subform characterized by a combination of solid deposition and subretinal fluid, in 19% of eyes. Overall, 62% of eyes showed an increase in the area of vitelliform deposition. Once the maximal area was reached, a progressive flattening of the vitelliform deposition took place, with subsequent flattening of the vitelliform lesion and formation of subretinal fluid. Hyperreflective foci (HF) increased in number as long as the vitelliform area continued to expand, with no variation in HF when the vitelliform lesion flattened or the subretinal fluid formed. Conclusions: The vitelliform stage reveals more subforms with clinical variations over the follow-up. Our data suggest that the substage before the flattening of the lesion, thus before the so-called subretinal fluid accumulates and when the visual acuity is still high, might offer the best opportunity for an optimal therapeutic approach. [ABSTRACT FROM AUTHOR]

Background: Fabry disease (FD) is an X-linked inherited storage disorder caused by deficiency of lysosomal alpha-Galactosidase A. Here we describe new retinal findings in patients with FD assessed by Spectral domain optical coherence tomography (SD-OCT) and their possible clinical relevance.Methods: 54 eyes of 27 FD patients and 54 eyes of 27 control subjects were included. The ophthalmic examination included visual acuity testing, tonometry, slit lamp and fundus examination. SD-OCT imaging of the macula was performed in all subjects. Central retinal thickness and retinal nerve fiber layer analysis were quantified. Vessel tortuosity was obtained by a subjective scoring and mathematically calculated. Inner retinal hyperreflective foci (HRF) were quantified, clinically graded and correlated with a biomarker of Fabry disease (lyso-Gb3).Results: In comparison to an age-matched control group, a significant amount of HRF was identified in macular SD-OCT images in FD patients. These HRF were localized within the inner retinal layers. Furthermore, lyso-Gb3 levels correlated significantly with the quantitative evaluation of HRF (p < 0,001). In addition, the vessel tortuosity was remarkably increased in FD patients compared to control persons and correlated significantly with lyso-G3 levels (p = 0.005). A further subanalysis revealed significantly higher HRF and vessel tortuosity scores in male patients with the classic FD phenotype.Conclusions: The observational, cross sectional, comparative study describes novel intraretinal findings in patients with FD. We were able to identify suspicious HRF within the inner retinal layers. These findings were not accompanied by functional limitations, as visual acuity remained unchanged. However, HRF correlated well with lyso-Gb3, a degradation product of the accumulating protein Gb3 and might potentially indicate Gb3 accumulation within the highly metabolic and densely vascularized macula. [ABSTRACT FROM AUTHOR]

• HRF occurred near the site where ELM or IS/OS line was injured after retinal reattachment • HRF in the outer retina increased in the initial three months after retinal reattachment, and then decreased gradually after 3 months. • The HRF number in the outer retina at postoperative 0.5 months was associated with favorable visual outcomes • The HRF number at 3 months was correlated with poor visual results. To assess the changes of hyperreflective foci (HRF) in rhegmatogenous retinal detachment (RRD) patients after successful reattachment surgery. Twenty-nine macula-off RRD eyes with successful reattachment surgery were retrospectively analyzed. Optical coherence tomography (OCT) was used to image macular regions and measure HRF in outer retina and inner retina at 0.5, 1, 3, 6, 12 months after surgery. The relationships between HRF and photoreceptor layer status, visual outcomes were evaluated. After retinal reattachment, HRF mainly distributed at the location where external limiting membrane (ELM) or inner and outer segment (IS/OS) line was disrupted. The HRF numbers in outer and inner retina were greater in eyes with discontinuous IS/OS line than eyes with continuous IS/OS line (all p <0.05). In the outer retina, HRF increased in the initial three months after retinal reattachment, and then decreased gradually after 3 months (p <0.05). The HRF number in the outer retina at postoperative 0.5 months was associated with favorable visual outcomes at 6 and 12 months (r =-0.487, p =0.025; r=-0.626, p =0.005, respectively), nevertheless, the HRF number at 3 months was correlated with poor visual results at 6 and 12 months (r =0.441, p =0.017; r =0.477, p =0.019, respectively). HRF mainly occurred near the site where ELM or IS/OS line was injured after retinal reattachment. In the outer retina, the number of HRF gradually increased in the first 3 months and then gradually decreased. The early appearance of HRF in the outer retina was associated with a good visual prognosis, while the late appearance may suggest a less favorable visual outcome. [ABSTRACT FROM AUTHOR]

AIM: To evaluate the potential role of hyperreflective foci (HF) as a prognostic indicator of visual outcome in patients with macular edema (ME) due to retinal vein occlusion (RVO). METHODS: We retrospectively reviewed 50 eyes of 50 patients with ME due to ischemic central retinal vein occlusion (CRVO), non-ischemic CRVO and branch retinal vein occlusion (BRVO) who were treated with anti-vascular endothelial growth factor (anti-VEGF) at Beijing Tongren Eye Center from January 2013 to July 2016. All patients underwent best-corrected visual acuity (BCVA), spectral domain optical coherence tomography (SD-OCT) at baseline and follow-up. Such factors were evaluated and compared among three groups as baseline and final BCVA, central retinal thickness (CRT), external limiting membrane (ELM) status and the numbers of HF in different position. Multiple linear regression analysis was employed to analyze the relationship between baseline HF and final BCVA. Changes of HF before and after treatment were evaluated too. RESULTS: Among three groups, HF could be located in each retinal layers, as well as in vitreous cavity. The mean HF in outer retinal layer (ORL) at baseline was 5.29±8.48 in ischemic CRVO with intact ELM, 1.93±2.76 in non-ischemic CRVO, and 1.75±2.05 in BRVO. With disrupted ELM, the mean HF in ORL increased. There was statistically difference of HF in ORL between intact and disrupted ELM. The numbers of HF in ORL were associated with poor visual outcome among three groups. However, HF in inner retinal layer (IRL) and vitreous cavity were not associated with poor visual outcome. Meanwhile, the baseline HF in ORL and vitreous cavity reduced significantly in non-ischemic CRVO and BRVO after anti-VEGF treatment. CONCLUSION: The numbers of HF in ORL are prognostic factors associated with the final BCVA in patients with ME due to RVO after anti-VEGF treatment.

Purpose: To describe the hyperreflective foci (HF) characteristics in eyes affected by Stargardt disease (STGD), correlating HF with the atrophy progression at 1-year follow-up.Methods: Prospective observational case series with 1-year follow-up. Twenty-eight eyes (14 patients) affected by STGD and 28 eyes (14 age- and sex-matched healthy patients) used as control group were recruited. All patients underwent a complete ophthalmologic examination including fundus autofluorescence and spectral-domain optical coherence tomography. The primary outcome was the identification of HF specific location in STGD and their modification over a 1-year follow-up. Secondary outcome included the correlation between the number and the location of HF and atrophic changes.Results: HF turned out to be more frequent in STGD patients compared with healthy controls (p < 0.001). In particular, mean number of HF in the pathological edge was significantly higher than in the healthy edge of the atrophy (p < 0.001) and in the foveal area (p < 0.001). A negative correlation was found between the total HF number in the pathological edge and the atrophic area at baseline. HF number in the outer retina of the pathological edge significantly decreased between the baseline and the final follow-up examination (p = 0.011). The enlargement of the atrophic area in eyes with more than five outer retinal HF in the pathological edge at baseline was significantly less than that found in the eyes with fewer than five HF (p = 0.010).Conclusions: HF are most common at the pathological margin of the central atrophy, with outer retina foci being more frequently found in smaller atrophic lesions. [ABSTRACT FROM AUTHOR]

Purpose: Fast and automated reconstruction of retinal hyperreflective foci (HRF) is of great importance for many eye-related disease understanding. In this paper, we introduced a new automated framework, driven by recent advances in deep learning to automatically extract 12 three-dimensional parameters from the segmented hyperreflective foci in optical coherence tomography (OCT)., Methods: Unlike traditional convolutional neural networks, which struggle with long-range feature correlations, we introduce a spatial and channel attention module within the bottleneck layer, integrated into the nnU-Net architecture. Spatial Attention Block aggregates features across spatial locations to capture related features, while Channel Attention Block heightens channel feature contrasts. The proposed model was trained and tested on 162 retinal OCT volumes of patients with diabetic macular edema (DME), yielding robust segmentation outcomes. We further investigate HRF's potential as a biomarker of DME., Results: Results unveil notable discrepancies in the amount and volume of HRF subtypes. In the whole retinal layer (WR), the mean distance from HRF to the retinal pigmented epithelium was significantly reduced after treatment. In WR, the improvement in central macular thickness resulting from intravitreal injection treatment was positively correlated with the mean distance from HRF subtypes to the fovea., Conclusion: Our study demonstrates the applicability of OCT for automated quantification of retinal HRF in DME patients, offering an objective, quantitative approach for clinical and research applications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Wang, Zhang, Ma, Kwapong, Ying, Lu, Ma, Yan, Yi and Zhao.)

Purpose: To present two consecutive cases of Central Retinal Artery Occlusion (CRAO) with unusual Optical Coherence Tomography (OCT) presentation of Hyperreflective Spots (HRS) in the posterior vitreous., Case Report: The first patient was a 59 years-old male who developed CRAO in the post-operative period after aortic valve replacement. OCT scans revealed the presence of many HRS in the posterior vitreous, remarkably decreased in number at two months follow-up. The second patient was a 74-year-old male who developed CRAO after arterial chemoembolization for recurrent hepatocellular carcinoma. OCT scans showed again the presence of hyperreflective spots in the posterior vitreous and their reduction at two months follow-up with inner retinal atrophy as the final outcome in both cases., Conclusions: HRS in the posterior vitreous have been described in inflammatory eye conditions such as uveitis, diabetic macular edema, post cataract surgery, and considered a clinical sign of inflammation. To our knowledge, the combination of CRAO and HRS has not been previously reported. The number of HRS seems to decrease over time, suggesting a role for inflammatory response in the acute stage of CRAO. A similar pathogenic process is known to occur during cerebral ischemia, where the inflammatory response may exacerbate brain injury and post-ischemic damage.

Purpose: To investigate the association between the characteristics of foveal cystoid spaces and short-term responsiveness to ranibizumab treatment for diabetic macular edema (DME) at 3 months from the initial injection.Methods: We retrospectively reviewed 66 eyes of 61 patients with center-involved DME who received three consecutive ranibizumab injections and following as-needed administrations. We evaluated the relationship between visual improvement at 3 months and the preoperative optical coherence tomography (OCT) parameters including hyperreflective foci, heterogeneous OCT reflectivity, mean levels of OCT reflectivity and height of foveal cystoid spaces.Results: Twenty-three eyes without preoperative hyperreflective foci in the foveal cystoid spaces had significantly greater improvement in the logarithm of the minimum angle of resolution visual acuity (logMAR VA) at 3 months than 43 eyes with foci (P = 0.006). That was similar to the greater reduction in CSF thickness in eyes without lesions after treatment at the same time point (P < 0.001). VA improvement at 3 months was not associated with the height (R = 0.215, P = 0.083) or the reflectivity levels (R = -0.079, P = 0.538) of foveal cystoid spaces. There were no differences in VA changes between eyes with and without heterogeneous reflectivity in foveal cystoid spaces (P = 0.297). Multivariate analyses showed that logMAR VA and the absence of hyperreflective foci in foveal cystoid spaces were associated with VA improvement at 3 months.Conclusion: Hyperreflective foci in foveal cystoid spaces at baseline predict poorer short-term responsiveness to ranibizumab injections for DME. [ABSTRACT FROM AUTHOR]

• OCT allows for qualitative and quantitative assessment of the many structural changes that occur in macular edema. • Structural changes seen on OCT may be predictive of response to treatment in macular edema. • The presence of hyperreflective foci (HRF) and serous macular detachment (SMD) is a negative predictor of recurrence in macular edema in the short term. • The increase in central foveal thickness in the 3rd month was more severe in the coexistence of HRF and SMD. To perform a longitudinal analysis of the effect of optic coherence tomography (OCT) biomarkers on macular thickness in patients with persistent macular edema secondary to diabetes mellitus and retinal vein occlusion who recieved intravitreal dexamethasone (DEX) implant. Eighty-nine patients were included in the retrospective study. Patients with anti-VEGF-resistant macular edema were included in the study. The effect of the presence or absence of OCT biomarkers before intravitreal DEX implant therapy on central foveal thickness (CFT) was evaluated. In addition, the change in biomarkers from the baseline visit to the final visit was evaluated. The evaluated OCT biomarkers were as follows: ellipsoid zone and external limiting membrane (ELM) integrity, hyperreflective foci (HRF), disorganization of inner retinal layers (DRIL), hard exudates, serous macular detachment (SMD), pearl necklace, posterior vitreous detachment and the epiretinal membrane (ERM). The mean age of the overall sample in the study was 64.4 ± 9.6. CFT decreased significantly from 625.3 ± 22.3 μm at baseline to 365.0 ± 21.7 μm in the 1st month but increased significantly to 430.2 ± 22.6 μm in the 3rd month. In the presence of HRF and SMD, recurrence of macular edema was significant in the 3rd month. The percentage of ELM disruption, DRIL, and ERM deteriorated significantly and the percentage of SMD improved significantly at the final visit. DEX implant therapy resulted in a satisfactory reduction in CFT in patients with DME and RVO. The presence of HRF and SMD is a negative predictor of recurrence in CFT in short term. DEX implant therapy resulted in satisfactory improvement in SMD. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate outcome predictors of aflibercept in neovascular age-related macular degeneration pretreated with ranibizumab based on a treat-and-extend regimen (TER). Methods: We performed a retrospective evaluation of 18-month follow-up of 45 consecutive patients with limited response to ranibizumab. Results: At month 18, mean central retinal thickness and intraretinal fluid (IRF) height were significantly reduced. The recurrence-free treatment interval (RFTI) increased from 7.0 ± 1.8 to 8.5 ± 2.4 weeks (p = 0.01); visual acuity remained stable. At month 18, 58.1% of patients showed a longer RFTI. At month 12, eyes with baseline subretinal fluid (SRF) had a shorter RFTI than those without SRF (p = 0.032). Eyes with baseline IRF showed a longer RFTI than those without IRF (p = 0.037). Baseline hyperreflective foci (HRF) presence indicated improvement in SRF (p = 0.024) and IRF at month 12 (p = 0.049). Conclusion: Baseline HRF presence predicted better morphological outcome, while SRF predicted a shorter RFTI and IRF a longer RFTI after switching from ranibizumab to aflibercept within a TER. [ABSTRACT FROM AUTHOR]

• New finding in multiple sclerosis: hyperreflective foci in the outer retina. • In vivo non-invasive visualization by optical coherence tomography. • Retinal hyperreflective foci may result from immune cell activity. • Methodology suited from repeated clinical examination. Hyperreflective granular elements with a transient presence in the retina can be detected non-invasively by optical coherence tomography (OCT). Such foci or dots may represent aggregates of activated microglia. However, in multiple sclerosis an increased number of hyperreflective foci has so far not been demonstrated in the intrinsically hyporeflective and avascular outer nuclear layer of the retina where there are no fixed elements in healthy eyes. Therefore, the present study intended to investigate the presence of hyperreflective foci in the outer nuclear layer in patients with relapsing- remitting multiple sclerosis (RRMS) by using a high-resolution OCT scanning protocol. This cross-sectional exploratory study examined 88 eyes in 44 RRMS patients and 106 eyes in 53 age- and sex-matched healthy subjects. None of the patients had any sign of retinal disease. All patients and healthy subjects each underwent one session of spectral domain OCT imaging. A total of 23,200 B-scans extracted from 8 × 8 mm blocks of linear B-scans at 60 μm intervals were analysed for hyperreflective foci in the outer nuclear layer of the retina. Analyses were made of the total block scan and a circular 6-mm diameter fovea-centered field in each eye. Multivariate logistic regression analysis was used to assess associations between parameters. Hyperreflective foci were observed in 31 out of 44 (70.5 %) multiple sclerosis patients compared to 1 out of 53 (1.8%) healthy subjects (p < 0.0001). From analyses of the total block scans, the median number of hyperreflective foci in the outer nuclear layer was 1 (range 0-13) in patients and 0 (range 0-2) in healthy subjects (p < 0.0001). In total, 66.2% of all hyperreflective foci were located within 6 mm of the center of the macula. There was no detectable association between the presence of hyperreflective foci and retinal nerve fiber layer or ganglion cell layer thickness. Hyperreflective granular foci in the avascular outer nuclear layer of the retina seen by OCT were almost completely absent in healthy subjects, whereas they were found, albeit at low density, in the majority of patients with RRMS. Hyperreflective foci can be repeatedly examined by non-invasive means and without pupil dilation, which opens a new field of investigation of infiltrating elements in an unmyelinated part of the central nervous system. [ABSTRACT FROM AUTHOR]

Purpose: The most widely used classifications of age-related macular degeneration (AMD) and its severity stages still rely on color fundus photographs (CFPs). However, AMD has a wide phenotypic variability that remains poorly understood and is better characterized by OCT. We and others have shown that patients with AMD have a distinct plasma metabolomic profile compared with controls. However, all studies to date have been performed solely based on CFP classifications. This study aimed to assess if plasma metabolomic profiles are associated with OCT features commonly seen in AMD., Design: Prospectively designed, cross-sectional study., Participants: Subjects with a diagnosis of AMD and a control group (> 50 years old) from Boston, United States, and Coimbra, Portugal., Methods: All participants were imaged with CFP, used for AMD staging (Age-Related Eye Disease Study 2 classification scheme), and with spectral domain OCT (Spectralis, Heidelberg). OCT images were graded by 2 independent graders for the presence of characteristic AMD features, according to a predefined protocol. Fasting blood samples were collected for metabolomic profiling (using nontargeted high-resolution mass spectrometry by Metabolon Inc). Analyses were conducted using logistic regression models including the worst eye of each patient (AREDS2 classification) and adjusting for confounding factors. Each cohort (United States and Portugal) was analyzed separately and then results were combined by meta-analyses. False discovery rate (FDR) was used to account for multiple comparisons., Main Outcome Measures: Plasma metabolite levels associated with OCT features., Results: We included data on 468 patients, 374 with AMD and 94 controls, and on 725 named endogenous metabolites. Meta-analysis identified significant associations (FDR < 0.05) between plasma metabolites and 3 OCT features: hyperreflective foci (6), atrophy (6), and ellipsoid zone disruption (3). Most associations were seen with amino acids, and all but 1 metabolite presented specific associations with the OCT features assessed., Conclusions: To our knowledge, we show for the first time that plasma metabolites have associations with specific OCT features seen in AMD. Our results support that the wide spectrum of presentations of AMD likely include different pathophysiologic mechanisms by identifying specific pathways associated with each OCT feature., Financial Disclosures: Proprietary or commercial disclosure may be found after the references., (© 2023 by the American Academy of Ophthalmology.)