The therapeutic response of anti-vascular endothelial growth factor (VEGF) differs among individuals. According to the changes of central retinal thickness, intraretinal fluid, subretinal fluid, best corrected visual acuity and other morphological or functional manifestations after treatment, the performance of the treated eyes can be classified as optimal response, poor response and non-response. A variety of factors could account for poor or non-response to anti-VEGF, such as genomic polymorphism and specific genomic risk alleles, lesion characteristics, vitreous and macular structural abnormalities, resistance to anti-VEGF drug, and the role of pericytes and others. The common counter measures include increasing the dosage, shortening the injection interval and replacing with another alternative drug, inhibition of pericytes, relieving vitreomacular anatomical abnormalities. It is still worthy of further exploration that how to assess individual reasons for non-response, so that we can give proper treatment to reduce the excessive use of anti-VEGF drugs and improve the clinical management of ocular neovascularization diseases.
Objective To explore the inhibitory effects of r-k4k5 on retinal neovascularization. Methods Eighty-eight one-week-old C57BL/6J mice were put into the environment with 75% oxygen for 5 days to establish models of vascular proliferation retinopathy. One eye of each mouse received an intravitreal injection of 500 ng of r-k4k5 (large-dosage group) and of 250 ng of r-k4k5(small-dosage group), and the same volume of BSS was injected into the other eye of the mice both in these two groups as a control. The ADPase histochemical staining was used for retinal flatmount to observe changes of retinal vessels. The inhibitory effects of r-k4k5 on retinal neovascularization were evaluated by counting the endotheliocyte nuclei of new vessels extending from retina to vitreous in the tissue-slice. Results Regular distributions and reduced density of retinal blood vessels in eyes in the treatment group were found in retinal flatmount. The number of the endotheliocyte nuclei of new vessels extending from retina to vitreous was less in the eyes in the treatment group than which in control group (Plt;0.001). The nuclei of new blood vessels in the large-dosage group were less than which in small-dosage group (Plt;0.001). No histologic evidence of retinal toxicity or inflammatory response was found in the tissue-slice after the injection of r-k4k5. Conclusions Retinal neovascularization can be inhibited by intravitreal injection of r-k4k5,which suggests that intravitreal injection of r-k4k5 may have potential therapeutic benifits in retinal vascular disease. (Chin J Ocul Fundus Dis，2003，19：121-124)
ObjectiveTo observe the clinical effect of prolonged photodynamic therapy (PDT) irradiation time combined with intravitreal injection of ranibizumab in the treatment of circumscribed choroidal hemangioma (CCH).MethodsA retrospective clinical study. From March 2012 to March 2018, 51 eyes of 51 patients diagnosed in Shenzhen Eye Hospital were included in the study. Among the patients, the tumor of 36 eyes were located in macular area, of 15 eyes were located outside macular area (near center or around optic disc). All patients underwent BCVA, color fundus photography, FFA, ocular B-scan ultrasonography and OCT examinations. The BCVA examination was performed using the international standard visual acuity chart, which was converted into logMAR visual acuity. OCT showed 48 eyes with macular serous retinal detachment. of 36 eyes with tumor located in macular area, the logMAR BCVA was 0.05±0.05, the tumor thickness was 4.5±2.2 mm, the diameter of tumor was 9.7±3.6 mm. Of 15 eyes with tumor located outside macular area, the logMAR BCVA was 0.32±0.15, the tumor thickness was 3.8±1.4 mm, the diameter of tumor was 7.7±1.9 mm. PDT was performed for all eyes with the irradiation time of 123 s. After 48 h, all patients received intravitreal injections of 0.5 mg ranibizumab (0.05 ml). At 1, 3 and 6 months after treatment, the same equipment and methods before treatment were used for related examination. BCVA, subretinal effusion (SRF), tumor leakage and size changes were observed. BCVA, tumor thickness and diameter before and after treatment were compared by t test.ResultsAt 6 months after treatment, the tumor was becoming smaller without scar formation. FFA showed that the blood vessels in the tumor were sparse compared with those before treatment, and the fluorescence leakage domain was reduced. OCT showed 43 eyes of macular serous detachment were treated after the combined treatment. The logMAR BCVA were 0.16±0.15 and 0.55±0.21 of the eyes with tumor located in or outside macular area, respectively. The difference of logMAR BCVA between before and after treatment was significant (t=－2.511, －2.676; P=0.036, 0.040). Both the tumor thickness (t=3.416, 3.055; P=0.011, 0.028) and diameter (t=4.385, 4.171; P=0.002, 0.009) of CCH patients were significantly reduced compared with that before treatment.ConclusionThe tumor of CCH can be reduced by prolonged PDT irradiation time combined with intravitreal injection of ranibizumab.
ObjectiveTo investigate the efficacy of laser photocoagulation and intravitreal ranibizumab treatment of retinopathy of premature(ROP). MethodsThis study included 49 ROP infants (96 eyes), including type 1 pre-threshold ROP (7 infants, 14 eyes), threshold ROP (38 infants, 44 eyes) and aggressive posterior ROP (AP-ROP, 4 infants, 8 eyes). According to the treatments received, all patients were divided into laser photocoagulation (LP) group (40 infants, 78 eyes) and intravitreal ranibizumab (IVR) treatment group (9 infants, 18 eyes). Generally, zoneⅡand stage 3 ROP with clear refractive media received laser photocoagulation, zoneⅠROP and AP-ROP, or eyes with unclear refractive media or infants with poor general condition received IVR. The infant gestational age, birth weight, corrected gestational age at first treatment and the cure rate of the first treatment were analyzed between the two groups, and between three disease types (type 1 pre-threshold, threshold and AP-ROP). ResultsThe gestational age and birth weight was no difference between the LP group and IVR group (t=0.827, 1.911; P > 0.05). The corrected gestational age at first treatment of LP group was significantly smaller than that in the IVR group (t=3.041, P < 0.05). In the LP group, 75 of 78 eyes (96.15%) was cured by the first treatment, 3 of 78 eyes (3.85%) progressed to stage 4A after the first treatment and was controlled by vitrectomy. In the IVR group, 8 of 18 eyes (44.44%) was cured by the first treatment, 10 of 18 eyes (55.56%) progressed to next stage after the first treatment and was controlled by additional laser photocoagulation or repeated IVR. The gestational age and birth weight was no difference between type 1 pre-threshold, threshold and AP-ROP infants (t=2.071, 0.664; P > 0.05). The corrected gestational age at first treatment of type 1 pre-threshold infants was the same of the threshold lesion infants (t=2.054, P > 0.05). The corrected gestational age at first treatment of AP-ROP infants was significantly smaller than that of type 1 pre-threshold and threshold lesion infants (t=3.250, P < 0.05). The cure rate was statistically significant (χ2=24.787, P < 0.05) between there three ROP lesions. ConclusionIVR treatment is suitable for zoneⅠlesions, AP-ROP and Plus lesions, while laser photocoagulation is appropriate for zoneⅡlesions with fibrosis and less vascular proliferation.
For choroidal neovascularization (CNV) secondary to pathological myopia, intravitreal injection of anti-VEGF has been widely used in clinic and achieved good outcome. However, due to the differences in the demographic characteristics, stages of disease progression and treatment procedure of CNV, the prognosis of the disease is variable. Complete ellipsoid band, smaller baseline choroidal neovascularization and better baseline vision are important predictors of good outcome of anti-vascular endothelial growth factor treatment. Chorioretinal atrophy or complications related to pathologic myopia indicate a poor prognosis. The influence of age, race, previous photodynamic therapy and early treatment on the prognosis of treatment need to be further studied.
Intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) drugs, including monoclonal antibodies (such as bevacizumab and ranibizumab) and fusion protein agents (such as aflibercept and conbercept) have been proven to be effective in the treatment of wet age-related macular degeneration (wAMD). However, there are still some patients with poor efficacy, such as no response to initial treatment or poor response, and even relapse during the course of treatment. In view of the different targets and molecular characteristics of anti-VEGF drugs, the switch of anti-VEGF drugs and the adjustment of delivery pattern, dosages and intervals have been the strategies to cope with the poor efficacy in clinic. However, there are some differences in the results of current studies. Overall, the recovery of retinal anatomical outcome achieves more benefits, and it is relatively difficult to improve visual acuity. To determine which regimen would get the biggest benefits, a large number of randomized controlled clinical trials and long study period will be needed.
Objective To observe the inhibitory effects and characteristics of intravitreal injection with bevacizumab on laser induced choroidal neovascularization (CNV).Methods Twelve male brown norway（BN）rats were divided into the bevacizumab group and control group with six rats in each group. One eye of rats were received a series of 8 diode laser esions around optic disc to induce CNV,then the rats in bevacizumab group and control group underwent intravitreal injection with 2 mu;l bevacizumab and ringer's lactate.On days 7,14,and 21，the morphology and leakage of CNV were observed by fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA).On day 21 after photocoagulation,the photocoagulated eyes were enucleated and processed for histopathologic examination, including hematoxylin and eosin (Hamp;E) staining and immunohistochemistry staining for vascular endothelial growth factor（VEGF）.Results On day 7 after photocoagulation,ICGA showed that CNV developed in the bevacizumab group and the control group. FFA showed that leakage intensity in the bevacizumab group was significantly lower than that in the control group，but the bevacizumab group gradually increased over time. The mean thickness of CNV significantly decreased in the bevacizumab group.The CNV in the bevacizumab group were negative for VEGF according to the result of immmuohistochemistry staining.Conclusions Early intravitreal injection with 2 mu;l bevacizumab can reduce the thickness of CNV and inhibit the leakage of CNV. However, bevacizumab could neither block the formation of CNV, nor suppress the permeability permanently. Combined other therapies with bevacizumab may be more potential to treat CNV effectively.
Objective To observe the effects of intravitreal injection of conbercept for aggressive posterior retinopathy of prematurity (AP-ROP). Methods It is a retrospective case study. Twenty-one patients (40 eyes) with AP-ROP were enrolled in this study. There were 9 males (18 eyes) and 12 females (22 eyes), with the mean gestational age of (28.30±1.79) weeks and the mean birth weight of (1 021.40±316.70) g. All the lesions of 40 eyes were located in posterior zone, with 24 eyes in zone I and 16 eyes in zone II. All the eyes were treated with intravitreal injection of conbercept 0.025 ml (0.25 mg). During follow-up, nonresponders or patients with deterioration were retreated with intravitreal injection of conbercept or photocoagulation; patients with progressive deterioration to stage 4 had received vitrectomy. At the 1, 2, 4, 8, 12, 16, 20, 24 weeks after treatments, the disappearance or decrease of retinal vessel tortuosity and neovascularization, and the growth of the normal retinal vessels toward the peripheral retina were evaluated. Results Thirty-six eyes were cured for only one injection, the cured rate was 90.00%. However, 2 eyes (5.00%) had progressed to stage 4 with contractive retinal detachment, which underwent vitrectomy. Two eyes (5.00%) had received twice injections, whose remaining avascular zone area treated by photocoagulation. No major systemic or ocular complications after injection appeared. All lens remained transparent and no iatrogenic retinal hole was occurred during the follow-up. Conclusion Intravitreal injection of conbercept is effective in the treatment of AP-ROP.
ObjectiveTo investigate the efficacy and safety of traditional laser photocoagulation, laser combined with intravitreal injection of anti-vascular endothelial factor (anti-VEGF) drugs and intravitreal injection of anti-VEGF drugs alone in Coats disease. MethodsThe patients diagnosed as Coats disease stage 2B-3A2 in Department of Ophthalmology, Eye and ENT Hospital of Shanghai Medical College of Fudan University from December 2016 to November 2019 were included in this study. Patients were divided into three groups, including laser group, combined group and drug group, according to the different treatment. In the laser group, the initial treatment was traditional laser photocoagulation alone. In the drug group, the anti-VEGF drug was injected into vitreous once a month for three months. The initial treatment of the eyes in the combined group was laser combined with intravitreal injection of anti-VEGF drugs, or laser treatment within 1 week after anti-VEGF drug treatment. The follow-up time was more than 6 months, and best-corrected visual acuity (BCVA), ultra-wide-angle fundus photography, and fluorescein fundus angiography were performed during follow-up. The treatment efficiency, subretinal fluid (SRF), macular edema, BCVA and complications were compared among the three groups. ResultsAmong 60 patients (60 eyes), there were 55 males (55 eyes) and 5 females (5 eyes), with the mean age of 17.1±2.0 years. Among 60 eyes, there were 26 eyes in 2B stage, 23 eyes in 3A1 stage, and 11 eyes in 3A2 stage. Twenty patients (20 eyes) was in the laser group, combined group and drug group, respectively. After the initial treatment of all eyes in the drug group, the abnormal blood vessels did not regress significantly; the absorption and increase of SRF were 4 (20.0%, 4/20) and 5 (25.0%, 5/20) eyes, respectively. Supplementary laser therapy was given to 16 eyes, and vitrectomy (PPV) was given to 4 eyes. Among the 16 eyes treated by laser, 10 eyes were effective (50.0%, 10/20); vitreous hemorrhage, fibrous membrane hyperplasia, and complicated cataract occurred in 1, 1, and 2 eyes during the treatment, respectively, and PPV was given again in all eyes. Recurrent and persistent macular edema occurred in 4 and 1 eyes, respectively. Among the eyes in the combined group, treatment were effective in 11 eyes (55.0%, 11/20); 5, 2, and 2 eyes had SRF, fibrous membrane hyperplasia, and complicated cataract during the treatment, and PPV was given again; the edema was repeated and persisted in 1 eye, respectively. Among the affected eyes in the laser group, 15 eyes (75.0%, 15/20) were treated effectively; 2, 2, and 1 eyes developed a large number of vitreous hemorrhage, fibrous membrane hyperplasia, and complicated cataract during the treatment, and PPV was given again. ConclusionsAnti-VEGF drugs alone are ineffective in the treatment of Coats disease, and ablation of other abnormal blood vessels is needed. In the treatment of Coats disease, anti-VEGF drugs can not only promote the absorption of SRF, but also may lead to its increase, and the application should be cautious.
Wet age-related macular degeneration (wAMD) is caused by choroidal neovascularization (CNV), which occurs when the choroidal new capillaries reach the RPE layer and photoreceptor cell layer through the ruptured Bruch membrane, leading to neovascularization bleeding, leakage, and scarring. In view of the important role of VEGF in the development of CNV, targeted therapy with various intraocular anti-VEGF drugs is the first-line treatment for wAMD. However, the efficacy of anti-VEGF drugs in the treatment of wAMD is affected by a variety of factors, and some patients still have problems such as unresponsiveness, drug resistence, tachyphylaxis, long-term repeated injections, and severe adverse effects. It is the direction of future researches to deeply explore the physiological and pathological process of wAMD, find the cause of CNV formation, and seek better therapies.