Short-term continuous intraparenchymal intracranial pressure monitoring in presumed idiopathic intracranial hypertension.

BACKGROUND: The management of idiopathic intracranial hypertension (IIH) depends on a reliable assessment of intracranial pressure (ICP), particularly when visual function measures or ophthalmoscopic indicators are confusing and when invasive surgical procedures are being considered. Although ICP monitoring has been widely applied in many neurologic conditions as a more reliable measure of ongoing ICP than lumbar puncture (LP), it has not often been widely used in the management of IIH. METHODS: We searched the records of the University of Michigan between 2001 and 2008 for patients with IIH who had undergone LP and continuous ICP monitoring with an intraparenchymal Codman ICP Monitoring System and in whom at least 1 year of follow-up information was available. Ten patients met entry criteria. RESULTS: There were no complications from the ICP monitoring. ICP monitoring influenced management in all 10 patients. In 8 patients, LP had shown elevated opening pressures; in 7 of them, ICP monitoring failed to confirm a consistently high ICP. In these patients, the decision to withdraw ICP-lowering agents or shunts, or not to revise indwelling shunts, produced no change in visual function or optic disc appearance over a follow-up period of at least 1 year. In 1 patient, ICP monitoring confirmed the high ICP suggested by LP, justifying placement of a ventriculoperitoneal shunt. In 1 patient, ICP monitoring was performed instead of LP because a petroclival mass posed a danger to the performance of LP; a shunt was subsequently placed due to elevated ICP. CONCLUSION: In providing more accurate information about ICP than about LP, short-term continuous ICP intraparenchymal monitoring may be a useful adjunct in the management of IIH when clinical data are confusing and invasive interventions are under consideration.

Lumbar flexion and dynamic EMG among persons with single level disk herniation pre- and postsurgery with radicular low-back pain.

OBJECTIVE: The paraspinal muscles often fail to relax on forward flexion in many persons with low-back pain. The goal of this prospective study was to determine whether this abnormal lack of a flexion-relaxation phenomenon corrects after lumbar diskectomy for symptoms of radiculopathy with low-back pain. DESIGN: Electromyographic testing was performed on 17 patients before and 30 days after lumbar diskectomy. RESULTS: Although pain improved significantly (P < 0.05), the flexion-relaxation phenomenon did not improve. CONCLUSIONS: Failure to recover muscle relaxation while pain is relieved suggests another mechanism for paraspinal activity.

Thrombin enhances glioma growth.

BACKGROUND: Our previous studies have demonstrated that argatroban, a specific thrombin inhibitor, reduces brain edema and neurological deficits in rat glioma models. The present study investigated whether or not thrombin enhances glioma growth in vivo and in vitro. METHODS: There were two parts in this study. In the first part, rat C6 glioma cells were treated with or without thrombin. These cells were then injected into the right caudate of adult male Fischer 344 rats. Rats underwent behavioral testing prior to sacrifice 12 days later for tumor mass measurement. In the second part, C6 cells were incubated in serum-free medium for 24 hours and then treated with thrombin with or without argatroban, a thrombin inhibitor. DNA synthesis was examined using a 5-bromo-2'-deoxyuridine (BrdU) ELISA kit. Cell proliferation was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. FINDINGS: Treatment of C6 cells with thrombin prior to intracerebral implantation resulted in a larger tumor mass and worse neurological deficits at dayl2. In vitro, thrombin increased DNA synthesis in C6 glioma cells, and this effect was blocked by argatroban. MTT assay showed that thrombin significantly increased glioma cell proliferation in vitro. CONCLUSIONS: In summary, thrombin enhances C6 glioma growth in vivo and cell proliferation in vitro suggesting that thrombin may be a target of glioma therapy.

Spinal canal size and clinical symptoms among persons diagnosed with lumbar spinal stenosis.

OBJECTIVE: Clinical symptoms associated with lumbar spinal stenosis (LSS) are believed to be due to neurogenic claudication caused by narrowing of the central and lateral spinal canals. However, there is a paucity of published data on these relationships. The purpose of the present study was to examine the relationship between clinical symptoms associated with LSS and osseous anterior-posterior (AP) spinal canal diameter as measured on axial magnetic resonance imaging. DESIGN: Cross-sectional study conducted at a University Spine Program. Fifty persons with a clinical diagnosis of LSS were administered measures of clinical pain and perceived function. Walking distance in the laboratory and community was also assessed. Participants also underwent magnetic resonance imaging of the spine. RESULTS: Using recommended upper limits from the literature, patients with smaller canals reported greater perceived disability, but no other group differences emerged. In the entire sample, AP spinal canal diameter was not significantly associated with any of the clinical symptom measures examined. Body mass index was found to be significantly related to walking distance, but not perceived function or pain. CONCLUSIONS: AP spinal canal diameter is not predictive of clinical symptoms associated with LSS. The findings also suggest that body mass may play a significant role in functional limitations observed in this population.

A new hippocampal model for examining intracerebral hemorrhage-related neuronal death: effects of deferoxamine on hemoglobin-induced neuronal death.

BACKGROUND AND PURPOSE: There is an urgent need to develop a model in which to study the mechanism of intracerebral hemorrhage-induced neuronal death in vivo. METHODS: This study was divided into 2 parts: (1) Rats received either an infusion of hemoglobin, ferrous iron, or saline into the right hippocampus; (2) Rats had an infusion of hemoglobin and then were treated with either deferoxamine or vehicle. Rats were killed for hippocampus size, DNA damage, and neuronal death measurements. RESULTS: Compared with saline, hemoglobin or iron injection caused hippocampal neuronal death. Systemic use of deferoxamine reduced hemoglobin-induced DNA damage, hippocampal neuronal death, and atrophy. CONCLUSIONS: This article demonstrates a new model and indicates that iron has a key role in hemoglobin-induced neuronal death.

Preconditioning with hyperbaric oxygen attenuates brain edema after experimental intracerebral hemorrhage.

OBJECT: Preconditioning with hyperbaric oxygen (HBO2) reduces ischemic brain damage. Activation of p44/42 mitogen-activated protein kinases (p44/42 MAPK) has been associated with preconditioning-induced brain ischemic tolerance. This study investigated if preconditioning with HBO2 protects against intracerebral hemorrhage (ICH)-induced brain edema formation and examined the role of p44/42 MAPK in such protection. METHODS: The study had three experimental groups. In Group 1, Sprague-Dawley rats received two, three, or five consecutive sessions of preconditioning with HBO2 (3 ata, 100% oxygen, 1 hour daily). Twenty-four hours after preconditioning with HBO2, rats received an infusion of autologous blood into the caudate. They were killed 1 or 3 days later for brain edema measurement. Rats in Group 2 received either five sessions of preconditioning with HBO2 or control pretreatment and were killed 24 hours later for Western blot and immunohistochemical analyses. In Group 3, rats received an intracaudate injection of PD098059 (an inhibitor of p44/42 MAPK activation) before the first of five sessions of preconditioning with HBO2. Twenty-four hours after the final preconditioning with HBO2, rats received an intracaudate blood infusion. Brain water content was measured 24 hours after ICH. RESULTS: Fewer than five sessions of preconditioning with HBO2 did not significantly attenuate brain edema after ICH. Five sessions of preconditioning with HBO2 reduced perihematomal edema 24 and 72 hours after ICH (p < 0.05). Strong p44/42 MAPK immunoreactivity was detected in the basal ganglia 24 hours after preconditioning with HBO2. Intracaudate infusion of PD098059 abolished HBO2 preconditioning-induced protection against ICH-induced brain edema formation. CONCLUSIONS: Preconditioning with HBO2 protects against brain edema formation following ICH. Activation of the p44/42 MAPK pathway contributes to that protection. Preconditioning with HBO2 may be a way of limiting brain injury during invasive neurosurgical procedures that cause bleeding.

Electromyographic and magnetic resonance imaging to predict lumbar stenosis, low-back pain, and no back symptoms.

BACKGROUND: Magnetic resonance imaging is commonly used to diagnose lumbar spinal stenosis. Some persons without symptoms have a small lumbar spinal canal. Electrodiagnosis has been used to diagnose spinal stenosis for over sixty years, but we are aware of no masked, controlled trials of the use of electrodiagnosis for that purpose. This study was performed to evaluate the relationships of magnetic resonance imaging measures and electrodiagnostic data with the clinical syndrome of spinal stenosis. METHODS: One hundred and fifty persons between the ages of fifty-five and eighty years old, including asymptomatic volunteers and persons referred for lumbar magnetic resonance imaging, underwent clinical examination, electrodiagnosis, and magnetic resonance imaging. Subjects were excluded if they had neuromuscular disease, sacral cancer, or inadequate test results, which left 126 subjects for the final analysis. The final cohort was divided into three groups--no back pain, mechanical back pain, and clinical spinal stenosis--on the basis of the impression of the examining physician, for whom the results of the magnetic resonance imaging and electrodiagnostic testing were masked. A spine surgeon also reviewed both the imaging and clinical examination data. RESULTS: The examining physician's diagnosis of clinical spinal stenosis was significantly related to the neurological findings on examination (p < 0.05) and to the spine surgeon's diagnosis (p < 0.001). The diagnosis of clinical spinal stenosis was also significantly related to the presence of fibrillations on electrodiagnostic testing (p < or = 0.003), the minimum anteroposterior diameter of the spinal canal on the magnetic resonance images (p = 0.016), and the average of the two smallest spinal canal diameters (p = 0.008) on the images. Measurements on magnetic resonance imaging did not differentiate subjects with clinical spinal stenosis from controls better than chance, whereas paraspinal mapping electrodiagnosis scores did. CONCLUSIONS: This prospective, controlled, masked study of electrodiagnosis and magnetic resonance imaging for older subjects showed that imaging does not differentiate symptomatic from asymptomatic persons, whereas electrodiagnosis does. We believe that radiographic findings alone are insufficient to justify treatment for spinal stenosis.

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.

Predictors of pain and function in persons with spinal stenosis, low back pain, and no back pain.

STUDY DESIGN: Longitudinal masked, double-controlled cohort study. OBJECTIVES: To determine prognosis and predictors of function and pain in persons with spinal stenosis. SUMMARY OF BACKGROUND DATA: The clinical syndrome of spinal stenosis is common and disabling, but not clearly related to anatomic measures. Prognosis not well studied. METHODS: Persons 55 to 80 years of age with and without stenosis on preliminary review of magnetic resonance imaging (MRI), and asymptomatic volunteers underwent screening, questionnaires, physical examination, ambulation testing, masked electromyogram (EMG), and masked MRI scans; these were repeated at >18 months. RESULTS: Twenty-three asymptomatic, 28 back pain, and 32 clinically diagnosed stenosis subjects underwent follow-up. Although initial and follow-up diagnosis tended to agree (kappa = 0.394, P < 001), there were substantial shifts between the three groups. Among persons with clinically diagnosed stenosis, every measure trended for improvement, including significant changes in pain, ambulation, and EMG. Ambulation velocity and Pain Disability Index at follow-up were predicted by initial disability measures. Pain was predicted by initial sleep difficulty but not initial pain. EMG and MRI did not predict function or pain. CONCLUSION: Clinically recognized spinal stenosis is fluctuating and largely improving, and in continuum with back pain and no symptoms. Since anatomic and neurologic deficits do not predict future function, they should not be weighed heavily in surgical risk-benefit discussions.

Spinal stenosis, back pain, or no symptoms at all? A masked study comparing radiologic and electrodiagnostic diagnoses to the clinical impression.

OBJECTIVE: To assess the relations between clinically recognized lumbar spinal stenosis and the conclusions of masked radiologists and electrodiagnosticians. DESIGN: Prospective, masked, double-controlled trial. SETTING: University spine center. PARTICIPANTS: One hundred fifty persons age 55 to 80 years with or without back pain and with or without magnetic resonance imaging (MRI)-demonstrated stenosis, screened for neuropathy risk, previous surgery, or cancer. INTERVENTIONS: Questionnaires on pain and function; ambulation testing and physical examination; and masked electrodiagnotics and MRI. MAIN OUTCOME MEASURE: Diagnostic impressions of the examining clinician, radiologist, and electrodiagnostician. RESULTS: Following application of post hoc exclusion criteria and elimination of patients due to incomplete or inadequate test data, the clinical diagnosis was lumbar stenosis in 50 subjects, back pain in 44 subjects, and no pain in 32 subjects. Radiologic and clinical impression had no relation (P = .80 vs asymptomatic, P = .99 vs back pain controls). Electrodiagnostic impression trended to relate to clinical impression (P = .14 vs asymptomatic, P = .09 vs back pain). Retrospective application of age-related electrodiagnostic norms for paraspinal electromyographic and limb motor unit changes, established in this study, reclassified 13 of the 17 asymptomatic persons whom the electrodiagnostician thought had stenosis. The clinical impression did correspond to history and physical examination findings typically associated with spinal stenosis and to the independent impression of a neurosurgeon who examined MRI and clinical, but not to the electrodiagnostic data. CONCLUSIONS: The impression obtained from an MRI scan does not determine whether lumbar stenosis is a cause of pain. Electrodiagnostic consultation may be useful, especially if age-related norms obtained in this study are applied.

Long-term effects of experimental intracerebral hemorrhage: the role of iron.

OBJECT: Intracerebral hemorrhage (ICH) causes brain atrophy and neurological deficits. The mechanisms of brain atrophy after ICH are poorly understood, although recent evidence suggests that some ICH-induced brain injury results from the products of hemoglobin degradation, including iron. In this study the authors examine the role of iron in brain atrophy and neurological deficits following ICH. METHODS: Male Sprague-Dawley rats received an infusion of either 100 microl autologous whole blood or saline into the right caudate. Hematoxylin and eosin staining was used for histological examination, and iron levels and ferritin immunoreactivities were also examined. Deferoxamine was used as an iron chelator. Over the duration of the experiment, the rats underwent behavioral testing (forelimb placing, forelimb use asymmetry, and corner turn tests). Brain atrophy in the caudate with prolonged neurological deficits occurred after ICH. Although partial functional recovery occurred with time, residual neurological deficits were still detectable at 3 months postprocedure. Iron accumulation and ferritin upregulation were present in the ipsilateral caudate. Deferoxamine reduced brain atrophy and improved behavioral outcomes, and it also reduced brain ferritin immunoreactivity. CONCLUSIONS: An ICH results in an accumulation of iron in the brain that is not cleared within 3 months and that contributes to brain tissue loss and neurological deficits posthemorrhage. Iron chelation may be a useful therapy for patients with ICH.

The role of complement C3 in intracerebral hemorrhage-induced brain injury.

Activation of the complement cascade contributes to brain injury after intracerebral hemorrhage (ICH). However, a recent study found that complement C5 deficient mice had enhanced ICH-induced brain injury. The present study, therefore, investigated the role of complement C3 (which is upstream from C5) in ICH. Male complement C3 deficient and sufficient mice had an intracerebral infusion of 30-muL autologous whole blood. The mice were killed and the brains were sampled for edema, Western blotting, immunohistochemistry and histologic analysis. Behavioral tests including forelimb use asymmetry test and corner turn were also performed before and after ICH. Compared to complement C3 sufficient mice, C3 deficient mice had less brain edema, lower hemeoxygenase-1 levels, less microglia activation and neutrophil infiltration around the clot after ICH. In addition, the C3-deficient mice had less ICH-induced forelimb use asymmetry deficits compared with C3-sufficient mice. These results suggest complement activation may affect heme metabolism and the inflammatory response after ICH suggesting that complement C3 is an important factor causing ICH-induced brain injury.

Tumor necrosis factor-alpha increases in the brain after intracerebral hemorrhage and thrombin stimulation.

OBJECTIVE: The goals of this study were 1) to determine the effects of intracerebral hemorrhage (ICH) on brain tumor necrosis factor (TNF)-alpha levels, which are still controversial; 2) to investigate the role of TNF-alpha in ICH-induced brain injury; 3) to examine the effects of thrombin on brain TNF-alpha levels; and 4) to elucidate the role of TNF-alpha in thrombin-induced neuroprotection. METHODS: Autologous whole blood and thrombin were injected into the right caudate of rats or mice. Brain TNF-alpha was then determined by enzyme-linked immunosorbent assay and immunohistochemistry. Brain edema and neurological deficits were also examined. RESULTS: Perihematomal TNF-alpha levels increased after ICH. ICH-induced brain edema was less in TNF-alpha knockout mice compared with wild-type mice (P < 0.05). Intracerebral infusion of thrombin also caused an increase in brain TNF-alpha levels. Thrombin preconditioning reduced thrombin-induced brain edema, but this effect was not blocked by a neutralizing TNF-alpha antibody. CONCLUSION: Increase of perihematomal TNF-alpha levels contributes to brain edema formation after ICH. Thrombin may be a major mediator of ICH-induced TNF-alpha production, but thrombin-induced brain tolerance may not be TNF-alpha mediated.

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.

The sensitivity and specificity of electrodiagnostic testing for the clinical syndrome of lumbar spinal stenosis.

STUDY DESIGN: Prospective, masked, double controlled diagnostic trial. OBJECTIVES: To determine the sensitivity and specificity of electrodiagnostic consultation (EDX) for the clinical syndrome of lumbar spinal stenosis. SUMMARY OF BACKGROUND DATA: EDX has been used for more than 50 years to diagnose spinal disorders but has not met the new standards of evidence-based medicine. METHODS: A total of 150 subjects (asymptomatic volunteers and patients with MRIs suggesting back pain or spinal stenosis; 55-80 years of age) underwent physiatrist history and physical examination, MRI, and review of this data by a neurosurgeon, with each clinician masked to any outside information, leading to a unanimous consensus on diagnosis in 55. After masked EDX testing, 7 subjects with undiagnosed neuromuscular disease were discovered. EDX findings were related to "clinical gold standard" diagnoses in 48 persons. RESULTS: Paraspinal mapping EMG score of >4 had 100% specificity and 30% sensitivity for stenosis compared with either the back pain or asymptomatic groups (each, P < 0.04). A composite limb and paraspinal fibrillation score had a sensitivity of 47.8% and specificity of 87.5% (P = 0.008), and H-wave sensitivity was 36.4, specificity 91.3 (P = 0.026) for stenosis versus all controls. CONCLUSIONS: This first masked study in the 60-year history of needle electromyography also introduces anatomically validated needle placement, quantified and reproducible examination of the paraspinal muscles, and dual control populations to EDX research in spinal disorders. EDX has statistically significant, clinically meaningful specificity for spinal stenosis and detects neuromuscular diseases that may masquerade as stenosis.

Estrogen therapy for experimental intracerebral hemorrhage in rats.

OBJECT: The aims of this study were to determine the following: whether there are sex differences in intracerebral hemorrhage (ICH) induced brain injury in rats, whether delayed administration of 17beta-estradiol can reduce ICH-induced brain damage, and whether these effects are estrogen receptor (ER)-dependent. METHODS: Male and female Sprague-Dawley rats received an infusion of 100 microl autologous whole blood into the right basal ganglia. Twenty-four hours later the rats were killed. The effects of 17beta-estradiol on ICH-induced brain injury were examined by measuring brain edema and neurological deficits. Both ER-alpha and hemeoxygenase (HO)-1 were investigated through Western blot and immunohistochemical analysis. Brain edema was significantly less severe in female compared with that in male rats. The ER antagonist ICI 182,780 exacerbated ICH-induced brain edema in female but not in male rats, indicating that ER-alpha activation during ICH is protective in female rats. Administration of exogenous 17beta-estradiol in male, but not in female, rats significantly attenuated brain edema, neurological deficits, and ICH-induced changes in HO-1 when given 2 hours after hemorrhage. The effects of exogenous 17beta-estradiol occurred through an ER-independent mechanism. CONCLUSIONS: Results in this study indicate that 17beta-estradiol could be a potential therapeutic agent for ICH.

Propionibacterium infection associated with bovine pericardium dural allograft. Case report.

Propionibacteria are known to play a part in postneurosurgical infections, primarily those involving ventricular shunts. Nevertheless, little is known about the association between dural allografts and propionibacterium infections. Two patients underwent craniotomy for supratentorial meningiomas and each received a dural allograft. Both patients subsequently presented with delayed epidural fluid collections several weeks after surgery. Propionibacterium species was cultured in samples from both patients. The allografts were removed and the patients were treated with appropriate antibiotic agents; one patient underwent an interval craniectomy. Both patients demonstrated neuroimaging and clinical improvement after surgery and antiobiotic therapy. These cases demonstrate the association of propionibacterium infections with dural allografts. Furthermore, in patients with latent and indolent infections, Propionibacterium spp. should be suspected and treated appropriately.

The deleterious or beneficial effects of different agents in intracerebral hemorrhage: think big, think small, or is hematoma size important?

BACKGROUND AND PURPOSE: Thrombin, heme oxygenase, complement, microglia activation, and leukocyte infiltration are all actively upregulated in intracerebral hemorrhage (ICH). Experimental evidence suggests that all these factors are involved in ICH-induced brain injury. This suggests a scenario whereby ICH actively (through gene and protein upregulation) induces pathways that result in brain injury. SUMMARY OF REVIEW: In this comment, we suggest a potential answer to this conundrum. The upregulation of these factors may have been an evolutionary adaptation to limit brain injury during small hematomas (microbleeds). There is evidence that low levels of thrombin and heme oxygenase limit brain injury. In contrast, the excessive upregulation of these same factors may have a harmful effect after a large hematoma. CONCLUSIONS: The mechanisms upregulated to limit brain injury after microbleeds may also induce injury after large hematomas. The effect of hematoma size on the mechanisms involved in ICH-induced brain injury and the implications of any such effect on clinical therapies merit further investigation.

Oxidative DNA injury after experimental intracerebral hemorrhage.

Our previous studies have demonstrated that DNA injury occurs in the brain after intracerebral hemorrhage (ICH). DNA damage can result from at least two pathways, either endonuclease-mediated DNA fragmentation or oxidative injury. The present study investigated the occurrence of the latter after ICH and the role of iron in such injury. Male Sprague-Dawley rats received an infusion of autologous whole blood or ferrous iron into the right basal ganglia. Control rats just had a needle insertion (sham). The rats were sacrificed 1, 3, or 7 days later. 8-Hydroxyl-2'-deoxyguanosine (8-OHdG) was analyzed by immunohistochemistry while the number of apurnic/apyrimidinic abasic sites (AP sites) was also quantified. 8-OHdG and AP sites are two hallmarks of DNA oxidation. Dinitrophenyl (DNP) was measured by Western blotting to compare the time course of protein oxidative damage to that of DNA. DNA repair Ku proteins were measured by Western blot analysis. DNA damage was also examined using DNA polymerase I-mediated biotin-dATP nick translation (PANT) labeling. An increase of 8-OHdG, AP sites and DNP levels and a decrease of Ku levels were observed. Abundant PANT-positive cells were also observed in the perihematomal area 3 days after ICH. In addition, intracerebral infusion of iron increased brain DNP levels and resulted in DNA injury. These results suggest that oxidative stress contributes to DNA damage and brain injury after ICH. Reducing DNA oxidative damage (for example, through iron chelation) may be a therapeutic target for ICH.

Holo-transferrin and thrombin can interact to cause brain damage.

BACKGROUND AND PURPOSE: Previous studies have suggested that delayed release of hemoglobin degradation products, particularly iron, is involved in intracerebral hemorrhage (ICH)-induced brain injury. However, a recent study found evidence of iron-induced brain injury soon after ICH. This study, therefore, examined whether another iron-containing component of blood, holo-transferrin (holo-Tf), might also induce brain injury either alone or in combination with thrombin, another factor involved in early ICH-induced brain injury. METHODS: Male Sprague-Dawley rats received an intracerebral infusion of holo-Tf, apo (noniron-loaded)-Tf, thrombin, or a combination of Tf with thrombin into the right basal ganglia. The rats were euthanized 24 hours later for measurement of brain edema and assessment of DNA damage (single- and double-strand breaks and 8-hydroxyl-2'-deoxyguanosine immunohistochemistry). Iron distribution was examined histochemically. RESULTS: Holo-Tf, apo-Tf, and the dose of thrombin used (1 U) all failed to induce brain edema when administered alone. However, the combination of holo-Tf with thrombin (but not apo-Tf with thrombin) caused brain edema, DNA damage, and intracellular iron accumulation in the ipsilateral basal ganglia. CONCLUSIONS: These results suggest that in addition to hemoglobin-bound iron, Tf-bound iron may contribute to ICH-induced brain injury and that thrombin may contribute to the latter by facilitating cellular iron uptake.