The Retinal Toxicity of the Antiepileptic Drug, Vigabatrin: In vivo Examination of Retinal Lesions and Pharmacological Neuroprotection

Abstract

Purpose: : The antiepileptic drug, vigabatrin, produces an irreversible constriction of the visual field with reduction in ERG amplitudes. However, it remains prescribed for infantile spasms and refractory epilepsy. In animals, retinal lesions are characterized by a retinal dysplasia. Because visual fields and ERGs are not always easy to perform in infants, we have investigated on animals whether in vivo imaging could provide a tool to follow the progression of these lesions while evaluating the efficacy of neuroprotective molecules.

Methods: : Rats were treated with vigabatrin (200mg/kg) for 65 days. Eye fundi were examined with the scanning laser microscope (SLO) under reflection or autofluorescence. Animals were then sacrificed, the eyes fixed in paraformaldehyde 4% at 4°C overnight to be embedded in OCT for cryostat sectioning after cryopreservation in different sucrose solutions.

Results: : When the retina of vigabatrin-treated rats was examined in vivo, eye fundi presented irregular patterns. Similar observations were obtained under both green and red illumination. Retinal areas presenting such modified aspects were localized preferentially in the dorsal area. This dorsal localization was consistent with histological observations showing greater retinal disorganization of the outer nuclear layer in the dorsal retina. Under autofluorescence mode, fluorescent puncta were detected in deep retinal layers consistent with the large autofluorescent bodies seen in the retinal pigment epithelium on histological sections. When neuroprotective molecules were evaluated to protect photoreceptors in vigabatrin-treated animals, these in vivo imaging techniques enabled us to follow the progression of the lesions and to predict the efficacy of the neuroprotective molecules. The efficacy of the neuroprotective molecules was then confirmed using photopic ERG measurements, quantifying both cone photoreceptor inner/outer segments and the length of disorganized retinal areas.

Conclusions: : These results demonstrate that vigabatrin-elicited retinal lesions can be monitored in vivo by imaging techniques classically used in ophthalmology clinics. These techniques could thus offer an alternative for the monitoring of retinal lesions in infants under vigabatrin therapy as well as for the future evaluation of combination therapies associating vigabatrin with a neuroprotective molecule.

Keywords: photoreceptors • pathology: experimental • inhibitory neurotransmitters