Tetsuo Hida

VEGF164-mediated Inflammation Is Required for Pathological, but Not Physiological, Ischemia-induced Retinal Neovascularization

Hypoxia-induced VEGF governs both physiological retinal vascular development and pathological retinal neovascularization. In the current paper, the mechanisms of physiological and pathological neovascularization are compared and contrasted. During pathological neovascularization, both the absolute and relative expression levels for VEGF164 increased to a greater degree than during physiological neovascularization. Furthermore, extensive leukocyte adhesion was observed at the leading edge of pathological, but not physiological, neovascularization. When a VEGF164-specific neutralizing aptamer was administered, it potently suppressed the leukocyte adhesion and pathological neovascularization, whereas it had little or no effect on physiological neovascularization. In parallel experiments, genetically altered VEGF164-deficient (VEGF120/188) mice exhibited no difference in physiological neovascularization when compared with wild-type (VEGF+/+) controls. In contrast, administration of a VEGFR-1/Fc fusion protein, which blocks all VEGF isoforms, led to significant suppression of both pathological and physiological neovascularization. In addition, the targeted inactivation of monocyte lineage cells with clodronate-liposomes led to the suppression of pathological neovascularization. Conversely, the blockade of T lymphocyte–mediated immune responses with an anti-CD2 antibody exacerbated pathological neovascularization. These data highlight important molecular and cellular differences between physiological and pathological retinal neovascularization. During pathological neovascularization, VEGF164 selectively induces inflammation and cellular immunity. These processes provide positive and negative angiogenic regulation, respectively. Together, new therapeutic approaches for selectively targeting pathological, but not physiological, retinal neovascularization are outlined.

Experimental and Clinical Observations of the Intraocular Toxicity of Commercial Corticosteroid Preparations

We tested the vehicles of six different commercially available depot corticosteroids (Celestone Soluspan, Depo-Medrol, Decadron, Decadron L. A., Aristocort, and Kenalog) for possible toxicity when injected intravitreally. When tested on rabbit eyes, the Celestone Soluspan and the Depo-Medrol vehicles caused remarkable retinal degeneration with preretinal membrane formation or cataracts in their standard concentrations. Three other vehicles (Decadron and Decadron L. A.) caused localized retinal degeneration in twice the standard concentration. Thus, toxic effects can be caused by preservatives or inadequate osmolarity of the vehicles alone. The development of proliferative vitreoretinopathy in some cases of injections of intraocular depot corticosteroid can be explained by retinal necrosis and repair processes caused by these vehicles.

Leukocytes mediate retinal vascular remodeling during development and vaso-obliteration in disease

Retinal ischemia can cause vision-threatening pathological neovascularization. The mechanisms of retinal ischemia are not fully understood, however. Here we have shown that leukocytes prune the retinal vasculature during normal development and obliterate it in disease. Beginning at postnatal day 5 (P5) in the normal rat, vascular pruning began centrally and extended peripherally, leaving behind a less dense, smaller-caliber vasculature. The pruning was correlated with retinal vascular expression of intercellular adhesion molecule-1 (ICAM-1) and coincided with an outward-moving wave of adherent leukocytes composed in part of cytotoxic T lymphocytes. The leukocytes adhered to the vasculature through CD18 and remodeled it through Fas ligand (FasL)-mediated endothelial cell apoptosis. In a model of oxygen-induced ischemic retinopathy, this process was exaggerated. Leukocytes used CD18 and FasL to obliterate the retinal vasculature, leaving behind large areas of ischemic retina. In vitro, T lymphocytes isolated from oxygen-exposed neonates induced a FasL-mediated apoptosis of hyperoxygenated endothelial cells. Targeting these pathways may prove useful in the treatment of retinal ischemia, a leading cause of vision loss and blindness.

Tuberculin skin testing in uveitis patients and treatment of presumed intraocular tuberculosis in japan

PURPOSE To evaluate the results of tuberculin skin testing in Japanese patients with intraocular inflammation and to assess the outcome of treatment for presumed intraocular tuberculosis in selected patients. DESIGN Prospective, noncomparative, interventional case series. PARTICIPANTS One hundred twenty-six patients, newly referred to the Ocular Inflammation Service at the Kyorin Eye Center from April 1998 to August 2000, underwent systemic evaluation for the diagnosis and/or treatment of uveitis. METHODS Tuberculin skin testing with purified protein derivative was performed as part of the systemic evaluation. The diagnosis of presumed intraocular tuberculosis was made when findings were consistent with possible intraocular tuberculosis, the tuberculin skin test was positive (induration more than 10 mm), and no other cause of uveitis was suggested by symptoms, signs, or ancillary testing. Using these criteria, 10 patients were given a diagnosis of presumed intraocular tuberculosis and treated with antituberculosis therapy consisting of isoniazid, with or without rifampicin. Some of these patients also received a tapered course of oral corticosteroids after the initiation of antituberculosis treatment. None of the patients had any signs or symptoms of acquired immunodeficiency syndrome. MAIN OUTCOME MEASURES Visual acuity and ophthalmologic examination to assess degree of intraocular inflammation. RESULTS Twenty-six of the 126 patients (20.6%) had a positive tuberculin skin test result. Ten of these 26 patients (38.5%) were treated for a diagnosis of presumed intraocular tuberculosis. Nine patients had no evidence of pulmonary tuberculosis, and one patient had presumed tuberculous hilar lymphadenitis. The predominant clinical finding was choroidal or optic disc nodule in three patients, retinal vasculitis in three patients, and choroiditis in four patients. Nine patients exhibited decreased intraocular inflammation with treatment. CONCLUSIONS Roughly one fifth of the uveitis patients who underwent systemic evaluation had a positive tuberculin skin test result, and 9 of 10 selected skin test-positive patients with clinical findings consistent with intraocular tuberculosis had a favorable response to antituberculosis therapy. These results suggest that intraocular tuberculosis continues to be a major diagnostic consideration for uveitis patients in Japan.

Comparison of scleral buckling and vitrectomy for retinal detachment resulting from flap tears in superior quadrants.

PURPOSE To compare the surgical results of vitrectomy and scleral buckling for uncomplicated superior retinal detachment caused by flap tears. METHODS Included in the study were 225 patients (225 phakic eyes) undergoing primary surgery by three surgeons between January 1990 and December 1996 for superior retinal detachment caused by flap tears (138 eyes by scleral buckling, 87 eyes by vitrectomy); all patients had been followed up for longer than 6 months after surgery. The choice of one of the two procedures was based on each surgeons preference. The surgical outcome and the rate of complications were retrospectively compared between the two groups of eyes. RESULTS Initial and final anatomical success rate were 92% and 100% after each procedure. Retinal redetachment after the initial procedure was due to new retinal breaks in 5 eyes, reopening of original breaks in 2 eyes of vitrectomy cases, and due to malpositioned buckle in 11 eyes of scleral buckling cases. Proliferative vitreoretinopathy occurred in 3 eyes of vitrectomy cases. CONCLUSION Primary vitrectomy was as successful as scleral buckling for treating superior rhegmatogenous retinal detachment. Even though the high incidence of postoperative cataract formation was the major drawback, vitrectomy had some advantages over scleral buckling.

Trans-Tenon’s retrobulbar triamcinolone infusion for the treatment of uveitis

Aim: To assess efficacy and complications of trans-Tenon’s retrobulbar infusion of triamcinolone acetonide for posterior uveitic inflammation. Methods: Non-randomised, uncontrolled, retrospective study of 51 eyes of 37 patients who underwent triamcinolone infusion for vitritis, cystoid macular oedema (CMO), or posterior retinal vasculitis using a long blunt cannula via an incision made through conjunctiva and Tenon’s capsule. Results: Overall clinical efficacy was 86%; 96% for vitritis, 82% for CMO, and 33% for posterior retinal vasculitis. Mean visual acuity improved within 1 month after triamcinolone infusion (p <0.05). Cataract progression and intraocular pressure elevation were observed in 31% and 27% of eyes, respectively. Conclusion: Trans-Tenon’s retrobulbar triamcinolone infusion may be a safe and effective treatment for posterior uveitic inflammation.

Improvement in efficacy of corticosteroid therapy in an animal model of proliferative vitreoretinopathy by pretreatment.

Intraocular injection of the corticosteroid triamcinolone acetonide reduces the incidence of retinal detachment in rabbit eyes injected with tissue-cultured fibroblasts. When the steroid was injected simultaneously with the cells, a reduction of retinal detachment from 93% (control) to 75% (treated) was achieved on day 28. When the steroid was injected 24 h preceding cell injection, the reduction of retinal detachment was from 85% (control) to 43% (treated). The development of retinal detachment is caused by proliferation of injected fibroblasts. Reduction of this proliferation is probably achieved partially through direct inhibition of mitosis, but more important may be the reduction of the reactive inflammatory process.

Temperature-Dependent Light Damage to the Retina

We examined the ability of hypothermic infusion fluid to reduce the risk of light damage to the retina from the intraocular fiberoptic probe during vitreous surgery. Following vitrectomy, we exposed the retina of rabbits to light from an intraocular fiberoptic probe during infusion of fluid at body temperature (39 C) and compared this with exposures during infusion of room temperature fluid (22 C). Retinal irradiance was 0.33 W/cm2. Damage was determined ophthalmoscopically and histologically. Cooling the infusion fluid from body to room temperature extended the damage threshold from approximately 25 to 60 minutes. A 35-minute exposure to body temperature fluid was compared with the same exposure during infusion of room temperature fluid. While retinal and retinal pigment epithelium damage was present after the body temperature exposure, no damage was detected after the room temperature exposure. Vitreoretinal surgeons should avoid warming intraocular infusion fluids to levels above room temperature.

Vitrectomy for myopic posterior retinoschisis or foveal detachment.

PurposeTo evaluate the efficacy of vitrectomy for posterior retinoschisis (RS) or foveal detachment (FD) associated with posterior staphyloma in myopic eyes.MethodsWe reviewed the records of 14 consecutive patients (53–77 years of age; 16 eyes) with progressive visual impairment as a result of myopic RS or FD. Optical coherence tomography demonstrated the presence of a variety of RS and FD characteristics. Five eyes had RS alone, and 11 eyes had RS and FD. Two eyes with RS and severe FD developed retinal detachment in conjunction with a tiny macular hole. Vitrectomy, including posterior vitreous separation in all eyes and internal limiting membrane (ILM) peeling in six eyes, had been performed. The patients were followed postoperatively for 6 to 66 months (mean, 24 months). The anatomical outcome and visual acuity were retrospectively analyzed in this study.ResultsAlthough the two eyes with RS and severe FD developed retinal detachment with a macular hole after an initial vitrectomy, final retinal reattachment was achieved in all 16 eyes. Visual acuity improved in nine eyes and remained unchanged in seven eyes.ConclusionsVitrectomy with posterior vitreous separation is effective for reattaching the macula and preventing a deterioration of vision, although eyes with RS and severe FD may be at risk for the development of a macular hole after the initial vitrectomy. Jpn J Ophthalmol 2006;50:53–61

Retinal toxicity of cyanoacrylate tissue adhesive in the rabbit.

N-butyl-2-cyanoacrylate tissue adhesive was injected into the preretinal space of rabbit eyes to study potential toxicity to the retina. Application of 3.3-10.0 ul of cyanoacrylate tissue adhesive showed localized but definite retinal toxicity. White halos appeared surrounding the preretinal cyanoacrylate immediately after injection with a gradual evolution of the white areas into pigmentary scars by 1 month. Histological examination confirmed severe focal necrosis of the retina. No identifiable distant toxic effects or electrophysiologic changes were observed during the 6-month follow-up period.