Some long-term outcomes of visual dysfunction arising from vigabatrin ocular toxicity

The purpose of this thesis was to assess long-term outcomes of the visual dysfunction arising from the ocular toxicity associated with the anti-epileptic drug vigabatrin (VGB). The risk of vigabatrin-associated visual field loss (VAVFL) with increasing exposure to VGB was modelled from retrospectively collected data from a cohort of 147 individuals (median exposure 7.9 years; IQR 3.6, 11.0). The modelled frequency of VAVFL increased with increasing exposure and plateaued at 75-80% after approximately 6 years duration and 5kg cumulative dose. The relationship between the numbers of retinal ganglion cell soma and axons, derived by standard automated perimetry and time-domain optical coherence tomography (TDOCT), respectively, was evaluated in 24 individuals with VAVFL and in 16 exposed to vigabatrin but with normal fields (VGBN). A strong linear association was present between the two outcomes, which was suggestive of an optic neuropathy, and was similar to the association for a control group of 18 individuals with open angle glaucoma. A follow-up visual field, after a median interval of 7.0 years (IQR 6.5, 7.6) was determined in 19 individuals with VAVFL and in 8 with VGBN, after a median withdrawal from VGB of 7.1 years (IQR 5.4, 8.4). No consistent trend was noted for either a deterioration or improvement in the field. A follow-up scan of the peripapillary retinal nerve fibre layer (RNFL) thickness, by TDOCT, after a median interval of 6.5 years (IQR 5.8, 6.9) was obtained in 13 individuals with VAVFL and in 4 with VGBN, after a median withdrawal from VGB of 8.0 years (IQR 5.3, 10.2). No consistent trend was noted for either a deterioration or improvement of the RNFL thickness. The macular thickness was evaluated by TDOCT in 32 individuals with VAVFL and in 14 with VGBN. No difference in thickness was noted between the two groups

The topographical relationship between visual field loss and peripapillary retinal nerve fibre layer thinning arising from long-term exposure to vigabatrin

Background The antiepileptic drug vigabatrin is associated with characteristic visual field loss (VAVFL) and thinning of the peripapillary retinal nerve fibre layer (PPRNFL); however, the relationship is equivocal. Objective The aim of this study was to determine the function–structure relationship associated with long-term exposure to vigabatrin, thereby improving the risk/benefit analysis of the drug. Methods A cross-sectional observational design identified 40 adults who had received long-term vigabatrin for refractory seizures, who had no evidence of co-existing retino-geniculo-cortical visual pathway abnormality, and who had undergone a standardized protocol of perimetry and of optical coherence tomography (OCT) of the PPRNFL. Vigabatrin toxicity was defined as the presence of VAVFL. The function–structure relationship for the superior and inferior retinal quadrants was evaluated by two established models applicable to other optic neuropathies. Results The function–structure relationship for each model was consistent with an optic neuropathy. PPRNFL thinning, expressed in micrometres, asymptoted at an equivalent visual field loss of worse than approximately − 10.0 dB, thereby preventing assessment of more substantial thinning. Transformation of the outcomes to retinal ganglion cell soma and axon estimates, respectively, resulted in a linear relationship. Conclusions Functional and structural abnormality is strongly related in individuals with vigabatrin toxicity and no evidence of visual pathway comorbidity, thereby implicating retinal ganglion cell dysfunction. OCT affords a limited measurement range compared with perimetry: severity cannot be directly assessed when the PPRNFL quadrant thickness is less than approximately 65 µm, depending on the tomographer. This limitation can be overcome by transformation of thickness to remaining axons, an outcome requiring input from perimetry

Modelling the risk of visual field loss arising from long-term exposure to the antiepileptic drug vigabatrin: a cross-sectional approach

Background: The antiepileptic drug vigabatrin has been used widely since 1989, but has only been approved for use in the US since 2009. The risk:benefit of vigabatrin is generally predicated upon an assumed frequency of associated visual field loss (VAVFL) of approximately 31 %. This estimate is based upon relatively short-term usage (up to 4–5 years) and it is essential to determine whether the frequency of VAVFL increases with longer-term usage. Objective: The aim of this study was to model, from cross-sectional evidence, over greater ranges of treatment duration and cumulative dose than previously evaluated, the risk (frequency) of VAVFL with increasing exposure to vigabatrin. Study Design and Setting This was a retrospective cohort study undertaken in a regional hospital epilepsy clinic. Patients: The cohort comprised 147 consecutive patients treated with vigabatrin for refractory complex partial (focal) seizures, who had all undergone ophthalmological examination and who had undertaken perimetry, reliably, according to a standard and robust protocol. The visual field plots were evaluated masked to treatment duration and dose. Main Outcome Measure: The risk (frequency) of VAVFL with increasing exposure to vigabatrin was modelled, from the cross-sectional evidence, by standard and plateau logistic regression. Results: The cohort comprised 80 females and 67 males (mean age 40.3 years, standard deviation 13.7). The median duration of vigabatrin exposure was 7.9 years (interquartile range 3.6–11.0, range 0.2–16.1 years); 46 patients (31 %) had received vigabatrin for over 10 years. Eighty-seven patients (59 %) exhibited VAVFL; the proportion with VAVFL was higher in males (66 %) than females (54 %). The plateau model for duration and for cumulative dose exhibited a better fit than the standard model (both p < 0.001). The modelled frequency of VAVFL increased with increasing exposure up to approximately 6 years duration and 5 kg cumulative dose, and plateaued at approximately 76 % (95 % CI 67–85) and 79 % (95 % CI 70–87), respectively. Severity of VAVFL, classified in terms of the visual field index Mean Deviation, was not significantly associated with either duration or cumulative dose of therapy. Conclusion: Clinicians and patients, in enabling informed choice, should be alert to the possible substantial increased risk:benefit for VAVFL with increasing long-term exposure to vigabatrin and the ensuing increased cost:benefit resulting from the necessary additional visual assessments

Modelling the Risk of Visual Field Loss Arising from Long-Term Exposure to the Antiepileptic Drug Vigabatrin: A Cross-Sectional Approach

Background: The antiepileptic drug vigabatrin has been used widely since 1989, but has only been approved for use in the US since 2009. The risk:benefit of vigabatrin is generally predicated upon an assumed frequency of associated visual field loss (VAVFL) of approximately 31 %. This estimate is based upon relatively short-term usage (up to 4–5 years) and it is essential to determine whether the frequency of VAVFL increases with longer-term usage. Objective: The aim of this study was to model, from cross-sectional evidence, over greater ranges of treatment duration and cumulative dose than previously evaluated, the risk (frequency) of VAVFL with increasing exposure to vigabatrin. Study Design and Setting This was a retrospective cohort study undertaken in a regional hospital epilepsy clinic. Patients: The cohort comprised 147 consecutive patients treated with vigabatrin for refractory complex partial (focal) seizures, who had all undergone ophthalmological examination and who had undertaken perimetry, reliably, according to a standard and robust protocol. The visual field plots were evaluated masked to treatment duration and dose. Main Outcome Measure: The risk (frequency) of VAVFL with increasing exposure to vigabatrin was modelled, from the cross-sectional evidence, by standard and plateau logistic regression. Results: The cohort comprised 80 females and 67 males (mean age 40.3 years, standard deviation 13.7). The median duration of vigabatrin exposure was 7.9 years (interquartile range 3.6–11.0, range 0.2–16.1 years); 46 patients (31 %) had received vigabatrin for over 10 years. Eighty-seven patients (59 %) exhibited VAVFL; the proportion with VAVFL was higher in males (66 %) than females (54 %). The plateau model for duration and for cumulative dose exhibited a better fit than the standard model (both p < 0.001). The modelled frequency of VAVFL increased with increasing exposure up to approximately 6 years duration and 5 kg cumulative dose, and plateaued at approximately 76 % (95 % CI 67–85) and 79 % (95 % CI 70–87), respectively. Severity of VAVFL, classified in terms of the visual field index Mean Deviation, was not significantly associated with either duration or cumulative dose of therapy. Conclusion: Clinicians and patients, in enabling informed choice, should be alert to the possible substantial increased risk:benefit for VAVFL with increasing long-term exposure to vigabatrin and the ensuing increased cost:benefit resulting from the necessary additional visual assessments