Is reduced ornithine-δ-aminotransferase activity the cause of vigabatrin-associated visual field defects?
BACKGROUND
A gabaergic antiepileptic drug, vigabatrin (VGB), is known to induce bilateral concentric visual field defects (VFD) in 30-40% of treated patients. Although the clinical and electrophysiological features of VFDs are well documented, the mechanism of retinal toxicity is still unclear.


OBJECTIVE
To determine if low basal ornithine-δ-aminotranspherase (OAT) activity is implicated in the etiology of VGB retinotoxicity, resulting in a phenotype of a mild form of gyrate atrophy.


METHODS
Assays of OAT activity in lymphocytes and GABA-transaminase activity in platelets were performed, and plasma levels of GABA, ornithine, lysine, glutamic acid and glutamine were measured, and visual fields were examined. A total of 47 subjects, aged 14-78 years, were examined. Twenty-one epileptic patients were off VGB more than 1 year; 11 patients with VGB-induced VFD and 10 with normal visual fields. Ten epileptic patients were on current VGB therapy more than 1 year; four patients with VGB-induced VFD and six with normal visual fields. The results were compared with those of 10 epilepsy patients taking tiagabine and six patients who suffered from gyrate atrophy (GA) or were obligate carriers of the disease.


RESULTS
In patients who had stopped VGB and who had VFDs, OAT activity was significantly reduced as compared with those who had normal visual fields (77.4pmol P5C/min/mgPro vs. 181.9pmol P5C/min/mgPro, p=0.002). In patients with ongoing VGB therapy, no difference was found between the patients with and without VFDs (149.4pmol P5C/min/mgPro vs. 159.1pmol P5C/min/mgPro).


CONCLUSIONS
: The results suggest that VGB retinotoxicity might be associated with elevated retinal ornithine mediated by low basal OAT activity.
Sorri
Iiris
I
Department of Ophthalmology, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland. Iiris.Sorri@kuh.fi
Brigell
Mitchell G
MG
Mályusz
Miklos
M
Mahlamäki
Eija
E
de Meynard
Capucine
C
Kälviäinen
Reetta
R
D000612:4-Aminobutyrate Transaminase / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D004827:Epilepsy / Q000188:drug therapy; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009953:Ornithine-Oxo-Acid Transaminase / Q000378:metabolism; D010468:Perceptual Disorders / Q000097:blood / Q000139:chemically induced* / Q000201:enzymology*; D020888:Vigabatrin / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D058609:Visual Field Tests; D014794:Visual Fields / Q000187:drug effects* / Q000502:physiology; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000097:blood
D000927:Anticonvulsants; D005680:gamma-Aminobutyric Acid; D009953:Ornithine-Oxo-Acid Transaminase; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin