Superselective intraophthalmic artery chemotherapy in a nonhuman primate model: histopathologic findings.

IMPORTANCE: We describe the histopathologic findings in a nonhuman primate (NHP) model of superselective intraophthalmic artery chemotherapy (SSIOAC), detailing ocular and orbital vascular adverse effects. OBJECTIVE: To further document, using comprehensive ocular and orbital histopathology, previously reported toxic effects observed with real-time ophthalmoscopy during SSIOAC in a NHP model. DESIGN: Comparative interventional case series. SETTING: Preclinical trial approved under the guidelines of the Institutional Animal Care and Utilization committee. PARTICIPANTS: Six adult male rhesus macaques (Macacca mulatta). INTERVENTIONS: The right eye of each NHP was treated with 3 cycles of SSIOAC using either melphalan (5 mg/30 mL) or carboplatin (30 mg/30 mL). Both eyes in each animal were enucleated 6 hours after the final procedure, before euthanasia and formalin perfusion of the NHP; we then performed orbital dissection of the arterial vasculature and optic nerves. MAIN OUTCOME MEASURES: Histopathologic examination of the eyes, optic nerves, and orbital vessels of the 6 treated NHPs. RESULTS: We found leukostasis with retinal arteriole occlusion in all treated eyes. Retinal endothelial cells stained positive for 2 inflammatory markers, intercellular adhesion molecule 1 and interleukin 8. Transmission electron microscopy revealed occlusion of the retinal vessels with ultrastructural changes in the endothelial cells and surrounding pericytes. Additional findings included nerve fiber layer infarcts, central retinal artery thrombosis, hypertrophy and occlusion of choroidal arteries with disruption of the internal elastic lamina, patchy choroidal inflammation, and birefringent intravascular foreign bodies. Orbital findings included ophthalmic artery and central retinal artery wall dissection, fracturing of the internal elastic lamina, intimal hyperplasia, and eyelid vessel damage. Optic nerves displayed hemorrhage, leukostasis, and foreign body crystallization. Control eyes, optic nerves, and orbital vessels were normal. CONCLUSIONS AND RELEVANCE: Histopathologic examination of our nonhuman primate model for SSIOAC revealed significant toxic effects in the ocular and orbital vasculature. These findings substantiate previous observations with real-time retinal imaging and parallel reported vascular toxic effects in children with retinoblastoma treated with SSIOAC.

Induction of experimental autoimmune anterior uveitis by a self-antigen: melanin complex without adjuvant.

PURPOSE: Experimental autoimmune anterior uveitis (EAAU) is an organ-specific autoimmune disease induced by immunization with bovine melanin-associated antigen (MAA) and two adjuvants (complete Freund's adjuvant and purified pertussis toxin). This study was undertaken to explore whether an adjuvant is required in the induction of EAAU. METHODS: Insoluble MAA was extracted from the bovine iris and ciliary body. Soluble bovine MAA was derived by treatment of insoluble MAA with the proteolytic enzyme, V8 protease. Lewis rats were immunized with the insoluble or soluble antigen, with or without adjuvant (complete Freund's adjuvant and purified pertussis toxin). Adoptive transfer of CD4+ and CD8+ T cells was performed to investigate the pathogenesis of EAAU. RESULTS: Experimental autoimmune anterior uveitis can be induced in Lewis rats by immunization with 100 g insoluble bovine MAA alone without the use of adjuvants. The disease can be adoptively transferred to naive syngenic rats by primed CD4+ T cells. In contrast, soluble bovine MAA was not uveitogenic unless adjuvants were employed. CONCLUSIONS: The data suggest that EAAU can be induced in the Lewis rat without addition of an adjuvant. Future studies concerning the pathogenesis of EAAU can now be performed without the possible confounding effect of an adjuvant.

Intraocular dexamethasone produces a harmful effect on treatment of experimental Staphylococcus aureus endophthalmitis.

BACKGROUND: We created a standardized model of severe Staphylococcus aureus endophthalmitis in the aphakic rabbit eye to test various treatment strategies involving corticosteroid administration in addition to vitrectomy and antibiotic treatment. MATERIALS AND METHODS: In 71 aphakic New Zealand albino rabbit eyes, experimental endophthalmitis was created by injecting 10(5) colony-forming units of Staphylococcal aureus. The animals were divided into 5 groups. One control group was followed up without treatment, while 4 groups were treated with vitrectomy and intraocular cefazolin injection. Two groups were also treated with intramuscular methylprednisolone, 1 group beginning on the day of surgery and 1 group beginning on the following day. In the final group, dexamethasone, 400 micrograms, was injected into the vitreous cavity at the close of surgery. Culture results were compared on the first 2 days after surgery. Inflammatory scores, including development of total corneal opacity, were assessed over a 21-day follow-up period, and histopathologic grading was carried out at the conclusion of the clinical observations. RESULTS: Simultaneous administration of systemic corticosteroids beginning on the day of vitrectomy decreased inflammatory scores 1 week after institution of therapy but did not affect final scores. Delay of initiation of intramuscular corticosteroid until the first postoperative day negated the positive effects. Administration of intraocular corticosteroids was associated with an increase in inflammatory scores throughout the period of observation, an increase in percentage of eyes that developed opaque corneas, an increase in choroidal inflammation graded moderate or severe, and an increase in retinal necrosis compared with vitrectomy and cefazolin injection alone. CONCLUSIONS: This data suggest caution in the use of intraocular corticosteroids in treatment of severe endophthalmitis.