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Shai M Bar-Sela, Shiri Zayit-Soudry, Amir Massarweh, Anat Loewenstein, Ido Perlman; Retinal Toxicity of Intravitreal Melphalan in Albino Rabbit. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):75.
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© ARVO (1962-2015); The Authors (2016-present)
Intravitreal melphalan injections at doses of 8-30µg have been successfully used for treating retinoblastoma with vitreous seeds, but there is insufficient data regarding their safety. This study was designed to evaluate the toxicity of intravitreal melphalan in a rabbit model.
Eighteen albino rabbits were treated with a single intravitreal melphalan injection (0.1ml) to the right eye (experimental eye): group 1: 5µg, n=4; group 2: 15µg, n=4; group 3: 30µg, n=5; group 4: 60µg, n=5. The left eye of each rabbit was injected with 0.1ml saline (control eye). Indirect ophthalmoscopic examination, electroretinography (ERG) and visual evoked potentials (VEP) testing were performed at baseline and periodically during 4-week follow-up. After 4 weeks the retinas were prepared for histological examination and glial fibrillary acidic protein (GFAP) immunocytochemistry. Analysis of variance for repeated measures was used for statistical analysis of the electrophysiological parameters.
Indirect ophthalmoscopy after injections revealed sclerotic retinal vessels and retinal whitening in the experimental eyes of groups 2, 3 and 4, but not in rabbits of group 1, injected with the lowest melphalan dose. Mean (±SD) dark-adapted (DA) ERG b-wave Vmax ratios (experimental eye/control eye) in groups 1-4, measured at 4-weeks after injection were 1.12±0.08, 0.77±0.20, 0.42±0.11 and 0±0, respectively, and light adapted (LA) b-wave amplitude ratios were 1.19±0.18, 0.77±0.27, 0.43±0.24 and 0±0, respectively. Thus, increasing melphalan dosage significantly predicted reduced DA b-wave Vmax ratios (p<0.013) and reduced LA b-wave amplitude ratios (p<0.026), indicating dose-dependent functional retinal damage induced by melphalan. However, similar flash VEP responses were found in experimental and control eyes of all groups, suggesting no melphalan induced functional damage to the optic nerve. Morphological studies supported the ERG findings demonstrating retinal structural damage and GFAP expression in Müller cells, at a magnitude that paralleled the ERG deficit.
Intravitreal melphalan dose of 5μg in rabbits, approximately equivalent to 10μg in human, appears to be safe to the retina. However, rabbit doses of 15μg and higher, roughly corresponding to human doses of 30μg and higher, are toxic, and their utilization for treating retinoblastoma should be executed with caution, particularly if visual potential exists.
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