Early cellular events in the penumbra of human spontaneous intracerebral hemorrhage

Spontaneous intracerebral hemorrhage causes high morbidity and mortality rates, and yet its treatment remains controversial, partly because of a poor understanding of the pathogenesis and timescale of injury in the surrounding brain. This study was undertaken to clarify the cellular reactions around human spontaneous intracerebral hematomas and relate these to hematoma duration and volume, in order to provide further data that might aid the development of therapeutic strategies. Brain tissue from the margin of the hematoma in 33 fatal cases of spontaneous intracerebral hemorrhage and corresponding tissue from 13 normal controls was studied using immunohistochemistry for heat-shock proteins, metallothionein, and various neuronal, glial, macrophage, and endothelial markers. Hematoma volumes were calculated from computed tomographic (CT) scans and autopsy measurements, whereas hematoma age was estimated from clinical records. The results showed that cellular events are time dependent, but not related to hematoma volume, and are identifiable in neurons, glia, and endothelium as early as 5 hours after hemorrhage. Peripheral macrophage infiltration begins at 5 days. The results suggest that the therapeutic window in humans for reperfusion of the ischemic penumbra of a hematoma is less than 5 hours, although progression of the infarcted core to the penumbral periphery within 1 to 3 days suggests a wider cytoprotective window. Edema, caused by blood-brain barrier breakdown, was also identified at 5 hours, and prompt treatment of this may reduce the space-occupying effects of the hematoma and, possibly, the morbidity and mortality.