Hirosuke Fujisawa

Effects of mild hypothermia on cerebral blood flow-independent changes in cortical extracellular levels of amino acids following contusion trauma in the rat.

The mechanism of hypothermic cerebroprotection after traumatic brain injury (TBI) is unknown. The present study was conducted to investigate the effects of mild hypothermia on the changes in cortical extracellular amino acids and cerebral blood flow (CBF) caused by cerebral contusion created in the rat parietal cortex by a weight-drop method. CBF in both normothermia (37 degrees C) and hypothermia (32 degrees C) groups, which was monitored using the hydrogen clearance technique, decreased significantly after contusion, but never fell below the threshold for ischemia. Cortical levels of glutamate, aspartate, glycine and taurine, which were measured by intracerebral microdialysis, were significantly increased after contusion in each group. However, these increases were greater in the hypothermic than in the normothermic rats. Normal plasma amino acid levels were high, and autoradiography following intravenous injection of 14C-labeled glutamate revealed marked extravasation of [14C]glutamate at the site of cortical impact. These results suggest that the post-traumatic increase in extracellular amino acids occurs independently of CBF reduction, and that extravasation of amino acids from the vascular compartment partly contributes to this increase. Hypothermic cerebroprotection in TBI is thus likely to occur through a mechanism other than reduction in interstitial excitatory amino acids. In TBI, it is postulated that the postsynaptic effects of hypothermia may be more important than the presynaptic effects, when CBF is kept above the ischemic threshold.

Feasibility of the Titration Method of Mild Hypothermia in Severely Head-injured Patients with Intracranial Hypertension

OBJECTIVE Clinical strategy to maximize effectiveness and to minimize adverse influences remains to be determined for mild hypothermia therapy for traumatic brain injury. This study was conducted to evaluate the clinical feasibility of the titration method of mild hypothermia in severely head-injured patients in whom a reduction in intracranial pressure was regarded as the target effect. METHODS Nine consecutive patients with severe head injury were studied. Patient age ranged between 18 and 66 years, Glasgow Coma Scale scores were equal to or less than 8, and intracranial pressures were equal to or greater than 20 mm Hg despite removal of intracranial hematoma and drugs, including glycerol and thiopental. During a maximum of 6 days of hypothermia therapy, jugular venous blood or cerebrospinal fluid temperature was titrated to reduce intracranial pressure to less than 20 mm Hg by means of repeated intragastric cooling with our nasoduodenal tube and surface cooling. The feasibility and the effects on systemic complications of this titration method of mild hypothermia were evaluated. RESULTS Intracranial pressure variably decreased from before to 3 hours after the beginning of all procedures of cooling. The mean intracranial pressure significantly decreased from 24 to 15 mm Hg with cooling, while temperature reduced an average of 2.0 degrees C. Four patients had systemic infection complications. Increased C-reactive protein and decreased platelet count were observed in all patients during hypothermia. The incidence of good recovery and moderate disability according to the Glasgow Outcome Scale was seven of nine patients. CONCLUSION The titration method of mild hypothermia to control intracranial hypertension in severely head-injured patients is clinically feasible. However, the method failed to reduce the incidence of infectious and hematological complications.

Changes in Nitric Oxide Synthesis and Epileptic Activity in the Contralateral Hippocampus of Rats Following Intrahippocampal Kainate Injection

Summary:  Purpose: To investigate the effects of nitric oxide (NO) on seizure activity observed in brain areas that are remote from a primary epileptic focus.

Pharmacological modification of glutamate neurotoxicity in vivo

The ability of five agents (dizocilpine [MK-801], 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline [NBQX], enadoline [CI-977], L-nitroarginine methyl ester [L-NAME] and BW 1003c87) with well defined, distinct pharmacological profiles and with established anti-ischemic efficacy, to modify neuronal damage has been examined in a simple in vivo model of glutamate excitotoxicity. Cortical lesions were produced in physiologically-monitored halothane-anesthetised rats by reverse dialysis of glutamate. The volume of the lesion was quantified histologically by image analysis of approximately 20 sections taken at 200 microm intervals throughout the lesion. The AMPA and NMDA receptor antagonists (NBQX and MK-801) and the inhibitor of nitric oxide synthase (L-NAME) significantly reduced the lesion volume by a similar extent (by approximately 30% from vehicle). Two agents (the kappa opioid agonist, CI-977 and the sodium channel blocker, BW 1003c87) which putatively inhibit the release of endogenous glutamate presynaptically, had dissimilar effects on lesion size. CI-977 failed to alter the amount of damage produced by exogenous glutamate, whereas BW 1003c87 reduced the lesion size by approximately 50%. Using this model, the neuroprotective effects of anti-ischemic drugs can be explored in vivo, uncomplicated in contrast to experimental ischemia by reduced oxygen delivery, drug effects on tissue blood flow and compromised energy generation. In consequence, additional mechanistic insight into anti-ischemic drug action in vivo can be obtained.

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 ≧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.

Effect of neuroprotective N-methyl-D-aspartate antagonists on increased intracranial pressure: studies in the rat acute subdural hematoma model.

Glutamate antagonists are the most powerful neuroprotective drugs in laboratory studies of focal cerebral ischemia. Because the majority of clinical conditions in which focal brain ischemia occurs are associated with high intracranial pressure (ICP), we have used the rat acute subdural hematoma model to evaluate the effects of three glutamate N-methyl-D-aspartate antagonists, MK-801, CGS 19755 (SELFOTEL), D-CPP-ene, and mannitol, upon ICP and also upon the volume of ischemic brain damage. Only mannitol produced a significant reduction in ICP and improved cerebral perfusion pressure. The three glutamate antagonists did not significantly affect ICP or cerebral perfusion pressure, but they were associated with a significantly smaller zone of focal brain damage, when compared to the mannitol and saline groups. N-methyl-D-aspartate antagonists do not increase ICP or jeopardize cerebral perfusion pressure when administered under anesthesia with a controlled PaCO2 level. Further studies in humans are indicated.

Effect of Neuroprotective N-Methyl-D-Aspartate Antagonists on Increased Intracranial Pressure

Glutamate antagonists are the most powerful neuroprotective drugs in laboratory studies of focal cerebral ischemia. Because the majority of clinical conditions in which focal brain ischemia occurs are associated with high intracranial pressure (ICP), we have used the rat acute subdural hematoma model to evaluate the effects of three glutamate N-methyl-D-aspartate antagonists, MK-801, CGS 19755 (SELFOTEL), D-CPP-ene, and mannitol, upon ICP and also upon the volume of ischemic brain damage. Only mannitol produced a significant reduction in ICP and improved cerebral perfusion pressure. The three glutamate antagonists did not significantly affect ICP or cerebral perfusion pressure, but they were associated with a significantly smaller zone of focal brain damage, when compared to the mannitol and saline groups. N-methyl-D-aspartate antagonists do not increase ICP or jeopardize cerebral perfusion pressure when administered under anesthesia with a controlled PaCO2 level. Further studies in humans are indicated.

Prognostic implications of meningiomas in the elderly (over 70 years old) in the era of magnetic resonance imaging.

SummaryDuring the 5 years from 1987 to 1991, 89 elderly patients, aged 70 years and over, were admitted to departments of neurosurgery in Yamaguchi prefecture with meningioma. The clinical features and prognostic implications of meningioma in the elderly were assessed retrospectively. Seventy-eight (88%) of the 89 patients underwent surgery, which was a higher rate than has been previously reported. The length of clinical history was also shorter than in previous studies, and was partly due to the recent introduction of magnetic resonance imaging (MRI). The incidence of poor prognosis (severe disability, vegetative or dead) in the elderly and a younger group aged less than 70 years was 13% and 7%, respectively, but the difference was not statistically significant. In the surgically treated elderly group, age did not influence the patients outcome. The factors affecting the outcome were pre-operative neurological deficit (p<0.05), histological malignancy (p<0.05), and multiple operations (p<0.05). Twenty-seven of the elderly meningioma patients were in good physical condition with minimal neurological involvement. They underwent total removal of the tumour at the first operation, and the histological diagnosis was benign. Twenty-five of these 27 patients fell into the best outcome category. Therefore, age alone was not a factor preventing proper surgical treatment of meningioma in the elderly.

Sequential changes in cerebral blood flow, early neuropathological consequences and blood-brain barrier disruption following radiofrequency-induced localized hyperthermia in the rat

We investigated the temperature distribution, early histological changes, blood brain barrier (BBB) disruption and sequential changes in cerebral blood flow (CBF) following hyperthermia ranging from 37 to 45 degrees C in a new rat model of radiofrequency-induced localized cerebral hyperthermia. Significant histological changes and BBB disruption were observed in brain regions heated to 43 degrees C and above. In the cortex heated to 41 degrees C, the CBF doubled 20 min after hyperthermia induction, and then returned gradually to the pre-hyperthermic level. In the cortex heated to 43 degrees C, the CBF increased to 134% of the baseline level 10 min after hyperthermia induction, and then fell gradually to reach its minimum level (31% of the baseline level). In the cortex heated to 45 degrees C, the CBF decreased immediately after hyperthermia induction to reach 10% of the baseline level. The results indicate that hyperthermia-induced cellular injury in the central nervous system is associated with cerebral ischaemia and the threshold temperature for such injury is 43 degrees C. This model is useful for investigating the effects of hyperthermia on various cerebral functions and the CBF changes demonstrated in the present study may provide key information for the analysis of other cerebral functions.

Effective suppression of hippocampal seizures in rats by direct hippocampal cooling with a Peltier chip

OBJECT The use of focal brain cooling to eliminate epileptic discharges (EDs) has attracted increasing attention in the scientific community. In this study, the inhibitory effect of selective hippocampal cooling on experimental hippocampal seizures was investigated using a newly devised cooling system with a thermoelectric (Peltier) chip. METHODS A copper needle coated with silicone and attached to the Peltier chip was used for the cooling device. The experiments were performed first in a phantom model with thermography and second in adult male Sprague-Dawley rats in a state of halothane anesthesia. The cooling needle, a thermocouple, and a needle electrode for electroencephalography recording were inserted into the right hippocampus. Kainic acid (KA) was injected into the right hippocampus to provoke the EDs. The animals were divided into hippocampal cooling (10 rats) and noncooling (control, 10 rats) groups. RESULTS In the phantom study, the cooling effects (9 degrees C) occurred in the spherical areas around the needle tip. In the rats the temperature of the cooled hippocampus decreased below 20 degrees C within a 1.6-mm radius and below 25 degrees C within a 2.4-mm radius from the cooling center. The temperature at the needle tip decreased below 20 degrees C within 1 minute and was maintained at the same level until the end of the cooling process. The amplitude of the EDs was suppressed to 68.1 +/- 4.8% of the precooling value and remained low thereafter. No histological damage due to cooling was observed in the rat hippocampus. CONCLUSIONS Selective hippocampal cooling effectively suppresses the KA-induced hippocampal EDs. Direct hippocampal cooling with a permanently implantable system is potentially useful as a minimally invasive therapy for temporal lobe epilepsy and therefore could be an alternative to the temporal lobectomy.