Central nervous system malformations induced by triamcinolone acetonide in nonhuman primates: pathology

Triamcinolone acetonide (TAC) was administered to pregnant macaques (Macaca mulatta [15] and M. radiata [7]) during gestational days (GD) 23 to 41 using various dosing schedules. A daily dose of 10 mg/kg is approximately equal to 100 x the human dose equivalent. The brains of the fetuses and infants were studied grossly and histologically. All cases displayed either the mild form of the TAC-induced syndrome (craniofacial dysmorphia, cranium bifidum occultum, meningocele, and mild distortion of the midbrain) or the more severe form (occipital encephalocele, hydrocephalus, severe distortion of the midbrain or midbrain "beaking," shunting of cerebrospinal fluid, and craniofacial malformations). The dysmorphology was dose-related, with severity increasing at higher doses or with increased numbers of treatments. Individual cases were assessed for the severity of the syndrome by comparison of like components between groups. The lesions observed were morphologically comparable to those described in spontaneous human cases; the TAC-induced occipital encephaloceles were associated with brainstem and cerebellar abnormalities, and, with the less severe form of the syndrome, brainstem abnormalities were occasionally present, with occipital meningoceles. Controversy exists concerning the significance and temporal development of the midbrain changes. However, the associated alteration in aqueduct conformation may have been responsible for functional compromise and ensuing hydrocephalus.