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Biomechanical alterations likely play a primary role in causing adjacent segment disease. Radiographically apparent, asymptomatic adjacent segment disease is common but does not correlate with functional outcomes. Potentially modifiable risk factors for the development of adjacent segment disease include fusion without instrumentation, protecting the facet joint of the adjacent segment during placement of pedicle screws,fusion length, and sagittal balance. Surgical management, when indicated, consists of decompression of neural elements and extension of fusion. Outcomes after surgery, however, are modest.

Background and Purpose-Evidence indicates that brain injury after intracerebral hemorrhage (ICH) is due in part to the release of iron from hemoglobin. Therefore, we examined whether such iron is cleared from the brain and the effects of ICH on proteins that may alter iron release or handling: brain heme oxygenase-1, transferrin, transferrin receptor, and ferritin. Methods-Male Sprague-Dawley rats received an infusion of 100 L autologous whole blood into the right basal ganglia and were killed 1, 3, 7, 14, or 28 days later. Enhanced Perl's reaction was used for iron staining, and brain nonheme iron content was determined. Brain heme oxygenase-1, transferrin, transferrin receptor, and ferritin were examined by Western blot analysis and immunohistochemistry. Immunofluorescent double labeling was performed to identify which cell types express ferritin. Results-ICH upregulated heme oxygenase-1 levels and resulted in iron overload in the brain. A marked increase in brain nonheme iron was not cleared within 4 weeks. Brain transferrin and transferrin receptor levels were also increased. In addition, an upregulation of ICH on ferritin was of very long duration. Conclusions-The iron overload and upregulation of iron-handling proteins, including transferrin, transferrin receptor, and ferritin, in the brain after ICH suggest that iron could be a target for ICH therapy.

Background and Purpose-In humans, intracerebral hemorrhage (ICH) causes marked perihematomal edema formation and neurological deficits. A rat ICH model, involving infusion of autologous blood into the caudate, has been used extensively to study mechanisms of edema formation, but an examination of behavioral outcome would improve its preclinical utility and provide a more rigorous assessment of the pathological cascade of events over time. The purpose of this study was to use a battery of sensorimotor function tests to examine the neurological effects of ICH in the rat and to examine which components of the hematoma are involved in generating those effects. Methods-The behavioral tests used were forelimb placing, preference for forelimb use for weight shifts during vertical exploration of a cylindrical enclosure, and a corner turn test. Rats were tested from day 1 to day 28 after injection of autologous whole blood; injection of blood plus hirudin (thrombin inhibitor), packed red blood cells, thrombin, or saline; or needle placement only. Results-The battery of tests indicated that there were marked neurological deficits by day 1 after ICH, with progressive recovery of function over 4 weeks. The forelimb placing score paralleled changes in edema. Injection of thrombin caused and injection of hirudin reduced the ICH-induced neurological deficits. Injection of packed red blood cells, which causes delayed edema formation, induced delayed neurological deficits Conclusions-These tests allow continuous monitoring of neurological deficits after rat ICH and assessment of therapeutic interventions. The time course of the neurological deficit closely matched the time course of cerebral edema for both ICH and injection of blood components. There was marked recovery of function after ICH, which may be amenable to therapeutic manipulation.

Hemoglobin causes brain edema, at least in part, through its degradation products. Limiting hemoglobin degradation coupled with the use of iron chelators may be a novel therapeutic approach to limit brain edema after ICH.

There have been few investigations of brain edema formation after intracerebral hemorrhage (ICH), despite the fact that mass effect and edema are important clinical complications. The present study was designed to investigate the time course for the formation and resolution of brain edema and to determine how changes in cerebral blood flow (CBF) and blood-brain barrier (BBB) permeability are temporally related to edema formation following ICH. Anesthetized adult rats received a sterile injection of 100 microliters of autologous blood into the caudate nucleus. Water and ion contents were measured immediately, at 4 and 12 hours, and daily to Day 7 (10 time points, six rats at each time) after experimental ICH. The water content of the ipsilateral basal ganglia increased progressively (p < 0.002) over the first 24 hours, then remained constant until after Day 5, when the edema began to resolve. Edema was most severe in the tissue immediately surrounding the hemorrhage; however, it was also present in the ipsilateral cortex, the contralateral cortex, and the basal ganglia. Measurements of local CBF (using [14C]-iodoantipyrine) and BBB permeability (using [3H]-alpha-aminoisobutyric acid) were obtained in separate groups of six to eight rats at various time intervals between 1 and 48 hours after ICH. Cerebral blood flow was reduced to 50% of control at 1 hour, returned to control values by 4 hours, but then decreased to less than 50% of control between 24 and 48 hours after ICH. The BBB permeability increased significantly prior to the occurrence of significant edema in the tissue surrounding the clot. However, BBB permeability in the more distant structures remained normal despite the development of edema. These results demonstrate a time course for the formation and resolution of brain edema following ICH similar to that observed during focal ischemia. Brain edema forms in the immediate vicinity of the clot as a result of both BBB disruption and the local generation of osmotically active substances and then spreads to adjacent structures. While local ischemia, due to the mass effect of the hemorrhage, may play a role in producing cytotoxic and vasogenic edema, the release of toxic substances from the clot should also be considered. Since edema is nearly maximal by 24 hours after ICH, therapy directed at reducing edema formation must be instituted within the 1st day.

These results demonstrate that RBCs play a potentially important role in delayed edema development after ICH and that RBC lysis and hemoglobin toxicity may be useful targets for therapeutic intervention.

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