Effect of Pro Re Nata regimen with anti-VEGF on Type 3 Macular Neovascularization - Long term outcomes.

(348 words) Introduction: The purpose of this study is to investigate long-term outcomes of intravitreal injections (IVI) of anti-vascular endothelial growth factor (VEGF) in neovascular age-related macular degeneration (nAMD) with type 3 macular neovascularization (MNV). METHODS: This retrospective study included 19 eyes of 17 patients with nAMD and type 3 MNV treated with anti-VEGF IVI with a loading dose and PRN regimen. Best corrected visual acuity (BCVA), central macular thickness (CMT), presence of macular intraretinal fluid (IRF) and subretinal fluid (SRF), flow area (FA), subfoveal choroidal thickness (CT) and macular atrophy (MA) were assessed at baseline (T0) and during follow up (T1, post loading phase; T2, one year; T3, two years, T4>2 years). The correlations between MA at the last follow-up and standard deviation (SD) values of CMT and CT during follow-up were assessed. The influence of the number of injections on the change in MA over time was also analysed. MA differences at T4 were assessed for pseudodrusen presence. RESULTS: BCVA improved significantly during follow-up (p=0.013) particularly increasing from baseline to post loading phase and then did not modify significantly thereafter. CMT significantly reduced from T0 to T1 and remained stable during follow-up (p = <0.001). MNV flow area showed a trend toward increase in the post loading phase that was not statistically significant (p=0.082) and CT decreased significantly during follow-up (p<0.001). MA changed significantly during follow-up (p<0.001) with significant increase from T0 to T3 and from T0 to T4 (p < 0.010). Cochrane Armitage test for trend showed a significant reduction (p=0.001) of macular IRF and SRF during follow-up. MA at T4 showed a significant positive correlation with SD (standard deviation) values of CMT (p=0.040) and CT (p=0.020). Indeed, the number of injections did not influence the change over time of MA (p=0.709). MA at T4 was not statistically significantly different between patients with pseudodrusen at baseline (p=0.497). CONCLUSIONS: Intravitreal anti-VEGF injections with PRN regimen in MNV type 3 showed functional and anatomical benefits. Variations of retinal thickness and choroidal thickness during treatment were related to MA modification over time.

Long-Term Follow-Up of Brolucizumab in Macular Neovascularization.

INTRODUCTION: The aim of the study was to evaluate functional and anatomical changes in type 1 and type 2 naïve macular neovascularization (MNV) patients treated with brolucizumab injections up to 1 year of treatment (week 48). METHODS: Thirty-eight eyes of 38 patients with active MNV were enrolled at the Ophthalmology Clinic of the University "G. d'Annunzio," Chieti-Pescara, Italy. All patients were scheduled for brolucizumab intravitreal injections as per label, according to the standard HAWK and HARRIER trials guidelines. Enrolled patients underwent complete ophthalmic evaluation, including optical coherence tomography (OCT) and OCT angiography. All measurements were evaluated at baseline and then monthly up to week 48. The main outcome measures were changes in best-corrected visual acuity (BCVA); central macular thickness (CMT); subfoveal choroidal thickness (SCT); pigment epithelial detachment presence and maximum height (PEDMH); intraretinal fluid (IRF) presence, subfoveal subretinal fluid (SSRF) presence and maximum height, macular atrophy area, and neovascular membrane flow area in the slab extending from the outer retina to choriocapillaris (ORCC flow). RESULTS: CMT and BCVA significantly changed in both groups over time. ORCC flow and SCT significantly reduced in both groups over time. Atrophy areas increased from 0 to 0.17 mm2 and from 0 to 0.23 mm2 in type 1 MNV and type 2 MNV patients, respectively. PEDMH reduced in type 1 MNV from 138 µm at T0 to 96 µm at T5. Changes in fluids were noted, with SSRF thickness reduction and IRF changes in both groups. CONCLUSION: Our one-year results of treatment confirm brolucizumab to be efficient and safe in both type 1 and type 2 MNV patients, proposing novel OCT parameters as possible biomarkers of treatment.

Choroidal and Retinal Imaging Biomarkers in Different Types of Macular Neovascularization.

BACKGROUND: The aim of this study was to investigate optical coherence tomography (OCT) and OCT angiography (OCTA) parameters in patients with neovascular age-related macular degeneration (nAMD) and macular neovascularization (MNV) type 1, type 2, and type 3. METHODS: In this retrospective study, 105 treatment-naïve eyes of 105 patients (60 men and 45 women) with a definite diagnosis of active nAMD and MNV of different types and 105 frequency-matched age and gender healthy subjects were evaluated (61 men and 44 women). All subjects underwent a full ophthalmic examination and multimodal imaging assessment, including spectral domain (SD) OCT and OCTA. The main outcome measures were choroidal vascularity index (CVI), subfoveal choroidal thickness (SFCT), central macular thickness (CMT), and outer retina to choriocapillaris (ORCC) MNV flow area (ORCCFA). RESULTS: Significant differences were found in terms of CVI, CMT, and ORCCFA between MNV 1 and the two other groups. CVI was significantly different between MNV 1 and healthy control patients (p < 0.001) and between MNV 1 and MNV 2 (p < 0.001). ORCCFA and CMT were significantly different between MNV1 and MNV2 (p < 0.005). The difference in subfoveal CT between the three groups was not statistically significant (p = 0.458). A significant negative correlation was found between CVI and ORCCFA. Furthermore, CVI showed a positive correlation with subfoveal CT.

Choroidal modifications assessed by means of choroidal vascularity index after oral eplerenone treatment in chronic central serous chorioretinopathy.

BACKGROUND: To investigate choroidal vascularity index (CVI) changes after oral eplerenone treatment in chronic central serous chorioretinopathy (cCSC) using the Spectral-domain (SD)-Optical Coherence Tomography (OCT) with enhanced depth imaging (EDI) mode. METHODS: Thirty-six eyes of 18 patients suffering from cCSC with monolateral foveal subretinal fluid (FSRF) successfully treated with oral eplerenone treatment and 18 age-matched healthy subjects were enroled in this retrospective study. EDI-OCT images obtained using Heidelberg Spectralis OCT device in patients with cCSC and FSRF (group 1); fellow eye (group 2) or healthy patients (healthy) were exported and then imported into image analysis ImageJ software for subsequent quantitative analysis. The main outcome measures were luminal area (LA) and CVI. RESULTS: A higher value of CVI was detected in group 1 compared to healthy eyes (p = 0.006). LA and CVI significantly reduced during follow up in group 1 and group 2. LA at 120 days was significantly lower compared to all previous time points both in group 1 and group 2 (p < 0.001). Median and [1st -3rd quartile] CVI values were 0.8 [0.7; 1.1] at baseline, 0.8 [0.7; 0.9] at 30 days; 0.7 [0.6; 0.9] at 60 and 90 days and 0.6 [0.5; 0.8] at 120 days in group 1 (p = 0.007) and 0.7 [0.6; 0.9] at baseline, 0.7 [0.7; 0.8] at 30 days; 0.7 [0.6; 0.7] at 60 and 90 days and 0.6 [0.6; 0.7] at 120 days in group 2 (p = 0.018). CONCLUSIONS: Choroidal vascularity index reduced in cCSC patients after oral eplerenone treatment during follow up both in eyes with SRF and fellow eyes thus demonstrating the effectiveness of mineral corticoid receptor antagonists in recovering choroidal morphology.

Intravitreal Dexamethasone Implant (IDI) Alone and Combined with Navigated 577 nm Subthreshold Micropulse Laser (SML) for Diabetic Macular Oedema.

BACKGROUND: The anatomical and functional changes after intravitreal dexamethasone implant (IDI) alone and combined with navigated subthreshold micropulse laser (NSML) in diabetic macular oedema (DMO) were compared. METHODS: Patients with a clinically confirmed diagnosis of non-proliferative diabetic retinopathy (NPDR) and DMO were enrolled in this prospective study and were randomly assigned to two different treatment groups: thirty patients were treated with IDI (IDI group), and the other 30 patients received IDI combined with NSML treatment (combined IDI/NSML group). All patients during a 6-month follow-up underwent best corrected visual acuity (BCVA) evaluation and spectral domain optical coherence tomography (SD OCT). The main outcome measures were: BCVA, central macular thickness (CMT); (3) choroidal vascularity index (CVI), subfoveal choroidal thickness (SCHT); and time to retreatment between IDI at baseline and the second implant in both groups. RESULTS: BCVA, CMT, and SCHT significantly decreased starting from the 1-month follow-up and CVI from 3 months in both groups. The between-group differences were significantly different from 1-month follow-up for BCVA, from 5-month follow-up for CMT and SCHT, and from 4-month follow-up for CVI. The Needed to Treat analysis indicated that six patients would have to be treated with SML after IDI in order for just one person to receive a benefit. CONCLUSIONS: the combined treatment showed good anatomical and functional outcomes for the treatment of DMO. In addition, IDI/SML seems to reduce injection frequency over time, improving patients' quality of life and reducing the socio-economic burden.

Brolucizumab intravitreal injection in macular neovascularization type 1: VA, SD-OCT and OCTA parameters changes during a 16-weeks follow up.

PURPOSE: to assess the anatomical and functional changes after brolucizumab intravitreal injection (BIVI) in macular neovascularization type 1 (MNV1). Setting/Venue: Ophthalmology Clinic, University "G. d'Annunzio" of Chieti-Pescara. METHODS: A total of 24 eyes of 24 patients suffering from naïve MNV1 candidates to BIVI as per label with q12/q8 dosing regimen after the loading dose were enrolled in this prospective study. Main outcome measures during a 16-weeks follow up period included changes of best corrected visual acuity (BCVA), central macular thickness (CMT), subfoveal subretinal fluid thickness (SSRFT), subfoveal sub-RPE fluid thickness (SSRPEFT), subfoveal choroidal thickness (SFCT) and pigment epithelial detachment (PED) maximum height (PED-MH). In addition, percentages of eyes with intraretinal fluid, subretinal fluid and sub-RPE fluid at different time points and percentages of eyes candidates to a q8 or q 12 injection interval after disease activity assessment at week 16 were evaluated. RESULTS: BCVA improved significantly from baseline (T0) to week 12 (T3) (p=0.028). CMT showed a significant reduction from 456.0±123.0 µm at T0 to 265.0±85.0 µm at T3 (p<0.001). SSRFT and SSRPEFT reduced significantly as well (p<0.001 and p=0.049 respectively). PED-MH reduced significantly from 162.0±110.0 µm at T0 to 94.1±38.9 µm at T3 (p=0.020) and SFCT from 203.0±56.9 µm at T0 to 146.0±64.2 µm at T3 (p=0.006). IRF presence changed significantly from 41.7% of eyes at T0 to 20.8% at T3 (p=0.045). SSRF reduced significantly during follow up, being present in 62.5% of eyes at T0 and 4.2% of eyes at T3 (p<0.001). Subfoveal sub-RPE fluid decreased significantly during time being present in 20.8% of eyes at T0 and 0% at T3 (p=0.013). Most of the eyes (18 eyes, 75%) at week 16 after disease activity assessment were shifted in the q12 interval and only a minority of eyes shifted in a q8 interval (6 eyes, 25%). CC Flow and ORCC flow did not show significant differences during follow up. CONCLUSIONS: Brolucizumab is efficient in reducing all retinal fluids during the loading phase and shows reduction of macular thickness, choroidal thickness, and PED height. Most eyes at disease activity assessment (75%) fall into 12 week-interval and the minority (25%) into the 8 week-interval.

Study of nonperfusion area changes after ranibizumab intravitreal injection for diabetic macular edema by means of widefield OCT angiography.

INTRODUCTION: To evaluate changes of retinal capillary non-perfusion areas (RCNPA) and the retinal capillary vessel density (RCVD) of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) using widefield optical coherence tomography angiography (WFOCTA) in patients with diabetic retinopathy (DR) and diabetic macular edema (DME) treated with intravitreal ranibizumab injection (IRI). MATERIALS AND METHODS: 24 eyes of 24 patients with DR and DME candidates to a loading dose of IRI were enrolled. All patients underwent WFOCTA with the PLEX Elite 9000 device with 15 × 9 mm scans centered on the foveal center at baseline (T0) and 1 month after each intravitreal injection at 30 days (T1), 60 days (T2), and 90 days (T3). In all patients, the variation of RCNPA and the RCVD of the of the SCP and DCP were calculated using automatic software written in Matlab (MathWorks, Natick, MA). RESULTS: The SCP showed a significant longitudinal variation of RCNPA (p = 0.04). Post-hoc analysis revealed a statistically significant reduction of RCNPA at T1 (p = 0.04) and a not significant reduction at T2 (p=0.18) and T3 (p=0.96). The DCP showed longitudinal changes of the RCNPA that tended to statistical significance (p = 0.09). Post-hoc analysis revealed a trend towards a statistically significant reduction of RCNPA at T3 (p = 0.09) not statistically significant, at T1 (p=0.17) and T2 (p=0.75). The RCVD of SCP and DCP showed no significant changes in any of the time points. CONCLUSIONS: Widefield OCT angiography showed a decrease of RCNPA after IRI, probably related to the reperfusion of retinal capillaries.

Short-term comparison between navigated subthreshold microsecond pulse laser and oral eplerenone for chronic central serous chorioretinopathy.

To compare the anatomical/functional changes after navigated subthreshold pulse laser (SML) and oral eplerenone therapy for chronic central serous chorioretinopathy (cCSC). A total of 36 eyes of 36 patients suffering from cCSC treated with navigated SML (Navilas® 577s; OD-OS GmbH, near Berlin, Germany) (18 eyes, SML group) and oral eplerenone (18 eyes, eplerenone group) were enrolled in this retrospective study. Main outcome measures during a 3-month follow up period included changes of best corrected visual acuity (BCVA), central macular thickness (CMT), foveal subretinal fluid thickness (FSRFT), and subfoveal choroidal thickness (SFCT). At baseline average duration of symptoms was 6.8 ± 0.6 months in SML group and 6.4 ± 0.9 months in eplerenone group (p = 0.127). Mean BCVA, CMT and FSRFT changed significantly over time (p < 0.001). From baseline to 90 days the BCVA improved from 0.3 ± 0.1 to 0.1 ± 0.1 logMAR in SML group and from 0.3 ± 0. to 0.2 ± 0.1 logMAR in eplerenone group, CMT reduced from 357.1 ± 104.3 to 210.6 ± 46.7 µm and from 428.7 ± 107.7 to 332.5 ± 27.5 µm in SML group and eplerenone group respectively, FSRFT reduced from 144.4 ± 108.2 to 22.6 ± 37.2 µm and from 217.1 ± 105.9 to 54.4 ± 86.2 µm in SML group and eplerenone group. 55.6% of patients in SML group and 66.7% in eplerenone group showed a complete resolution of FSRFT during follow up. The interaction between group and time was statistically significant with greater absolute variation for CMT and FSRFT in SML group compared to eplerenone group (p < 0.001 and p = 0.043). SFCT did not change significantly during follow up (p = 0.083) for both groups. Both navigated SML and oral eplerenone were effective treatments showing recovery of retinal morphology and related visual acuity improvement in cCSC.

Widefield Swept Source OCTA in Retinitis Pigmentosa.

(1) Background: To evaluate superficial capillary plexus (SCP), deep capillary plexus (DCP), choriocapillaris (CC), perfusion density (PD), and vessel length density (VLD) in macular and near/mid periphery regions in patients with retinitis pigmentosa (RP) using widefield swept source optical coherence tomography angiography (WSS-OCTA). (2) Methods: Twelve RP patients (20 eyes) and 20 age-matched subjects (20 eyes) were imaged with the SS-OCTA system (PLEX Elite 9000, Carl Zeiss Meditec Inc., Dublin, CA, USA). Quantitative analysis was performed in the macular and peripheral regions. The main outcome measures were SCP, DCP, CC, PD, and VLD in central and peripheral areas. (3) Results: Mean visual acuity, central macular thickness, and microperimetry were significantly reduced in RP patients compared to normal subjects (p < 0.05). The perfusion density and VLD of SCP, DCP, and CC were significantly reduced in RP patients compared to normal controls both in the central and peripheral retina (p < 0.05). A significant direct correlation was found in RP patients between PD of the 1.5 mm central retina both in DCP and CC and microperimetry at 4° and 8°. (4) Conclusions: Widefield SS-OCTA shows an impairment of retinal and choroidal perfusion density and vessel length density in central and peripheral retina of RP patients. The reduction of flow features correlates with the macular function.

Correlation between Choriocapillaris Density and Retinal Sensitivity in Stargardt Disease.

The aim of this work was to characterize the choriocapillaris (CC) in patients with Stargardt disease (STGD) using the swept source widefield optical coherence tomography angiography (SS WF OCTA) and to compare CC perfusion density to retinal sensitivity, analyzed using microperimetry (MP). This cross-sectional study included 9 patients (18 eyes) with STGD and central CC atrophy (stage 3 STGD). The CC was analyzed using SS WF OCTA and areas of different CC impairment were quantified and correlated with retinal sensitivity analyzed using MP. The main outcome measures were the percent perfused choriocapillaris area (PPCA), retinal sensitivity, and correlation between PPCA and retinal sensitivity. Seventeen eyes of 9 patients suffering from stage 3 STGD were analyzed. SS WF OCTA revealed a vascular rarefaction in central atrophic zones and a near atrophy halo of choriocapillaris impairment. In all eyes were noticed a central atrophy (CA) area with absolute absence of CC that corresponded to 0 dB points at MP, a near atrophy (NA) zone of PPCA impairment that included points with decreased sensitivity at MP and a distant from atrophy (DA) zone with higher PPCA and retinal sensitivity values. The mean difference of PPCA and retinal sensitivity between NA and CA and DA and CA was statistical significantly different (p < 0.01), the latter showing higher values. A direct relationship between PPCA and retinal sensitivity was found (p < 0.001). Choriocapillaris damage evaluated using SS WF OCTA correlates with MP, these data suggest that CC impairment may be a predictor of retinal function in patients with STGD.

Foveal avascular zone area and parafoveal vessel density measurements in different stages of diabetic retinopathy by optical coherence tomography angiography.

AIM: To investigate foveal avascular zone (FAZ) and parafoveal vessel densities (PRVD) by means of optical coherence tomography angiography (OCTA) in diabetic patients with or without diabetic retinopathy (DR) and to assess the reproducibility of FAZ and PRVD measurements. METHODS: Sixty diabetic patients (60 eyes) with different stage of DR (graded according to the International Clinical Severity Scale for DR) and 20 healthy subjects underwent FAZ area and PRVD measurements using OCTA by two experienced examiners. FAZ area in all patients was also assessed using fluorescein angiography (FA). RESULTS: In subject with proliferative DR and with moderate-severe non proliferative DR, FAZ area was significantly increased compared to healthy controls (P=0.025 and P=0.050 respectively measured with OCTA and P=0.025 and P=0.048 respectively measured with FA). OCTA showed significantly less inter-observer variability compared to FA. Concordance correlation coefficient (CCC) for FAZ area measurements was 0.829 (95%CI: 0.736-0.891) P<0.001 with FA and 1.000 (95%CI: 0.999-1.000) P<0.001 with OCTA. CCC was 0.834 (95%CI: 0.746-0.893) P<0.001 and 0.890 (95%CI: 0.828-0.930) P<0.001 for parafoveal superficial and deep vessel density measurements, respectively. CONCLUSION: OCTA shows progressive increase of FAZ area and reduction of PRVD in both superficial and deep plexus at increasing DR severity. FAZ area and PRVD measurements using OCTA are highly reproducible.

Immunohistochemical study of corneal inflammation after femtosecond laser clear corneal incisions or manual surgery.

PURPOSE: To use immunohistochemical staining to evaluate corneal inflammation and apoptosis induced after femtosecond laser incisions or manual incisions. SETTING: Ophthalmology Clinic, University G. d'Annunzio, Chieti, Italy. DESIGN: Experimental study. METHODS: Ninety human cadaver corneas were cut manually or with the femtosecond laser at different energies and analyzed by immunohistochemistry after 5 minutes or 4 hours. The corneas were divided into 5 groups: untreated (Group 1), cut manually (Group 2), and treated with the femtosecond laser with increasing energies (Groups 3 to 5; 3.0 µJ, 6.0 µJ, and 15.0 µJ, respectively). RESULTS: At 5 minutes, increased expression of interleukin (IL)-18 was observed in the femtosecond laser groups compared with the manual group (P < .01). Interferon gamma (IFNγ) positivity was significantly higher in Groups 4 and 5 than in Group 2 and between Groups 3 and 4 (P < .05). The terminal uridine deoxynucleotidyl nick end-labeling (TUNEL) positivity increased with higher energy (Group 2 versus Group 4 and Group 2 versus Group 5; P < .05). After 4 hours, IFNγ positivity was higher in Group 5 than in Group 2 (P = .0021) and between Group 5 and Groups 3 and 4 (P < .05). No sign of IL-18 positivity was found after 4 hours in any sample. Group 5 showed significant higher TUNEL positivity than all other groups (P < .0001). CONCLUSION: The femtosecond laser technique at high energies induced a higher corneal inflammatory response and a higher corneal cell apoptosis than the manual technique. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned.

Morphology and Function over a One-Year Follow Up Period after Intravitreal Dexamethasone Implant (Ozurdex) in Patients with Diabetic Macular Edema.

BACKGROUND: To investigate changes in macular morphology and function after an intravitreal dexamethasone implant for diabetic macular edema (DME). METHODS: Twenty-seven eyes in 27 treatment-naive patients affected by DME were treated with intravitreal Ozurdex® injections (IVOI) and followed up 12 months to evaluate morphological and functional changes by means of best-corrected visual acuity (BCVA), microperimetry (MP1), multifocal electroretinography (mfERG), pattern electroretinography (PERG) and spectral domain optical coherence tomography (SD-OCT). RESULTS: Both BCVA and retinal sensitivity improved significantly at one month after the IVOI (p = 0.031 and p<0.0001, respectively). After five months, the improvement of BCVA remained statistically significant compared with baseline values (p = 0.022); retinal sensitivity improvement was statistically significant for up to four months after the IVOI (p = 0.059). Moreover, central macular thickness significantly decreased for up to four months. Interestingly, PERG and mfERG values did not change significantly for up to four months post-IVOI, but then began to worsen. CONCLUSIONS: In eyes with DME, intravitreal dexamethasone implant determined morphological and functional improvement as soon as one month and for up to four months after the treatment.

Macular pseudohole development after sustained-release dexamethasone intravitreal implant for macular edema due to central retinal vein occlusion.

PURPOSE: To report a case of macular pseudohole (MPH) development after sustained-release dexamethasone intravitreal implant for chronic macular edema due to central retinal vein occlusion (CRVO). METHODS: A 70-year-old man with cystoid macular edema (CME) due to CRVO underwent sustained-release dexamethasone intravitreal implant. En face optical coherence tomography (OCT) was performed before and after treatment. RESULTS: One month after dexamethasone intravitreal implant, best-corrected visual acuity (BCVA) improved from 1.0 to 0.5 logMAR. At 2 months, BCVA decreased from 0.5 to 1.3 logMAR. En face OCT detected the development of MPH due to exacerbation of centripetal vitreomacular transverse tractional forces on the overlying retina. CONCLUSIONS: Macular pseudohole seems to be a complication of intravitreal therapy in patients with coexisting vitreomacular traction. En face OCT gives useful information to understand the mechanism of MPH development after sustained-release dexamethasone intravitreal implant.