Introduction

In 1989, Vigabatrin (Sabril, Hoechst Marion Roussel/Aventis Ltd) was introduced as a new and effective second-line antiepileptic drug for the treatment of uncontrolled complex partial seizures and infantile spasms.1, 2 Since 1997 there have been numerous reports of concentric and/or binasal visual field defects associated with the use of Vigabatrin making this the most concerning safety issue with the use of the drug at present.3, 4, 5, 6 Previous studies have confirmed the high prevalence of visual field defects (up to 30–40%) and the lack of evidence for significant progression or resolution of these defects on cessation of the drug.3, 7, 8 To date, there is little information with regard to the natural history of visual field defects in patients who continue on Vigabatrin.3, 9 Our study aimed to look at the natural history of visual field defects in a group of patients with known Vigabatrin-associated field loss who opted to continue on the drug because of good seizure control and consequent improvement in quality of life.

Materials and methods

In all, 16 patients who were taking Vigabatrin alone or in combination with other antiepileptic drugs for at least 5 years (range 5–12 years) and who had been noted to have unequivocal Vigabatrin-associated visual field defects were included in the study. Patient ages ranged from 26 to 60 years, average 40 years. All patients had opted to continue on Vigabatrin despite documented field loss because of good seizure control. No patient had symptomatic field loss. Each patient was followed up at 6-monthly intervals for not less than 18 months (range 18–43 months) after discovery of the field defect. At each visit patients were asked with regard to subjective visual problems. Best-corrected distance (snellen) and near acuity were recorded. Colour vision was assessed using the 17 number plate version of the Ishihara pseudoisochromatic test. Goldmann kinetic perimetry to the V4e and I4e isopters was performed on the same regularly calibrated machine. Following already published methodology 7 monocular mean radial degrees (MRDs) to the I4e isopter was calculated for the right eye at the time of discovery of the visual field defect and after a follow-up of not less than 18 months. All patients underwent a slit-lamp examination and direct and indirect dilated fundus examination at each visit.

Results

During the follow-up no patient had any subjective deterioration in visual function. All patients had an initial best-corrected distance acuity of at least 6/9 and N6 for near which did not vary significantly at subsequent visits. All, except one male who was known to be red/green colour blind, managed at least 16 out of the 17 colour plates correctly at each visit. Examination of fundi did not reveal any significant disc or macular abnormalities.

At initial detection of a visual field defect, the mean right eye visual field of the 16 patients was 36.98 MRD (range 22.25–51.0 MRD). Three patients fell into the category of having a severe visual field defect (VF≤30 MRD). After a minimal follow-up of 18 months, the mean visual field was 38.40 MRD (range 22.5–49.75 MRD). There was no significant change in MRD between the first and final follow-up visits (P=0.338) (Figure 1). Only one patient had a significant deterioration in visual field (≥10 MRD) and was advised to discontinue Vigabatrin after 19 months follow-up (Table 1 , case 3 and Figures 2 and 3) . None of the three patients with severe constriction of visual field showed any further deterioration over at least 22 months follow-up. One of these patients with an initial mean visual field of 22.25 MRD had a final mean visual field of 22.5 MRD after 41 months follow-up (Table 1).

Figure 1
figure 1

Visual fields in MRD at first recording of a defect plotted against visual field in MRD after a minimum follow-up of 18 months.

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Table 1 (MRDs) field at first assessment and final follow-up
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Figure 2
figure 2

Initial visual field of right eye of patient 3.

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Figure 3
figure 3

Visual field of right eye of patient 3 after 19 months follow-up.

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Discussion

Although the exact pathophysiological mechanisms of vigabatrin-associated visual field defects remain unclear the site of toxicity is proposed to be located at the inner retina, where vigabatrin causes irreversible inhibition of GABA aminotransferase with consequent elevation of GABA, a major inhibitory transmitter in the brain and retina.10, 11 Male preponderance and a lack of relationship between visual loss and cumulative dosage has given rise to the suggestion that an idiosyncratic drug reaction within the neurosensory retina may underlie the pathogenesis of the visual field loss with interindividual susceptibility.7 If this was the case, the acquired visual field defect would be expected to remain reasonably stable whether treatment was ceased or not. A recent study by Newman et al7 showed no evidence of progression or resolution of visual field defects in 21 patients on discontinuing the drug.

Although there have been a few reported cases of improvement in visual field after withdrawal of vigabatrin,12, 13, 14 other larger studies suggest that field loss is irreversible.3, 15, 16, 17 Several studies have also found no correlation between either treatment duration or cumulative dosage and visual field loss.3, 7, 8 The question as to whether field loss is not only irreversible but progressive with continued use of vigabatrin is less clear. Evidence from this study suggests that visual field defects do not progress significantly or at least appear to plateau with continued use of the drug and do not appear to be dose dependent. Recently, Nousiainen et al3 found that after discontinuation of the drug, no significant recovery was observed in visual fields during follow-up, but conversely, no progression was found with continued therapy.

Paul et al9 showed similar findings in their study. This evidence lends further support to the idea that an idiosyncratic drug reaction may underlie the pathogenesis in some patients. Genetically determined variations in local tissue drug or metabolite deactivation or clearance most probably in the retina are likely to be relevant.7 This may have important implications for the quality of life in some patients in whom seizure control with other antiepileptic medication has been difficult to achieve. If the risk from uncontrolled seizures outweighed the risk of progressive field loss patients then neurologists might be more confident at opting to continue vigabatrin. In the meantime patients should continue to be fully informed of the prevalence of visual field defects in vigabatrin users.