The neonatal cat model of kaolin-induced hydrocephalus is associated with progressive and severe ventriculomegaly. In this experiment we studied the evolution of the histopathological changes in hydrocephalic (n = 23) cats from 5-168 days after the induction of hydrocephalus along with age-matched controls (n = 10). In the periventricular white matter, extracellular edema and axonal damage were present within days of the onset of hydrocephalus. This was followed by reactive gliosis, white matter atrophy, and in some animals gross cavitation of the white matter. Even in the chronic, apparently compensated state there was ongoing glial cell death. Six cats were shunted an average of 23.6 +/- 6.5 days after the induction of hydrocephalus because they were no longer able to feed independently. In spite of clinical improvement the white matter changes persisted. Overt cortical changes were minimal except where areas of white matter destruction encroached upon the deep layers. The white matter changes are very similar to those seen in periventricular leukomalacia and suggest that ischemia plays a role in neonatal brain injury caused by hydrocephalus.