Retinal Function in Rabbits Does Not Improve 4–5 Months after Terminating Treatment with Vigabatrin

Abstract

Kjellström 2Keywords: Vigabatrin, electroretinogram, immunohistochemistry, drug toxicity. AbstractPurpose: We have previously reported changes in retinal function and histopathology in rabbits treated with vigabatrin. The purpose of the present study was to evaluate retinal function and histopathology of retina in rabbits 4-5 months after terminating vigabatrin medication. Methods: Five rabbits were treated with a daily per oral dose of vigabatrin during 12-13 months. After terminating treatment an observation period of 4-5 months followed. Six rabbits receiving water served as controls. Standardized full-field electroretinograms were performed every 6-8 weeks, using a Burian-Allen bipolar contact lens. After 18 months the rabbits were sacrificed and the morphology of the sectioned retina was studied. The antibodies used for staining were GABA, GFAP, GAD, and vimentin. Results: After 12-13 months of treatment full-field ERG was reduced in all rabbits treated with vigabatrin. There was a statistically significant difference in the dark adapted cone b-wave amplitude between treated animals and controls (Wilcoxon signed ranks test, p=0.043). This difference was consistent also 4-5 months after terminating treatment. Immunohistology of the sectioned retina demonstrated no significant difference in immunoreactivity between treated animals and controls. All treated rabbits demonstrated elevated serum concentration of the drug during medication. Conclusion: Four to five months after terminating treatment with vigabatrin the rabbit full-field ERG remains reduced in isolated cone bwave amplitude indicating that vigabatrin induced retinal dysfunction may be irreversible. However, immunohistology is normal after a period without treatment, implying that the previously described changes in retinal morphology and glial cell activity are reversible, and probably exist only during treatment.

Dose-related changes in retinal function and PKC-alpha expression in rabbits on vigabatrin medication

“…In the present study, OPs were decreased in both high-dose and low-dose rabbits, reflecting disturbances in inner retinal function, in accordance with several clinical studies revealing OP alterations [11,13,18,19,23,[25][26][27][28]. b-wave amplitudes derived from the isolated cone responses both in rabbits [37,38] and humans [16,49], a well-known phenomenon in VGB treatment [11, 13, 16, 18-20, 22-25, 49],which also has been described in rats [39]. One drawback of the present study is that these results were not repeated.…”

“…In other studies [9,10,14,15,17,23,35,36], however, neither maximal daily dose nor cumulative dose or length of medication have been correlated to visual field defects or ff-ERG alterations. In prior pilot studies [37,38], we have shown ff-ERG alterations and, occasionally, glial reactions of the retina [37] in rabbits treated with vigabatrin. Similar results are shown by Duboc et al [39], revealing ff-ERG alterations and morphological changes in Müller cells in rats.…”

“…In our first studies, the Burian-Allen lens was used to mimic human ff-ERG measurements, though in this investigation we have applied a gold lens electrode (Doran, Littleton, MA, USA), since it gave more stable implicit times and no double curves of the 30 Hz flicker ERG, phenomena which are previously described for the Burian-Allen lens [41]. Another parameter differing between our previous studies [37,38] and the present one is the lack of significant disturbances of rod-derived rod ff-ERG amplitudes in the previous studies. The reason for this could be a smaller sample size, since the rod-derived amplitudes of the ff-ERG always have a wider range, making it more difficult to gain significance for this parameter in small materials.…”

“…The discrepancy of doses between the studies is due to different aims of the treatment. In our first studies [37,38] the aim was to give the rabbits as high VGB doses as possible, constantly titred to the highest dose tolerated. In the present study, on the other hand, we wanted all rabbits in the same group to receive identical VGB doses, enabling comparison of the reactions to two different doses, and since some specimens are more sensitive to the medication than others, doses had to be generally lower.…”

A new strategy to replace the natural vitreous by a novel capsular artificial vitreous body with pressure-control valve

“…Electroretinograms were obtained in rabbits at 8 weeks with a full-field dome method similar to clinical electroretinography (ERG) 19 methods specified by the International Society for Clinical Electrophysiology of Vision (ISCEV) standard. 20 The eyes were dilated with 0.5% tropicamide and dark-adapted for at least 30 min.…”