Subfoveal Neuroretinal Detachment Research Articles

Sex Differences in Inflammation-Related Biomarkers Detected with OCT in Patients with Diabetic Macular Edema

PurposeTo investigate sex-based differences in inflammation-related biomarkers on Spectral-Domain Optical Coherence Tomography (SD-OCT). DesignCross-sectional study. ParticipantsPatients with diabetic macular edema (DME) between February 1, 2019, and March 31, 2023, without intravitreal anti–vascular endothelial growth factor (anti-VEGF) injection within the prior six months. MethodsWe reviewed each patient’s medical record for age, biological sex, race and ethnicity, most recent glycated hemoglobin level (HbA1c), visual acuity (VA), and central macular thickness (CMT). OCT biomarkers that have been found in literature to be associated with inflammation, including disorganization of retinal inner layers (DRIL), retinal hyperreflective foci (HRF), hyperreflective choroidal foci (HCF), subfoveal neuroretinal detachment (SND), and perturbation in retinal nerve fiber layer (RNFL) thickness, ganglion cell layer (GCL) thickness, and inner nuclear layer (INL) thickness were evaluated by graders masked to the clinical characteristics of the patients. We performed multivariable regression analyses with the OCT biomarkers as the outcome variables and sex, age, HbA1c, and CMT as independent variables. Main Outcome MeasuresOCT inflammation-related biomarkers as listed above ResultsFemale patients were on average two years older than male patients (P = 0.041). There were no significant differences in race and ethnicity, HbA1c, VA, or CMT between male and female patients. After controlling for age, HbA1c, and CMT, we found male sex to be associated with more HRF (incidence rate ratio [IRR] = 1.19, 95% confidence interval [CI] = 1.10 – 1.29), more HCF (odds ratio = 2.01, 95% CI = 1.12 – 3.64), and thicker INL (7 μm thicker in males, 95% CI = 2 – 12). Sex was not a significant predictor for either DRIL or SND in the multivariable regression models. Patients with higher HbA1c were more likely to have more HRF (IRR = 1.02 per 1 point increase, 95% CI = 1.00 – 1.04) after controlling for other factors. ConclusionsMale sex was correlated with more inflammation-related biomarkers on OCT including more HRF, more HCF, and thicker INL, after accounting for age, glycemic control, and amount of DME. Further studies are needed to evaluate the potential implications of these sex-based differences for individualized treatment.

Optical coherence tomography biomarkers DROL, PROS, SND, hyperreflective walls of foveal cystoid spaces as predictors of central macular thickness and visual acuity in diabetic macular edema treated with intravitreal ranibizumab.

This study aims to establish DROL (disruption of retinal outer layers), PROS (photoreceptor outer segment length), SND (subfoveal neuroretinal detachment), and hyperreflective walls of foveal cystoid spaces (HRW) as optical coherence tomography (OCT) biomarkers and predictors of central macular thickness (CMT) and visual acuity in diabetic macular edema (DME) treated with intravitreal ranibizumab (IVR). In this prospective, interventional study performed at a tertiary care center over a span of 1 year from December 2021 to December 2022, 50 eyes of 46 patients of DME were included. Visual acuity and spectral domain OCT imaging were performed at baseline. Using inbuilt calipers on SD-OCT, the horizontal extent of DROL and the vertical extent of PROS were measured manually. SND and HRW were assessed qualitatively. IVR was administered and patients were followed up at 4, 8, and 12 weeks. The eyes without DROL had statistically significant (P < 0.05) lesser CMT and better BCVA (best-corrected visual acuity) (P < 0.05) after pro re nata injection of IVR. There was a positive correlation between the extent of baseline DROL with final CMT (P < 0.05) and final logMAR BCVA (P > 0.05), whereas negative correlation with the extent of baseline PROS with final CMT (P < 0.05) and final logMAR BCVA (P > 0.05). The presence of HRW and SND predicted non-resolution of CMT and worse visual acuity after treatment with IVR in DME. DROL, PROS, SND, and hyperreflective walls of foveal cystoid spaces may be utilized as qualitative as well as quantitative biomarkers to predict the post-treatment CMT and visual acuity in DME.

OCT biomarkers as predictors of visual improvement in diabetic macular edema eyes receiving dexamethasone implants

BackgroundSeveral optical coherence tomography (OCT) biomarkers have been proposed as predictors for functional and anatomical outcomes in Diabetic Macular Edema (DME). This study aims to examine the impact of these OCT features on the visual acuity improvement of patients with DME after long-acting Dexamethasone intravitreal implants (DEX-I) injection. Furthermore, the safety and impact of DEX-I on clinical parameters, including intraocular pressure (IOP) were assessed.MethodsIn this retrospective observational study, we reviewed the medical records of naïve and non-naïve eyes with DME who received at least one DEX-I. The primary endpoint was visual acuity improvement of ≥ 5 ETDRS letters at 1 month and 4 months after treatment. Secondary outcomes were the changes in OCT biomarkers and the impact of DEX-I on IOP at 1 and 4 months of follow-up. Linear panel regression analysis was used to test for differences in central subfield thickness (CST) over time and it was stratified according to biomarkers at baseline. Finally, a logistic regression analysis was used to identify factors predicting visual improvement at 1 and 4 months.ResultsWe included 33 eyes of which 63.6% were at an advanced stage of DME. Overall, CST, cube average thickness (CAT), cube volume (CV), and intraretinal cystoid spaces > 200 μm (ICS) decreased following DEX-I injection (p < 0.001). Additionally, a thicker CST at baseline was observed in eyes with better visual improvement at one month (p = 0.048). After logistic regression analysis, CST was retained as the only predictor for visual improvement at one month (p = 0.044). Furthermore, panel regression analysis identified a relation between subfoveal neuroretinal detachment (SND) at baseline and CST increase at four months. Lastly, only 15.2% of the eyes necessitated topical medication for IOP reduction, with no differences observed when stratifying between naïve and non-naïve eyes.ConclusionOur analyses suggest that a ticker baseline CST may serve as a positive predictor of early visual improvement and SND presence at baseline may be a negative prognostic factor for CST increase 4 months after DEX-I injection. Other well-known biomarkers, such as disorganization of the inner retinal layers (DRIL) and hyperreflective foci (HF), did not demonstrate prognostic value on visual outcomes, at least within the first four months following the injection.

Imaging biomarkers and clinical factors associated with the rate of progressive inner and outer retinal thinning in patients with diabetic macular edema

The aim of this study was to assess the relationship of clinical characteristics to the rate of retinal thinning in eyes with diabetic macular edema (DME) treated with anti-vascular endothelial growth factor (VEGF) therapy. We analyzed subjects with a long-term follow-up (≥ 3 years) and evidence of resolved DME after the initiation of anti-VEGF therapy (baseline visit). To measure the long-term rate of retinal thinning during treatment, a second visit (first visit with evidence of resolved DME after 3 years) was also considered. A longitudinal quantitative topographical assessment of the inner and outer retinal thicknesses was provided. Clinical characteristics were associated with the rate of longitudinal retinal thinning. We included 56 eyes (50 patients) in the analysis. A significant longitudinal thinning in the inner and outer retina was detected in all the analyzed regions (p values between 0.027 and < 0.0001). In the multivariable analysis, type of diabetes (type 2 vs. type 1) was associated with increased foveal inner retinal thinning (p = 0.019). A higher number of subfoveal neuroretinal detachment during follow-up (p = 0.006) was associated with faster rates of foveal outer retinal thinning. Type of diabetes (p < 0.0001), higher age (p = 0.033) and cystoid macular edema phenotype (p = 0.040) were associated with increased parafoveal inner retinal thinning. Gender (p = 0.003) and diabetic retinopathy stage (p = 0.013) were associated with faster rates of perifoveal inner retinal thinning, while diabetic retinopathy stage (p = 0.036) was associated with increased perifoveal outer retinal thinning. In conclusion, clinical factors, including DME phenotypes, were associated with the rates of retinal thinning in patients undergoing anti-VEGF treatment.

Intravitreal Ranibizumab and Dexamethasone Implant Injections as Primary Treatment of Diabetic Macular Edema: The Month 24 Results from Simultaneously Double Protocol

Purpose To compare efficacy of simultaneously administered intravitreal dexamethasone implant (DEX implant) and ranibizumab (simultaneous double protocol) injections with ranibizumab monotherapy for diabetic macular edema (DME) at month 24. Methods This is a prospective, consecutive, clinical interventional study. Naïve eyes with DME were randomized into two groups: 34 eyes received simultaneous double-protocol therapy and 34 eyes received ranibizumab monotherapy. The primary efficacy endpoint was change in visual acuity in month 24. The secondary efficacy endpoints were to evaluate gain of ≥15 letters, morphological changes and central foveal thickness. Decreased vision from DME (study eye BCVA, 20/40 or worse Snellen equivalent using ETDRS testing), the presence of DME with ≥300 μm foveal intraretinal cystoid spaces (within 1000 μm of the centre of the fovea), subfoveal neuroretinal detachment (SND), intraretinal hyperreflective foci (HRF, within 500 μm of the centre of the fovea) or foveal lipid exudates and external limiting membrane (ELM) and ellipsoid zone (EZ) disruption (within 500 μm of the centre of the fovea) on SD-OCT were eligible to enrol. Results The mean baseline BCVA was 48 ± 23 letters in double protocol group and 52 ± 14 letters ranibizumab monotherapy group (p = 0.416). The mean number of ETDRS letters changed from baseline at 12 months versus change from baseline at month 24 in double protocol group and ranibizumab monotherapy group were +21.6 versus +20.2 and +9.6 versus +9.1, respectively. At the month 24 time point, 65.4% of patients in double protocol group and 26.2% of patients in ranibizumab monotherapy group had gained ≥15 ETDRS letters in BCVA from baseline (p < 0.001). The external limiting membrane (ELM) and ellipsoid zone (EZ) integrity were better in the double protocol group in comparison to ranibizumab monotherapy group at month 24. In addition, there was no statistically significant increase in the proportion of patients with epiretinal membrane in double protocol group at month 24, by the contrast with ranibizumab monotherapy group (p = 0.06 and p = 0.04 in the double protocol and ranibizumab monotherapy groups, respectively). From baseline to month 24, the mean central foveal thickness (CFT) was 672 ± 293 μm reduced to 278 ± 84 μm in double protocol group and was 631 ± 279 μm reduced to 356 ± 108 μm in ranibizumab monotherapy group (p < 0.001 and p < 0.001). From baseline to month 24, 38% (13/34) of eyes in double protocol group and 18% (6/34) of eyes in ranibizumab monotherapy group had at least 5 mmHg of IOP elevation (p = 0.012). Two grades or more increased cataract density were detected 27% (6/22) of eyes in the double protocol group and in 12.5% (3/24) of eyes in the ranibizumab monotherapy group from baseline to month 24 (p = 0.032). Conclusion According to the improvements in visual acuity and morphological changes achieved at month 24, the simultaneous double protocol therapy can be an effective treatment option for DME with inflammatory biomarkers on OCT or/and decreased visual acuity.

Optical coherence tomography as retinal imaging biomarker of neuroinflammation/neurodegeneration in systemic disorders in adults and children.

The retina and the optic nerve are considered extensions of the central nervous system (CNS) and thus can serve as the window for evaluation of CNS disorders. Spectral domain optical coherence tomography (OCT) allows for detailed evaluation of the retina and the optic nerve. OCT can non-invasively document changes in single retina layer thickness and structure due to neuronal and retinal glial cells (RGC) modifications in systemic and local inflammatory and neurodegenerative diseases. These can include evaluation of retinal nerve fibre layer and ganglion cell complex, hyper-reflective retinal spots (HRS, sign of activated microglial cells in the retina), subfoveal neuroretinal detachment, disorganization of the inner retinal layers (DRIL), thickness and integrity of the outer retinal layers and choroidal thickness. This review paper will report the most recent data on the use of OCT as a non invasive imaging biomarker for evaluation of the most common systemic neuroinflammatory and neurodegenerative/neurocognitive disorders in the adults and in paediatric population. In the adult population the main focus will be on diabetes mellitus, multiple sclerosis, optic neuromyelitis, neuromyelitis optica spectrum disorders, longitudinal extensive transverse myelitis, Alzheimer and Parkinson diseases, Amyotrophic lateral sclerosis, Huntington’s disease and schizophrenia. In the paediatric population, demyelinating diseases, lysosomal storage diseases, Nieman Pick type C disease, hypoxic ischaemic encephalopathy, human immunodeficiency virus, leukodystrophies spinocerebellar ataxia will be addressed.

Effectiveness of a Hydrophilic Curcumin-Based Formulation in Coadjuvating the Therapeutic Effect of Intravitreal Dexamethasone in Subjects With Diabetic Macular Edema.

Purpose: This study evaluates if the addition of a curcumin formulation with a polyvinylpyrrolidone-hydrophilic carrier (CHC; Diabec®, Alfa Intes, Italy) to intravitreal injections of dexamethasone (DEX-IVT) can affect the morphological retinal characteristics, extending the steroid re-treatment period in patients with diabetic macular edema (DME). Methods: A randomized controlled clinical trial was carried out in DME patients, randomly assigned to receive DEX-IVT or DEX-IVT and a CHC. The evaluation of the mean difference of central retinal thickness (CRT) was the primary aim. Secondary aims were the evaluations of best-corrected visual acuity, differences in the predetermined retinal layer thickness, the number/time of re-treatment, and the assessment of safety. Results: A total of 73 DME patients were included (35 in the control group and 38 in the combined therapy group). In both the control and combined therapy groups, the mean CRT change from T0 to the 6 months’ evaluation was significant (p = 0.00). The mean CRT result was significantly different at month 4 (p = 0.01) between the control and combined therapy groups, with a greater reduction in the combined therapy group, in particular, in patients with ≤10 years of diabetes. A trend of CRT reduction in the combined therapy group has been observed also considering patients with subfoveal neuroretinal detachment. In addition, we observed that the reduction of inner retinal layer thickness was greater in the combination group, in comparison with controls. Conclusion: The combination of a CHC to DEX-IVT is a promising therapeutic option in case of DME, in particular, for patients with early-stage diabetes and with an inflammatory phenotype. Further studies will be necessary to confirm these findings.

Temporal variation of optical coherence tomography biomarkers as predictors of anti-VEGF treatment outcomes in diabetic macular edema.

To report a longitudinal analysis of specific optical coherence tomography (OCT) features in eyes with diabetic macular edema (DME) treated with anti-VEGF. A total of 133 eyes of 103 consecutive patients with center-involving DME were included in the study. The eyes were treated between August 2008 and April 2019 with three monthly intravitreal anti-VEGF injections, either with or without prompt or deferred laser, followed by pro re nata (PRN) re-treatment. The following OCT biomarkers were evaluated: subfoveal neuroretinal detachment (SND) (defined as present (SND+) or absent (SND-)), hyperreflective retinal foci (HRF) number (defined as: absent/few(HRF-) or moderate/many (HRF+)), external limiting membrane (ELM) integrity, central macular thickness (CMT), and central retinal thickness (CRT). Changes in SND status and in the number of HRF were evaluated at each DME recurrence throughout the follow-up(FU) period. Mutual correlation among OCT biomarkers and their relationship with visual and anatomic outcomes were assessed both at baseline and over the FU period. The mean FU was 71.2 months (SD 28.4; min. 12-max. 111). At baseline, the prevalence of SRD+ was 27.8% and a high number of HRF were detected in 41.4% of the eyes. A significant reduction in the number of HRF, CMT, CRT, and in the prevalence of SND was recorded in the post-loading phase (p-value <0.0001). In DME recurrences, the presence of SND+ and HRF+ was significantly more frequent in eyes with baseline SND+ and HRF+ compared to eyes presenting baseline SND- and HRF- (p-value <0.0001). No role of SND (p-value: 0.926) and HRF (p-value: 0.281) as baseline predictors of visual and anatomic outcomes was demonstrated, while a worse visual outcome was significantly correlated with a higher incidence of relapsing SND+ (p-value <0.0001) and HRF+ (p-value <0.0028) throughout the FU period. In this study, SND and HRF were frequently present in DME recurrences with the same pattern exhibited at baseline, suggesting that these OCT biomarkers may characterize a specific pattern of DME that repeats over time. Moreover, the results suggested that the persistence and recurrence of SND and HRF may account for a decrease in visual function more than the baseline prevalence of these biomarkers. Further studies are required to confirm these findings.

Optical Coherence Tomography (Angiography) Biomarkers in the Assessment and Monitoring of Diabetic Macular Edema.

Retinopathy is one of the most severe diabetes-related complications, and macular edema is the major cause of central vision loss in patients with diabetes mellitus. Significant progress has been made in recent years in optical coherence tomography and angiography technology. At the same time, various parameters have been attributed the role of biomarkers creating the frame for new monitoring and treatment strategies and offering new insights into the pathogenesis of diabetic retinopathy and diabetic macular edema. In this review, we gathered the results of studies that investigated various specific OCT (angiography) parameters in diabetic macular edema, such as central subfoveal thickness (CST), cube average thickness (CAT), cube volume (CV), choroidal thickness (CT), retinal nerve fiber layer (RNFL), retinal thickness at the fovea (RTF), subfoveal choroidal thickness (SFCT), central macular thickness (CMT), choroidal vascularity index (CVI), total macular volume (TMV), central choroid thickness (CCT), photoreceptor outer segment (PROS), perfused capillary density (PCD), foveal avascular zone (FAZ), subfoveal neuroretinal detachment (SND), hyperreflective foci (HF), disorganization of the inner retinal layers (DRIL), ellipsoid zone (EZ), inner segment/outer segment (IS/OS) junctions, vascular density (VD), deep capillary plexus (DCP), and superficial capillary plexus (SCP), in order to provide a synthesis of biomarkers that are currently used for the early diagnosis, assessment, monitoring, and outlining of prognosis.

A Real-World Study of Dexamethasone Implant in Treatment-Naïve Patients with Diabetic Macular Edema: Efficacy and Correlation Between Inflammatory Biomarkers and Treatment Outcome.

PurposeThere has been an increasing clinical interest in specific retinal parameters as non-invasive biomarkers of retinal inflammation in diabetic macular edema (DME) that have been shown to have prognostic value, such as hyperreflective retinal fields (HRFs) and subfoveal neuroretinal detachment (SND).MethodsWe conducted a prospective, non-comparative study of treatment-naïve patients with DME to evaluate the efficacy of a Pro Re Nata (PRN) regimen of intravitreal dexamethasone implant 0.7 mg (DexI, Ozurdex™). After administration, patients underwent subsequent injections according to PRN criteria in case of edema relapse, but not earlier than 4 months after the previous treatment. Patients were evaluated at baseline, within 15 days of injection, and every month thereafter. During all visits, best-corrected visual acuity (BCVA) was recorded; central retinal thickness (CRT), type of edema, presence of SND, and presence and number of HRFs were evaluated using swept-source optical coherence tomography (SS-OCT) 3D. Treatment outcome was defined as changes in BCVA, CRT, SND and HRFs at 12 (T12) and 24 (T24) months compared with baseline (T0).ResultsThe study enrolled 24 eyes of 18 patients. The mean duration of follow-up was 18±6.6 months; for all eyes, T12 data were available, while follow-up reached T24 for 12 eyes. BCVA improved significantly and CRT decreased significantly during treatment; the edema was no longer detectable in 13/24 eyes at T12 and 8/12 eyes at T24. No patient presented SND at T12 and T24, and the mean number of HRFs decreased significantly during treatment. Results with CRT and HRFs correlated with BCVA at 12 and 24 months. No significant adverse events were observed.ConclusionIn patients with DME, the intravitreal dexamethasone implant was effective and safe in improving both functional and tomographic parameters. This result is consistent with improvement in biomarkers of inflammation.

Intravitreal ranibizumab and dexamethasone implant injections as primary treatment of diabetic macular edema: simultaneously double protocol

PurposeTo assess the 12-month efficacy and safety of simultaneously administered intravitreal dexamethasone implant (DEX implant) and ranibizumab (simultaneous double protocol) injections in comparison with ranibizumab monotherapy as the first-line treatment of diabetic macular oedema (DMO).MethodsProspective, consecutive, clinical interventional study. Patients were randomized into two groups: 24 naive DMO patients (34 eyes) who received simultaneous double-protocol therapy and 22 DMO patients (34 eyes) who received ranibizumab monotherapy were included. Monthly ranibizumab (0.5 mg) was administered for the first 6 months and later on, an as-needed treatment basis. DEX implant injection was performed at any time during the loading dose of the three consecutive monthly injections of ranibizumab, and with as-needed reinjections of ranibizumab from 6th month onwards. Change in visual acuity was the primary efficacy endpoint. Secondary efficacy endpoints were a gain of ≥15 letters and a change in the central foveal thickness.ResultsMean BCVA increased from baseline to month 12 in the simultaneously double-protocol therapy group compared with the ranibizumab monotherapy group (21.6 versus 9.6 letters [P < 0.001]). The corresponding proportions of eyes gaining ≥15 letters were 60% versus 29.4% (P < 0.0001). Moreover, the mean reductions in the central foveal thickness were 413 versus 282 µm (P = 0.001). At 12 month, the simultaneous double-protocol therapy decreased a significant number of foveal cysts and subfoveal neuroretinal detachment compared with those by ranibizumab monotherapy.ConclusionsThe simultaneous addition of DEX implant at any time during the three monthly loading doses of ranibizumab in patients with DMO significantly improved the visual outcomes and revealed superior anatomic outcomes than those with the ranibizumab monotherapy.

Quantitative Analysis of Foveal Microvascular Differences in Diabetic Macular Edema with and without Subfoveal Neuroretinal Detachment.

Purpose This study is aimed at quantifying the difference of the foveal microvasculature in the eyes with diabetic macular edema (DME) with and without subfoveal neuroretinal detachment (SND+ and SND-, respectively). Methods This retrospective, cross-sectional study included 48 eyes from 42 patients with DME (20 SND+ and 28 SND- eyes). Data collection included fundus color photographs, optical coherence tomography angiography (OCTA), and best-corrected visual acuity. The following parameters were evaluated with OCTA: foveal avascular zone (FAZ) parameters and vessel density in a width of 300 μm around the FAZ, superficial capillary plexus, deep capillary plexus (DCP), and choriocapillary plexus. The number of retinal hyperreflective spots (HRS) and the area of SND in the central 3 mm were evaluated at 0 degrees using B-scans. Results Parafoveal vessel densities of DCP were significantly lower in SND+ than in SND- eyes (p < 0.001). The number of HRS was significantly higher in SND+ than in SND- eyes (p < 0.001). The number of HRS was significantly higher in SND+ than in SND- eyes (r = 0.389, p < 0.001). The number of HRS was significantly higher in SND+ than in SND- eyes (Conclusion DME with SND correlated with larger numbers of HRS and significant macular microvascular impairment in the DCP. The pathophysiology of decline of parafoveal vessel density in the DCP with an increase in the number of HRS in the eyes with DME with SND needs further investigation.

Diabetic macular edema with neuroretinal detachment: OCT and OCT-angiography biomarkers of treatment response to anti-VEGF and steroids.

To assess and compare early changes in neuroinflammatory and vascular parameters in diabetic macular edema (DME) with subfoveal neuroretinal detachment (SND) after treatment with intravitreal dexamethasone (DEX-I) and ranibizumab (IVR). Thirty-three eyes (33 patients) with treatment naïve DME with SND were retrospectively evaluated at baseline and 2months after DEX-I (15 eyes) and 1month after 3 monthly IVR injections (18 eyes). Inclusion criteria were: complete eye examination, good quality OCT and OCT-A images. OCT parameters included: central macular thickness (CMT); number of hyper-reflective retinal spots (HRS) in inner, outer (IR, OR) and full retina; choroidal thickness (CT), extent of disorganization of inner retinal layers (DRIL), outer retina integrity (OR). On OCT-A: foveal avascular zone (FAZ) parameters in the superficial capillary plexus (SCP); cysts area and perfusion density (PD) in SCP and deep capillary plexus (DCP) and flow voids (FV) in choriocapillaris. FAZ was analyzed using ImageJ, perfusion parameters and FV using MATLAB. BCVA increased equally after both treatments (13.0 ± 10.0 ETDRS letters, p < 0.0001). There was a similar decrease (p < 0.05) in: height of SND, cysts area at SCP, central and mean CT, increase in FAZ perimeter and OR integrity, after both treatments. A greater decrease in DEX-I versus IVR group was found in: CMT (- 38.7% vs. - 22.2%, p = 0.012), HRS number in IR (- 29.2% vs. - 14.0%, p = 0.05) and full retina (- 24.7% vs. - 8.0%, p = 0.03), DRIL extension (- 62.0% vs. - 24%, p = 0.008), cysts area at DCP (- 68.7% vs. - 26.1%, p = 0.03), FAZ-CI (- 19.1% vs. - 8.3%, p = 0.02), PD at DCP (- 27.5% vs. + 4.9%, p = 0.02). FV did not change. More pronounced changes in specific inflammatory parameters in the inner retina are documented after steroid versus anti-VEGF treatment. These include reduction in HRS number, DRIL extension, CMT, cysts area at DCP. These data may help in further study of noninvasive imaging biomarkers for better evaluation of treatment response.

This issue of ACTA

This issue of ACTA

Dexamethasone for unresponsive diabetic macular oedema: optical coherence tomography biomarkers.

To analyse the effects of intravitreal dexamethasone implant (DEX) in patients with diabetic macular oedema (DME) unresponsive to ranibizumab treatment, in relation to the inflammatory optical coherence tomography (OCT) retinal features, subfoveal neuroretinal detachment (SND) and hyperreflective retinal spots (HRS). Patients with DME poorly responsive to three injections of ranibizumab were treated with DEX. Best-corrected visual acuity (BCVA) and central macula thickness (CMT, measured by Spectralis SD-OCT) were assessed at baseline and at 1, 3, and 6months. Overall, 44 eyes were included in the study. In the whole group, mean BCVA (baseline 51.5±8.3 letters) increased significantly at 1month (to 56.9±8.8 letters; Tukey HSD p=0.017) and was 55.5±8.8 letters at 3months (Tukey HSD p=0.128). Central macula thickness (CMT) reduced significantly at 1 and 3months (417±149μm and 469±128μm, respectively, both Tukey HSD p<0.001 versus baseline). Subgroup analysis showed a significant BCVA increase at 1month in eyes with SND+HRS (from 51.2±9.2 to 58.2±9.0, p=0.029), and a trend to BCVA increase in eyes with HRS (from 52.3±6.4 to 56.8±7.9, p=0.080), with a significant CMT decrease in both groups (p<0.001). No changes of either parameter were found in eyes without SND and HRS. Spectral domain OCT is useful in identifying some inflammatory features in DME. Among DME eyes 'poorly responsive' to ranibizumab, those with SND and HRS responded better to DEX implants than those without these features.

Evaluation of markers of outcome in real-world treatment of diabetic macular edema

ObjectiveTo evaluate short-term markers of outcome in diabetic macular edema (DME).MethodsProspective interventional case series included 122 eyes of 122 patients with recently diagnosed DME. Eyes were treated with a 3-monthly loading dose of ranibizumab or aflibercept and pro re nata thereafter. Serial enhanced deep imaging SD-OCT high resolution scans were used to measure subfoveal choroidal thickness (SFCT) and central retinal thickness (CRT). Anatomic (10% CRT decrease) and functional responses (best corrected visual acuity, BCVA gain ≥5 letters) were assessed at 3 months and 6 months using univariate and multivariate analyses. Parameters tested were gender, duration of diabetes, HbA1c, hypertension, CRT, SFCT, BCVA, ellipsoid zone (EZ) status, subfoveal neuroretinal detachment (SND), anti-VEGF used and laser naivety. A logistic regression model was applied to find independent markers outcome.ResultsBCVA increased, CRT and SFCT decreased at 3 months and 6 months. Good metabolic control (p = 0.003), intact baseline EZ (p = 0.030), EZ re-grading at 3 M (p < 0.001) and laser naivety (p = 0.001) were associated with better functional outcome. The multivariate linear regression model showed that baseline SND and CRT are predictors of anatomic response, while lower baseline BCVA and intact EZ are predictors of functional response.ConclusionThe presence of SND predicts anatomic response only, while an intact EZ is critical to achieve a good functional outcome in DME.

This issue of ACTA

The cover illustration shows a prolene thread inserted into Schlemm′s canal as reported by Grieshaber et al. in this issue of Acta. Klemp et al. in Copenhagen describe exudative retinal detachment, cataract formation and melanocytic tumours as the characteristic ocular findings in uveal melanocytic proliferation. Campos et al. in Portugal consider the role of the choroid in diabetic macular oedema and how OCT studies of the choroid advance this field of research. Jørstad et al. in Oslo found positive results with aflibercept in AMD eyes which were resistant to ranibizumab and bevacizumab injections. Many eyes required more than bimonthly aflibercept injections. Vujosevic et al. in Italy emphasize inflammatory biomarkers in diabetic macular oedema such as hyperreflective retinal spots, subfoveal neuroretinal detachment and increased foveal autofluorescence. These biomarkers improved with dexamethasone treatment. Subhi and Lykke Sørensen in Denmark correlated systemic leucocyte activity with onset and size of neovascular lesions in AMD. They suggest that inflammation plays a role in the pathophysiology. Sauer et al. in Germany used fluorescence lifetime imaging to map pigment distribution and evaluate its role in macular hole formation. Hamoudi et al. in Denmark found no difference in corneal endothelial density between combined and separated phacoemulsification and vitrectomy for epiretinal membrane. Makdoumi et al. in Sweden and the USA used blue light and riboflavin to kill resistant staphylococci and suggest this approach may work in corneal infections. Margulis et al. in the Netherlands, Spain and Denmark examined use of nonsteroidal anti-inflammatory eye drops. These were used with cataract surgery and for allergic conjunctivitis. Pärssinen and Kauppinen in Finland found astigmatism to increase with myopia. Corneal astigmatism predominates. Grieshaber et al. in South Africa and Switzerland recommend the Stegmann Schlemm′s canal expander to lower intraocular pressure in patients with moderate to advanced open angle glaucoma. Quérat and Chen in Sweden recommend ICARE® self-tonometry. Day-to-day variations are seen in most patients. Mrowicka et al. in Poland propose that insufficient antioxidant capacity may play a role in age related macular degeneration. This hypothesis is based on study of enzymes and genes related to antioxidant activity. Pilat et al. in UK used hand-held OCT to image anterior segment dysgenesis in children. The following articles are published electronically only and are accessible on www.actaophtalmologica.com, where you can also access the printed articles. Nitta et al. in Japan report an increase in retinal oximetry readings in retinal venules following glaucoma surgery and lowering of intraocular pressure. Tanito et al. in Japan recommend microhook trabeculotomy in glaucoma patients. It lowers IOP and reduces need for glaucoma medications. Mansouri and Shaarawy in the USA and Switzerland fond similar outcomes with scanning laser trabeculoplasty and selective laser trabeculoplasty. Lanza et al. in Italy used light backscattering with in vivo corneal confocal microscopy to evaluate changes in corneal layers in patients with Sjögren syndrome and dry eyes. Shimada et al. in Japan found reduced anterior chamber bacterial contamination with either 0.025% povidone-iodine or 0.0025% polyvinyl alcohol iodine irrigation of ocular surface. Peiretti et al. in Italy, the Netherlands, Saudi Arabia and the USA examined retinal folds following retinal detachment repair. This was not influenced by use of heavy liquids in surgery or postoperative positioning. Chan et al. in Hong Kong, Singapore and UK seek ways to measure and control emulsification of intraocular silicone oil. Kang et al. in Korea measured greater choroidal thickness in eyes with vitreoretinal traction. This was reversed following epiretinal membrane surgery and release of the traction. Jonas et al. in India and Germany found myopic retinopathy to be rare in rural India. It was associated with open angle glaucoma. Carreño et al. in Spain, USA and UK measured several inflammatory cytokines in tear fluid in uveitis patients. Bray et al. in UK suggest that portable electronic vision enhancement systems are cost-effective to improve near vision. However, it may not provide cost-effective improvement in quality of life. Babeau et al. in France comment on an article on using adaptive optics for screening chloroquine retinopathy. Parrovano et al. in Italy used OCT angiography to monitor reduction in neovascular lesions. Van Asten et al. in the Netherlands found positive outcomes with aflibercept in AMD patients unresponsive to bevacizumab. Lytvynchuk in Ukraine surgically removed a retinal branch artery embolus. Dimopoulos et al. in Germany used autologous thrombocyte serum for macular hole surgery. Grewal et al. in USA used intraoperative OCT to guide placement of Argus II retinal prosthesis. Huynh et al. in the USA found no benefit from dilated fundus examination in patients with spontaneous subconjunctival haemorrhage. Qu-Knafo et al. in France suggest that eyes with DME and serous retinal detachment may show greater improvement with ranibizumab than eyes without serous detachment. I hope you are enjoying a pleasant summer and Acta fits into your summer reading schedule.

Diabetic Macular Edema With and Without Subfoveal Neuroretinal Detachment: Two Different Morphologic and Functional Entities

To assess specific morphologic and functional characteristics in eyes with diabetic macular edema (DME) with subfoveal neuroretinal detachment (SND+) vs DME without SND (SND-). Cross-sectional, prospective, comparative case series. Seventy-two patients (72 eyes: 22 eyes SND+ and 50 eyes SND-) with treatment-naïve, center-involving DME were evaluated. Data gathering included fundus color photographs, fluorescein angiography, spectral-domain optical coherence tomography (SD-OCT), best-corrected visual acuity (BCVA), and microperimetry. The following parameters were evaluated with SD-OCT: central macular thickness (CMT [including SND]); central retinal thickness (CRT [excluding SND]); choroidal thickness (CT); nasal and temporal retinal thickness (RT) at 500μm and 1500μm from the fovea; the number of hyperreflective retinal spots (HRS) in the central 3000μm; and the presence of SND and integrity of the external limiting membrane (ELM). Retinal sensitivity (RS) was evaluated within 4 degrees and 12 degrees of the fovea. Correlation among CT, RS, and HRS in patients with and without SND was determined. CMT (P= .032), temporal RT at 1500μm (P= .03), mean CT (P= .009), and mean number of HRS (P= .0001) were all higher in SND+ vs SND- eyes. CRT, BCVA, HbA1c, and prevalence of systemic arterial hypertension were not different between the 2 groups. RS within 4 degrees (P= .002) and 12 degrees (P= .015) was lower in SND+ vs SND- eyes. SND correlated significantly with disruption of the ELM (54.55% vs 24%, P= .01) and lower RS. A direct correlation was found between the number of HRS, presence of SND, CT, and RS within 12 degrees in SND- eyes, and an inverse correlation was found between CT and RS within 12degrees in SND+ eyes. These data may improve characterization of DME in eyes with SND. DME with SND correlates with greater CT, more HRS, disruption of the ELM, and significant macular functional impairment (RS decrease) vs SND-.

Imaging retinal inflammatory biomarkers after intravitreal steroid and anti-VEGF treatment in diabetic macular oedema.

To evaluate changes of specific retinal imaging biomarkers [intraretinal hyper-reflective retinal spots: HRS ; subfoveal neuroretinal detachment: SND; and increased foveal autofluorescence: IFAF after intravitreal steroid or anti-vascular endothelial growth factor treatment in diabetic macular oedema (DME)] as possible indicators of retinal inflammatory condition. Retrospective analysis of images and clinical charts of 49 eyes (49 patients) with DME treated with intravitreal dexamethasone (dexamethasone, 23 eyes) or intravitreal ranibizumab (ranibizumab, 26 eyes). All patients had fundus colour photograph, spectral domain optical coherence tomography (SD OCT) and fundus autofluorescence (FAF), best-corrected visual acuity (BCVA) and microperimetry recorded before and 1month after the end of treatment. Central macular thickness (CMT), number of HRS and presence of SND were evaluated by SD OCT. Fundus autofluorescence images were evaluated for area of (IFAF). Retinal sensitivity within 4° and 12° from fovea was quantified by microperimetry. Changes in morphologic and functional parameters were assessed, and correlation was performed by Pearson's correlation. Best-corrected visual acuity and CMT improved in all patients, (p<0.05, for both groups). Mean number of HRS decreased after both treatments (p<0.0001). Subfoveal neuroretinal detachment resolved in 85.7% dexamethasone-treated eyes (p=0.014) and in 50% ranibizumab-treated eyes (p=0.025). Mean IFAF area decreased in both groups, (p<0.0001, for both). A significantly higher decrease in CMT was observed in dexamethasone- versus ranibizumab-treated eyes, (p=0.032). In dexamethasone group, higher number of HRS at baseline and larger IFAF were correlated with higher increase in retinal sensitivity; eyes with SND at baseline had major decrease in CMT versus those without SND, (p=0.003). Higher number of HRS, larger area of IFAF and presence of SND may indicate a prevalent inflammatory condition in DME with specific response to targeted treatment.

Scanning laser ophthalmoscopy in the retromode in diabetic macular oedema

To determine the validity of scanning laser ophthalmoscopy in the retromode (RM-SLO) versus other imaging modalities in the diagnosis of diabetic macular oedema (DME). Two hundred and sixty-three eyes were examined. Inclusion criteria were any stage of untreated or treated diabetic retinopathy and four imaging modalities of the macula carried out on the same day: time domain optical coherence tomography (OCT), fundus autofluorescence (FAF), RM-SLO and fluorescein angiography (FA). Two masked retinal specialists independently graded all images. Agreement between RM-SLO and OCT, FA and FAF in evaluating the presence and patterns of DME was evaluated by kappa statistics, sensitivity, specificity, observed proportional agreement, and proportional agreement in positive and negative cases. The agreement in evaluating the presence/absence of DME between RM-SLO and OCT, FA and FAF was good: κ = 0.73 (confidence interval; CI, 0.64-0.83), κ = 0.71 (CI, 0.61-0.81) and κ = 0.73 (CI, 0.63-0.83), respectively. The agreement in evaluating cystoid pattern of DME was almost perfect between RM-SLO and OCT, RM-SLO and FA, κ > 0.8; and good between RM-SLO and FAF, κ > 0.7. The agreement in evaluating the presence/absence of subfoveal neuroretinal was almost perfect between RM-SLO and OCT (κ = 0.83; 95% CI, 0.70-0.96). Subfoveal neuroretinal detachment did not show any specific pattern on FA or FAF. Sensitivity and specificity of RM-SLO in evaluating DME was 97.7% and 71.9% versus OCT, 97.4% and 68.1% versus FA and 96.1% and 73.3% versus FAF. Retinal thickness of 233 μm represented the cut-off value to define DME by RM-SLO. The combined use of non-invasive imaging techniques can improve the diagnostic interpretation of different aspects of DME.