Retinal Cone Toxicity in an Ovarian Cancer Patient Treated with Irofulven

Abstract

Abstract: : Purpose: Four of 19 patients at one center with platinum-resistant, advanced epithelial ovarian cancer in a phase II clinical trial using high doses of Irofulven developed signs and symptoms consistent with retinal cone dysfunction. Each complained of photophobia and reduced vision in bright light, while 3 noted various positive visual phenomena. ERG results revealed predominantly cone abnormalities. Improvement in symptoms, visual function testing, and ERG responses occurred with lower doses or cessation of Irofulven. One woman, who received cisplatin prior to entering the trial and carboplatin afterwards, developed AML 10 weeks after her visual symptoms began and died. We describe the clinical, perimetric, electroretinographic, retinal histopathology and immunocytochemistry features of this patient. Methods: The patient underwent comprehensive neuro-ophthalmic evaluation including Goldmann visual fields and electroretinography. Post mortem eyes of the patient and age matched normal human eyes were processed for histopathology and immunocytochemistry. Mouse monoclonal antibodies specific for cones and rods and a rabbit polyclonal antibody against glial fibrillary acidic protein (GFAP; specific for astrocytes and reactive Müller cells) were used. Results: The visual acuities were 20/30 and she identified 3/10 Ishihara color plates OU. Goldmann visual fields revealed dense midperipheral and paracentral scotomas. Dilated fundus examination was unremarkable and carcinoma associated retinopathy testing was negative. Two months later her vision off Irofulven was 20/30 OD; 20/25 OS and 10/10 color plates. The ERG was extinguished under bright photopic conditions and 30 Hz flicker testing revealed markedly low b-wave amplitudes and prolonged implicit times. Scotopic conditions showed prolonged implicit times and borderline b-wave amplitudes. Compared to normal retinas the patient’s retina had reduced numbers of macular cones and almost no cones in the peripheral retina. Near normal numbers of rods were present in all regions examined. Müller cells had undergone reactive gliosis and were positive for GFAP, consistent with retinal cone cell death. Conclusions: High dose Irofulven may cause cone specific retinal toxicity with relative sparing of rods.

Keywords: photoreceptors • immunohistochemistry