Vigabatrin toxicity

In a letter it has been discussed whether, in view of recent findings which demonstrate vigabatrin toxicity in the retina and also in the brain, it is still justified to continue to treat patients with infantile spasm with this drug [359 ]. 

Akqakaya AA, Gokgeer S, Erbil HH, I ik N, Ozdoker L, Salar S, Aykan F, Aydin T, Yaylali SA, Kesim O. Detecting retinal vigabatrin toxicity in patients with partial symptomatic or cryptogenic epilepsy. Eur J Ophthalmol 2010 20(4) 763-9. 

Vigabatrin Irreversibly inhibits GABA-transaminase 70% bioavailable not bound to plasma proteins not metabolized, ti/2 5-7 h (not relevant because of mechanism of action) Partial seizures, infantile spasms Toxicity Drowsiness, dizziness, psychosis, visual field loss Interactions Minimal... 

The pharmacologic activity and the toxic effects of vigabatrin is associated only with S(+) enantiomer. The R(—) enantiomer appears to be entirely inactive [78]. Because the target enzyme, GABA transaminase (GABA-T), has a longer half-life than the drug itself [79, 80]. The... 

There has been significant concern with respect to a potentially serious toxicity of vigabatrin in humans as a result of the microvacuolization of white matter demonstrated in rodents and dogs. In all animal studies the microvacuolization was not dose-dependent and was completely reversible with discontinuation of the drug [73]. 

Another major concern for toxicity of vigabatrin is sever persistent visual field constriction associated with retinal cone system dysfunction [63, 82], The effect did not appear to be reversible upon discontinuation of the drug. Vigabatrin also causes GABA to accumulate in retinal glial cells in rats, suggesting a mechanism for the toxic effect [83]. 

Doses of vigabatrin up to 10 g have been taken without serious effects. Toxic manifestations include vertigo, tremor, sedation, coma, myoclonic jerks, and psychosis. Gastric lavage within 1-2 hours is recommended after doses in excess of 12 g in adults and 2 g in children (SEDA-22,85). The development of discontinuous partial complex status epilepticus in a patient with partial epilepsy who had taken a 20 g overdose 6 days earher was considered to be a possible effect of withdrawal (SEDA-22, 85). 

Malmgren K, Ben-Menachem E, Frisen L. Vigabatrin visual toxicity evolution and dose dependence. Epilepsia 2001 42(5) 609-15. 

One patient who developed impaired vision while taking topiramate for symptomatic epilepsy had signs of a maculopathy [309" ]. The topiramate was withdrawn, but vision failed to improve significantly over 6 months of follow-up. The authors speculated that topiramate, like vigabatrin, may cause persistent visual impairment through direct retinal toxicity. 

Until now, the incidence ofvigabatrin-asso-ciated retinal toxicity in Asian populations has not been studied. In 18 Chinese patients, 8 men and 10 women, who had taken vigabatrin for 13 months to 5 years, mean dosage 1581 mg/day, there were significant bilateral visual field defects in 20 eyes, and 80% showed a concentric pattern, compared with none in the control group [433 ]. 

Four children who had been exposed to vigabatrin in utero all had normal visual fields and retinal nerve fiber layer thicknesses, suggesting that vigabatrin does not cause visual toxicity in children exposed to vigabatrin prenatally [435 J. 

Treatment of metamfetamine dependence with vigabatrin has been suggested. Possible cardiovascular adverse effects induced by the co-administration of these substances and the possible interaction between vigabatrin and metamfetamine have been evaluated in a double-blind, placebo-controlled, parallel-group study in healthy volunteers [436. Vigabatrin did not alter metamfetamine or amfetamine plasma concentrations or toxicity. There were no serious adverse events and the total number of adverse effects was similar in the two groups. There were no significant differences in systolic or diastohc blood pressures or heart rate. 

Langmsin, L.J. Kaliciak, HA. Boone, SA. Fatal acute topiramate toxicity, JAncd.ToxicoL, 2003, 27, 323-324. [topiramate LC-MS gabapentin vigabatrin droperidol is internal standard]... 

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