Mean Choroidal Neovascularization Area Research Articles

Microsecond Pulsing Laser for Choroidal Neovascularization Associated with Central Serous Chorioretinopathy

Purpose To analyze the efficacy and safety of microsecond pulsing laser therapy (MLT) in the management of central serous chorioretinopathy (CSCR) complicated by choroidal neovascularization (CNV). Methods Patients with CSCR complicated by CNV defined as the presence of characteristic OCT angiography features were randomly assigned to either study or control group. All patients of the study group underwent MLT targeting CNV area using navigated laser system followed by at least 6-month follow-up. Sham treatment was performed in the control group. No other treatment or anti-VEGF therapy was used during the follow-up. Main outcome measure was complete resolution of subretinal fluid at the end of follow-up. Results Twenty-three eyes (13 males and 10 females, mean age 58.2 ± 8.0 years) with a mean CNV area 0.62 ± 0.77 mm2 were included in the study group. Fourteen (60.9%) patients achieved complete resolution of SRF, five (21.7%) patients demonstrated some reduction of SRF, and four (17.4%) patients demonstrated no improvement after MLT in the study group. Twelve eyes (8 males and 4 females, mean age 59.8 ± 4.6 years) were included in the control group where none of them demonstrated resolution of SRF at the end of the follow-up (p = 0.0018 compared to the study group). No adverse effects, such as changes of CNV size, deterioration of exudation, or decline in visual acuity were observed in the study group. Conclusion Microsecond pulsing laser is an effective and safe option for the treatment of CSCR complicated by relatively small CNV and achieves complete resolution of SRF in 61% of cases.

OCTA evaluation of treatment-naïve flat irregular PED (FIPED)-associated CNV in chronic central serous chorioretinopathy before and after half-dose PDT.

To qualitatively and quantitatively evaluate the features of treatment-naïve flat irregular pigment epithelial detachment (FIPED)-associated choroidal neovascularization (CNV) in chronic central serous chorioretinopathy (CSC) using swept-source (SS) optical coherence tomography angiography (OCTA) before and after half-dose photodynamic therapy (PDT). Retrospective case series. The multimodal imaging data of the eyes with FIPED-associated CNV in chronic CSC were reviewed. The features of FIPED-associated CNVs were evaluated by SS-OCTA. Records of twenty-one patients (21 eyes) were reviewed. The mean age was 56.62 ± 6.87 years. After half-dose PDT, all patients have improved best spectacle-corrected visual acuity from 0.49 at baseline to 0.25 at 6-month visit, and subfoveal choroidal thickness decreased with subretinal fluids absorbed. By OCTA, the features of CNV at baseline included long filamentous linear vessels (21/21), branching into other large mature vessels with rare anastomoses (21/21); and/or a 'dead tree' appearance at the vessel's termini (20/21); and no perilesional hypointense halo (21/21). Compared to those at baseline, the mean vessel density of CNV showed no significant change at 1-,3-,6-month follow-up, while the mean area of CNV was significantly larger at the 6-month follow-up (p = 0.013). OCT angiography allows to qualitatively and quantitatively evaluate CNV in chronic CSC. The features of FIPED-associated CNV on OCTA illustrated its quiescent characteristic and further guided therapy. Half-dose PDT showed favorable effects on chronic CSC complicated with FIPED-associated CNV.

Asthma Promotes Choroidal Neovascularization via the Transforming Growth Factor Beta1/Smad Signalling Pathway in a Mouse Model

Introduction: The association between age-related macular degeneration and asthma is controversial. Transforming growth factor beta (TGF-β), which plays a critical role in asthma, has been extensively studied with regard to its function in choroidal neovascularization (CNV). In the present study, we aimed to investigate the role of TGF-β and the possible mechanism of CNV formation complicated with asthma and to explore the effect of a TGF-β inhibitor on CNV development in asthma mouse models. Methods: Laser-induced CNV and ovalbumin-induced asthma mouse models were divided into 5 groups: control group, acute asthma group, chronic asthma group, inhibitor-treated acute asthma group, and inhibitor-treated chronic asthma group. The gene expression patterns of angiogenic cytokines, vascular endothelial growth factor (VEGF) receptors and inflammasomes in the control group, acute asthma group, and chronic asthma group were detected using a QuantiGene Plex 6.0 Reagent System. Fundus fluorescein angiography and histology of CNV lesions stained with haematoxylin-eosin were performed to evaluate CNV formation. Quantitative real-time PCR and western blotting were used to assess TGF-β1, TGF-β2, and VEGF expression and Smad2/3, AKT, p38 MAPK, and ERK1/2 signal transduction and phosphorylation in retinal and choroidal tissues from each group. Results: In this study, we verified that laser treatment led to more CNV and vascular leakage in asthmatic mice than that in control mice. The changes were particularly notable in the chronic asthma group. The respective TGF-β1, VEGF, and phosphorylated Smad2/3 (p-Smad2/3) mRNA and protein levels in retinal and choroidal tissues were significantly upregulated in both the acute and chronic asthma groups. After injection of a TGF-β inhibitor, a distinct decline in VEGF, TGF-β1, and p-Smad2/3 protein and mRNA levels was observed, and the mean CNV area also decreased. Conclusion: We provide new evidence that asthma could be a risk factor for CNV development via the TGF-β1/Smad signalling pathway. A TGF-β inhibitor can be applied as a useful, adjunctive therapeutic strategy for preventing CNV formation in asthmatic patients.

Influence of CNV vascular morphology in exudative age-related macular degeneration on development of visual acuity and need for anti-VEGF therapy after 1 year

The aim of this pilot study was to investigate vascular morphological characteristics of choroidal neovascularization (CNV) at the time of the initial diagnosis of exudative age-related macular degeneration (nAMD), which enable a prognosis for the development of visual acuity and the necessity for treatment in the first year. In 57patients with the initial diagnosis of nAMD, CNV was detected by optical coherence tomography angiography (OCT-A) and an automated quantitative vessel analysis was performed with respect to area, total vessel length, flow value and average vessel caliber of the CNV. After 12months patients were divided into 2 groups based on visual acuity (visual loss vs. visual gain) and necessity of anti-VEGF therapy (<7 intravitreal injections, IVOM vs. ≥7 IVOM). The mean CNV area was 0.95 mm2 ± 1.07 mm2 (group visual loss 1.56 mm2 ± 1.54 mm2; group visual gain 0.65 mm2 ± 0.53 mm2; p = 0.002/<7 IVOM 1.05 mm2 ± 1.40 mm2; ≥7 IVOM 0.98 mm2 ± 0.94 mm2, p = 0.60). The average total vessel length of the CNV was 9.84 mm ± 11.35 mm (visual loss 16.00 mm ± 16.58 mm; visual gain 6.74 mm ± 5.42 mm; p < 0.003/<7 IVOM 11.21 mm ± 15.10; ≥7 IVOM 9.90 mm ± 9.68 mm; p = 0.68). The mean flow value of the CNV was 0.40 ± 0.06 (visual loss 0.37 ± 0.04; visual gain 0.41 ± 0.07; p = 0.004/<7 IVOM 0.42 ± 0.08; ≥7 IVOM 0.38 ± 0.06; p = 0.02). The average vessel caliber was 28.86 µm ± 2.93 µm (visual loss 28.39 µm ± 2.97 mm; visual gain 29.32 µm ± 3.05 µm; p = 0.24/<7 IVOM 30.26 µm ± 3.49 µm; ≥7 IVOM 28.23 µm ± 2.25 µm; p = 0.02). The results show that amathematical quantification of the CNV in nAMD is possible using OCT‑A. This analysis confirmed again that the size of the CNV (area and total vessel length) is decisive for the prognosis of visual acuity. It also shows that alarger flow value as asign of awell-differentiated CNV is associated with abetter functional prognosis. The number of IVOMs required, however, depends primarily on the composition of the CNV (flow value and vascular caliber). More precise imaging and larger examination cohorts could possibly reveal further relevant biomarkers.

Imaging of Therapeutic Effects of Anti-Vascular Endothelial Growth Factor Inhibitors by Optical Coherence Tomography Angiography in a Rat Model.

PurposeThe aim of the study was to investigate optical coherence tomography angiography (OCTA) as a high-resolution in vivo imaging modality for monitoring therapeutic response to different vascular endothelial growth factor inhibitors in the rat model of laser-induced choroidal neovascularization (CNV). Further, OCTA findings were compared with fluorescein angiography (FA) and fluorescence microscopy.MethodsLaser treatment at day (D)0 was followed by intravitreal injection of aflibercept, AF564, and NaCl in dark agouti rats. Imaging with OCTA and FA was performed at D2, D7, D14, and D21. OCTA was compared to FA as well as confocal imaged flat mounts and analysis included quantification of CNV area, pixel intensity, vessel density, and number of vessel junctions.ResultsWithin laser lesions, neovascularization were visible especially in deeper retinal layers on OCTA, but not on FA images. Using OCTA, mean CNV area (D21) at the level of the outer nuclear layer (ONL) was 0.017 mm² following aflibercept administration, 0.016 mm² following AF564 and 0.026 mm² following NaCl injection (P = 0.04 and P = 0.03). Similar differences between treatment groups were determined by FA and histology, although the overall CNV area was always larger on FA due to dye leakage (P ≤ 0.0001, all layers).ConclusionsCompared to FA, OCTA imaging allows for a more precise and quantitative analysis of new blood vessel formation and therapeutic response to vascular endothelial growth factor (VEGF)-inhibitors, whereas it does not permit assessment of leakage.Translational RelevanceThese findings suggest that OCTA may be particularly useful for the investigation of new treatment targets in the animal model.

Detection of Nonexudative Choroidal Neovascularization and Progression to Exudative Choroidal Neovascularization Using OCT Angiography

To detect nonexudative choroidal neovascularization (CNV) in age-related macular degeneration (AMD) with OCT angiography (OCTA) and determine the risk of exudative CNV developing compared with eyes without nonexudative CNV. Prospective, longitudinal, observational study. Consecutive patients with drusen and pigmentary changes in the study eye and exudative neovascular AMD in the fellow eye. In this prospective observational study, participants underwent spectral-domain OCTA (AngioVue; Optovue, Inc, Fremont, CA), clinical examination, and structural OCT at baseline and 6-month intervals for 2 years. OCT angiography images were exported for custom processing to remove projection artifact and calculate CNV vessel area. Rate of developing exudation in eyes with and without nonexudative CNV as detected by OCTA on regular follow-up. Sixty-three study participants were followed up every 6 months and 48 completed the 2-year study. Mean age was 78 years and 60.3% were female. On the baseline visit, 5 eyes (7.9%) were found to have nonexudative CNV by OCTA, and 3 of them demonstrated exudation. Of 58 eyes with a normal OCTA on baseline visit, 5 eyes developed nonexudative CNV during a follow-up visit. All 5 of these nonexudative CNV went on to develop exudation in subsequent visits. Overall, 8 of the 10 eyes with nonexudative CNV developed exudation with a mean time of 8 months and mean CNV area growth rate of 20% per month (P= 0.014, exponential model). Initiation of antiangiogenic treatment halted their growth. In comparison, exudation occurred in only 6 of the 53 eyes (11%) that lacked a precursor nonexudative CNV. Cox proportional hazard analysis showed that having nonexudative CNV detected was associated with an 18.1-fold increase in the rate of exudation subsequently developing (P < 0.0001). Nonexudative CNV frequently is detected by OCTA in the fellow eyes of those with exudative CNV. These lesions carry a high risk of exudation developing within the first year after detection and could benefit from close monitoring. The high risk of progression may justify prophylactic treatment; further studies are needed.

VASCULAR REMODELING OF CHOROIDAL NEOVASCULARIZATION AFTER ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY VISUALIZED ON OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

To describe the qualitative and quantitative changes in choroidal neovascularization (CNV) flow pattern after anti-vascular endothelial growth factor therapy, by optical coherence tomography angiography (OCTA). Consecutive patients with neovascular age-related macular degeneration underwent multimodal imaging, including OCTA at initial examination and at last visit. High-flow networks in the choriocapillaris segmentation of OCTA were qualitatively and quantitatively analyzed at baseline and at follow-up, to characterize vascular flow changes after anti-vascular endothelial growth factor treatment and to correlate these changes with final exudation signs on spectral domain optical coherence tomography. Seventeen eyes were included. Mean follow-up was of 11.7 ± 3.3 months. Baseline images showed six medusa pattern (35.3%), four seafan pattern (23.5%), and seven indistinct network patterns (41.2%). Mean CNV area at baseline was 1.58 ± 1.72 mm. Final OCTA images revealed a decrease in CNV total area of 21.6%. In 6/17 eyes, the baseline neovascular pattern was unchanged; these cases were associated with exudation at the final spectral domain optical coherence tomography examination (P = 0.034) and a decrease in CNV area of 34.1%. Conversely, in 11/17 eyes (64.7%), the initial pattern had changed to a pruned vascular tree pattern, with variable exudative status on spectral domain optical coherence tomography at the final visit and a decrease in total CNV area of 0.07%. The vascular flow remodeling induced by recurrent anti-vascular endothelial growth factor treatment can be assessed by OCTA. Optical coherence tomography angiography may help to accurately evaluate treatment response and to recognize patterns usually associated with recurrent exudative activity.

Quantitative Vascular Density Changes in Choriocapillaris Around CNV After Anti-VEGF Treatment: Dark Halo.

The authors have observed and quantified choriocapillaris vascular density changes ("dark halo") around choroidal neovascularization (CNV) before and after anti-vascular endothelium growth factor (VEGF) injections by optical coherence tomography angiography (OCTA). Forty-three flow density areas of 11 eyes with CNV were evaluated before and after treatment in this observational case series. Four cases were CNV type 1 and seven were CNV type 2. All the patients were evaluated by a spectral-domain OCT system. The scans were registered at baseline before injection, between 6 days and 14 days after injection, and monthly thereafter. The dark halo was automated assessed by Image J software. The authors observed a fluctuation of the dark halo around the CNV, the dark halo being larger in 95.4% of the cases before treatment and decreasing after injection. Correspondingly, the mean CNV area decreased in 83.7% of the cases after injection. The mean CNV area before treatment was 0.44 mm2 (± 0.40 mm2) and 0.34 mm2 (± 0.29 mm2) after treatment. The dark halo mean area before treatment was 0.34 mm2 (± 0.27 mm2) and 0.25 mm2 (± 0.23 mm2) after treatment. CNV area and dark halo area reductions after injection were statistically significant (P < .001). CNV-to-halo ratio was statistically significant, decreasing after injection (P < .001). OCTA is a noninvasive vascular imaging tool able to detect CNV flow and features. OCTA is also suitable to highlight choriocapillaris vascular density changes around neovascularization after treatment. The dark halo around CNV seen by OCTA showed a fluctuation after anti-VEGF treatment. These results might be useful in clinical practice. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:918-924.].

Hydrogel Arrays and Choroidal Neovascularization Models for Evaluation of Angiogenic Activity of Vital Pulp Therapy Biomaterials

This study intended to evaluate the angiogenic properties of vital pulp therapy materials including white mineral trioxide aggregate (WMTA), calcium hydroxide (Ca[OH]2), Geristore (Den-Mat, Santa Maria, CA), and nano WMTA biomaterials. WMTA, Ca(OH)2, Geristore, and nano WMTA disks were prepared, dispersed into 2mL Milli-Q (Millipore, ThermoFisher, Hanover Park, IL) distilled water, and centrifuged to obtain 2mL supernatant elution. Thirty-five wells of polyethylene glycol hydrogel arrays were prepared and divided into 5 groups of 7 (n=7). Mice molar endothelial cells (ECs) were placed on hydrogel arrays. The elution prepared from each sample was diluted in growth medium (1:3) and added to the hydrogel arrays. The EC medium alone was used for the control. For the choroidal neovascularization (CNV) model, thirty-five 6-week-old female mice were lasered and divided into 5 groups, and elution from each sample (2μL) or saline (control) was delivered by intravitreal injection on the day of the laser treatment and 1 week later. The mean number of nodes, the total length of the branches in the hydrogel arrays, and the mean area of CNV were calculated using ImageJ software (National Institutes of Health, Bethesda, MD) and analyzed by 1-way analysis of variance and post hoc Tukey honest significant difference tests. The comparison of results regarding the number of nodes showed the values of control>Geristore>nano WMTA>WMTA>Ca(OH)2. Regarding the total branch length and the CNV area, the comparison of results showed values of Geristore>control>nano WMTA>WMTA>Ca(OH)2. All tested materials showed minimal antiangiogenic activity, whereas Geristore and nano WMTA showed a higher proangiogenic activity than WMTA and Ca(OH)2.

Long-term Progression of Type 1 Neovascularization in Age-related Macular Degeneration Using Optical Coherence Tomography Angiography

To analyze the long-term growth patterns of type 1 neovascularization (NV) in eyes with age-related macular degeneration (AMD) receiving anti-vascular endothelial growth factor (VEGF) therapy. Retrospective cohort study. Patients were enrolled from 2 eye centers and underwent optical coherence tomography angiography (OCTA) imaging with follow-up greater than 1 year. Choroidal neovascularization (CNV) was manually segmented on OCTA images and compared between time points. CNV growth was subdivided into 3 categories based on OCTA area measurement: CNV doubling, modest growth of less than 50%, and shrinkage. These growth rates were correlated with OCTA morphologic features. Forty-one eyes were analyzed. Mean CNV area was 1.60 ± 1.84mm2 at baseline and 1.80 ± 1.84mm2 at 1 year. Thirty-three eyes (80%) displayed an increase in CNV area at 1 year with a mean increase of 0.20 ± 0.38mm2 (P= .001). Eleven eyes (27%) underwent CNV doubling, 19 eyes (46%) illustrated modest growth, and 6 (15%) showed shrinkage. Anatomic features including a capillary fringe (odds ratio [OR]= 5.3, P= .036) and immature lesion morphology (OR= 4.2, P= .015) were significantly associated with CNV doubling. CNV growth occurred in 3 predominant patterns: "symmetric" growth, "asymmetric" growth, and "finger-like projections," which reflected the orientation of expansion of CNV. "Symmetric" and "asymmetric" growth together correlated with greater frequency of CNV doubling (OR= 15, P= .0048). OCTA provides noninvasive measurement of the area of neovascular lesions in AMD. Sustained growth of type 1 NV can be identified in the majority of lesions (80%) that display characteristic patterns of progression despite ongoing anti-VEGF therapy.

Correlation Between Hyperreflective Foci and Clinical Outcomes in Neovascular Age-Related Macular Degeneration After Switching to Aflibercept.

To assess the correlation between hyperreflective foci (HF) and visual and anatomical outcomes in treatment-resistant neovascular age-related macular degeneration (AMD) using spectral-domain optical coherence tomography (SD-OCT). This was a prospective interventional case series. Thirty-three eyes of 30 consecutive patients with treatment-resistant neovascular AMD were enrolled. Intravitreal aflibercept injections were performed at week 0 (baseline), week 4, and week 8. Spectral-domain OCT images were obtained before each injection and 4 weeks after the third injection. The main focus was on the measurement of choroidal neovascularization (CNV) size in the cross-sectional area in the B-scan through the fovea, and HF number along line segments of 1- and 3-mm length passing through the fovea. Mean number of HF in the radius of 500 μm decreased from 8.36 ± 7.58 to 4.15 ± 3.39 (P = 0.02). Mean number of HF in the radius of 1500 μm was reduced from 21.30 ± 12.47 to 10.45 ± 6.34 (P < 0.001). Mean CNV area decreased from 0.35 ± 0.22 to 0.22 ± 0.16 mm2 (P < 0.001). There was a significant positive correlation between HF reduction in the radius of 500 μm and decrease in central subfield thickness (CST) (r = 0.43, P = 0.01), but no statistically significant correlation was found between HF decline in the radius of 1500 μm and other parameters. Switching from ranibizumab to aflibercept caused significant decrease in the number of HF 1 month after aflibercept upload, and HF decrease in the radius of 500 μm was correlated positively with the reduction in CST.

The effect of triamcinolone acetonide on laser-induced choroidal neovascularization in mice using a hypoxia visualization bio-imaging probe.

Hypoxic stress is a risk factor of ocular neovascularization. Hypoxia visualization may provide clues regarding the underlying cause of angiogenesis. Recently, we developed a hypoxia-specific probe, protein transduction domain-oxygen-dependent degradation domain-HaloTag-Rhodamine (POH-Rhodamine). In this study, we observed the localization of HIF-1α proteins by immunohistochemistry and the fluorescence of POH-Rhodamine on RPE-choroid flat mounts. Moreover, we compared the localization of POH-Rhodamine with pimonidazole which is a standard reagent for detecting hypoxia. Next, we investigated the effects of triamcinolone acetonide (TAAC) against visual function that was evaluated by recording electroretinogram (ERG) and choroidal neovascularization (CNV) development. Mice were given laser-induced CNV using a diode laser and treated with intravitreal injection of TAAC. Finally, we investigated POH-Rhodamine on CNV treated with TAAC. In this study, the fluorescence of POH-Rhodamine and HIF-1α were co-localized in laser-irradiated sites, and both the POH-Rhodamine and pimonidazole fluorescent areas were almost the same. Intravitreal injection of TAAC restored the reduced ERG b-wave but not the a-wave and decreased the mean CNV area. Furthermore, the area of the POH-Rhodamine-positive cells decreased. These findings indicate that POH-Rhodamine is useful for evaluating tissue hypoxia in a laser-induced CNV model, suggesting that TAAC suppressed CNV through tissue hypoxia improvement.

Effect of ranibizumab on high-speed indocyanine green angiography and minimum intensity projection optical coherence tomography findings in neovascular age-related macular degeneration.

The purpose of this 1-year prospective study was to investigate how induction/pro re nata ranibizumab intravitreal treatment of eyes with neovascular age-related macular degeneration affects the anatomy of choroidal neovascularization (CNV) and the overlying outer retinal tissue. High-speed indocyanine green (HS-ICG) angiography measurements provided quantification of the CNV size in 60 patients followed for 1 year. Minimum intensity projection optical coherence tomography (MinIP OCT), a novel algorithm assessing minimum optical intensity between the internal limiting membrane and retinal pigment epithelium, measured the area of outer retinal disruption overlying the CNV. Fluorescein angiography was also assessed to evaluate late retinal leakage. After 1 year, the mean area of CNV measured with indocyanine green angiography decreased by 5.8%. The mean area of MinIP OCT of outer retinal disruption overlying the CNV decreased by 4.2%. Mean area of fluorescein angiography leakage decreased by 6.3%. Both the area of outer retinal disruption measured with MinIP OCT and the area of leakage on fluorescein angiography typically exceeded the area of CNV on indocyanine green angiography at baseline and 1 year. Choroidal neovascularization treated with induction/pro re nata intravitreal ranibizumab for 1 year essentially remained static. Minimum intensity projection optical coherence tomography suggests that the area of outer retinal disruption overlying the CNV may be greater than the CNV itself and often correlates with the leakage area on fluorescein angiography. Additionally, there was minimal change in the area of outer retinal disruption on MinIP OCT even when fluid resolved. Measurements of the extent of CNV lesions based on indocyanine green angiography and MinIP OCT may provide useful outcome variables to help assess the CNV complex longitudinally and warrant further validation.

Intravitreal tanibirumab, a fully human monoclonal antibody against vascular endothelial growth factor receptor 2, partially suppresses and regresses laser-induced choroidal neovascularization in a rat model.

The study investigated the effect of intravitreally administered tanibirumab, a fully human monoclonal antibody against vascular endothelial growth factor receptor 2, in a rat model of laser-induced choroidal neovascularization (CNV). CNV was induced by laser photocoagulation on day 0 in the eyes of Brown Norway rats. Intravitreal injection of tanibirumab or phosphate-buffered saline (PBS) was done on day 0 (prevention arm) or day 7 (treatment arm). Seven days after injection, the eyes were enucleated and retinal pigment epithelium-choroid-sclera flat mounts were prepared. Areas of CNV were determined in the flat mounts using tetramethylrhodamine isothiocyanate Bandeiraea simplicifolia (BS) isolectin labeling and intravenously administered fluorescein isothiocyanate-dextran and quantified using an image analysis program. In the prevention arm, the mean area of CNV measured by BS isolectin labeling was reduced by 28.2% and 53.9% in tanibirumab-treated eyes (20 and 60 μg, respectively) compared with PBS-treated control eyes on day 7 (P=0.038 and P<0.001, respectively). In the treatment arm, the mean area of CNV measured by BS isolectin labeling was reduced by 28.7% and 46.0% in tanibirumab-treated eyes (20 and 60 μg, respectively) compared with PBS-treated control eyes on day 14 (P=0.048 and P<0.001, respectively). Intravitreally administered tanibirumab partially suppressed the formation of new CNV and partially regressed preformed laser-induced CNV in the rat model. Tanibirumab may be a feasible treatment for CNV associated with age-related macular degeneration or other causes.

Stereotactic Radiotherapy for Neovascular Age-Related Macular Degeneration: Year 2 Results of the INTREPID Study

To determine the safety and efficacy of low-voltage, external-beam, stereotactic radiotherapy (SRT) for patients with neovascular age-related macular degeneration (AMD). Randomized, double-masked, sham-controlled, multicenter, clinical trial. A total of 230 participants with neovascular AMD who received ≥ 3 ranibizumab or bevacizumab injections within the preceding year and requiring treatment at enrollment. Participants received 16 Gray, 24 Gray, or sham SRT. All arms received pro re nata (PRN) ranibizumab for 12 months, with PRN bevacizumab or ranibizumab thereafter. Mean number of PRN injections; best-corrected visual acuity (BCVA); loss of <15 Early Treatment of Diabetic Retinopathy Study letters; change in optical coherence tomography central subfield thickness; and change in angiographic total lesion area and choroidal neovascularization (CNV) area. At year 2, the 16 and 24 Gray arms received fewer PRN treatments compared with sham (mean 4.5, P = 0.008; mean 5.4, P = 0.09; and mean 6.6, respectively). Change in mean BCVA was -10.0, -7.5, and -6.7 letters for the 16 Gray, 24 Gray, and sham arms, respectively, with 46 (68%), 51 (75%), and 58 participants (79%), respectively, losing <15 letters. Mean central subfield thickness decreased by 67.0 μm, 55.4 μm, and 33.3 μm, respectively. Mean total active lesion area increased by 1.0, 4.2, and 2.7 mm(2), respectively. Mean CNV area decreased by 0.1 mm(2) in all groups. An independent reading center detected microvascular abnormalities in 6 control eyes and 29 SRT eyes, of which 18 were attributed to radiation; however, only 2 of these possibly affected vision. An exploratory subgroup analysis found that lesions with a greatest linear dimension ≤ 4 mm (the size of the treatment zone) and a macular volume greater than the median (7.4 mm(3)) were more responsive to SRT, with 3.9 PRN injections versus 7.1 in comparable sham-treated participants (P = 0.001) and mean BCVA 4.4 letters superior to sham (P = 0.24). A single dose of SRT significantly reduces intravitreal injections over 2 years. Radiation can induce microvascular change, but in only 1% of eyes does this possibly affect vision. The best response occurs when AMD lesions fit within the treatment zone and they are actively leaking.

Improvement and optimization of standards for a preclinical animal test model of laser induced choroidal neovascularization.

BackgroundAs the murine model of laser-induced choroidal neovascularization (CNV) is becoming the most established and commonly utilized model worldwide for studying the pathogenesis of CNV and its response to treatment, specific operating standards are yet to be clarified. The purpose of this study is to compare the lesion size of CNV in mice with different ages, sex, durations of CNV process, and treated positions of laser spots, to make recommendations that may improve and optimize the quality of the model.Methods and ResultsC57/BL6 mice of different ages were treated with diode laser photocoagulation per eye and perfused with PBS containing fluorescein-labeled dextran at different time of observation. Choroid flat mounts, were then examined by fluorescence microscopy for the measurement of CNV area. Messenger-RNA expression levels of several angiogenic cytokines in eye cups of male and female C57BL/6 mice at 5–8 and 16–20 week-old were analyzed by real-time RT-PCR assay. The results showed significantly more CNV area in eyes of female mice compared to male mice with the expression level of several angiogenic cytokines elevated. 16–20-week-old female mice developed the biggest area of CNV. The mean area of CNV increased significantly at the 14th day after photocoagulation. Laser spots delivered 1PD away from the optic disc induced the biggest area of CNV compared to those 2PD or 3PD away. Interaction of NV was observed in laser spots delivered less than 1PD away from each other.ConclusionThe current results suggest that 16–20-week-old female C57BL/6 mice developed the most distinct CNV lesion size with laser spots delivered 1PD away from the optic disc. The best time to observe and analyze is the 14th day after photocoagulation.

Suppression and regression of choroidal neovascularization in mice by a novel CCR2 antagonist, INCB3344.

PurposeTo investigate the effect of an intravitreally administered CCR2 antagonist, INCB3344, on a mouse model of choroidal neovascularization (CNV).MethodsCNV was induced by laser photocoagulation on Day 0 in wild type mice. INCB3344 or vehicle was administered intravitreally immediately after laser application. On Day 14, CNV areas were measured on retinal pigment epithelium (RPE)-choroid flat mounts and histopathologic examination was performed on 7 µm-thick sections. Macrophage infiltration was evaluated by immunohistochemistry on RPE-choroid flat mounts and quantified by flow cytometry on Day 3. Expression of vascular endothelial growth factor (VEGF) protein in RPE-choroid tissue was examined by immunohistochemistry and ELISA, VEGF mRNA in sorted macrophages in RPE-choroid tissue was examine by real-time PCR and expression of phosphorylated extracellular signal-regulated kinase (p-ERK 1/2) in RPE-choroid tissue was measured by Western blot analysis on Day 3. We also evaluated the efficacy of intravitreal INCB3344 to spontaneous CNV detected in Cu, Zn-superoxide dismutase (SOD1) deficient mice. Changes in CNV size were assessed between pre- and 1week post-INCB3344 or vehicle administration in fundus photography and fluorescence angiography (FA).ResultsThe mean CNV area in INCB3344-treated mice decreased by 42.4% compared with the vehicle-treated control mice (p<0.001). INCB3344 treatment significantly inhibited macrophage infiltration into the laser-irradiated area (p<0.001), and suppressed the expression of VEGF protein (p = 0.012), VEGF mRNA in infiltrating macrophages (p<0.001) and the phosphorylation of ERK1/2 (p<0.001). The area of spontaneous CNV in Sod1 −/− mice regressed by 70.35% in INCB3344-treated animals while no change was detected in vehicle-treated control mice (p<0.001).ConclusionsINCB3344 both inhibits newly forming CNV and regresses established CNV. Controlling inflammation by suppressing macrophage infiltration and angiogenic ability via the CCR-2/MCP-1 signal may be a useful therapeutic strategy for treating CNV associated with age-related macular degeneration.

Photodynamic therapy for subretinal choroidal neovascularization in patients with multifocal choroiditis

Objective To observe the clinical effect of photodynamic therapy (PDT)based comprehensive treatment for choroidal neovascularization (CNV) in patients with multifocal choroiditis (MC).Methods Nine eyes of 8 MC patients (7 females and 1 male) with CNV who had undergone PDT based comprehensive treatment were enrolled in this study.The patients aged from 25 to 54 years with the mean of (41.8±10.6) years.The examinations of best-corrected visual acuity (BCVA),slit lamp microscope,indirect ophthalmoscopy,fundus fluorescein angiography and optical coherence tomography were performed.The BCVA ranged from 20/333 to 20/50 (mean logMAR 0.68±0.32).The mean CNV area was (0.767±0.445) mm2.The central retinal thickness (CRT) was (355.2±65.2) μm.Among the 8 patients,4 eyes received only PDT,2 eyes received PDT and oral corticosteroid,1 eye received PDT and intravitreal injection of 1.25 mg bevacizumab,2 eyes received PDT and subtenon injection of 40 mg triamcinolone acetonide.The follow-up period ranged from 3 to 22 months,with the mean of (14.0± 5.7)months.The BCVA,mean CNV area and CRT before and after treatment were analyzed.Results By the end of last visit,the BCVA improved to 20/250 to 20/25 (mean logMAR 0.58±0.37),but the difference was not statistically significant (t=1.890,P=0.095).Visual acuity improved 3 lines in 3 eyes (33.3 ％),improved 1.5 lines in 1 eye ( 11.1 ％),unchanged in 4 eyes (44.4 ％ ) and decreased 1.5 lines in 1 eye (11.1 ％ ).The mean CNV area decreased to (0.684 ± 0.371) mm2,but the difference was not statistically significant (t=0.996,P=0.349).The CRT decreased to (295.3±79.4) μm,but the difference was not statistically significant (t=2.242,P=0.055).Conclusion PDT can stabilize visual acuity in patients with subretinal CNV secondary to MC,especially when combined with intravitreal injection of anti-vascular endothelial growth factor drugs or steroid. Key words: Choroidal neovascularization/therapy; Photochemotherapy; Choroiditis/complications

MicroRNAs Regulate Ocular Neovascularization

In this study, we used ischemia-induced retinal neovascularization (NV) as a model to investigate the possible role of microRNAs in a clinically important disease process. Microarray analysis demonstrated seven microRNAs (miR-106a, -146, -181, -199a, -214, -424, and -451) that were substantially increased and three microRNAs (miR-31, -150, and -184) that were substantially decreased in ischemic retina. Potential targets for the upregulated microRNAs were not identified, but bioinformatic analysis suggested target genes for the downregulated microRNAs, and these were confirmed using a luciferase reporter assay. Real-time reverse transcriptase PCR confirmed that the substantial levels of miR-31, -150, and -184 present in normal retina were significantly reduced in ischemic retina. Interestingly, constitutive levels of miR-31 and -184 are high in the cornea and lens, two avascular tissues. Intraocular injection of pre-miR-31, -150, or -184 significantly reduced ischemia-induced retinal NV, and injection of pre-miR-31 or -150 also significantly reduced choroidal NV. These data suggest that alteration of microRNA levels contributes to two types of ocular NV, and that injection or enhanced expression of microRNAs is a potential therapeutic strategy.

Ranibizumab: the evidence of its therapeutic value in neovascular age-related macular degeneration

Neovascular age-related macular degeneration (AMD) is the leading cause of severe, irreversible visual impairment in people over 60 years of age. Neovascular AMD is characterized by abnormal growth of blood vessels under the retina, specifically the macula. These vessels leak blood and fluids, damaging the retina and its photoreceptors, resulting in permanent loss of central vision. Vascular endothelial growth factor-A (VEGF-A) has been shown to play a critical role in the pathogenesis of neovascular AMD. In the US, ranibizumab, a VEGF-A blocker, is approved and indicated for the treatment of patients with neovascular AMD. To review the clinical evidence for ranibizumab in the treatment of neovascular AMD. Phase III clinical trial data have established ranibizumab as a safe and well-tolerated treatment for neovascular AMD. Monthly intravitreal injections of ranibizumab result in a statistically significantly greater proportion of patients losing <15 letters of visual acuity (VA) and statistically significant increases in the mean number of letters gained compared with controls. Anatomically, ranibizumab results in stabilization in the mean area of choroidal neovascularization (CNV) and statistically significant reductions in the mean area of leakage compared with controls. Although there is limited economic evidence available, ranibizumab therapy for neovascular AMD appears to deliver a significant degree of value gain in terms of quality of life when compared with other neovascular AMD interventions. Clinical evidence establishes ranibizumab as a first-line therapy option for virtually all treatable neovascular AMD patients. Updating neovascular AMD treatment guidelines to reflect the evidence base for ranibizumab as a preferred first-line therapy would be beneficial for physicians in making informed treatment choices and ultimately helping to ensure the best care for patients.