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Neurology India, Vol. 54, No. 4, October-December, 2006, pp. 352-353 Invited Commentaries Inflammation in intracerebral hemorrhage: Clearly present, but what is its role? Butcher Ken Department of Neurology, University of Alberta, Edmonton, Alberta Code Number: ni06127 The pathological consequences of primary intracerebral hemorrhage (ICH) include the immediate primary injury and more delayed secondary processes.[1] The former results from compressive and shear forces introduced by extravasated blood. The etiology of secondary injury in the peri-hematomal region has been the source of speculation for some time. Ischemia, inflammation, excitotoxicity and apoptosis have all been implicated in animal models of ICH.[2] Clinical and experimental evidence indicates a very limited if any role for ischemia, while inflammation increasingly appears to be a significant factor. In this issue of Neurology India, Zhang et al report an extensive study of peri-hematomal edema, morphological changes and six inflammatory markers (TNF- α , IL-6, ICAM-1, VEGF, NF-κB, C3 and CR2) in an autologous blood injection rodent model of ICH. Although several previous studies have demonstrated evidence of inflammatory markers in this region, this investigation is novel in that it describes the time course of cytokine levels in the first week post-ictus. The authors found that inflammatory markers peaked at 48-72h, at the same time as peri-hematomal brain water content. Whilst this does add further evidence that transient inflammation is present after ICH, the temporal association with edema growth does not demonstrate causality. Although inflammation may contribute to an increase in brain water content, the oncotic effects of proteins such as thrombin are likely more important in early edema formation. These forces tend to draw plasma from the vasculature as well as the contracting blood clot into peri-hematomal tissue. There is also evidence that thrombin actually initiates inflammation after ICH.[3] A recently proposed and intriguing hypothesis is that the regulatory pathways activated in ICH are actually protective in smaller hematomas, but harmful in large hemorrhages.[4] Thus, inflammatory processes may ultimately serve to remove blood products from the brain, albeit with deleterious effects in large hemorrhages. The question of relevance to clinical ICH must always be considered when examining animal model results. There are clear similarities between the two, such as the development and growth of peri-hematomal edema. Clinically, edema is restricted to the ipsilateral hemisphere, whereas increased brain water content was observed bilaterally in the animal model described by Zhang et al . This is presumably due to the closer anatomical relationship between the external capsule/corpus callosum and caudate-putamen in rats. There is also evidence of an active inflammatory response following ICH in humans.[5] This has been hypothesized to be related to secondary injury and even ICH expansion, although once again the association does not indicate causality.[6] The study by Zhang et al suggests that therapies aimed at attenuating the inflammatory response are most likely to be effective if administered within the first 48h. Of course the timing, nature and pathophysiological role of the inflammatory response in humans may all be substantially different from those in animal models. References
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