Effects of intravitreally injected bevacizumab on vascular endothelial growth factor in fellow eyes.

PURPOSE: Whether an intravitreal injection of bevacizumab in 1 eye will have any effect on the fellow eye has been discussed. The aim of this study was to determine the level of vascular endothelial growth factor (VEGF) in the fellow eyes after an intravitreal injection of bevacizumab in 1 eye with proliferative diabetic retinopathy. METHODS: Eight patients who had similar findings of proliferative diabetic retinopathy in both eyes were studied. Four patients had rubeosis (rubeosis group), and 4 patients did not have rubeosis (no-rubeosis group) in the anterior chamber. All patients received an intravitreal injection of bevacizumab (1.25 mg) in 1 eye. Samples of aqueous humor were collected from the injected eyes just before the injection of bevacizumab and 1 day after the first injection just before vitrectomy. Samples of aqueous humor from the fellow eyes were collected just before a second injection of bevacizumab in the fellow eye at 7 days after the first injection. The concentration of VEGF in the aqueous humor was measured by enzyme-linked immunosorbent assay. RESULTS: After 1 day, the concentration of VEGF in injected eyes was significantly reduced from 3,230.3±2,136.8 to 3.1±3.6 pg/mL (P<0.05) in eyes with rubeosis and 465.0±78.8 to 0 pg/mL (P<0.05) in those without rubeosis. After 7 days, the VEGF level of the fellow eyes was still significantly lower than that in the injected eye just before the injection of bevacizumab (688.5±443.1 pg/mL) in the rubeosis group, and it was 7.8±13.2 pg/mL in the no-rubeosis group (P<0.05). CONCLUSIONS: A single intravitreal injection of bevacizumab significantly reduced the VEGF concentrations in the aqueous humor of the fellow untreated eye. Thus, we need to be observant of the fellow eyes after a unilateral injection and also examine the patients for systemic changes.

Characteristics of age-related macular degeneration in patients with diabetic retinopathy.

PURPOSE: The purpose of this study was to determine the clinical characteristics of age-related macular degeneration (AMD) in patients with diabetic retinopathy (DR). METHODS: Retrospective, consecutive case series. Twenty-six eyes of 25 Japanese patients were studied. All patients were diagnosed as having exudative AMD with DR. Patients with no apparent DR, dry AMD, neovascular maculopathy associated with high myopia, and age <50 years were excluded. The clinical characteristics of AMD in patients with DR, e.g., gender, age, stage of DR, and type of AMD were evaluated. RESULTS: In the 26 eyes, 2 eyes (7.7%) were classified as mild nonproliferative DR (NPDR), 7 (27.0%) with moderate NPDR, 16 (61.5%) with severe NPDR and 1 eye (3.8%) with PDR. Of the 26 eyes with exudative AMD, 21 eyes (80.8%) were classified as neovascular AMD, 4 (15.4%) as polypoidal choroidal vasculopathy and 1 eye (3.8%) as a retinal angiomatous proliferation. Among the eyes with neovascular AMD, 9 eyes (42.9%) were classified as predominantly classic choroidal neovascularization (CNV). CONCLUSIONS: There is a predominance of men, neovascular AMD and predominantly classic CNV in Japanese AMD patients with DR. The exudative AMD in patients with DR may have different clinical characteristics from those without DR.

Relationship between pigment epithelium-derived factor (PEDF) and renal function in patients with diabetic retinopathy.

PURPOSE: Diabetic retinopathy and nephropathy are microvascular complications in patients with diabetes that are considered to be related. Pigment epithelium-derived factor (PEDF), a strong inhibitor of angiogenesis, is significantly elevated in the blood of diabetic patients, especially those with proliferative diabetic retinopathy (PDR). The level of PEDF in the blood, on the other hand, is reported to be low in a diabetic nephropathy. The aim of this study was to determine the relationship between PEDF and renal function in patients with diabetic retinopathy. METHODS: A total of 243 type 2 diabetic patients were studied. The relationship between the diabetic retinopathy and levels of PEDF, HbA1c, blood urea nitrogen (BUN), and creatinine were evaluated. RESULTS: The mean plasma PEDF level in patients with PDR (7.69+/-6.14 microg/ml; mean+/-standard error) was significantly higher than that of mild-to-moderate nonproliferative diabetic retinopathy (5.07+/-4.37 microg/ml, p=0.02). The level of BUN and creatinine increased significantly as the stage of diabetic retinopathy advanced. The plasma PEDF levels were significantly correlated with the levels of BUN and creatinine (r=0.54, p<0.0001; r=0.57, p<0.0001, respectively). CONCLUSIONS: The levels of plasma PEDF increases with advances in both diabetic retinopathy and nephropathy. Thus, increased levels of PEDF in the blood may indicate microvascular damages in diabetic patients and may be predictor of the progression of retinopathy and nephropathy.

Plasma concentration of pigment epithelium-derived factor in patients with diabetic retinopathy.

CONTEXT: Pigment epithelium-derived factor (PEDF) is a strong inhibitor of angiogenesis. Eyes with diabetic retinopathy have low levels of ocular PEDF; however, the PEDF levels in the blood of diabetics have still not been determined. OBJECTIVES: Our objective was to determine the plasma levels of PEDF in diabetic patients and to determine the relationship with the stage of the diabetic retinopathy. DESIGN AND SETTING: This study was designed as a cross-sectional, institutional study. PATIENTS OR OTHER PARTICIPANTS: A total of 145 Japanese were studied; 112 had type 2 diabetes mellitus, and 33 were healthy controls. INTERVENTION: There was no intervention. MAIN OUTCOME MEASURES: The plasma level of PEDF was measured by ELISA, and the stage of diabetic retinopathy was determined by ophthalmic examinations. Clinical systemic status of diabetic patients was also examined. RESULTS: The plasma PEDF level in diabetic patients (6.68 +/- 0.54 microg/ml; mean +/- sem) was significantly higher than that in controls (4.38 +/- 0.59 microg/ml, P = 0.03), and the level was especially high in patients with proliferative diabetic retinopathy (7.78 +/- 0.98 microg/ml; n = 45; P = 0.005). The gender (P = 0.03), blood urea nitrogen (P = 0.005), and triglycerides (P = 0.04) were significant and independent determinants of plasma PEDF levels in diabetic patients. CONCLUSIONS: The PEDF level in the plasma was significantly elevated in diabetic patients, especially those with proliferative diabetic retinopathy. High levels of PEDF in the plasma may be related to the progression of diabetic retinopathy.

Senescence in cultured trabecular meshwork cells.

BACKGROUND: It has been suggested that replicative senescence might be involved in the pathophysiology of age-related diseases. AIM: To study the process of senescence in trabecular meshwork (TM) cells. METHODS: Porcine TM tissues were obtained and placed in primary cultures with Dulbecco's modified Eagle's medium/Ham's F-12 medium. After 2-3 weeks, migrated and proliferated TM cells were trypsinised and cultured in serial passages, and identified with fluorescein-labelled low-density lipoprotein (DiI-Ac-LDL), a marker of TM cells. Staining for senescence-related beta-galactosidase activity was performed at population doubling level (PDL) 2, 8 and 16 at pH 6. Terminal restriction fragment (TRF) length was examined by Southern blot analysis using a (32)P-labelled telomere-specific sequence (TTAGGG)(3) at each PDL. RESULTS: DiI-Ac-LDL staining revealed that most (nearly 100%) of the cells in the culture were TM cells, which were flattened in shape and positive for senescence-related beta-galactosidase staining at PDL 16. Reduction of TRF length as a function of population doubling was also shown. CONCLUSIONS: TM cells exhibited characteristics of senescence at PDL 16 in vitro. The results demonstrated that cellular senescence may be related to the pathophysiology of primary open-angle glaucoma.

Pars plana vitrectomy with removal of posterior hyaloid face in treatment of refractory diabetic macular edema resistant to triamcinolone acetonide.

BACKGROUND: Triamcinolone acetonide (TA) has recently been used to treat diabetic macular edema (DME) but its effectiveness is limited. CASES: Three patients (three eyes) with unresolved diffuse DME who did not respond to a posterior sub-Tenon's injection of TA underwent vitrectomy. OBSERVATIONS: Intraoperatively, it was found that all of the eyes had a posterior hyaloid face that was adherent to a large area of the posterior pole retina, although this had not been detected by slit-lamp biomicroscopy or optical coherence tomography. After vitrectomy and removal of the posterior hyaloid face, there was a significant reduction in the central macular thickness of all three eyes and an improvement in the visual acuity of the patients. CONCLUSIONS: When TA treatment is not effective for DME, vitrectomy with the complete removal of the posterior hyaloid face, including removal of the internal limiting membrane, should be considered.

Trans-Tenon's retrobulbar injection of triamcinolone acetonide for diffuse diabetic macular edema.

PURPOSE: To determine whether a trans-Tenon's retrobulbar injection of triamcinolone acetonide (TA) is a safe and effective treatment for diffuse diabetic macular edema. METHODS: Thirty-nine eyes of 30 diabetic patients with persistent macular edema were treated with 20 mg of TA injection. Central macular thickness (CMT) determined by optical coherence tomography (OCT) and visual acuity were evaluated before the injection and at 1, 2, 3, and 6 months, and up to 1 year in some eyes, after the injection. RESULTS: The CMT decreased significantly from 478 +/- 129 microm (mean +/- SD) before injection to 316 +/- 102 microm at 1 month, 307 +/- 104 microm at 2 months, and 275 +/- 89 microm at 3 months after a single injection of TA. A 20% reduction of CMT from the initial value was maintained by a single injection of TA in 27 of 39 eyes (69.2%) at 3 months, in 14 of 22 eyes (63.6%) at 6 months, and in 5 of 7 eyes at 12 months. A recurrence of macular edema was observed in 10% of the eyes at 3 months, and in 22.7% at 6 months. The 17 eyes in which vitrectomy had been carried out had a more significant improvement in CMT than the eyes without vitrectomy. CONCLUSION: A 20-mg trans-Tenon's retrobulbar TA injection is a safe and effective treatment for diabetic macular edema.

[Vitrectomy for proliferative diabetic retinopathy].

PURPOSE: We reviewed the outcome of vitrectomy for proliferative diabetic retinopathy (DR) and evaluated factors affecting the final visual outcome. METHODS: We performed primary vitreous surgery for proliferative DR in 148 eyes of 118 cases in three years from July 1999 to August 2002. All cases were followed for at least 3 months. We excluded vitreous surgery for diabetic maculopathy. Ages ranged from 24 to 80 (mean 57) years. Average postoperative follow-up period was 15 months. We evaluated the stage of DR by the new Fukuda classification. RESULT: Preoperative classification consisted of BIV (54 eyes, 36%), BV (94 eyes, 64%), and BV + VI (36 eyes). Final visual acuity was improved by 2 lines or more in 102 eyes (69%), remained unchanged in 28 eyes (19%), and decreased by two lines or more in 18 eyes (12%). There was a statistical correlation between preoperative visual acuity and final visual acuity. Earlier stages of DR had better visual outcome. Compared to the surgical outcome in the 1990s, the percentage of worsened eyes decreased. CONCLUSION: Vitrectomy for proliferative DR may be beneficial if performed in the earlier stages of DR or if the patient has better visual acuity before vitrectomy.

Polypoidal choroidal vasculopathy: incidence, demographic features, and clinical characteristics.

OBJECTIVE: To clarify the incidence, demographic features, and clinical characteristics of polypoidal choroidal vasculopathy (PCV) in Japanese patients. METHODS: Consecutive patients with presumed neovascular age-related macular degeneration (AMD) who met the eligibility criteria were examined between January 1, 1999, and October 31, 2001. All patients underwent complete ophthalmologic examination and fluorescein and indocyanine green angiography. RESULTS: Among 471 eyes of 418 patients who met the criteria, 110 eyes (23%) of 100 patients were diagnosed as having PCV and 361 eyes (77%) of 318 patients as having neovascular AMD. Mean age of patients with PCV was 68.4 years, with a male preponderance (63% of patients); involvement was mostly unilateral (90% of patients), and polypoidal vascular lesions were located mainly in the macula (85% of eyes). Retinal manifestations of PCV were characterized by serous macular detachment (52% of eyes), submacular hemorrhage (30% of eyes), and retinal pigment epithelium degeneration (10% of eyes). There were few subretinal fibrovascular proliferations (7% of eyes). Mean visual acuity was 0.31 in eyes with PCV and 0.18 in eyes with AMD. The incidence of severe visual loss (0.2 or worse) was 35% in PCV and 53% in AMD. CONCLUSIONS: The incidence of PCV in Japanese patients is high, and the incidence and demographic features vary in different ethnic groups. The clinical manifestations of PCV and AMD resemble each other; however, PCV is characterized by low incidence of subretinal fibrovascular proliferation, slow progression of vascular abnormality, and minimal association with conventional choroidal neovascularization. These factors seem to lead to a more favorable visual outcome in PCV compared with neovascular AMD.

Polypoidal choroidal vasculopathy: natural history.

PURPOSE: The present study was performed to clarify the long-term natural history of polypoidal choroidal vasculopathy (PCV). DESIGN: Prospective, consecutive observational case series. METHODS: Fourteen eyes of 12 consecutive patients with PCV were prospectively followed in our clinic for at least 2 years without any treatment after a first visit to the clinic between February 1996 and November 1998. All patients underwent complete ophthalmologic examination, color fundus photography, and fluorescein and indocyanine green (ICG) angiography at regular intervals. Inclusion criteria were as follows: eyes had serous and/or hemorrhagic pigment epithelium detachment (PED) and retinal detachment in the posterior pole, and ICG angiography revealed a branching vascular network with polypoidal dilations at the terminals of the network. Exclusion criteria were as follows: other diseases such as exudative age-related macular degeneration, high myopia, angioid streaks, and presumed ocular histoplasmosis syndrome, and patients who previously underwent any ocular surgery. RESULTS: Patients were followed for mean of 39.9 months (range, 24-54 months). PCV was present in 10 (83%) men and two women and in the elderly (mean age 68.1 years), usually unilateral (83%) with vascular lesions located at the macula (93%). The PCV manifested in two patterns, exudative and hemorrhagic. In the exudative pattern, serous PED and retinal detachment were predominant at the macula. The hemorrhagic pattern was characterized by hemorrhagic PED and subretinal hemorrhage at the macula. ICG angiography revealed polypoidal choroidal neovascularization that was changeable in appearance and repeatedly grew and spontaneously regressed, but the vascular network persisted. In some eyes, a collection of small aneurysmal dilations of vessels resembling a cluster of grapes appeared and all of them had marked bleeding and leakage and worse outcome. CONCLUSION: Polypoidal choroidal vasculopathy is a long persistent chronic disease and the patients had a variable course. Fifty percent of the patients had a favorable course. In the remaining half of the patients, the disorder persisted for a long time with occasional repeated bleeding and leakage, resulting in macular degeneration and visual loss. Eyes with a cluster of grapes-like polypoidal dilatations of the vessels had a high risk for severe visual loss.

Expression of pigment epithelium-derived factor in normal adult rat eye and experimental choroidal neovascularization.

PURPOSE: Pigment epithelium-derived factor (PEDF) is a protein produced by the retinal pigment epithelial (RPE) cells. Recent studies have implicated PEDF in activities that are inhibitory to angiogenesis. In this study, the expression of PEDF was investigated in normal rat eyes and in eyes with experimentally induced choroidal neovascularization and compared with the expression of vascular endothelial growth factor (VEGF). METHODS: Choroidal neovascularization was induced by laser photocoagulation in rat eyes. At intervals of up to 2 weeks after photocoagulation, the eyes were removed and prepared for in situ hybridization and immunohistochemical study. In situ hybridization was performed with digoxigenin-labeled PEDF riboprobes. Protein expression of PEDF and VEGF was studied immunohistochemically. RESULTS: In normal adult rat eyes, PEDF mRNA was observed mainly in the corneal epithelial and endothelial cells, lens epithelial cells, ciliary epithelial cells, retinal ganglion cells, and the RPE cells. During the development of choroidal neovascularization, PEDF mRNA, PEDF protein, and VEGF protein were strongly detected in many cells within the laser lesions at 3 days after photocoagulation, after which levels gradually declined. However, PEDF was still expressed in the RPE cells that proliferated and covered the neovascular tissues at 2 weeks, whereas VEGF protein was weakly expressed in endothelial cells in choroidal neovascularization. CONCLUSIONS: PEDF is expressed in different cell types of normal rat eyes. The expression of PEDF was detected in the choroidal neovascular tissues induced by photocoagulation, and these findings suggest that PEDF may modulate the process of choroidal neovascularization.