Histopathologic clues to the pathways of neuronal death following ischemia/hypoxia

This review describes histopathologic observations made with both light and electron microscopy using both conventional staining techniques and histochemistry. Several conditions are analyzed: Ischemic cell change; delayed neuronal death; selective vulnerability. The histopathologic support for the calcium hypothesis and for the excitotoxic hypothesis explaining neuronal death is also reviewed. The findings lead to several suggestions relevant to attempts at developing interventional therapies administered after the onset of ischemia/hypoxia. (1) Except in gerbils, delayed neuronal death and more rapid neuronal death appear to be on the same continuum of cellular events. The lag between ischemia and either onset or termination of these shared events depends upon the severity and/or duration of ischemia/hypoxia. We still do not know whether the "delay," when it occurs, is a delay between ischemia and initiation of the lethal sequence or is, instead, a delay between an immediate initiation of the sequence and its lethal termination. (2) Selective vulnerability (e.g., of CA1 sector in hippocampus) is only relative. The changes are again those of ischemic cell change and are identical to the changes seen elsewhere in more severe ischemia. (3) There is histopathologic support for both the calcium hypothesis and for the cytotoxic hypothesis. Indeed, there is histopathologic support linking the two hypotheses and linking these mechanisms to the appearance of ischemic cell change. However, the histopathologic data are surprisingly sparse. The role of either hypothesis in explaining neuronal death in all areas of brain, in all types of ischemic insult, and at all times following such an insult remains to be established. (3) Apoptosis may be an important mode of neuronal death following ischemia. It differs from acute ischemic cell change; nevertheless, both calcium overload and/or excitotoxic neurotransmitters may trigger apoptosis. (4) Third cell change has been described: Eosinophilic neurons that are not shrunken and whose nuclei are not pyknotic but contain clumped chromatin. The pathogenesis and fate of these neurons remains uncertain. It is possible that they represent early apoptotic neurons. Adequate assessment of apoptosis and its relationship (to both these neurons and to neurons displaying classical ischemic cell change) may depend upon dual staining with conventional aniline dyes and with histochemical techniques designed to detect intranuclear fragments of DNA.