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Junzo Kinoshita, Noriaki Iwata, Takanori Maejima, Tomofumi Kimotsuki, Mitsuya Yasuda; Retinal Function and Morphology in Monkeys with Ethambutol-Induced Optic Neuropathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2446.
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Ethambutol optic neuropathy is a well-recognized adverse ocular event. However, pathophysiology of the retina in ethambutol optic neuropathy is unclear. Therefore, retinal function and morphology were investigated in monkeys treated with ethambutol.
Ethambutol was orally administered to three cynomolgus monkeys at 400 to 800 mg/kg/day for a maximum of 39 weeks. Standard full-field electroretinograms (ERGs) [rod response, combined rod-cone response (standard flash), combined rod-cone response (bright flash), oscillatory potentials, single-flash cone response (white light flashes under white background light: W/W) and 30 Hz flicker] and single-flash cone responses (red light flashes under blue background light: R/B) were recorded at intervals of approximately one month. All the ethambutol-treated monkeys were euthanized, and their retinas in addition to tissues of central and peripheral nervous system, were examined histopathologically. In addition, another three cynomolgus monkeys received single intravitreal injection of tetrodotoxin (TTX), an agent that selectively blocks Na+-dependent action potentials of inner retinal neurons including the retinal ganglion cells (RGCs). The single-flash cone response (R/B) was recorded from the monkeys receiving TTX.
No obvious changes were observed in waveform of the standard full-field ERGs in any animals receiving ethambutol. On the other hand, selective attenuation of photopic negative response (PhNR) of the single-flash cone response (R/B) was observed in two out of three ethambutol-treated monkeys and all TTX-treated monkeys. Histopathology of the ethambutol-treated monkeys with decreased PhNR revealed single cell necrosis of the RGCs, decreased RGCs in parafovea and increased glial cells in the nerve fiber layer in the retina, in addition to demyelination and increased glial cells in the optic nerve, optic chiasm and optic tract. No changes were detected histopathologically in any other layers in the retina.
The change in the PhNR and histopathology of the retina indicated that RGCs were markedly impaired in terms of both function and morphology in monkeys with ethambutol-induced optic neuropathy. From the results obtained in monkeys in this study, it is suggested that RGCs are initially and predominantly affected in the retina of patients with ethambutol optic neuropathy.
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