Diverse effects of hypothermia therapy in patients with severe traumatic brain injury based on the computed tomography classification of the traumatic coma data bank.

A multicenter randomized controlled trial of patients with severe traumatic brain injury who received therapeutic hypothermia or fever control was performed from 2002 to 2008 in Japan (BHYPO). There was no difference in the therapeutic effect on traumatic brain injury between the two groups. The efficacy of hypothermia treatment and the objective of the treatment were reexamined based on a secondary analysis of the BHYPO trial in 135 patients (88 treated with therapeutic hypothermia and 47 with fever control). This analysis was performed to examine clinical outcomes according to the CT classification of the Traumatic Coma Data Bank on admission. Clinical outcomes were evaluated with the Glasgow Outcome Scale and mortality at 6 months after injury. Good recovery and moderate disability were defined as favorable outcomes. Favorable outcomes in young patients (≤50 years old) with evacuated mass lesions significantly increased from 33.3% with fever control to 77.8% with therapeutic hypothermia. Patients with diffuse injury III who were treated with therapeutic hypothermia, however, had significantly higher mortality than patients treated with fever control. It was difficult to control intracranial pressure with hypothermia for patients with diffuse injury III, but hypothermia was effective for young patients with an evacuated mass lesion.

Survey of brain temperature management in patients with traumatic brain injury in the Japan neurotrauma data bank.

The goal of this study was to evaluate the clinical characteristics and effects of brain temperature management in patients with severe traumatic brain injury (TBI). A total of 1091 patients were registered from the Japan Neurotrauma Data Bank Project 2009. Those with a Glasgow Coma Scale (GCS) score of 9 or more, a GCS score of 3, bilateral dilated pupils, or cardiopulmonary arrest on arrival were excluded. This left a total of 401 patients. Patients were classified into three groups: no temperature management, with no intervention for brain temperature (225 patients, 56.1%), intensive normothermia (129 patients, 32.2%), and hypothermia (47 patients, 11.7%). Patient age, GCS score, pupillary abnormality, Injury Severity Score (ISS), intracranial pressure (ICP) monitoring, and outcome according to CT classification (Traumatic Coma Data Bank classification) on admission were examined. Patients were significantly older in the no temperature management group (average age 61.5 years) compared with normothermia (53.6 years) and hypothermia (46.9 years). ICP monitoring was significantly decreased in 85.1% of patients with hypothermia, 42.6% with normothermia, and 14.7% in no temperature management group. Favorable outcome rate was significantly higher with hypothermia (52.4%) compared with normothermia (26.9%) and no temperature management (20.7%) with evacuated mass lesions in contrast to diffuse injury. Multivariate analysis in patients with evacuated mass lesions showed that GCS (≥6 pts), and hypothermia were independent factors related to a favorable outcome. Appropriate thermoregulation of the brain for individual patients with various types of TBI are important.

Cortical damage following traumatic brain injury evaluated by iomazenil SPECT and in vivo microdialysis.

[(123)I] iomazenil (IMZ) single photon emission computed tomography (SPECT) has been reported to be a useful marker of neuronal integrity. We evaluated cortical damage following traumatic brain injury (TBI) with IMZ SPECT at the acute stage. After conventional therapy for a cranial trauma, an IMZ SPECT re-evaluation was performed at the chronic stage. A reduction in IMZ uptake in the location of cerebral contusions was observed during the TBI acute phase; however, images of IMZ SPECT obtained during the chronic phase showed that areas with decreased IMZ distribution were remarkably reduced compared with those obtained during the acute phase. As a result of in vivo microdialysis study, the extracellular levels of glutamate in the cortex, where decreased IMZ distribution was shown during the acute phase, were increased during the 168-h monitoring period. During the chronic phase, IMZ uptake in the region with the microdialysis probes was recovered. The results suggest that this reduction in IMZ uptake might not be a sign of irreversible tissue damage in TBI.

Progression of stenosis into occlusion of the distal posterior cerebral artery supplying an occipital arteriovenous malformation manifesting as multiple ischemic attacks: case report.

A 31-year-old healthy male presented with a rare case of cerebral arteriovenous malformation (AVM) manifesting as repeated ischemic attacks and cerebral infarction causing left sensori-motor disturbance. Neuroimaging revealed cerebral infarction in the right thalamus as well as right occipital AVM without bleeding. The AVM was mainly fed by the right angular artery, and the right posterior cerebral artery (PCA) showed mild stenosis and segmental dilation at the P(2)-P(3) portion. After referral to our hospital, transient ischemic attacks causing left homonymous hemianopsia, and left arm and leg numbness were frequently recognized. Additional imaging revealed a new ischemic lesion in the occipital lobe, and repeated cerebral angiography showed right PCA occlusion at the P(2)-P(3) segment. Cerebral AVM presenting with cerebral infarction due to occlusion of feeding arteries is rare. In our case, intimal injury due to increased blood flow or spontaneous dissection of the artery were possible causes. We should monitor any changes in the architecture and rheology of the feeding vessels during the clinical course to prevent ischemic complications.

External carotid artery stenting and superficial temporal artery to middle cerebral artery anastomosis for internal carotid artery occlusion with external carotid artery severe stenosis: case report.

Superficial temporal artery (STA) to middle cerebral artery (MCA) anastomosis may have inadequate effects in patients with internal carotid artery (ICA) occlusion and severe stenosis of the ipsilateral external carotid artery (ECA), because poor blood flow in the STA leads to insufficient flow to the MCA. In these patients, dilation of the stenotic ECA is required to improve the blood flow in the STA before STA-MCA anastomosis. A 71-year-old man presented with left hemiparesis and dysarthria. Magnetic resonance imaging revealed an old watershed infarction in the right cerebral hemisphere. Right carotid angiography showed right ICA occlusion and severe ipsilateral ECA stenosis. Single photon emission computed tomography (SPECT) demonstrated severe hemodynamic insufficiency in the right MCA territory. Instead of endarterectomy of the ECA, angioplasty and stenting (CAS) for ECA was performed to ensure adequate blood flow in the STA, due to the history of myocardial infarction and bifurcation of the common carotid artery at a high level (C2 level). Then STA-MCA anastomosis was performed 1 month later. Postoperative SPECT demonstrated marked improvement of hemodynamic insufficiency in the right MCA territory. After treatment, the patient had no ischemic events. This case suggests external CAS together with STA-MCA anastomosis is a good therapeutic option for a patient with symptomatic ICA occlusion and severe stenosis of the ipsilateral ECA if external CEA is difficult to perform.

p.Arg332Cys mutation of NOTCH3 gene in two unrelated Japanese families with CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is a cerebrovasuclar disease caused by NOTCH3 mutations, usually localized to exons 3 and 4. This report describes the clinical and neuroradiological findings of 2 subjects of two unrelated Japanese families who shared a common p.Arg332Cys mutation. The subject from family A presented syncope attacks as the sole clinical presentation at the beginning of his disease course. The subject from family B showed recurrent ischemic attacks, followed by a large intracranial hemorrhage. This is the first report to describe the detailed phenotypes of patients with a rare p.Arg332Cys mutation in Japan.

Significance of differences between brain temperature and core temperature (δ T) during mild hypothermia in patients with diffuse axonal injury.

The differences between brain and bladder temperature (delta T), and the relationship of delta T to cerebral perfusion pressure (CPP) and jugular venous oxygen saturation (SjO(2)) were studied during hypothermia in 11 patients with severe traumatic brain injury, of whom 5 underwent conservative treatment for diffuse axonal injury (DAI) (DAI group) and 6 who underwent decompressive craniectomy for hematoma (SDH group). All patients underwent hypothermia treatment. Brain temperature was monitored via an intraparenchymal catheter. Bladder temperature was used as the core temperature. SjO(2) was measured continuously. The outcome of all patients was evaluated at discharge using the Glasgow Outcome Scale. Delta T in the SDH group was significantly lower than that in the DAI group. No relationship was found between delta T and CPP during the investigation period. A significant correlation between delta T and SjO(2) was seen in the DAI group, but not in the SDH group. Decompressive craniectomy affects the brain temperature through external environmental factors. Measurement of brain temperature may be a reliable indicator of cerebral blood flow and brain metabolism in patients with DAI and closed cranium during hypothermia. Further experience is required to test this proposal.

Neuroprotective effects of ebselen following forebrain ischemia: involvement of glutamate and nitric oxide.

Ebselen is a mimic of glutathione peroxidase that reacts with peroxynitrite and inhibits nitric oxide (NO) synthase. Ebselen has beneficial effects on the neurological outcome of patients with stroke. In this study, the mechanisms by which ebselen can elicit neuroprotective effects against ischemic brain injury were investigated in male Wistar rats. Experimental forebrain ischemia was induced by bilateral common carotid artery occlusion with hemorrhagic hypotension. Ebselen was administered to animals in the treatment group 2 hours prior to the induction of forebrain ischemia, and placebo was administered in the control group. Cerebral blood flow (CBF) was measured by the hydrogen clearance method. Cortical extracellular levels of excitatory amino acids (EAAs) and NO were evaluated using in vivo microdialysis. Neuronal damage in the CA1 subfield of the hippocampus was assessed in brains harvested after a 24-hour period of survival. CBF did not recover to normal physiological levels after ischemic insults in either the control or treatment groups. The differences in the sequential changes in extracellular EAA and NO levels between groups were not statistically significant. There was a significantly larger mean density of intact, undamaged neurons in the CA1 subfield in the treatment group than in the control group. The neuroprotective effects of ebselen were reflected in the histological findings, without significant inhibition of glutamate release or NO synthesis during the acute phase of experimentally induced cerebral ischemia.

Survey of current neurotrauma treatment practice in Japan.

BACKGROUND: The Japanese Society of Neurotraumatology announced guidelines for management of severe traumatic brain injury (TBI) in 2000. To evaluate subsequent implementation of these guidelines, we investigated current severe TBI practices in Japan. METHODS: A questionnaire regarding management of severe TBI was sent to each of the 384 Japanese Neurosurgical Society specialist training medical centers and answers were received by mail from 233 centers (60.7%). RESULTS: Of the medical centers, 29% have neurosurgeons in their emergency department. Initial TBI treatment responsibility resided in the Departments of Neurosurgery in 34% of the medical centers, in the emergency department in 29%, and in 36% responsibility is assigned to both departments. Surgery was performed by neurosurgeons in 90% of the centers and postoperative management was assigned to neurosurgeons in 76%. Acute stage magnetic resonance imaging was done in 52% of the centers. An intracranial pressure sensor was inserted in 55%, and jugular venous oxygen saturation was measured in 21%. Hypothermia therapy was performed in 47%, positive normothermia therapy was administered in 76%, and barbiturate therapy was administered in 70%. Of the centers, 94% acknowledged the guidelines but only 72% of the centers implemented protocols that conformed to the guidelines. CONCLUSIONS: Neurosurgeons in Japan are positively involved in management of severe TBI, but few medical centers monitor TBI patients. Many medical centers find it difficult to conform to the guidelines due to lack of neurosurgeons and equipment. These problems can be addressed by consolidation of neurosurgeons into centralized centers and improvement of the medical insurance system.

[Cyst formation after radiosurgery for brain arteriovenous malformation treated with cystoperitoneal shunt].

Gamma knife and CyberKnife radiosurgery are well established and less invasive treatments for arteriovenous malformation. Delayed cyst formation is a rare but well-known complication of radiosurgery for arteriovenous malformations. The optimal treatment of cysts forming after radiosurgery remains debatable. We present a case of cyst formation after radiosurgery for brain arteriovenous malformation that was treated with a cystoperitoneal shunt (C-P shunt). A 36-year-old woman presented with left hemiparesis and numbness. Computed tomography (CT) revealed intracranial hemorrhage in the right basal ganglia. Digital subtraction angiography revealed arteriovenous malformation in the brain. Intravascular embolization was performed three times and radiosurgery was performed twice, whereby complete obliteration of the nidus was achieved. Six and a half years later, routine follow-up magnetic resonance imaging revealed cyst formation, and the patient gradually developed left hemiparesis. First, we performed stereotactic cyst aspiration. This initially resulted in a reduction in the size of the cyst and disappearance of left hemiparesis, but within a short time, the cyst increased in size again and there was recurrence of hemiparesis. Therefore, an Ommaya reservoir was established; aspiration of the cyst through this reservoir brought about an initial reduction in cyst size and alleviation of symptoms; however, no further reduction in cyst size or improvement in symptoms could be achieved. Twenty months after the placement of the Ommaya reservoir, we performed a C-P shunt operation. After the operation, further reduction in the cyst size and complete symptomatic recovery were observed.

Recovered neuronal viability revealed by Iodine-123-iomazenil SPECT following traumatic brain injury.

We evaluated cortical damages following traumatic brain injury (TBI) in the acute phase with [(123)I] iomazenil (IMZ) single photon emission computed tomography (SPECT). In all, 12 patients with cerebral contusion following TBI were recruited. All patients underwent IMZ SPECT within 1 week after TBI. To investigate the changes in distribution of IMZ in the cortex in the chronic phase, after conventional treatment, patients underwent IMZ SPECT again. A decrease in the accumulation of radioligand for the central benzodiazepine receptor in the cortex corresponding to the contusion revealed with computed tomography (CT) scans and magnetic resonance imaging (MRI) were shown on IMZ SPECT in the acute phase in all patients. In 9 of 12 patients (75%), images of IMZ SPECT obtained in the chronic phase of TBI showed that areas with a decreased distribution of IMZ were remarkably reduced in comparison with those obtained in the acute phase. Both CT scans and MRI showed a normal appearance of the cortex morphologically, where the binding potential of IMZ recovered in the chronic phase. Reduced binding potential of radioligand for the central benzodiazepine receptor is considered to be an irreversible reaction; however, in this study, IMZ accumulation in the cortex following TBI was recovered in the chronic phase in several patients. [(123)I] iomazenil SPECT may have a potential to disclose a reversible vulnerability of neurons following TBI.

Preoperative prediction of outcome in 283 poor-grade patients with subarachnoid hemorrhage: a project of the Chugoku-Shikoku Division of the Japan Neurosurgical Society.

BACKGROUND: The management of patients with poor-grade subarachnoid hemorrhage (SAH) continues to be controversial. The objective of this study was to examine predictors of outcome of poor-grade SAH after surgical obliteration of the aneurysm. METHODS: The study was performed as a retrospective review of 283 patients with poor-grade SAH who underwent surgical obliteration of the aneurysm at multiple centers in Chugoku and Shikoku, Japan. RESULTS: A favorable outcome at discharge was achieved in 97 of the 283 patients (34.3%). Age (p < 0.001), World Federation of Neurosurgical Societies (WFNS) grade V at admission (p = 0.002), improvement in WFNS grade after admission (p = 0.002), Fisher grade (p = 0.039) and a low-density area (LDA) associated with vasospasm on computed tomography (CT; p < 0.001) showed a significant association with outcome. Further analysis of WFNS grades indicated that most patients who only improved to preoperative grade IV from grade V at admission did not have a favorable outcome. Multivariate analysis identified age (especially of > or =65 years; p < 0.001), WFNS grade V (p < 0.001) and LDA associated with vasospasm on CT (p < 0.001) as predictors of a poor outcome, and improvement in WFNS grade (p = 0.001) as a predictor of a favorable outcome after surgical obliteration of the aneurysm. CONCLUSIONS: Advanced age, WFNS grade V, improvement in WFNS grade, and LDA associated with vasospasm on CT were found to be independent predictors of clinical outcome, whereas rebleeding, early aneurysm surgery and treatment modality (surgical clipping or Guglielmi detachable coil embolization) were not independently associated with outcome in patients with poor-grade aneurysm.

Operative open intra-aneurysmal thrombectomy for ruptured cerebral aneurysm and peripheral ischemia associated with vasospasm.

The endovascular approach has become the standard treatment for ruptured aneurysms during the vasospasm risk period following subarachnoid hemorrhage; however, it may be disadvantageous under certain conditions. We report a patient with a ruptured middle cerebral artery aneurysm with severe vasospasm and thrombosis within the aneurysm immediately after angiography. Emergent operative open thrombectomy of the intra-aneurysmal thrombus restored blood flow to the ischemic penumbra territory demonstrated by single photon emission CT scan and diffusion-weighted MRI.

Vaccine therapy with dendritic cells transfected with Il13ra2 mRNA for glioma in mice.

OBJECT: The Il13ra2 gene is often overexpressed in brain tumors, making Il13ra2 one of the vaccine targets for immunotherapy of glioma. In this study, using a mouse glioma model, the authors tested the hypothesis that vaccination using dendritic cells transfected with Il13ra2 mRNA induces strong immunological antitumor effects. METHODS: A plasmid was constructed for transduction of the mRNAs transcribed in vitro into dendritic cells. This was done to transport the intracellular protein efficiently into major histocompatibility complex class II compartments by adding a late endosomal/lysosomal sorting signal to the Il13ra2 gene. The dendritic cells transfected with this Il13ra2 mRNA were injected intraperitoneally into the mouse glioma model at 3 and 10 days after tumor cell implantation. The antitumor effects were estimated based on the survival rate, results of histological analysis, and immunohistochemical findings for immune cells. RESULTS: The group treated by vaccination therapy with dendritic cells transfected with Il13ra2 mRNA survived significantly longer than did the control groups. Immunohistochemical analysis revealed that greater numbers of T lymphocytes containing CD4+ and CD8+ T cells were found in the group vaccinated with dendritic cells transfected with Il13ra2 mRNA. CONCLUSIONS: These results demonstrate the therapeutic potential of vaccination with dendritic cells transfected with Il13ra2 mRNA for the treatment of malignant glioma.

Continuous hypertension and tachycardia after resection of a hemangioblastoma behind the dorsal medulla oblongata: relationship to sympathetic overactivity at the neurogenic vasomotor center.

A very rare case of continuous hypertension and tachycardia after excision of a cerebellar hemangioblastoma at the dorsal medulla oblongata is presented. This 21-year-old man was admitted to the authors' hospital with a headache and dizziness. Radiological examination revealed a tumor located behind the dorsal medulla oblongata and compressing it substantially. The tumor was completely resected, but after the surgery the patient experienced prolonged hypertension and tachycardia. Postoperative MR imaging showed a small injury at the dorsocaudal medulla that was located at the caudal site of the nucleus of the tractus solitarius (NTS). Because the NTS has been reported to play a central role in cardiovascular regulation along with the rostral ventrolateral medulla, the authors considered it possible that the NTS injury was the cause of the prolonged elevation of sympathetic tone.

Epileptiform discharges and neuronal plasticity in the acute peri-infarct cortex of rats.

While the peri-infarct cortex is thought to be responsible for functional recovery, the site is also a strong candidate for post-stroke seizures. Since it is crucial to identify the conditions when the site is changed with such beneficial or detrimental results, the peri-infarct changes were investigated before and just after inducing a focal infarct on rat cortex. The receptive fields in the peri-infarct cortex began to increase a few hours after the infarct, and reached a statistical significance at 6 hours (Dunnett post hoc tests; p<0.05). In temporal association with these changes, EEG in the peri-infarct cortex showed epileptiform activities containing large-amplitude spike-and-wave discharges. The gross amplitude, peak-to-peak amplitude and burst frequency showed statistically significant increases within 4 hours, in comparison to those of the controls (Dunnett post hoc tests; p<0.05). FFT power spectrum analyses showed a distinct increase in approximately 25 Hz frequency bands in the post-stroke groups. The homogeneous area of the contralateral hemisphere in the infarct group, in contrast, did not show such plastic or excitability changes. This study demonstrated, for the first time, that the peri-infarct cortex acquires the characteristics of potential epileptogenesis and functional recovery within hours of a stroke.

Elevated concentrations of sphingosylphosphorylcholine in cerebrospinal fluid after subarachnoid hemorrhage: a possible role as a spasmogen.

This study investigates the role of sphingosylphosphorylcholine (SPC) in the mechanisms underlying cerebral vasospasm after subarachnoid hemorrhage (SAH). The levels of SPC were measured in cerebrospinal fluid (CSF) of patients with SAH and also in an experimental canine model. CSF samples were collected from 11 patients with SAH, and from dogs that had received an injection of SPC into the cisterna magna to examine SPC kinetics in the CSF. SPC was assayed using solid-phase extraction and triple quadrupole mass spectrometry. The SPC concentrations in SAH patients on days 3, 8, and 14 after the onset of SAH were significantly higher than those in normal CSF. In the canine model, rapid dilution of SPC in CSF was observed. In combination with data from previous studies, these results suggest that SPC is involved in the development of cerebral vasospasm. Rapid dilution of SPC in CSF suggests that SPC is released into CSF at higher concentrations than those measured in the present study.

Cerebrovascular moyamoya disease in a 5-year-old girl who underwent interruption of the right common carotid artery in the neonatal period.

The authors report on the case of a girl with cerebrovascular moyamoya disease born with severe respiratory failure caused by a congenital diaphragmatic hernia. Cardiopulmonary management included extracorporeal membrane oxygenation until the diaphragm defect was repaired. The right common carotid artery (CA) was interrupted and cannulated for extracorporeal membrane oxygenation. When she was 5 years of age, the patient experienced ischemic symptoms in her right extremities. Angiography revealed stenosis of the terminal portion of the internal CA (ICA) with the development of moyamoya vessels on the left side of the brain; the right ICA was supplied by extracranial anastomotic arteries. Indirect extracranial-intracranial bypass surgery was performed in the left hemisphere, and the hypoperfusion improved. The same change in the intracranial ICA with the development of moyamoya vessels occurred on her right side when she was 7 years old. Decreased cerebral blood flow occurred twice, and the moyamoya vessels developed to compensate for the cerebral ischemia. However, the occlusion of the extracranial common CA in infancy induced extracranial anastomosis rather than moyamoya vessel proliferation, and collateral circulation was formed at the lesion site. This finding indicates that neoangiogenesis requires both cerebral ischemia and growth factors derived from the lesion.

The influence of focal brain cooling on neurophysiopathology: validation for clinical application.

OBJECT: Focal brain cooling has been recognized to have a suppressive effect on epileptiform discharges or a protective effect on brain tissue. However, the precise influence of brain cooling on normal brain function and histology has not yet been thoroughly investigated. The aim of this study was to investigate the neurophysiopathological consequences of focal cooling and to detect the threshold temperature that causes irreversible histological change and motor dysfunction. METHODS: The experiments were performed in adult male Sprague-Dawley rats (weighing 250-350 g) after induction of halothane anesthesia. A thermoelectric chip (6 x 6 x 2 mm) was used as a cooling device and was placed on the surface of the sensorimotor cortex after a 10 x 8-mm craniotomy. A thermocouple was placed between the chip and the brain surface. Focal cooling of the cortex was performed at the temperatures of 20, 15, 10, 5, 0, and -5 degrees C for 1 hour (5 rats in each group). Thereafter, the cranial window was repaired. Motor function was evaluated using the beam-walking scale (BWS) every day for 7 days. The rats were killed 7 days after the operation for histological examination with H & E, Klüver-Barrera, glial fibrillary acidic protein, and terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick-end labeling stainings. The authors also euthanized some rats 24 hours after cooling and obtained brain sections by the same methods. RESULTS: The BWS score was decreased on the day after cooling only in the -5 degrees C group (p < 0.05), whereas the score did not change in the other temperature groups. Histologically, the appearance of cryoinjury such as necrosis, apoptosis, loss of neurons, and marked proliferation of astrocytes at the periphery of the lesion was observed only in the -5 degrees C group, while no apparent changes were observed in the other temperature groups. CONCLUSIONS: The present study confirmed that the focal cooling of the cortex for 1 hour above the temperature of 0 degrees C did not induce any irreversible histological change or motor dysfunction. These results suggest that focal brain cooling above 0 degrees C has the potential to be a minimally invasive and valuable modality for the treatment of severe brain injury or to assist in the examination of brain function.

Mechanistic insight into neurotoxicity of tissue plasminogen activator-induced thrombolysis products in a rat intraluminal middle cerebral artery occlusion model.

Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) after ischemic stroke is effective. However, rtPA potentiates neuronal damage, and interactions between rtPA and thrombolysis products (TLP) have been reported to play a role in this. In the present study we investigated the mechanisms underlying rtPA- and TLP-induced neurotoxicity. Adult male Sprague-Dawley rats were subjected to 60-min intraluminal middle cerebral artery (MCA) occlusion, and then treated with rtPA (10 mg/kg), TLP, or saline. To evaluate the effects of a free radical scavenger, treatment with edaravone and TLP was evaluated. To investigate the role of red blood cells (RBCs), RBC-depleted TLP was used. Neurological deficit scores, infarct volume, and immuno-histochemical localization of oxidative end products for lipid and DNA (4-hydroxy-2-nonenal [4-HNE] and 8-hydroxy-deoxyguanosine [8-OHdG]) were evaluated. TLP increased the infarct volume, worsened the neurological deficits, and increased accumulations of 4-HNE and 8-OHdG. Edaravone treatment significantly reduced the lesion volume and improved the neurological score. Both infarct volume and accumulation of oxidative products were significantly suppressed when RBC-depleted TLP was used. In this mechanical model of MCA occlusion, rtPA-induced TLP, especially in the presence of RBCs, contributed to neuronal damage by accelerating free radical injury.