Julian T. Hoff

Mechanisms of brain injury after intracerebral haemorrhage

The past decade has resulted in a rapid increase in knowledge of mechanisms underlying brain injury induced by intracerebral haemorrhage (ICH). Animal studies have suggested roles for clot-derived factors and the initial physical trauma and mass effect as a result of haemorrhage. The coagulation cascade (especially thrombin), haemoglobin breakdown products, and inflammation all play a part in ICH-induced injury and could provide new therapeutic targets. Human imaging has shown that many ICH continue to expand after the initial ictus. Rebleeding soon after the initial haemorrhage is common and forms the basis of a current clinical trial using factor VIIa to prevent rebleeding. However, questions about mechanisms of injuries remain. There are conflicting data on the role of ischaemia in ICH and there is uncertainty over the role of clot removal in ICH therapy. The next decade should bring further information about the underlying mechanisms of ICH-induced brain injury and new therapeutic interventions for this severe form of stroke. This review addresses our current understanding of the mechanisms underlying ICH-induced brain injury.

Adjacent segment disease after lumbar or lumbosacral fusion: review of the literature.

Study Design. Review of the literature. Objectives. Review the definition, etiology, incidence, and risk factors associated with as well as potential treatment options. Summary of Background Data. The development of pathology at the mobile segment next to a lumbar or lumbosacral spinal fusion has been termed adjacent segment disease. Initially reported to occur rarely, it is now considered a potential late complication of spinal fusion that can necessitate further surgical intervention and adversely affect outcomes. Methods. MEDLINE literature search. Results. The most common abnormal finding at the adjacent segment is disc degeneration. Biomechanical changes consisting of increased intradiscal pressure, increased facet loading, and increased mobility occur after fusion and have been implicated in causing adjacent segment disease. Progressive spinal degeneration with age is also thought to be a major contributor. From a radiographic standpoint, reported incidence during average postoperative follow-up observation ranging from 36 to 369 months varies substantially from 5.2 to 100%. Incidence of symptomatic adjacent segment disease is lower, however, ranging from 5.2 to 18.5% during 44.8 to 164 months of follow-up observation. The rate of symptomatic adjacent segment disease is higher in patients with transpedicular instrumentation (12.2–18.5%) compared with patients fused with other forms of instrumentation or with no instrumentation (5.2–5.6%). Potential risk factors include instrumentation, fusion length, sagittal malalignment, facet injury, age, and pre-existing degenerative changes. Conclusion. 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.

Barbiturate Protection in Acute Focal Cerebral Ischemia

We have found that anesthetic technique modifies the neurological and pathological sequelae of unilateral middle cerebral artery and internal carotid artery occlusion in dogs. Occlusion was performed in seven groups of six dogs during each of the following anesthetic regimens: light (0.8%) halothane, “awake,” deep (1.9%) halothane, deep halothane with mean arterial pressure reduced to 55 torr, pentobarbital (56 mg per kilogram), light halothane plus 40 mg per kilogram thiopental begun just before cerebral artery occlusion, and light halothane plus 40 mg per kilogram thiopental begun 15 minutes after occlusion. Body temperature, arterial Pco2 Po2 pH, and blood pressure (except as noted above) were maintained normal. Neurological examinations were performed daily. On the seventh day the dogs were killed and their brains removed for pathological study. Hemiparesis occurred in five of six dogs under light halothane and five of six awake dogs; a mean of 10.8% and 9.6%, respectively, of their right hemispheres were infarcted. In the deep halothane groups, all of the normotensive and five of the six hypotensive dogs became severely hemiplegic; mean infarction size was 28.2% and 34.1%, respectively. Only one of the 18 dogs who received a barbiturate sustained a neurological deficit — a transient unilateral weakness. Means of 1.4%, 2.7%, and 0.1% of the right hemisphere were infarcted in the barbiturate animals. The protective action of barbiturates in canine acute focal cerebral ischemia suggests that they should be considered for anesthesia in surgery requiring cerebral vessel occlusion and perhaps even for treatment of acute stroke.

Behavioral Tests After Intracerebral Hemorrhage in the Rat

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.

Middle cerebral artery occlusion in rats: a neurological and pathological evaluation of a reproducible model.

Middle cerebral artery occlusion (MCAO) in rats produces an infarct of varying size. We examined three factors that may influence this variability: animal weight, vascular anatomy, and extent of occlusion in rats undergoing MCAO. We also developed a four-point neurological evaluation scale and validated its usefulness by comparing it with a four-grade pathological determination of the size of the infarct. Of 82 animals subjected to a standard MCAO, 34 developed small cortical infarcts (pathological grades I-II; infarct size less than 25 mm2, 6-17% of the ipsilateral cortex surface area), and 48 large infarcts (pathological grades III-IV, infarct size greater than 25 mm2, 20-56% of surface area). We were able to predict the size of infarction from the neurological evaluation in 83% of the animals, and this accuracy reached 91% when grades I and II and III and IV were considered together (P less than 0.001). In 41 animals subjected to a more extensive vascular occlusion, 89% exhibited large infarcts. Four vascular patterns were identified but none played a significant role in the incidence or size of the cortical stroke. However, rats weighing less than 300 g showed a smaller lesion size than did rats greater than 300 g. Our proposed new MCAO technique appears useful in reproducing large-sized infarcts of the frontoparietal cortex.

Iron and Iron-Handling Proteins in the Brain After Intracerebral Hemorrhage

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 &mgr;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.

Skull x-ray examinations after head trauma. Recommendations by a multidisciplinary panel and validation study.

The value of skull radiography in identifying intracranial injury has not yet been satisfactorily defined. A multidisciplinary panel of medical experts was assembled to review the issue of skull radiography for head trauma. The panel identified two main groups of patients--those at high risk of intracranial injury and those at low risk of such injury--and developed a management strategy for imaging in the two groups. The high-risk group consists primarily of patients with severe open or closed-head injuries who have a constellation of findings that are usually clinically obvious. These patients are candidates for emergency CT scanning, neurosurgical consultation, or both. The low-risk group includes patients who are asymptomatic or who have one or more of the following: headache, dizziness, scalp hematoma, laceration, contusion, or abrasion. Radiographic imaging is not recommended for the low-risk group and should be omitted. An intermediate moderate-risk group is less well defined, and skull radiography in this group may sometimes be appropriate. A prospective study of 7035 patients with head trauma at 31 hospital emergency rooms was conducted to validate the management strategy. No intracranial injuries were discovered in any of the low-risk patients. Therefore, no intracranial injury would have been missed by excluding skull radiography for low-risk patients, according to the protocol. We conclude that use of the management strategy is safe and that it would result in a large decrease in the use of skull radiography, with concomitant reductions in unnecessary exposure to radiation and savings of millions of dollars annually.

Acute inflammatory reaction following experimental intracerebral hemorrhage in rat.

Previous studies on intracerebral hemorrhage (ICH) indicate that brain edema increases progressively in the first 24 h and remains elevated for several days. The cause of secondary brain injury and edema formation is uncertain. We hypothesized that inflammatory mediators released from the blood after cerebral hemorrhage might cause secondary brain injury and edema formation. This study investigates if, when and where inflammation occurs after ICH in rat. Immunocytochemistry for polymorphonuclear leukocyte marker (myeloperoxidase, MPO), microglia marker (OX42) and intracellular adhesion molecule-1 (ICAM-1) was performed in control, and 1, 3, 7 and 10 days after the injection of 100 microliter autologous blood in the right basal ganglia. Double labeling immunohistochemistry was used to identify ICAM-1 positive cells. The results show that an inflammatory response occurred in and around the blood clot after ICH, characterized by the infiltration of neutrophils and macrophages as well as activation of microglia. ICAM-1 immunoreactivity was observed in blood vessels adjacent to the clot, as well as in activated microglia and neurons in the ipsilateral hemisphere. The present study demonstrates there is an inflammatory response in the brain after ICH. Infiltrating leukocytes and activated microglia may release cytotoxic mediators contributing to secondary brain injury.

Use of factor IX complex in warfarin-related intracranial hemorrhage.

OBJECTIVE Anticoagulation-treated patients presenting with intracranial hemorrhage, including subdural hematoma, epidural hematoma, subarachnoid hemorrhage, and intracerebral hemorrhage, require urgent correction of their coagulopathy to prevent worsening hemorrhage and to facilitate surgical intervention when necessary. In this study, we compared the use of fresh frozen plasma (FFP) with that of Factor IX complex concentrate (FIXCC) to achieve rapid correction of warfarin anticoagulation. METHODS Patients admitted to a tertiary care center with computed tomography-proven intracranial hemorrhage and a prothrombin time of more than 17 seconds were considered for inclusion in the study protocol. Complete data sets were obtained for eight patients randomized to treatment with FFP and five patients randomized to treatment with FFP supplemented with FIXCC. The prothrombin time and International Normalized Ratio were measured every 2 hours for 14 hours. Correction of anticoagulation was defined as an International Normalized Ratio of < or =1.3. RESULTS A difference in repeated International Normalized Ratio measurements during the first 6 hours of correction was observed between the FIXCC and FFP groups (P < 0.03). The rate of correction was greater (P < 0.01) and the time to correction was shorter (P < 0.01) for the FIXCC-treated group. No difference in neurological outcomes was detected between groups, but a higher complication rate was observed for the FFP-treated group. CONCLUSION The use of FIXCC accelerated correction of warfarin-related anticoagulation in the presence of intracranial hemorrhage.

Brain Injury After Intracerebral Hemorrhage: The Role of Thrombin and Iron

Intracerebral hemorrhage (ICH) is a subtype of stroke with high morbidity and mortality. The mechanisms underlying ICH-induced brain injury have become better understood during the past decade. Experimental investigations have indicated that thrombin formation, red blood cell lysis, and iron toxicity play a major role in ICH-induced injury and that these mechanisms may provide new therapeutic targets. This article reviews the role of thrombin and iron in ICH-induced injury.