Neurotoxic effects of GABA‐transaminase inhibitors in the treatment of epilepsy: ocular perfusion and visual performance

Abstract

Vigabatrin is a GABA (gamma-aminobutyric acid) transaminase inhibitor that elicits an antiepileptic effect by enhancing inhibitory neurotransmission in the brain. Vigabatrin has been previously associated with concentric peripheral visual field loss and visual electrophysiological abnormalities. Recently, visual function deficits of the central retina have been identified in a proportion of patients receiving vigabatrin; these include disturbances in colour perception, contrast sensitivity and short-wavelength automated perimetry. Consequently, it is suggested that vigabatrin-associated retinal toxicity is diffuse inducing subtle central visual dysfunction and more severe peripheral visual defects. Reductions in cerebral blood flow and cerebral metabolic rate for glucose occur in epilepsy patients receiving antiepileptic drug therapy. Despite the known cerebral haemodynamic alterations in epilepsy and the visual consequences of vigabatrin therapy, ocular blood flow has only recently been investigated in this group. We present findings from a series of novel investigations that identify compromised retinal microvascular perfusion and pulsatile ocular blood flow (POBF) in epilepsy patients. The reduction in POBF was exacerbated in epilepsy patients treated with vigabatrin compared to conventionally treated epilepsy patients. A number of theories are presented to explain compromised ocular blood flow in vigabatrin treated epilepsy patients, and the possibility of a GABAergic mechanism of toxicity is discussed.

Altered behavioral development in Nrf2 knockout mice following early postnatal exposure to valproic acid

“…The Nrf2 knockout mice did improve significantly over five trials to the level of the saline-treated wild type mice indicating that they can learn and swim as well as the wild type mice and therefore it appears that they do not have impairments in their motorabilities. There are reports of vision defects in individuals taking valproic acid, however it is related to long term treatment and to the GABAergic effects of valproic acid (Hosking and Hilton, 2002; Tilz et al, 2007). Since the water maze test was run 6 days after the valproic acid exposure, there is no longer GABA agonist action.…”

Vigabatrin, the GABA‐transaminase inhibitor, damages cone photoreceptors in rats

“…9,21,22 In fact, measurements of visual acuity suggested that the deficit might not be limited to the periphery. 11,22 Visual deficits were associated with decreases in amplitude of the photopic ERG, flicker ERG, and oscillatory potentials. 13,22 The light/dark ratio of standard EOG measurements also was decreased even in some patients with no detected visual field loss, suggesting it may provide an early indicator of visual dysfunction.…”

“…29 Retinal hypoxia also could occur in VGB treatment as indicated by the decrease in ocular perfusion 11 and the EOG alteration 10 representative of the relationship between the retinal pigment epithelium and photoreceptors. In this context, note that an epileptic patient (Case 3) treated with VGB and carbamazepine for 75 months had a retinal detachment before the age of 28 years, although it is unclear whether it was related to the VGB treatment.…”

“…7,9,10 Central vision dysfunction were subsequently reported. 11 In visual electrophysiology, the main change was an amplitude decrease in the photopic electroretinogram (ERG), which can be interpreted as a dysfunction of the cone photoreceptor pathway. 8,10,[12][13][14] This alteration was sometimes associated with a reduction in the scotopic ERG b-wave, suggesting additional perturbations in the rod pathway.…”

Retinal amino acid neurochemistry in health and disease

“…Altered GABA uptake or metabolism is the method used to manage a wide range of conditions, including epilepsy . One of these drugs, vigabatrin, a selective GABA‐degradation enzyme inhibitor causes permanent peripheral visual field deficits, retinal electrophysiological changes and other visual disturbances . Although the exact mechanism is unknown, the inhibited enzyme, GABA transaminase, is essential for recycling the GABA carbon skeleton (succinate) which would be an energy source for the retina .…”