Cellular pathology and apoptosis in experimental and human acute and chronic compressive myelopathy.

Abstract

Evidence suggests that apoptosis of neurons and glia may play an important role in the pathophysiology and functional outcome of spinal cord compression. In the current thesis, chronic and acute rodent experimental models analysed the functional, cellular and apoptotic marker changes produced by compression and subsequent surgical decompression. In experimental mild chronic compression there was a loss of posterior white matter maximal at the compression site. Total cross-sectional area decreased with a longer duration of compression (3 weeks) but resolved with decompression (e.g. 3 week group mean 3.05mm² increasing following decompression at 3 weeks to 5.75 mm²). A significant increase in posterior white matter area was found above and below the site at 3 weeks. Caspase-9, PARP, AIF and active caspase-3 staining was found in glia at, above and below the site in all groups. Caspase-3 was greater expressed in the 24 hour (mean 0.32, p = 0.01) and 3 week (mean 0.31, p = 0.02) decompression groups when compared with the 9 week compression group (mean 0.19). APP axonal immunopositivity was frequently seen after decompression. Following experimental acute compression, central necrosis was seen, surrounded by axonal swellings and inflammatory infiltrate. Glial positivity using TUNEL occurred at 24 hours and 1 week post-injury. PARP, DNA-PKcs and AIF immunopositivity occurred in glia at, above and below the site. APP immunopositivity was present in axonal swellings. In human chronic compression, axonal swellings, loss of anterior horn cells, and cystic change were seen in severe cases. TUNEL, DNA-PKcs, PARP and AIF immunopositivity in glia wereas seen at, above and below the compression. APP immunopositivity was seen in axonal swellings. In human acute compression, the central cord showed haemorrhagic necrosis and inflammatory cells. TUNEL, DNA-PKcs and PARP immunopositive glia were found at, above and below the site. Axonal swellings, a subset of which were APP immunopositive, occurred in the penumbra. APP immunopositive axonal swellings were found above and below the site of compression, indicating widespread changes in fast axoplasmic transport. We conclude that mild, chronic, fixed posterior compression results in a potentially reversible reduction of white matter at the site and increased white matter above and below the site of compression. This, combined with evidence of axonal injury, may indicate altered axoplasmic transport. Decompressive surgery results in increased immunostaining for apoptotic markers and increased axonal injury despite restoration of spinal cord anatomy. These studies provide novel evidence that neuronal and glial apoptosis occurs in acute and chronic compressive myelopathy at various time points of compression, maximal at the site of injury.