SUBRETINAL LIPID GLOBULES AN EARLY BIOMARKER OF MACULAR NEOVASCULARIZATION IN EYES WITH INTERMEDIATE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To explore the association between subretinal lipid globules (SLGs) detected in eyes with intermediate age-related macular degeneration with the presence of nonexudative macular neovascularization. METHODS: This was a retrospective analysis of 113 consecutive patients with bilateral intermediate age-related macular degeneration (226 eyes) followed for a least 6 months. All eyes underwent multimodal imaging with fundus autofluorescence, spectral-domain optical coherence tomography, and optical coherence tomography angiography. Subretinal lipid globules were identified on spectral-domain optical coherence tomography as round hyporeflective lesions measuring 31 to 157 µ m located between the ellipsoid zone and the retinal pigment epithelium/Bruch membrane complex. Nonexudative macular neovascularization was detected with optical coherence tomography angiography. The features of NE-MNV lesions detected in eyes with SLGs were compared with those in eyes without SLGs. RESULTS: Subretinal lipid globules were identified in 15 eyes of which 14 eyes (93.3%) demonstrated NE-MNV on optical coherence tomography angiography. In the remaining 98 eyes without SLGs, 18 (18.4%) displayed NE-AMD on optical coherence tomography angiography. The macular neovascularization area was larger in the SLG subgroup (+0.38 vs. +0.21 mm 2 , P = 0.008) and showed faster horizontal growth (+727 µ m, CI 95% 250.4, 1,205.4) than MNV in eyes without SLGs (+64.9 µ m, CI 95%, 24.3, 154) on optical coherence tomography B-scans. After a mean of 11.6 months, the conversion rate to exudative MNV was similar between eyes with SLGs and those without SLGs [8/26 (38.5%) versus 3/13 (27.3%), P = 0.56)]. CONCLUSION: The detection of SLGs in eyes with intermediate age-related macular degeneration was strongly correlated with the presence of NE-MNV. Although these MNV lesions were larger and grew faster than NE-MNV detected in eyes lacking SLGs, the rates of conversion to exudative MNV appeared similar.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY CHARACTERIZATION OF EVOLVING LESIONS IN FELLOW EYES OF EXUDATIVE TYPE 3 MACULAR NEOVASCULARIZATION PATIENTS.

PURPOSE: To investigate fellow eyes of newly diagnosed unilateral exudative Type 3 (T3) macular neovascularization (MNV) patients by assessing the presence and progression of a preclinical neovascular component during a 3-year follow-up. METHODS: This is a longitudinal study involving three retinal referral centers. Patients affected by unilateral exudative treatment-naive T3 MNV were enrolled. RESULTS: Twenty-four eyes of 24 patients (79 ± 6 years old) were enrolled. Nine eyes (37%) displayed a nonexudative T3 MNV at baseline that developed exudation after a mean of 9 ± 9 months. Fifteen eyes that did not display a nonexudative Type 3 MNV at baseline. Five eyes (21%) did not display neovessels at baseline, but showed a nonexudative T3 after 13 ± 9 months, and exudation after 8 ± 3 months. Five eyes (21%) developed active exudative T3 MNV after 23 ± 9 months, with no detectable nonexudative stage at baseline. Five eyes (21%) did not show MNV, but progressed to geographic atrophy by 36 months of follow-up. Overall, T3 MNV in the fellow eye accounted for 79%, all developing exudation over 3 years of follow-up. CONCLUSION: The occurrence of a nonexudative T3 MNV is a frequent event in the fellow eye of patients newly diagnosed with unilateral exudative T3 MNV and it precedes the development of exudation over 3 years (prevalence of 37% and cumulative incidence of 79%). Optical coherence tomography angiography approach may be used to perform an early diagnosis and treatment of patients with T3 MNV.

Biallelic Inactivating TUB Variants Cause Retinal Ciliopathy Impairing Biogenesis and the Structure of the Primary Cilium.

Inherited retinal degeneration (IRD) represents a clinically variable and genetically heterogeneous group of disorders characterized by photoreceptor dysfunction. These diseases typically present with progressive severe vision loss and variable onset, ranging from birth to adulthood. Genomic sequencing has allowed to identify novel IRD-related genes, most of which encode proteins contributing to photoreceptor-cilia biogenesis and/or function. Despite these insights, knowledge gaps hamper a molecular diagnosis in one-third of IRD cases. By exome sequencing in a cohort of molecularly unsolved individuals with IRD, we identified a homozygous splice site variant affecting the transcript processing of TUB, encoding the first member of the Tubby family of bipartite transcription factors, in a sporadic case with retinal dystrophy. A truncating homozygous variant in this gene had previously been reported in a single family with three subjects sharing retinal dystrophy and obesity. The clinical assessment of the present patient documented a slightly increased body mass index and no changes in metabolic markers of obesity, but confirmed the occurrence of retinal detachment. In vitro studies using patient-derived fibroblasts showed the accelerated degradation of the encoded protein and aberrant cilium morphology and biogenesis. These findings definitely link impaired TUB function to retinal dystrophy and provide new data on the clinical characterization of this ultra-rare retinal ciliopathy.

Microvasculature Changes of Myopic Choroidal Neovascularization and the Predictive Value of Feeder Vessel Disappearance after Ranibizumab Treatment Revealed Using Optical Coherence Tomography Angiography.

AIM: To investigate vascular changes of myopic choroidal neovascularization (mCNV) after ranibizumab treatment using optical coherence tomography-angiography (OCTA). METHODS: Consecutive subjects with a diagnosis of mCNV were included. Patients underwent intravitreal injection of ranibizumab treatment with a 6-month follow-up. All patients underwent a complete ophthalmological examination and OCTA evaluation. The 3 × 3 OCTA en face images were analyzed for the absence/presence of mCNV, CNV area, and CNV network morphology. In particular, the morphology of the mCNV was analyzed in order to detect the presence/absence of feeder vessels. RESULTS: Eleven subjects were evaluated. At baseline, the mCNV was identified in all cases on OCTA. At 6 months, the mean mCNV area was not statically significantly reduced in comparison with baseline values (p > 0.05), while the morphologic analysis revealed a complete disappearance of the feeder vessel in 6 eyes. The subgroup analysis of these latter showed that the CNV area was significantly reduced, visual acuity had improved, and only one intravitreal injection was administrated over the entire follow-up period. CONCLUSIONS: OCTA allowed the detection of qualitative and quantitative vascular changes in mCNV. The disappearance of the feeder vessel was associated with better anatomical as well as functional outcomes at the last follow-up visit.

Treatment of Diabetic Macular Edema with Multiple Dexamethasone Intravitreal Implants: Evidence from Real-Life Experience.

OBJECTIVE: To gain information about multiple dexamethasone intravitreal implant (DEX-I) injections in diabetic macular edema (DME) eyes in real-life clinical settings. METHODS: Patients with DME treated with multiple (≥5) DEX-I injections between January 1, 2014, and December 31, 2018, were retrospectively enrolled regardless of previous treatment with anti-VEGF agents. All patients were evaluated with best-corrected visual acuity (BCVA) in logMAR, ocular fundus, and spectral domain optical coherence tomography (SD-OCT) at baseline and at 3 months after the last DEX-I injection. Multiple DEX-I injections were administered when necessary in case of DME recurrence. Main efficacy measures were changes in BCVA and central retinal thickness (CRT) from baseline to 3 months after the last DEX-I injection; main secondary measures were an increase in intraocular pressure (IOP), the need for cataract surgery, endophthalmitis, and vitreous hemorrhage. RESULTS: Seventeen patients (18 eyes) with DME and mean age (± SD) of 54.3 ± 8.16 years were treated with DEX-I injections between 2014 and 2018. The majority of eyes (77.8%) had been treated with a mean of 6.3 ± 3.2 anti-VEGF agents before switching to DEX-I. During a mean follow-up period of 37.6 months and after a mean number of 5.9 DEX-I injections, visual acuity improved or stabilized in 77.8% of all eyes, accompanied by a significant reduction in CRT. An increase in IOP was recorded in 38.8% of all patients, while a surgical procedure was needed for cataract in 73.3% of all phakic patients. CONCLUSIONS: In this real-life experience in Italy, multiple DEX-I treatments showed good efficacy with no new safety concerns. The follow-up duration of >3 years and a greater number of DEX-I intravitreal injections compared to other observations confirm the positive balance between risks and benefits of DEX-I in the long term.

Glutathione transferase P silencing promotes neuronal differentiation of retinal R28 cells.

Glutathione transferases (GSTs) play an important role in retinal pathophysiology. Within this family, the GSTP isoform is known as an endogenous regulator of cell survival and proliferation pathways and of cellular responses to oxidative stress. In the present study we silenced GSTP in R28 cells, a retinal precursor cell line with markers of both glial and neuronal origin, and obtained stable clones which were viable and, unexpectedly, characterized by a more neuronal phenotype. The degree of neuronal differentiation was inversely correlated with GSTP residual expression levels. The clone with the lowest expression of GSTP showed metabolic reprogramming, a more favorable redox status and, despite its neuronal phenotype, a sensitivity to glutamate and 4-hydroxynonenal toxicity comparable to that of control cells. Altogether, our evidence shows that near full depletion of GSTP in retinal precursor cells, triggers neuronal differentiation and prosurvival metabolic changes.

OLIMPIC: a 12-month study on the criteria driving retreatment with ranibizumab in patients with visual impairment due to myopic choroidal neovascularization.

PURPOSE: To evaluate criteria driving retreatment with ranibizumab in Italian patients with myopic choroidal neovascularization (mCNV). METHODS: OLIMPIC was a 12-month, phase IIIb, open-label study. Patients with active mCNV were treated with ranibizumab 0.5 mg according to the European label. The study assessed local criteria in Italy driving retreatment decisions with ranibizumab; and the efficacy, safety, and tolerability of ranibizumab. RESULTS: The mean (standard deviation [SD]) age of treated patients (N = 200) was 61.8 (12.7) years; range 22-85 years. The multivariate regression model indicated that presence of active leakage (odds ratio [OR] 95% confidence interval [CI]: 11.30 [1.03-124.14]), presence of intraretinal fluid (OR [95%CI]: 28.21 [1.55-513.73]), and an improvement in best-corrected visual acuity (BCVA) from baseline < 10 letters (OR [95%CI]: 17.60 [1.39-222.75]) were the factors with the greatest effect on retreatment with ranibizumab. The mean (SD) BCVA gain from baseline to month 12 was 8.4 (12.8) letters (P < 0.0001). The mean (SD) number of injections was 2.41 (1.53); range 1-9. Ocular and non-ocular adverse events were reported in 41 (20.5%) and 30 (15.0%) patients, respectively. CONCLUSIONS: Individualized treatment with ranibizumab was effective in improving BCVA in patients with mCNV over 12 months. Both anatomical and functional variables had significant effects on causing retreatment. There were no new safety findings. TRIAL REGISTRATION: www.ClinicalTrials.Gov (NCT No: NCT02034006).

CHRONIC CENTRAL SEROUS CHORIORETINOPATHY: Early and Late Morphological and Functional Changes After Verteporfin Photodynamic Therapy.

PURPOSE: To describe early and late morphological and functional changes in subjects receiving photodynamic therapy (PDT) for chronic central serous chorioretinopathy. METHODS: Patients with chronic central serous chorioretinopathy were prospectively enrolled and received standard PDT. At the baseline examination, each subject underwent complete ophthalmological examination, including best-corrected visual acuity (BCVA) assessment, fluorescein angiography and indocyanine green angiography, spectral domain optical coherence tomography, and microperimetry. Spectral domain optical coherence tomography, microperimetry, and BCVA assessment were repeated in multiple sections over 7 days after PDT and at 1-, 3-, and 12-month intervals. Main outcome measures were: identification of early changes (1-week examination) in BCVA, retinal sensitivity, and spectral domain optical coherence tomography parameters and their influence on outcomes at the 1-year follow-up. RESULTS: Three main patterns of early response to PDT were identified during the 1-week examination. The neurosensory retinal detachment most frequently decreased rapidly (12/19 pts), with complete resolution in 50% of cases. An increase in neurosensory retinal detachment height was registered in 16% (3/19) of cases, whereas in 21% (4/19), a large fluctuation in neurosensory retinal detachment was encountered. Best-corrected visual acuity declined significantly in 5/12 patients in the first group and was stable or improved in the remaining cases. Overall, retinal sensitivity diminished in 16/19 subjects, with a mean worsening of 2.56 dB (P = 0.0002). At the 12-month examination, final mean BCVA improved by 14.4 letters (P = 0.001) and a similar progressive recovery in the retinal sensitivity was observed (+2.69 dB, P = 0.0039). The neurosensory retinal detachment completely resolved in 18/19 (95%) cases, with a parallel significant reduction in central foveal choroidal thickness (P < 0.0001). CONCLUSION: Three patterns of early response to standard PDT can be identified. Although an early and abrupt reduction in BCVA and retinal sensitivity after treatment is possible, this does not compromise a final improvement in visual functions.

Microvascular Retinal and Choroidal Changes in Retinal Vein Occlusion Analyzed by Two Different Optical Coherence Tomography Angiography Devices.

PURPOSE: To investigate retinal and choroidal microvascular changes and structural choroidal involvement in retinal vein occlusion (RVO). METHODS: Retrospective analysis of treatment-naïve macular edema secondary to RVO, studied by optical coherence tomography (OCT) and OCT angiography (OCTA), before and after the loading phase of intravitreal injections of ranibizumab (IVR-LP). OCTA was performed using two different devices: AngioVue RTVue XR Avanti (spectral-domain OCTA) and Zeiss PLEX® Elite 9000 (swept-source OCTA). RESULTS: 30 eyes of 30 consecutive patients (17 branch and 13 central RVO) were included. Central macular thickness and subfoveal choroidal thickness (SCT) were significantly reduced after IVR-LP (p < 0.001 and p = 0.046, respectively). 23 eyes were eligible for OCTA analysis. Baseline vessel density (VD) in deep capillary plexus (DCP) was significantly reduced in RVO eyes compared with fellow eyes (p = 0.03 and p = 0.002 for PLEX® Elite and AngioVue, respectively). After IVR-LP, no significant VD changes in any vascular layer was found. PLEX® Elite VD analysis showed significant differences in DCP between ischemic versus non-is-chemic eyes (p = 0.011). CONCLUSION: OCTA suggests a retinal vascular impairment of DCP but no involvement of choroid in RVO eyes. A greater baseline SCT could be due to a choroidal exudation. OCTA imaged with PLEX® Elite allowed to differentiate ischemic and non-ischemic patients at baseline.

Gene Therapy in Retinal Dystrophies.

Inherited retinal dystrophies (IRDs) are a group of clinically and genetically heterogeneous degenerative disorders. To date, mutations have been associated with IRDs in over 270 disease genes, but molecular diagnosis still remains elusive in about a third of cases. The methodologic developments in genome sequencing techniques that we have witnessed in this last decade have represented a turning point not only in diagnosis and prognosis but, above all, in the identification of new therapeutic perspectives. The discovery of new disease genes and pathogenetic mechanisms underlying IRDs has laid the groundwork for gene therapy approaches. Several clinical trials are ongoing, and the recent approval of Luxturna, the first gene therapy product for Leber congenital amaurosis, marks the beginning of a new era. Due to its anatomical and functional characteristics, the retina is the organ of choice for gene therapy, although there are quite a few difficulties in the translational approaches from preclinical models to humans. In the first part of this review, an overview of the current knowledge on methodological issues and future perspectives of gene therapy applied to IRDs is discussed; in the second part, the state of the art of clinical trials on the gene therapy approach in IRDs is illustrated.

Ranibizumab Plus Panretinal Photocoagulation versus Panretinal Photocoagulation Alone for High-Risk Proliferative Diabetic Retinopathy (PROTEUS Study).

PURPOSE: Comparison of the efficacy of ranibizumab (RBZ) 0.5 mg intravitreal injections plus panretinal photocoagulation (PRP) versus PRP alone in the regression of the neovascularization (NV) area in subjects with high-risk proliferative diabetic retinopathy (HR-PDR) over a 12-month period. DESIGN: Prospective, randomized, multicenter, open-label, phase II/III study. PARTICIPANTS: Eighty-seven participants (aged ≥18 years) with type 1/2 diabetes and HR-PDR (mean age, 55.2 years; 37% were female). METHODS: Participants were randomized (1:1) to receive RBZ+PRP (n = 41) or PRP monotherapy (n = 46). The RBZ+PRP group received 3 monthly RBZ injections along with standard PRP. The PRP monotherapy group received standard PRP between day 1 and month 2; thereafter, re-treatments in both groups were at the investigators' discretion. MAIN OUTCOME MEASURES: The primary outcome was regression of NV total, on the disc (NVD) plus elsewhere (NVE), defined as any decrease in the area of NV from the baseline to month 12. Secondary outcomes included best-corrected visual acuity (BCVA) changes from baseline to month 12, time to complete NV regression, recurrence of NV, macular retinal thickness changes from baseline to month 12, need for treatment for diabetic macular edema, need for vitrectomy because of occurrence of vitreous hemorrhage, tractional retinal detachment or other complications of DR, and adverse events (AEs) related to treatments. RESULTS: Seventy-seven participants (88.5%) completed the study. Overall baseline demographics were similar for both groups, except for age. At month 12, 92.7% of participants in the RBZ+PRP group presented NV total reduction versus 70.5% of the PRP monotherapy participants (P = 0.009). The number of participants with NVD and NVE reductions was higher with RBZ+PRP (93.3% and 91.4%, respectively) versus PRP (68.8% and 73.7%, respectively), significant only for NVE (P = 0.048). Complete NV total regression was observed in 43.9% in the RBZ+PRP group versus 25.0% in the PRP monotherapy group (P = 0.066). At month 12, the mean BCVA was 75.2 letters (20/32) in the RBZ+PRP group versus 69.2 letters (20/40) in the PRP monotherapy group (P = 0.104). In the RBZ+PRP group, the mean number of PRP treatments over month 12 was 3.5±1.3, whereas in the PRP monotherapy group, it was 4.6±1.5 (P = 0.001). No deaths or unexpected AEs were reported. CONCLUSIONS: Treatment with RBZ+PRP was more effective than PRP monotherapy for NV regression in HR-PDR participants over 12 months.

FACTORS INFLUENCING VISUAL ACUITY IN PATIENTS RECEIVING ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR FOR MYOPIC CHOROIDAL NEOVASCULARIZATION.

PURPOSE: To identify the prognostic variables relative to myopic choroidal neovascularization (CNV) treated with intravitreal ranibizumab/bevacizumab. METHODS: Forty-eight patients with myopic CNV were enrolled in a prospective, interventional, non-randomized 12-month study. Intravitreal ranibizumab/bevacizumab was administered in a pro-re-nata regimen and re-treatment was performed in the presence of angiographic leakage, intraretinal/subretinal fluid on optical coherence tomography, new hemorrhages, five-letter decrease and increased metamorphosia. The primary outcome measures were the identification of the predictive value of symptom duration, patient's age, refractive error, best-corrected visual acuity (BCVA), central macular thickness (CMT), CNV area, CNV location, retinal hemorrhages, atrophy, lacquer cracks, and CNV-fundus autofluorescence pattern (hyper-fundus autofluorescence/patchy pattern). The secondary outcomes were patients requiring either one or two injections to achieve CNV stabilization. RESULTS: The mean BCVA improved from 0.49 ± 0.30 (logarithm of minimal angle resolution, Snellen equivalent 20/63) to 0.39 ± 0.32 (20/49) at 1-year follow-up (P = 0.043). Univariate and multiple stepwise linear regression analysis identified baseline BCVA (P = 0.0003), symptom duration (P = 0.005), CMT (P = 0.02), and fundus autofluorescence pattern (P = 0.005) as the explanatory variables on the final BCVA and the change in the mean BCVA. Overall, patients with better baseline BCVA, early diagnosis, lower CMT, or disclosing a hyperfundus autofluorescence CNV pattern achieved better visual outcomes. Patients responding with just one to two intravitreal injections (45.8%) obtained better visual outcomes compared with patients receiving three or more injections, and this group consisted of younger patients with lesser CMT, smaller CNV area, and fewer baseline hemorrhages. CONCLUSION: Ranibizumab/bevacizumab therapy was effective in improving and maintaining visual acuity in myopic choroidal neovascularization. Early diagnosis, better baseline BCVA, and hyperfundus autofluorescence CNV pattern were strongly associated with better functional outcomes. Moreover, CNV distinguished by its small size and low CMT responded more favorably, achieving a better visual outcome.

Long-Term Follow-Up of Choroidal Neovascularization due to Angioid Streaks with pro re nata Intravitreal Anti-VEGF Treatment.

PURPOSE: To evaluate the long-term outcomes of intravitreal anti-vascular endothelial growth factor (VEGF) drugs with a pro re nata (PRN) regimen for the treatment of choroidal neovascularization (CNV) secondary to angioid streaks (AS). METHODS: This is a retrospective, multicenter, noncomparative case series of consecutive AS eyes affected by treatment-naïve CNV. A complete ophthalmologic examination was performed every 30-45 days after the loading phase, including fluorescein angiography and/or optical coherence tomography. RESULTS: In all, 52 eyes of 39 patients were treated with intravitreal bevacizumab and/or ranibizumab and followed up for a mean of 33.8 months. The best corrected visual acuity at baseline was 20/40, and it deteriorated by an average of 6.8 ETDRS letters per year (p < 0.001). We performed an average of 5.1, 6.5, and 6.8 injections at the 1-, 2-, and 3-year follow-up, respectively. CONCLUSIONS: Intravitreal anti-VEGF drugs in a PRN regimen with close monitoring appear to slow the progression of CNV in AS, but they do not prevent the affected eyes from progressive visual loss.

Single Retinal Layer Evaluation in Patients with Type 1 Diabetes with No or Early Signs of Diabetic Retinopathy: The First Hint of Neurovascular Crosstalk Damage between Neurons and Capillaries?

PURPOSE: To analyze the retinal-choroidal changes in type 1 diabetes mellitus (DM1) patients with no or early signs of diabetic retinopathy (DR). METHODS: Seventy-six eyes of 38 DM1 patients and 26 control eyes were included. Nine individual retinal layer thickness measurements were obtained using the spectral domain-optical coherence tomography automated segmentation algorithm. RESULTS: The retinal nerve fiber layer was slightly thinner in all explored quadrants, even if the reduction was not significant in DM1 eyes versus control eyes. The inner nuclear layer (INL) thickness was thicker in all DM1 eyes versus control eyes in all quadrants (p < 0.050). Analyses adjusting for inner retinal thickness in all sectors confirmed INL thickening by about 4%, and also found a significant thinning of the ganglion cell layer (GCL) by about 3.5% in all DM1 subjects versus controls (p < 0.050). CONCLUSION: DM1 patients with no or early signs of DR present retinal changes particularly at the INL and GCL that might be correlated to initial findings of neurodegeneration.

Müller glia activation by VEGF-antagonizing drugs: An in vitro study on rat primary retinal cultures.

The effects of the anti-Vascular Endothelial Growth Factor (VEGF) drugs ranibizumab and aflibercept were studied in Müller glia in primary mixed cultures from rat neonatal retina. Treatment with both agents induced activation of Müller glia, demonstrated by increased levels of Glial Fibrillary Acidic Protein. In addition, phosphorylated Extracellular-Regulated Kinase 1/2 (ERK 1/2) showed enhanced immunoreactivity in activated Müller glia. Treatment with aflibercept induced an increase in K(+) channel (Kir) 4.1 levels and both drugs upregulated Aquaporin 4 (AQP4) in activated Müller glia. The results show that VEGF-antagonizing drugs influence the homeostasis of Müller cells in primary retinal cultures, inducing an activated phenotype. Upregulation of Kir4.1 and AQP4 suggests that Müller glia activation following anti-VEGF drugs may not depict a detrimental gliotic reaction. Indeed, it could represent one of the mechanisms able to contribute to the therapeutic effects of these drugs, particularly in the presence of macular edema.

INTRAVITREAL AFLIBERCEPT FOR CHOROIDAL NEOVASCULARIZATION DUE TO AGE-RELATED MACULAR DEGENERATION UNRESPONSIVE TO RANIBIZUMAB THERAPY.

PURPOSE: To assess the efficacy of intravitreal injection of aflibercept for treating choroidal neovascularization due to age-related macular degeneration unresponsive to ranibizumab. METHODS: Prospective noncomparative study. Indication for conversion to aflibercept (2.0 mg) was a failed response to ranibizumab, defined as persistent or recurrent subretinal and/or intraretinal fluid on spectral domain optical coherence tomography. Best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study letter score), fluorescein angiography, indocyanine green angiography, and spectral domain optical coherence tomography were performed at baseline. Patients were followed up monthly, and retreatment was considered at physician discretion based on functional and morphological patterns. RESULTS: Ninety-two eyes were included in the study. At 12 months, mean best-corrected visual acuity (±SD) change was +1.8 (±10.3), Early Treatment Diabetic Retinopathy Study letters and central retinal thickness (±SD) decreased on average by 112 (±173) µm. Patients received a mean of 3.5 ± 1.8 injections. No significant adverse event was observed during the follow-up. CONCLUSION: A low number of intravitreal aflibercept injections reversed the preswitching trend toward losing vision and produced stable visual acuity and morphological improvements for up to 12 months in patients with neovascular age-related macular degeneration, not responding to ranibizumab.

INTRAOCULAR PRESSURE IN PATIENTS WITH DIABETIC MACULAR EDEMA TREATED WITH DEXAMETHASONE INTRAVITREAL IMPLANT IN THE 3-YEAR MEAD STUDY.

PURPOSE: To evaluate the occurrence, management, and clinical significance of increases in intraocular pressure (IOP) in patients with diabetic macular edema treated with dexamethasone intravitreal implant (DEX implant). METHODS: Randomized, multicenter, 3-year, Phase III study. Patients (N = 1,048) with diabetic macular edema were randomized to DEX implant 0.7-mg, DEX implant 0.35-mg, or sham procedure with retreatment allowed at ≥6-month intervals (seven injections maximum). RESULTS: In the DEX implant 0.7-mg, DEX implant 0.35-mg, and sham groups, respectively, ≥10-mmHg IOP increases from baseline occurred in 27.7%, 24.8%, and 3.7% of patients, and their frequency did not increase with repeat injections. IOP-lowering medication was used by 41.5%, 37.6%, and 9.1% of patients. Only one patient (0.3%) in each DEX implant group had filtering surgery to manage a steroid-induced IOP increase. Among DEX implant 0.7-mg-treated patients with and without a ≥10-mmHg IOP increase, 21.9% (21 of 96) and 22.4% (57 of 255), respectively, achieved ≥15-letter best-corrected visual acuity gain at the end of the study, and mean average change in central retinal thickness from baseline was -127 µm and -106 µm, respectively. CONCLUSION: DEX implant demonstrated clear benefit of treatment despite increases in IOP. Sequential implants had no cumulative effect on IOP.

Aflibercept administration in neovascular age-related macular degeneration refractory to previous anti-vascular endothelial growth factor drugs: a critical review and new possible approaches to move forward.

PURPOSE: The recent introduction of anti-VEGF drugs has widely changed the prognosis of exudative age-related macular degeneration (AMD), even if a variable percentage of patients showed an insufficient response. Aflibercept is a new anti-VEGF drug approved by FDA for the treatment of exudative AMD with a wider binding capacity than either bevacizumab or ranibizumab. Therefore, the purposes were as follows: (i) to report anatomical and functional outcomes of switching from bevacizumab/ranibizumab to aflibercept previously described in the scientific literature, (ii) to hypothesize the possible pathophysiological mechanisms of the resistance and tachyphylaxis to anti-VEGF drugs, and (iii) to suggest possible clinical actions to increase the chances of success for such difficult cases. METHODS: We reviewed the available scientific literature in Medline, Cochrane database, Current Contents, PubMed, and cross-referencing from identified articles, regarding the treatment of exudative AMD patients refractory to bevacizumab and/or ranibizumab and switched to aflibercept monotherapy. We included in this review all the cases in which the diagnosis of refractory or resistant exudative AMD was properly made, and the results of at least one aflibercept injection were described. FINDINGS: We reported the outcomes of 21 papers for a total of 1066 eyes affected by exudative AMD resistant to previous anti-VEGF drug injections and switched to aflibercept. Enrolled reports were divided into two groups: 5 prospective reports and 16 retrospective reports. All the reported papers conclude their analysis, stating that switching from bevacizumab/ranibizumab to aflibercept injections can improve outcomes successfully in refractory neovascular AMD patients. IMPLICATIONS: Analysis of the papers reported in this review demonstrates that switching from bevacizumab/ranibizumab to aflibercept injections can improve outcomes successfully in refractory neovascular AMD patients. The mechanism for these effects is not yet completely understood.

Acute central serous chorioretinopathy: a correlation study between fundus autofluorescence and spectral-domain OCT.

PURPOSE: To evaluate the correlation between fundus autofluorescence (FAF) and spectral-domain OCT (SD-OCT) morphological analysis in eyes with acute central serous chorioretinopathy (CSCR). METHODS: Thirty-one patients with a first episode of CSCR and symptom duration of less than 6 weeks were prospectively enrolled. FAF and SD-OCT examination were performed at baseline and at 2-month intervals. Main outcome measure was the correlation between FAF and SD-OCT retinal morphology. RESULTS: At baseline, 30/31 and 29/31 eyes showed a macular hypo-AF, corresponding to the neurosensory retinal detachment (SRD), on shortwave-FAF (SW-FAF) and near-infrared-FAF (NIR-FAF), respectively. While the SRD resolved, both FAF techniques showed a granular hyper-AF in 31 eyes. At first examination, SD-OCT confirmed the SRD with a photoreceptor outer-segment (OS) elongation in all cases. During SRD resolution, the photoreceptor layer appeared thicker and fragmented. Multiple hyper-reflective precipitates were detected in the outer plexiform and nuclear layer and between the photoreceptors and appeared colocalized with the hyper-AF dots composing the granular hyper-AF. After SRD resolution, the hypo-AF area reverted to a normal pattern on SW-FAF in all eyes and in 25/31 on NIR-FAF. Examination at 12 months showed that the granular hyper-AF was still detectable in 54 % eyes, whereas 6/31 eyes showed hypo-AF dots on NIR-FAF. On SD-OCT, the junction IS/OS was identifiable in 11/31 eyes soon after the SRD resolution and appeared completely restored in all patients at the final visit. CONCLUSION: The simultaneous acquisition of FAF and SD-OCT provides detailed findings of retinal abnormalities of CSCR and may help to understand the evolving process linked to CSCR.

DEXAMETHASONE IMPLANT FOR MACULAR EDEMA SECONDARY TO CENTRAL RETINAL VEIN OCCLUSION IN PATIENTS YOUNGER THAN 50 YEARS.

PURPOSE: To evaluate the effects of dexamethasone implant for macular edema secondary to central retinal vein occlusion in patients younger than 50 years. METHODS: Patients with no previous treatment, macular edema with central foveal thickness >250 µm and best-corrected visual acuity between 1.30 LogMAR and 0.30 LogMAR were prospectively recruited for a 12-month follow-up study. After baseline dexamethasone implant, re-treatment was performed starting from the fourth month if a best-corrected visual acuity deterioration with central foveal thickness >250 µm occurred after an initial improvement. The primary outcome was the change in the best-corrected visual acuity. Secondary outcomes included the proportion of eyes gaining at least 3 Early Treatment Diabetic Retinopathy Study lines, the change in the central foveal thickness, and the number of treatments. RESULTS: Mean best-corrected visual acuity changed significantly from 0.60 ± 0.38 LogMAR at baseline to 0.43 ± 0.48 at the 12-month examination (P = 0.03). Eight of 16 eyes (50%) gained 3 Early Treatment Diabetic Retinopathy Study lines. Mean central foveal thickness improved significantly from 705 ± 202 µm at baseline to 408 ± 196 µm at 12-month visit (P < 0.001). The patients received a mean of 1.8 ± 0.9 implants with 8/16 eyes and 3/16 receiving 1 and 2 implants, respectively. CONCLUSION: This present investigation indicates that dexamethasone implant can provide a 3-line improvement in half of the patients younger than 50 years and affected by macular edema secondary to central retinal vein occlusion.