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

Kjellström, Ulrika; Bruun, Anitha; Ghosh, Fredrik; Andréasson, Sten; Ponjavic, Vesna

doi:10.1007/s00417-009-1093-7

Cited by 12 publications

(11 citation statements)

References 57 publications

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“…These previous studies are consistent with our observation of folds in the outer nuclear layer of the retina. Although the formation of folds is closely related to vigabatrin dose [21] and duration of light exposure [9], [11], we observed that genetic mutations could also influence fold efficiency. In this study, we tested mice that carried mutations that affected rod or cone photoreceptor signaling and observed decreased folding formation.…”

Section: Discussionmentioning

confidence: 72%

Vigabatrin-Induced Retinal Toxicity Is Partially Mediated by Signaling in Rod and Cone Photoreceptors

et al. 2012

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Vigabatrin (VGB) is a commonly prescribed antiepileptic drug designed to inhibit GABA-transaminase, effectively halting seizures. Unfortunately, VGB treatment is also associated with the highest frequencies of peripheral visual field constriction of any of the antiepileptic drugs and the mechanisms that lead to these visual field defects are uncertain. Recent studies have demonstrated light exposure exacerbates vigabatrin-induced retinal toxicity. We further assessed this relationship by examining the effects of vigabatrin treatment on the retinal structures of mice with genetically altered photoreception. In keeping with previous studies, we detected increased toxicity in mice exposed to continuous light. To study whether cone or rod photoreceptor function was involved in the pathway to toxicity, we tested mice with mutations in the cone-specific Gnat2 or rod-specific Pde6g genes, and found the mutations significantly reduced VGB toxicity. Our results confirm light is a significant enhancer of vigabatrin toxicity and that a portion of this is mediated, directly or indirectly, by phototransduction signaling in rod and cone photoreceptors.

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Section: Discussionmentioning

confidence: 72%

Vigabatrin-Induced Retinal Toxicity Is Partially Mediated by Signaling in Rod and Cone Photoreceptors

et al. 2012

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“…Cases have been described as symptomatic or asymptomatic, bilateral, persistent, and concentric with the nasal field often affected more extensively than the temporal field. 5,69,70 Vigabatrin-associated visual field defects have been linked to nasal quadrant retinal nerve fiber layer thinning, and this nasal attenuation may precede visual field loss. 71 Although a detailed pathophysiologic explanation for the defects remains to be elucidated, retinal damage is most often cited as the underlying defect.…”

Section: Adverse Eventsmentioning

confidence: 99%

“…Vigabatrin has been implicated as causing reductions of specific rod and cone wave amplitudes and other changes supporting damage to the inner retina. 70 One theory regarding vigabatrin-associated visual field defects asserts that retinal toxicity may be related to coding variations in genes that transport vigabatrin into the retina. 72 Attempts to investigate correlations between duration or dosing parameters of vigabatrin and vigabatrinassociated visual field defects have typically resulted in conflicting results, some investigations have revealed associations with these parameters whereas others have not.…”

Section: Adverse Eventsmentioning

confidence: 99%

Vigabatrin for Infantile Spasms

2011

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Infantile spasms describe a pediatric epilepsy syndrome characterized by frequent clusters of brief symmetric muscle contractions; the condition is often associated with developmental delay. When infantile spasms are accompanied by hypsarrhythmia on electroencephalogram, the condition is labeled West syndrome. The mainstay of treatment for infantile spasms is adrenocorticotropic hormone; however, vigabatrin, a vinyl derivative of γ-aminobutyric acid, has been used for the treatment of infantile spasms in Europe since 1989. In 2009, vigabatrin was approved by the United States Food and Drug Adminstration (FDA) for use as monotherapy in the treatment of infantile spasms in patients aged 1 month-2 years when the benefits of treatment outweigh the risks. Results from numerous trials examining the role of vigabatrin in infantile spasms have been published; many of these trials were small, open-label, or noncontrolled. Although clinical trials have provided some insight into the utility of vigabatrin for the treatment of infantile spasms, these studies have notable limitations. In addition, vigabatrin is associated with a black-box warning that describes the potential for permanent bilateral concentric visual field defects. Currently, vigabatrin is available through a manufacturer-sponsored program in accordance with its FDA-approved Risk Evaluation and Mitigation Strategy. Although several guidelines recommend vigabatrin as a first-line therapy for infantile spasms, specifically infantile spasms related to tuberous sclerosis, it is still unclear whether vigabatrin should supersede hormone therapy as first-line therapy. Further research comparing the two therapies is needed.

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“…2004) as well as altered expression of proteins in Müller cells (Ponjavic et al. 2004; Kjellstrom et al. 2009) and in rod bipolar cells (Kjellstrom et al.…”

Section: Introductionmentioning

confidence: 99%

Attenuation of the retinal nerve fibre layer and reduced retinal function assessed by optical coherence tomography and full‐field electroretinography in patients exposed to vigabatrin medication

Kjellström

Andréasson

Ponjavic

2013

Acta Ophthalmologica

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ABSTRACT.Purpose: To investigate the clinical value of assessment of peripapillary retinal nerve fibre layer (RNFL) thickness with OCT in addition to the evaluation of retinal function measured by full-field electroretinography (ff-ERG) in patients with suspected vigabatrin (VGB)-attributed visual field defects. Methods: Visual fields from adult patients in our clinical follow-up program for VGB medication were analysed. Twelve patients with suspected VGB-attributed visual field defects were selected for the study. They were re-examined with computerized kinetic perimetry, ff-ERG and OCT (2D circle scan). Results: Constricted visual fields were found in all patients. Comparative analysis of ff-ERG parameters showed reduced b-wave amplitudes for the isolated and the combined rod and cone responses (p < 0.0001). The a-wave, reflecting photoreceptor activity, was reduced (p = 0.001), as well as the summed amplitude of oscillatory potentials (p = 0.029), corresponding to inner retinal function. OCT measurements demonstrated attenuation of the RNFL in nine of 12 patients, most frequently superiorly and ⁄ or inferiorly. No temporal attenuation was found. Significant positive correlations were found between the total averaged RNFL thickness, superior and inferior RNFL thickness and reduced ff-ERG parameters. Positive correlations were also found between RNFL thickness and isopter areas. Conclusion: OCT measurements can detect attenuation of the RNFL in patients exposed to VGB medication. RNFL thickness correlates with reduced ff-ERG parameters and isopter areas of constricted visual fields, indicating that VGB is retino-toxic on several levels, from photoreceptors to ganglion cells. The study also supports previous studies, suggesting that OCT measurement of the RNFL thickness may be of clinical value in monitoring patients on vigabatrin therapy.

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

Cited by 12 publications

References 57 publications

Vigabatrin-Induced Retinal Toxicity Is Partially Mediated by Signaling in Rod and Cone Photoreceptors

Vigabatrin-Induced Retinal Toxicity Is Partially Mediated by Signaling in Rod and Cone Photoreceptors

Vigabatrin for Infantile Spasms

Attenuation of the retinal nerve fibre layer and reduced retinal function assessed by optical coherence tomography and full‐field electroretinography in patients exposed to vigabatrin medication

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