Neuropathologic findings in patients receiving long-term vigabatrin therapy for chronic intractable epilepsy.
Vigabatrin is a new antiepileptic drug that acts by the irreversible inhibition of gamma-aminobutyric acid (GABA) aminotransferase. During animal safety testing, vigabatrin was found to cause reversible intramyelinic edema in the brains of rodents and dogs but not in primates. In humans, the drug is well tolerated, and extensive clinical, neurophysiologic, neurochemical, and psychometric testing has failed to demonstrate any evidence of neurotoxicity. Neuropathologic examination has now been carried out on 62 patients with refractory epilepsy, who were on vigabatrin therapy either prior to undergoing neurosurgery for their epilepsy or before death. A further ten similar cases have been included in the study from age-matched patients with refractory epilepsy who had not been treated with vigabatrin prior to surgery or death. None of the neuropathologic changes seen in the preclinical animals studies have been observed in the human cases. In no case was there considered to be any evidence of myelin microvacuolation or myelin sheath splitting that could be attributed to vigabatrin treatment. Demyelination has never been observed in either the animal or human material. These findings support the clinical tolerability seen in long-term treatment.
Marion Merrell Dow Research Centre, Winnersh, Berkshire, UK.
D J
DJ
Cannon
W H
WH
Butler
J P
JP
Mumford
P J
PJ
Lewis
D000293:Adolescent; D000328:Adult; D000368:Aged; D000614:Aminocaproates / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects*; D001706:Biopsy; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology; D002648:Child; D004827:Epilepsy / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D008134:Long-Term Care; D008297:Male; D008875:Middle Aged; D051381:Rats; D014617:Vacuoles / Q000187:drug effects / Q000648:ultrastructure; D020888:Vigabatrin
D000614:Aminocaproates; D000927:Anticonvulsants; D020888:Vigabatrin