Structural and functional investigations of vigabatrin toxicity

The purpose of this thesis was to investigate visual dysfunction arising from vigabatrin (VGB) toxicity: structural investigation utilising optical coherence tomography (OCT) and functional investigation using multifocal electrophysiology. OCT of the retinal nerve fibre layer (RNFL) based upon a fixed diameter circle scan and enabling reference to the manufacturers' large proprietary normative database, revealed a specific finding associated with vigabatrin-attributed visual field loss (VAVFL) namely, a characteristic pattern of nasal quadrant attenuation with a normal temporal quadrant thickness. This was present in all 11 individuals (including 2 learning-disabled adults) with VAVFL. A further 4 of 16 (including 3 learning- disabled adults and three children) VGB-exposed individuals with normal visual fields (VGB-E) also manifested this pattern as did two of three individuals (one learning-disabled adult and two children) exposed to VGB but unable to undertake perimetry. The pattern was absent in all 13 individuals treated with non-gabaergic anti-epileptic drugs manifesting normal fields and in 9 normal children. OCT is readily achievable in children as young as 3 years and in learning-disabled adults and should be essential for identifying VAVFL. A re-analysis of RNFL thickness for quadrant/sector differences by OCT and by scanning laser ophthalmoscopy (Heidelberg Retinal Tomography (HRT)) on 13 individuals with VAVFL, 8 VGB-E and 21 normal individuals previously published (Wild et al., 2006) confirmed the abnormal nasal/normal temporal pattern of attenuation. Four children, exposed to VGB in utero, from three mothers (two with VAVFL and nasal RNFL attenuation) yielded normal visual fields and RNFL thicknesses. The amplitudes and implicit times of the mfERG waveform were normal in all 5 VAVFL and in 9 VGB-E, when compared to 13 normal individuals. This suggests that neither bipolar cell nor photoreceptor cell dysfunction, respectively, is implicated in VGB toxicity. The mfVEP amplitudes were normal in all 5 VAVFL and in all 9 VGB-E, when compared to 16 normal individuals. The lack of abnormality may arise from the mismatch between cortical functional topography and the characteristics of VAVFL and the technical limitations associated with the monocular analysis of the mfVEP