Ocular function and morphology in humans and rabbits exposed to vigabatrin medication

Abstract: Vigabatrin is an antiepileptic drug that is known to cause visual field defects and retinal dysfunction measured by full-field electroretinography (ff-ERG). Underlying mechanisms have not yet been elucidated. The aims of this thesis were to investigate parameters of vigabatrin treatment; reversibility of visual dysfunction, prevalence of retinal dysfunction in children, role of drug-dose and evaluation of alternative methods for follow-up. A translational approach was applied, investigating issues in an experimental rabbit model and in clinical investigations. Reversibility of reduced retinal function was studied in our rabbit model, showing reduced cone function both during treatment and after withdrawal of medication. No changes in immuno labelling patterns of vimentin, glial fibrillary acidic protein (GFAP), γ-aminobutyric acid (GABA) and GAD (glutamic acid decarboxylase) were found. Re-evaluation of visual field defects and retinal function in patients five years after withdrawal of vigabatrin demonstrated irreversible reduction of the isolated rod and cone function and the combined rod-cone function. Also the 30 Hz flicker implicit time was altered. Indications of progressive decline of the combined response were observed. No changes in visual fields were found. In the rabbit model, dose-related changes of retinal function (rod, combined rod-cone and oscillatory potentials, OPs) and expression of proteins were found. In rod bipolar cells, protein kinase C-α (PKC- α) labelling showed a reduced number of labelled cells and translocation of enzyme activity. Müller cells showed deviant vimentin labelling. In children, vigabatrin medication was associated with reduced rod and cone function. Alterations of cone responses were found in 24% of treated children. Young children were affected more often, showing reduced retinal function in 33% of the subjects. The younger group had received higher daily drug-doses and had started medication at younger age than the older group. No differences were found concerning cumulative drug-doses. Alternative methods for detection of vigabatrin toxicity were tested, indicating that attenuation of the retinal nerve fibre layer (RNFL) can be detected with optical coherence tomography (OCT) in patients with vigabatrin-attributed visual field defects and ff-ERG alterations. Correlations between RNFL thickness and reduced ff-ERG amplitudes were found. Multi focal visual evoked potentials (mfVEP) were not useful.