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Optical coherence tomography (OCT) allows us to identify, into retinal layers, new morphological entities, which can be considered clinical biomarkers of retinal diseases. According to the literature, solitary, small (<30 µm), medium level hyperreflective (similar to retinal fiber layer) retinal foci (HRF) may represent aggregates of activated microglial cells and an in vivo biomarker of retinal inflammation. The identification and quantification of this imaging biomarker allows for estimating the level and possibly the amount of intraretinal inflammation in major degenerative retinal disorders, whose inflammatory component has already been demonstrated (diabetic retinopathy, age-related macular degeneration, radiation retinopathy). Currently, diabetic retinopathy (DR) probably represents the best clinical model to apply this analysis in the definition of this clinical biomarker. However, the main limitation to the clinical use of HRF is related to the technical difficulty of counting them: a time-consuming methodology, which also needs trained examiners. To contribute to solve this limitation, we developed and validated a new method for the semi-automatic detection of HRF in OCT scans. OCT scans of patients affected by DR, were analyzed. HRF were manually counted in High Resolution spectral domain OCT images. Then, the same OCT scans underwent semi-automatic HRF counting, using an ImageJ software with four different settings profiles. Statistical analysis showed an excellent intraclass correlation coefficient (ICC) between the manual count and each of the four semi-automated methods. The use of the second setting profile allows to obtain at the Bland-Altman graph a bias of -0.2 foci and a limit of agreement of ±16.3 foci. This validation approach opens the way not only to the reliable and daily clinical applicable quantification of HRF, but also to a better knowledge of the inflammatory component-including its progression and regression changes-of diabetic retinopathy., 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., (Copyright © 2021 Midena, Torresin, Velotta, Pilotto, Parrozzani and Frizziero.)

Subthreshold micropulse laser (SMPL) is a tissue-sparing technique whose efficacy is demonstrated for diabetic macular edema (DME) treatment. However, its mechanism of action is poorly known. A prospective observational study was performed on naïve DME patients treated with SMPL, to evaluate the changes of aqueous humor (AH) inflammatory and vaso-active biomarkers after treatments. AH samples of eighteen DME eyes were collected before and after SMPL. Ten non-diabetic AH samples served as controls. Full ophthalmic evaluation, spectral domain optical coherence tomography (SD-OCT) and fluorescein angiography were performed in DME group. Glass chip protein array was used to quantify 58 inflammatory molecules. Central retinal thickness (CRT) and visual acuity were also monitored. Several molecules showed different concentrations in DME eyes versus controls (p value < 0.05). Fas Ligand (FasL), Macrophage Inflammatory Proteins (MIP)-1α, Regulated on Activation Normal T Cell Expressed and Secreted (RANTES) and Vascular Endothelial Growth Factor (VEGF) were increased in DME at baseline versus controls and decreased after SMPL treatments (p < 0.05). CRT reduction and visual acuity improvement were also found. Inflammatory cytokines, mainly produced by the retinal microglia, were significantly reduced after treatments, suggesting that SMPL may act by de-activating microglial cells, and reducing local inflammatory diabetes-related response.

Purpose: To evaluate, by means of optical coherence tomography (OCT) and OCT angiography (OCTA), early retinal, choroidal and macular perfusion changes induced by a local inflammatory reaction secondary to uncomplicated cataract surgery., Methods: Selected eyes undergoing cataract surgery were enrolled in a prospective study. OCT and OCTA were performed before cataract surgery (T0) and at day: 1 (T1), 7 (T7), 30 (T30) and 90 (T90). Inner (IR) and outer retinal (OR) volumes, choroidal volume, hyper-reflective retinal spots (HRS) in IR and OR changes were measured at OCT. Macular perfusion was analysed in superficial (SCP), intermediate (ICP) and deep retinal capillary plexuses (DCP)., Results: Nine eyes of nine selected patients were consecutively enrolled. Mean IR volume changed after surgery (p=0.0001), increasing progressively from 4.391±0.231 mm³ at T0 to 4.573±0.241 mm³ at T30, p=0.0002. Both mean OR and choroidal volume increased, mainly at T30, but not significantly (p=0.4360 and p=0.2300, respectively). Mean HRS changed during follow-up, increasing at first in IR and later in OR (at T1 and T7, respectively, both p<0.0001). Macular ICP and DCP perfusion increased at T1, whereas macular SCP perfusion did not change. At T90, all OCT and OCTA parameters had almost reached baseline levels., Conclusions: The increase of HRS at first in IR and later in OR seems to confirm their inflammatory nature. Early OCTA changes (underline) underscore a selective susceptibility of DCP and ICP to a localised inflammatory reaction induced by cataract surgery., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To better pathophysiologically characterize macular edema secondary to eye irradiation, analyzing the presence of optical coherence tomography (OCT) hyperreflective spots., Methods: Twenty-five consecutive eyes affected by radiation maculopathy, secondary to irradiation for a primary uveal melanoma, without macular involvement in the irradiation field, were consecutively enrolled. All subjects underwent full ophthalmologic examination, including fluorescein angiography, color fundus photography, and spectral domain OCT, even in en face modality. Optical coherence tomography central subfield thickness was stratified into the following 3 categories: <400 μm, 400 to 600 μm, and >600 μm. Spectral domain OCT images were analyzed to measure and localize hyperreflective spots by two independent masked graders., Results: Hyperreflective spots were documented in all eyes (100%). Hyperreflective spots significantly increased in number according to OCT central subfield thickness (<400 μm, 400-600 μm, >600 μm, P < 0.05). The intergrader agreement was at least substantial for all measurements (intraclass correlation coefficient: 0.80)., Conclusion: Spectral domain OCT documents discrete intraretinal reflectivity changes (hyperreflective spots) in all (studied) eyes affected by radiation maculopathy. Hyperreflective spots increase in number with increasing central subfield thickness and could be considered as a new clinical biomarker of intraretinal inflammation in patients affected by macular edema secondary to irradiation for uveal melanoma.

Purpose: To detect and quantify geographic atrophy (GA) secondary to age-related macular degeneration using en face optical coherence tomography (OCT) and to correlate it to GA measured with fundus autofluorescence (FAF)., Methods: Twenty-four consecutive patients (27 eyes) were studied with both standard (STD)- and enhanced depth imaging (EDI)-OCT. En face OCT images were obtained at the outer retinal layer (OR) and at the choroidal layer (CH) level for both STD- and EDI-OCT. Areas of GA were measured on the en face OCT images and were correlated with the GA areas measured on blue (B)- and near infrared (NIR)-wavelength FAF images., Results: The intraoperator agreement in GA measurement was excellent with en face OCT at both OR and CH levels (intraclass correlation coefficient [ICC] = 0.99 in EDI and 0.98 in STD at OR level; 0.99 in EDI and 0.99 in STD at CH level). The interoperator agreement was excellent at OR level (ICC = 0.97 in EDI and 0.98 in STD), good at CH level (ICC = 0.95 in EDI, 0.90 in STD). The geographic atrophy area, at both B-FAF and NIR-FAF, was significantly equivalent to the GA area at OR level (B-FAF versus SDT-OR and EDI-OR: P = 0.0057 and 0.0090, respectively; NIR-FAF versus STD-OR and EDI-OR: P = 0.0131 and 0.0036, respectively), but not at CH level., Conclusions: En face OCT is a reliable method to detect and quantify GA, particularly when analyzed at the OR level, where the photoreceptors' loss creates an abrupt transition in OCT reflectivity.

Purpose: To analyse changes in choroidal thickness and retinal sensitivity (Se) in patients with geographic atrophy (GA) with or without choroidal neovascularisation (CNV) in the fellow eye., Participants: Patients with bilateral GA (B-GA group) and patients with unilateral GA and CNV in the fellow eye (U-GA group) were followed every 6 months, and enhanced depth imaging optical coherence tomography (OCT), blue and near infrared-wavelength fundus autofluorescence (B- and NIR-FAF), and microperimetry were evaluated., Methods: GA area, choroidal thickness, and Se were measured in the eye with GA at baseline and every 6 months up to the last follow-up visit., Results: 19 patients (8 in the B-GA group (16 eyes) and 11 in the U-GA group (11 eyes)) were studied. The mean±SD follow-up was 1.66±0.71 years (range 0.74-2.60 years) in the U-GA group, and 1.51±0.86 years (range 0.58-2.95 years) in the B-GA group (p=0.6766). Mean GA area was not significantly different between groups at baseline (p=0.4118 in the B-FA and p=0.6806 in the NIR-FAF) or at follow-up (p=0.5734 in the B-FAF and p=0.8945 in the NIR-FAF). Mean GA area significantly increased in both groups during follow-up (p=0.0050 for B-FAF and p=0.0052 for NIR-FAF in the U-GA group; p=0.0049 for B-FAF and p=0.0072 for NIR-FAF in the B-GA group). Choroidal thickness was significantly greater in the B-GA group compared with the U-GA group both at baseline (mean choroidal thickness 170.5±78.5 μm vs 129.1±36.1 μm; p=0.0371) and at last follow-up (173.2±86.1 μm vs 123±32.1 μm; p=0.0340). During follow-up mean choroidal thickness significantly decreased only in the U-GA group (p=0.0276); conversely mean Se significantly decreased only in B-GA group (p=0.0405)., Conclusions: During follow-up, changes in Se and choroidal thickness differed in patients with GA with or without CNV in the fellow eye. These results identify at least two GA phenotypes, in which the development and progression of GA may be primarily due to different pathophysiologic mechanisms., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To compare static (during a pure fixation task) versus dynamic (during microperimetry) quantification of fixation stability using microperimetry in normal and pathologic eyes, by means of 2 available (clinical and bivariate contour ellipse area [BCEA]) classification methods., Design: Prospective comparative observational study., Participants: One hundred and forty-nine eyes (110 patients) with different macular diseases and 171 normal eyes (109 subjects)., Methods: In all eyes studied, fixation stability was acquired during an isolated fixation task (static fixation) and during microperimetry (dynamic fixation). All fixation data were analyzed and compared by means of a clinical classification and by means of BCEA quantification., Results: Pathologic eyes were classified as follows: 41 eyes with diabetic macular edema (DME group), 13 eyes with vitreoretinal interface disease, 60 eyes with age-related macular degeneration (AMD group), and 35 eyes with primary open-angle glaucoma. Fixation stability was not uniform among groups according to clinical classification in both static and dynamic modalities (p < 0.0001). AMD group showed larger BCEA areas compared with all other groups (p < 0.0001). All pathologic groups showed more unstable fixation in dynamic fashion according to both clinical and BCEA methods (p < 0.0001). The variation of fixation stability of control group in dynamic task was highlighted only by BCEA analysis (p < 0.0001). A deterioration of retinal fixation according to clinical method matches a significant increase in BCEA areas (p < 0.0001)., Conclusions: The detection of clinical fixation stability changes improves when acquired in the dynamic modality. BCEA analysis provides more accurate evaluation of fixation stability and may detect minimal quantitative changes of the fixation area. However, a standard clinical classification can also detect changes in fixation stability in pathologic eyes. Both methods are useful tools in the evaluation of fixation stability., (© 2013 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Objective: To analyze correlation among microperimetry, inner and outer retinal layers, and fundus autofluorescence (FAF) changes in eyes with progressing geographic atrophy (GA) secondary to age-related macular degeneration., Methods: Microperimetry, spectral-domain optical coherence tomography (SD-OCT), standard short-wavelength FAF (SW-FAF), and near-infrared-wavelength FAF (NIR-FAF) were performed for all patients at both baseline and follow-up visits. FAF pattern, integrity of photoreceptor inner segment/outer segment (IS/OS) junction, total retinal thickness (RT), inner retinal layers (IRL), and outer retinal layers (ORL) thickness changes of every microperimetry extrafoveal tested point were analyzed., Results: A total of 366 microperimetry tested points were analyzed (6 patients, 7 eyes). Mean retinal sensitivity significantly decreased (p = 0.0149), and the percentage of dense scotomas significantly increased (p = 0.0125). Mean RT and mean ORL thickness significantly decreased (both p < 0.0001). Mean IRL thickness significantly increased (p = 0.0001). The decrease of ORL thickness was inversely correlated to the IRL thinning (rho = -0.710). FAF pattern at baseline was correlated to RT and ORL thickness (both p < 0.0001) and was significantly correlated to the risk to evolve to dense scotoma during follow-up (p = 0.0001 at SW-FAF, p < 0.0001 at NIR-FAF). Tested points showing at baseline the loss of photoreceptor IS/OS junction had a greater risk for evolving to dense scotoma compared with those with intact photoreceptor IS/OS junction (odds ratio 3.56, 95% CI 2.41-5.27)., Conclusions: Retinal sensitivity changes are correlated to IRL and ORL thickness changes, and to photoreceptor IS/OS junction integrity. FAF patterns remain a relevant factor in predicting GA evolution. Microperimetry, SW-FAF and NIR-FAF, and SD-OCT should be combined to obtain adequate morphologic and functional prospective information., (© 2013 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the presence of hyperreflective spots (HRS) in diabetic patients without clinically detectable retinopathy (no DR) or with nonproliferative mild to moderate retinopathy (DR) without macular edema, and compare the results to controls., Methods: 36 subjects were enrolled: 12 with no DR, 12 with DR, and 12 normal subjects who served as controls. All studied subjects underwent full ophthalmologic examination and spectral domain optical coherence tomography (SD-OCT). SD-OCT images were analyzed to measure and localize HRS. Each image was analyzed by two independent, masked examiners., Results: The number of HRS was significantly higher in both diabetics without and with retinopathy versus controls (P < 0.05) and in diabetics with retinopathy versus diabetics without retinopathy (P < 0.05). The HRS were mainly located in the inner retina layers (inner limiting membrane, ganglion cell layer, and inner nuclear layer). The intraobserver and interobserver agreement was almost perfect (κ > 0.9)., Conclusions: SD-OCT hyperreflective spots are present in diabetic eyes even when clinical retinopathy is undetectable. Their number increases with progressing retinopathy. Initially, HRS are mainly located in the inner retina, where the resident microglia is present. With progressing retinopathy, HRS reach the outer retinal layer. HRS may represent a surrogate of microglial activation in diabetic retina.

Purpose: To evaluate the ability of confocal scanning laser ophthalmoscope (cSLO) in the retromode imaging modality in detecting retinal changes secondary to exudative age-related macular degeneration (AMD)., Methods: Seventeen eyes of 13 consecutive patients affected by CNV secondary to AMD were evaluated with optical coherence tomography (OCT) to detect neuroretinal detachment (NRD), pigment epithelial detachment (PED), cystoid macular edema (CME), and epiretinal membranes (ERM). All eyes were examined with a cSLO equipped with infrared retromode (RM) imaging modality. Infrared and fundus autofluorescence images were also obtained (IR and FAF). The intermethod agreement between OCT and cSLO was evaluated considering single cSLO imaging modality separately (IR, FAF, and RM), and all imaging modalities together., Results: Eight eyes (47 %) had NRD at OCT; intermethod agreement was poor for any single cSLO imaging modality considered separately (k: 0.14, 0.01, and 0.29 for cSLO IR, FAF, and RM, respectively). Four eyes had PED at OCT (24 %); intermethod agreement was mild for cSLO RM, poor for IR and FAF (k: 0.51, 0.16, and 0.00, respectively). CME was present in eight eyes (47 %); intermethod agreement was excellent for cSLO RM, poor for IR and FAF (k: 0.88, 0.38, and 0.26, respectively). ERM was present in three eyes (18 %); intermethod agreement was mild for cSLO IR, poor for FAF, and excellent for RM (k: 0.59, 0.00, and 0.76, respectively)., Conclusions: cSLO RM imaging is a useful and reproducible technique in detecting retinal features associated with CNV, particularly CME.

Purpose: Diabetic macular edema (DME) shows variable clinical characteristics with unpredictable results to local treatment, probably reflecting different phenotypes. The purpose of this study was to evaluate the role of structural and functional macular imaging in the characterization of DME patterns., Methods: One hundred fifty-one eyes of 92 diabetic patients with untreated clinically significant macular edema (CSME) underwent best corrected visual acuity (BCVA) determination (logMAR), slit lamp biomicroscopy; fluorescein angiography; optical coherence tomography (OCT; mean central retinal thickness [CRT], volume, and DME pattern); fundus autofluorescence (FAF; absent or increased [i]FAF, single or multiple spots; iFAF area quantification); and microperimetry. Linear correlation, data agreement and three-way analysis of covariance were used for statistics., Results: Thirty-five (23.2%) eyes had normal FAF; and 116 eyes had iFAF: 48 (31.8%) single-spot iFAF, 68 (45%) multiple-spot iFAF. Retinal sensitivity in areas with iFAF was 11.5±5.3 dB (vs. 15.1±3.9 dB in normal areas, P<0.005). Retinal sensitivity of the central field was 15.1±3.9 dB in normal FAF, 12.4±4.8 dB in single-spot iFAF and 11.4±4.9 dB in multiple-spot iFAF (P<0.05). OCT CRT and volume were not significantly different between the FAF groups. OCT volume correlated to OCT CRT (r=0.68), retinal sensitivity in iFAF (r=-0.50) and BCVA (r=0.42). Cystoid OCT pattern and FA edema patterns correlated with iFAF presence (P<0.0001)., Conclusions: In CSME, FAF correlates better with OCT patterns and central field microperimetry rather than with visual acuity. FAF is a rapid, noninvasive technique that may give new insight into the evaluation of DME. The validity of FAF in the follow-up and treatment outcomes in DME remain to be assessed.

Purpose: To investigate fixation pattern and retinal sensitivity in patients with serpiginous choroiditis (SC)., Methods: Twenty-eight eyes (14 patients) with SC were evaluated. Best-corrected visual acuity, color fundus photography, fundus autofluorescence, and fluorescein and indocyanine green angiography were performed. Microperimetry was used to assess fixation pattern and retinal sensitivity., Results: Of 28 eyes, 16 (57%) had central, one (4%) poor central, and 11 (39%) eccentric fixation; and 18 (64%) had stable, four (14%) relatively unstable, and six (21%) unstable fixation. In patients with posterior pole symmetrically involved in both eyes, the better eye had stable and central fixation in all cases. Atrophic lesions were characterized by a dense scotoma in all cases, with a relative scotoma at their margins in ten eyes (38%). In two cases of active disease, a dense scotoma correlated to an active lesion could be detected. A relative scotoma was documented in areas not involved by the disease at the posterior pole in eight eyes (28%), and in the peripapillary area in 11 eyes (39%)., Conclusions: Quantification of retinal sensitivity and fixation pattern by microperimetry offers new data about the impact of visual impairment in patients with SC. A reduction of retinal sensitivity in an apparently healthy area suggests a wider functional involvement of the retina, undetectable by morphologic evaluation alone.

Purpose: To evaluate the characteristics of retinal fixation in patients with diabetic macular edema using microperimetry., Methods: One hundred seventy nine eyes (98 patients) with untreated diabetic macular edema underwent best corrected visual acuity determination (Early Treatment Diabetic Retinopathy Study charts), digital color stereoscopic fundus photos, fluorescein angiography and Optical Coherence Tomography assessment of macula. Fixation and retinal thresholds were determined with an automatic microperimeter., Results: Best corrected visual acuity (approximate Snellen equivalent) was: 20/25 or better in 90 (52%) eyes, 20/50 to 20/32 in 39 (22.5%) eyes, 20/200 to 20/62.5 in 35 (20.2%) eyes and inferior to 20/200 in 9 (5.2%) eyes. Fixation was central in 128 (71.51%), poor central in 26 (14.53%) and predominantly eccentric in 25 (13.97%) eyes; stable in 133 (74.3%), relatively unstable in 42 (23.46%) and unstable in 4 (2.23%) eyes. Both fixation location and stability were not significantly influenced by edema characteristics (diffuse, focal, cystoid, spongelike, with or without subfoveal neuroretinal detachment), (P > 0.05), whereas they were significantly influenced by the presence of subfoveal hard exudates, (P = 0.004 and P = 0.0046, respectively). Site and stability of fixation were significantly associated, (P < 0.0001). Retinal pseudofovea would have been covered by laser photocoagulation in 24 (47%) eyes with poorly central and predominantly eccentric fixation and in 29 (63%) eyes with relatively unstable and unstable fixation., Conclusion: Microperimetry shows that fixation location and stability in patients with diabetic macular edema are independent of edema characteristics, except when subfoveal hard exudates are present. Location of pseudofovea may influence treatment strategy.

Purpose: To compare the changes in macular sensitivity (microperimetry) and macular thickness with different degrees of diabetic macular edema., Methods: Sixty-one eyes of 32 consecutive diabetic patients were included in this cross-sectional study. All included eyes underwent functional and morphologic examination of the macular area. Best corrected visual acuity (ETDRS charts), macular sensitivity, and macular thickness were quantified. Lesion-related macular sensitivity and retinal fixation were investigated with an advanced, automatic microperimeter. Optical coherence tomography (OCT) was used to quantify macular thickness., Results: The 61 included eyes were graded, by two retinal specialists, for diabetic macular edema as follows: 16 were graded as no macular edema (NE), 30 as non-clinically significant macular edema (NCSME), and 15 as clinically significant macular edema (CSME). Macular thickness significantly increased from the NE to the CSME group (P<0.0001), whereas macular sensitivity significantly decreased from the NE to the CSME group (P<0.0021). A significant correlation coefficient was noted between retinal sensitivity and normalized macular thickness (r=-0.37, P<0.0001). Linear regression analysis showed a decrease of 0.83 dB (P<0.0001) for every 10% of deviation of retinal thickness from normal values. Visual acuity and central macular sensitivity correlated significantly in the NCSME group (r=-0.6, P=0.0008), but not in the NE (r=-0.144, P=0.6) or in the CSME (r=-0.46, P=0.11) groups., Conclusions: Macular edema may be better documented by adding macular sensitivity mapping by microperimetry to macular thickness measurement by OCT and visual acuity determination because macular sensitivity seems to be a relevant explanatory variable of visual function, independent of macular thickness data. Moreover, microperimetry may be of value in predicting the outcome of diabetic macular edema, because it incorporates a functional measure that may supplement the predictive value of OCT and visual acuity.

Purpose: To investigate the effects of subfoveal choroidal neovascularizzation (CNV) secondary to age-related macular degeneration (AMD) on macular functional parameters quantified with an automatic fundus perimeter., Methods: 118 eyes of 98 consecutive patients with subfoveal CNV secondary to AMD were evaluated. Best corrected visual acuity (ETDRS charts), fundus photography, and fluorescein angiography were performed. Microperimetry (fundus-related perimetry) was used to quantify macular sensitivity and fixation pattern (location and stability)., Results: Of 118 eyes: 26 (21.9%) had central, 18 (15.1%) poor central and 74 (63.0%) eccentric fixation; 31 (26.0%) had stable, 42 (35.6%) relatively unstable and 45 (38.4%) unstable fixation. In 75 eyes (63.4%) a dense central scotoma was found. Angiographic classification of subfoveal CNV (occult versus classic) was not significantly related to fixation pattern (location: P = 0.274; stability: P = 0.385), and presence of dense scotoma (P = 0.41)., Conclusion: Microperimetric quantification of macular sensitivity and fixation pattern in eyes with subfoveal CNV secondary to AMD offers new data about the impact of visual impairment in these eyes. Moreover, microperimetry improves the functional evaluation of subfoveal CNV in AMD.

Introduction: Microglia (MG) is suggested to play an immunopathological role of in Multiple Sclerosis (MS). Since hyper-reflective foci (HRF) might mark MG activation, in vivo analysis by Optic Coherence Tomography (OCT) in MS patients under disease modifying therapies may help to clarify MS immunopathology as well as drug's mechanism of intrathecal action. Objective: To analyze HRF in patients treated with Natalizumab (NTZ), a high efficacy therapy for MS. Materials and methods: The effect of NTZ on the retina of 36 Relapsing-Remitting MS patients was investigated in a prospective, single-center study. OCT was performed immediately before the first infusion and then between infusion 3 and 4, infusion 6 and 7, infusion 11 and 13. Peripapillary and macular scans were acquired, evaluating peripapillary RNFL thickness, macular volumes (vertical scans), and HRF count (horizontal scan) in Ganglion Cell Layer (GCL), Inner Plexiform Layer (IPL) and Inner Nuclear Layer (INL). Clinical examination was performed every six months. Results: HRF count significantly increased under NTZ therapy (p<0.001) in both GCL (18.85 ± 6.93 at baseline, 28.24 ± 9.55 after 12 months) and IPL (25.73 ± 7.03 at baseline, 33.21 ± 8.50 after 12 months) but remained stable in INL (33.65 ± 7.76 at baseline, 36.06 ± 6.86 after 12 months, p=0.87), while no relevant modification of pRNFL and macular volumes were observed during the study. EDSS remained stable and no clinical relapse was observed between month 6 and 12. Conclusion: In RRMS NTZ affects HRF count in GCL and IPL, but not in INL, suggesting that NTZ does not impact on some aspects of MS immunopathology. [ABSTRACT FROM AUTHOR]

The disorganization of retinal inner layers (DRIL) is an optical coherence tomography (OCT) biomarker strictly associated with visual outcomes in patients with diabetic macular edema (DME) whose pathophysiology is still unclear. The aim of this study was to characterize in vivo, using retinal imaging and liquid biopsy, DRIL in eyes with DME. This was an observational cross-sectional study. Patients affected by center-involved DME were enrolled. All patients underwent spectral domain optical coherence tomography (SD-OCT) and proteomic analysis of aqueous humor (AH). The presence of DRIL at OCT was analyzed by two masked retinal experts. Fifty-seven biochemical biomarkers were analyzed from AH samples. Nineteen eyes of nineteen DME patients were enrolled. DRIL was present in 10 patients (52.63%). No statistically significant difference was found between DME eyes with and without DRIL, considering the AH concentration of all the analyzed biomarkers except for glial fibrillary acidic protein (GFAP), a biomarker of Müller cells dysfunction (p = 0.02). In conclusion, DRIL, in DME eyes, seems to strictly depend on a major dysfunction of Müller cells, explaining its role not only as imaging biomarker, but also as visual function Müller cells-related parameter. [ABSTRACT FROM AUTHOR]

Purpose: von Hippel-Lindau (VHL) disease is caused by a mutation of the VHL gene and characterized by the development of retinal hemangioblastomas (RH). Current pathophysiologic mechanisms of RH development and progression are still insufficient to predict RH behavior. VHL gene is involved in the cellular response to hypoxia and in many intracellular signaling pathways expressed both in angiogenesis and inflammation. Optical coherence tomography (OCT) allows to identify hyper-reflective retinal foci (HRF) known as aggregates of activated microglial cells as possible in vivo biomarker of local inflammation. The aim of the present study was to investigate the presence of HRF in patients with genetically confirmed VHL disease. Methods: In this cross-sectional study, patients with VHL underwent complete ophthalmological examination and OCT with HRA + OCT Spectralis. HRF were manually identified and calculated in inner (IR), outer (OR) and full retina. Age-matched healthy subjects were enrolled as controls. Results: 113 eyes of 63 VHL patients and 56 eyes of 28 healthy subjects were evaluated. HRF number was significantly higher in VHL than in controls in IR (28.06 ± 7.50 vs 25.25 ± 6.64, p = 0.042). No difference was observed in OR and in full retina (OR: 7.73 ± 2.59 vs 7.95 ± 2.51, p = 0.599; full retina: 35.79 ± 8.77 vs 33.20 ± 7.47, p = 0.093). Conclusion: The increase of HRF, which mirror retinal microglial activation, characterizes VHL eyes. The role of activated microglia in the retina of VHL eyes needs to be better investigated, mainly considering local VHL disease manifestations. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence suggests that retinal hyper-reflecting foci (HRF) might be clusters of activated and proliferating microglia. Since microglia are widespread activated in multiple sclerosis (MS) brain, its evaluation in retina may help to understand and monitor MS-related pathology. Aim: This study aims at investigating the association of HRF with cerebrospinal fluid (CSF) cytokines and MRI parameters in relapsing–remitting MS (RRMS). Methods: Nineteen RRMS at clinical onset and 15 non-inflammatory neurological disorders (NIND) underwent brain 3T MRI and CSF examination. Optical coherence tomography (OCT) analysis, including HRF count, was performed on RRMS patients. Sixty-nine cytokines/chemokines were analyzed in the CSF by multiplex technology. Results: In RRMS, HRF count in the ganglion cell layer (GCL) was associated with IL-1Ra, IL-9, IL-15, IFN-γ, and G-CSF. Moreover, in RRMS patients CSF concentrations of IL-1Ra and G-CSF associated with global cortical thickness. The HRF count in the inner nuclear layer (INL) correlated with IL-22, IL-34, IL-35, CXCL-2, CXCL-10, and CXCL-13, and multivariate analysis confirmed a strong association (r2: 0.47) with both CXCL-2 (β: -0.965, p = 0.0052) and CXCL-13 (β: 0.241, p = 0.018). This latter cytokine increased in RRMS with high HRF count compared with NIND and RRMS with low HRF count. Finally, the CXCL-13/CXCL-2 ratio strongly associated with HRF count (r: 0.8, p < 0.005) and cortical lesion volume (r: 0.5, p < 0.05). Conclusions: The association of HRF with intrathecally produced monocyte/microglia-derived cytokines confirms their microglial origin and indicates they are worth further evaluating as markers of activated microglia. [ABSTRACT FROM AUTHOR]

To analyze the early microvascular retinal changes and oscillatory potentials alterations secondary to diabetic retinal damage, 44 eyes of 22 diabetic patients without and with mild diabetic retinopathy (DR) and 18 eyes of 9 healthy controls were examined. All subjects underwent spectral domain optical coherence tomography (SD-OCT), OCT angiography (OCTA), and electroretinography of oscillatory potentials (OPs). At OCTA, vessel area density (VAD), vessel length fraction (VLF), and fractal dimension (FD) were significantly reduced in the superficial vascular plexus (SVP), VLF and FD in the intermediate capillary plexus (ICP), and FD in the deep capillary plexus (DCP) in the diabetic group compared to the control group. The amplitude (A) of OP2, OP3, OP4 and the sum of OPs were significantly reduced in the diabetic group versus the controls, and the last two parameters were reduced also in patients without DR versus the controls. Moreover, in the diabetic group, a significant direct correlation was found between the A of OP1, OP2, OP3 and sOP and the VLF and FD in the SVP, while a statistically significant inverse correlation was found between the A of OP3 and OP4 and the VDI in the ICP and DCP. The reduced oscillatory potentials suggest a precocious involvement of amacrine cells in diabetic eyes, independently of DR presence, and their correlation with vascular parameters underlines the relevance of the crosstalk between these cells and vascular components in the pathophysiology of this chronic disease. [ABSTRACT FROM AUTHOR]

Histopathologic studies of diabetic choroid suggest that diabetic choroidopathy is a key aspect secondary to diabetes. Recently, hyperreflective choroidal foci (HCF) have been introduced as novel optical coherence tomography (OCT) parameter. The aim of this study was to identify and quantify HCF in diabetic subjects with retinopathy, with or without diabetic macular edema (DME). Eighty-five diabetic subjects with different degrees of DR were enrolled: 37 without DME and 48 with DME. All subjects underwent full ophthalmologic examination including spectral domain optical coherence tomography (OCT). OCT images were analyzed to quantify and localize HCF. Each image was analyzed by two independent, masked examiners. OCT images showed that all subjects (100%) had HCF in the different layers of the choroid. The number of HCF was significantly higher in diabetics with DME versus those without DME (p < 0.0001). HCF showed variable size, shape and location inside the choroid. They were mainly located in choriocapillaris and Sattler's layer, on the edges of blood vessels. The intraobserver and interobserver agreement was almost perfect (ICC >0.9). This study suggests that hyperreflective foci in the choroid of subjects with DR may be accurately identified with structural OCT. Their number significantly increases with the progression of DME. These HCF may represent, as in the retina, a sign of infiltration of inflammatory cells (mainly migrating microglia) into the choroid, according to the hypothesis raised by Jerry Lutty. HCF may confirm in vivo the histopathologic findings suggesting that diabetic choroidopathy may be primarily a neuroinflammatory disorder. • Diabetic choroidopathy is a key aspect secondary to diabetes. • Hyperreflective choroidal foci (HCF) are novel OCT biomarkers. • HCF seems to be a marker of disease severity and progression in diabetic eyes. • HCF is a sign of infiltration of microglial cells from the retina into the choroid. • HCF may confirm that diabetic choroidopathy is a neuroinflammatory disorder. [ABSTRACT FROM AUTHOR]