Ida G. Schmidt

Studies on the Neurotoxicity of Ethambutol and Its Racemate for the Rhesus Monkey

A toxicological study in the rhesus monkey employing graded doses of the antituberculosis drug ethambutol revealed a series of neurological symptoms which, in general, were found to be associated with specific neuroanatomical changes. With the largest doses of ethambutol, 1200 to 1600 mg./kg. administered daily for 4 months or somewhat longer, neurological symptoms appeared within 2 to 3 months after the beginning of treatment and increased in severity until the death of the animal. Symptoms consisted principally of incoordination of the limbs and associated reactions, muscular weakness, and apparent loss of vision. The major neuroanatomical findings included: (1) an extensive, centrally placed lesion in the optic chiasm and optic tracts with complete necrosis and gitter cells in its interior, and lesions of varying intensities in the optic nerves; (2) a large, oval, bilateral lesion in the reticular formation of the lower medulla consisting of spongiform degeneration with gitter cells, continuing to a lesser degree into the upper cervical cord; (3) ehromatolysis of large cells in the nucleus ruber, and of varying numbers of motor reticular cells of the upper pons and anterior horn cells of the spinal cord; and (4) pronounced swelling and at least partial demyelination of fibers in the pyramidal decussation, crossed fibers, and lateral pyramidal tracts, extending as far as the upper cervical cord. Treatment with graded doses of ethambutol indicated that the first lesions to appear were those in the optic chiasm alone, or in the optic chiasm and optic tracts, followed shortly by those in the optic nerves. These were the only lesions of significance when small doses of ethambutol were given over a long period of time with slight ataxia as the only symptom, or when large, acutely toxic doses were administered for short periods with resultant severe neurological symptoms of brief duration. The lesion in the reticular formation of the medulla included the areas of the lateral reticulospinal tracts and only appeared after prolonged treatment with high doses of ethambutol and prolonged neurological symptoms. Chromatolysis of large cells in the nucleus ruber and other areas was a late development; the number of cells affected varied with the dosage employed and the duration of treatment. Swelling and demyclination of decussating and crossed pyramidal fibers was likewise a late development but appeared only after prolonged treatment with high doses of ethambutol. Although ethambutol-racemate was only half as active as ethambutol in the treatment of tubereulous disease, it had at least twice as much neurotoxicity. At doses of 400 or 800 mg., the racemate provoked similar, but much more severe, neurological symptoms and neuroanatomical lesions than comparable doses of ethambutol. After higher doses, the symptoms appeared sooner and persisted only briefly before death occurred. Prominent lesions were present in the optic chiasm, optic tracts, and optic nerves.