Hydrogen does not Exert Neuroprotective Effects or Improve Functional Outcomes in Rats After Intracerebral Hemorrhage.

AIM: Increasing evidence suggests that reactive oxygen species damage the blood-brain barrier and increase brain edema after intracerebral hemorrhage (ICH). Recently, strong clinical and experimental evidence has shown that hydrogen has potent protective cellular effects in various diseases. However, the effect of hydrogen on ICH remains unclear. The present study investigates whether hydrogen has neuroprotective effects and improves functional outcome in the rat ICH model. MATERIAL AND METHODS: ICH model was generated by injecting 50 µl autologous tail artery blood stereotactically into the right caudate nucleus of Sprague-Dawley rats. Rats were randomly divided into four groups: sham, ICH/vehicle, ICH/hydrogen gas, and ICH/hydrogen-rich saline groups. Hydrogen treatment was performed for 3 days. The evaluation of functional outcome was done before, and at 24 and 72 hours after ICH. Hemorrhage volume, immunohistochemistry for 8-hydroxy-2'-deoxyguanosine (8-OHdG), and brain water content were evaluated at 72 hours after ICH. RESULTS: Hydrogen administration reduced the expression of 8-OHdG in the brain, but did not attenuate brain water content or improve functional outcome, regardless of administration route. CONCLUSION: Hydrogen administration without surgery has no neuroprotective effect in the blood injection rat ICH model.

Electrocardiograph abnormalities in intracerebral hemorrhage.

This study investigated the prevalence and type of electrocardiography (ECG) abnormalities, and their possible association with the clinical/radiological findings in 118 consecutive patients with non-traumatic, non-neoplastic intracerebral hemorrhage (ICH). ECG frequently demonstrates abnormalities in patients with ischemic stroke and subarachnoid hemorrhage, but little is known of ECG changes in ICH patients. Clinical and radiological information was retrospectively reviewed. ECG recordings that were obtained within 24 hours of the initial hemorrhage were analyzed. Sixty-six patients (56%) had one or more ECG abnormalities. The most frequent was ST depression (24%), followed by left ventricular hypertrophy (20%), corrected QT interval (QTc) prolongation (19%), and T wave inversion (19%). The logistic regression analysis demonstrated the following: insular involvement was an independent predictive factor of ST depression (p<0.001; odds ratio OR 10.18; 95% confidence interval [CI] 2.84-36.57); insular involvement (p<0.001; OR 23.98; 95% CI 4.91-117.11) and presence of intraventricular hemorrhage (p<0.001; OR 8.72; 95% CI 2.69-28.29) were independent predictive factors of QTc prolongation; deep hematoma location (p<0.001; OR 19.12; 95% CI 3.82-95.81) and hematoma volume >30 ml (p=0.001; OR 6.58; 95% CI 2.11-20.46) were independent predictive factors of T wave inversion. We demonstrate associations between ECG abnormalities and detailed characteristics of ICH.

[High-Definition Exoscope System for Microneurosurgery:Use of an Exoscope in Combination with Tubular Retraction and Frameless Neuronavigation for Microsurgical Resection of Deep Brain Lesions].

The high-definition exoscope (VITOM®, Karl Storz GmbH & Co., Tuttlingen, Germany) is a new equipment that can be used as an alternative to the operating microscope in neurosurgery. Several neurosurgeons have recently reported that the exoscope allows for long working distances and great depth of field. Herein, we review reported cases of exoscope use in neurosurgery. We also describe the advantages of the exoscope compared to the operating microscope and endoscope. Furthermore, we introduce a novel technique for microsurgical resection of deep brain lesions, in which the exoscope is used along with tubular retraction and frameless neuronavigation. Before the operation, neuronavigation is registered and the surgical trajectory is planned to avoid damaging the functional cortex and eloquent white matter tracts. By using intraoperative neuronavigation, the tubular retractor (NICO BrainPath®, NICO Corporation, Indianapolis, US), which is designed to split the white matter when gently inserted, is inserted transcortically into the brain to reach the lesion, along the preplanned trajectory. After insertion, the tubular retractor is fixed in place using a self-retaining arm. This creates a narrow corridor that enables the use of the exoscope (for optimum visualization), bimanual dissection technique, and long bayoneted surgical instruments. The large focal distance of the exoscope allows it to be placed sufficiently further away from the surgical site, permitting the passage of long surgical instruments under the scope. Although obtaining surgical access to deep-seated brain lesions is challenging, we consider that this technique facilitates a safe surgical approach for lesions in deep locations.

Hydrogen improves neurological function through attenuation of blood-brain barrier disruption in spontaneously hypertensive stroke-prone rats.

BACKGROUND: Enhanced oxidative stress occurs in spontaneously hypertensive stroke-prone rats (SHRSP), and is important in blood-brain barrier (BBB) disruption. Hydrogen can exert potent protective cellular effects via reduction in oxidative stress in various diseases. The present study investigated whether long-term hydrogen treatment can improve neurological function outcome in the SHRSP model, and the effects of hydrogen on BBB function, especially the oxidative stress and the activity of matrix metalloproteinases (MMPs) in this model. Fifty-six animals were randomly assigned to 2 groups and treated as follows: SHRSP treated with hydrogen-rich water (HRW) (HRW group, n = 28); and SHRSP treated with regular water (control group, n = 28). The effect of HRW on overall survival and neurological function, and the effects of HRW on reactive oxygen species, BBB function, and MMP activities were examined. RESULTS: HRW treatment improved neurological function and tended to improve overall survival but without significant difference. The numbers of bleeds and infarcts were lower in the cortex and hippocampus in the HRW group. The HRW group exhibited a significantly lower number of 8-hydroxy-2'-deoxyguanosine-positive cells and vessels of extravasated albumin in the hippocampus compared with the control group. MMP-9 activity was reduced in the hippocampus in the HRW group compared with the control group. CONCLUSIONS: The present study suggests that ingestion of HRW can improve neurological function outcome in the SHRSP model. This beneficial effect may be due to attenuation of BBB disruption via reduction in reactive oxygen species and suppression of MMP-9 activity in the hippocampus.

Surgical removal of the solitary metastasis of renal cell carcinoma in the third ventricle using an interhemispheric transcallosal trans-choroidal approach.

We herein describe a case of a solitary metastasis of renal cell carcinoma (RCC) in the third ventricle, which was totally removed via an interhemispheric trans-callosal trans-choroidal approach. The histological examination revealed a solitary metastasis of RCC. The postoperative course was uneventful. A stereotactic cyber knife was additionally used for the tumor cavity. As of 2 years after surgery, the patient has been doing well without recurrence. This case highlights the urgent need for an early diagnosis and surgical treatment for solitary metastasis of RCC to the third ventricle due to its critical course.

Treatment of spontaneous intracranial hypotension with intravenous Factor XIII administration: initial clinical experience.

AIM: Coagulation Factor XIII plays an important role in wound healing by stabilizing the fibrin clot. We hypothesized that Factor XIII administration might promote the repair of cerebrospinal fluid leak sites and lead to resolution of the orthostatic headache in patients with spontaneous intracranial hypotension (SIH). The aim of this study was to investigate the efficacy of intravenous Factor XIII administration in SIH patients. MATERIAL AND METHODS: A retrospective review of nine patients (four men, five women; mean age 42.3 yr) with SIH resistant to conservative treatment (bed rest, hydration and analgesics) was performed. All patients had an orthostatic headache. Intravenous administration of Factor XIII (1200 units per day for at least five days) was additionally performed on all patients. RESULTS: The orthostatic headache completely resolved and never reoccurred in six patients (67%), and partially resolved in two patients (22%). One patient (11%) had no change in headache activity. No complications occurred in any patients treated with Factor XIII. CONCLUSION: This study may suggest that intravenous administration of Factor XIII is useful for treating SIH, even if the patients are resistant to conservative treatment.

Recanalization of a large supraclinoid carotid aneurysm via elicited vertebral artery-internal carotid artery anastomosis: a case report.

Proximal ligation of the internal carotid artery (ICA) with high-flow bypass is one of the surgical strategies for treating large, unclippable ICA aneurysms. We encountered a rare case of recanalization of a large ICA aneurysm that disappeared after high-flow bypass surgery, and subsequently reappeared via an elicited vertebral artery (VA)-ICA anastomosis (anastomosis between the anterior meningeal artery branching from the right VA, and the ascending pharyngeal artery branching (APA) from the right ICA). To the best of our knowledge, this is the first case report describing angiographical recurrence of a large ICA aneurysm after the surgery. Periodic long-term follow-up by neuroimaging may be necessary after this surgery, particularly in cases of ICA proximal ligation with the ICA aneurysm, when the APA has not been clearly identified as a branch from the ipsilateral external carotid artery on the preoperative angiogram.

Decompressive craniectomy for arteriovenous malformation-related intracerebral hemorrhage.

Arteriovenous malformation (AVM)-related intracerebral hemorrhage (ICH) is the cause of approximately 2-3% of ICH and is an important factor in the significant morbidity and mortality in patients with AVM. Decompressive craniectomy (DC) is a surgical procedure to relieve malignant elevation of intracranial pressure. The use of DC to treat patients with AVM-ICH has been much less common. The present study describes our experience with DC for AVM-ICH and discusses the safety of this procedure. The present retrospective analysis compared 12 consecutive patients treated with DC for AVM-ICH with 23 patients treated with DC for hypertensive ICH. Nine patients were male and three were female, aged from 11 to 53 years (mean, 31.7 years). Hematoma volumes ranged from 50 to 106 ml (mean, 75.8 ml). The outcomes were good recovery in one patient, moderate disability in three, severe disability in seven, and vegetative state in one. Complications after DC included subdural hygroma in four patients, hydrocephalus in one, intracranial infection in two, and intracranial hemorrhage in one. No significant difference was found in the incidence of complications between DC for large AVM-ICH and DC for hypertensive ICH. In conclusion, the present study found no significant difference in the incidence of complications between DC for large AVM-ICH and DC for hypertensive ICH. Further investigations including a prospective randomized trial are needed to confirm the safety and efficacy of DC for the treatment of large AVM-ICH.

[CT and histological findings and treatment outcomes after carotid endarterectomy for symptomatic cervical carotid artery stenosis in octogenarians].

Symptomatic cervical carotid artery stenosis is one of the common causes of ischemic stroke in octogenarians. The records for 90 consecutive patients with symptomatic cervical carotid artery stenosis treated by carotid endarterectomy(CEA)were analyzed retrospectively. The patients were divided into two groups:21 patients aged 80 years or over and 69 patients aged less than 80 years. CT angiography revealed that ulcer formation was significantly more common and the length of carotid artery stenosis was significantly greater in the octogenarians. Histological examination of the plaque revealed no significant difference between the two groups in terms of ulcer formation, lipid content, and intraplaque hemorrhage. However, all three of these pathological findings were present in a significantly higher number of octogenarians. No significant difference was observed for new ischemic lesions on diffusion-weighted MR imaging, neurological complications, or cardiac and pulmonary complications. However, treatment with an albumin preparation and loop diuretics was significantly more common in octogenarians after CEA. The present study suggests that with careful postoperative management CEA can be safely performed in symptomatic patients aged 80 years or over with almost the same risk as that for patients aged less than 80 years.

Effects of intravenous infusion of hydrogen-rich fluid combined with intra-cisternal infusion of magnesium sulfate in severe aneurysmal subarachnoid hemorrhage: study protocol for a randomized controlled trial.

BACKGROUND: The failures of recent studies intended to prevent cerebral vasospasm have moved the focus of research into delayed cerebral ischemia away from cerebral artery constriction towards other mechanisms. Recent accumulating evidence has suggested that early brain injury is also involved in the development of delayed cerebral ischemia, and that hydrogen can prevent early brain injury. Therefore, we have established a combination therapy of intravenous hydrogen infusion and intra-cisternal magnesium sulfate infusion for the treatment of both early brain injury and cerebral vasospasm. The present randomized controlled clinical trial is designed to investigate the effects of this novel therapeutic strategy on the occurrence of cerebral vasospasm, delayed cerebral ischemia, and clinical outcomes after high-grade subarachnoid hemorrhage. METHODS: This study is a randomized, double-blind, placebo-controlled design to be conducted in two hospitals. A total of 450 patients with high-grade subarachnoid hemorrhage will be randomized to one of three arms: (i) Mg + H2 group, (ii) Mg group, and (iii) control group. Patients who are assigned to the Mg + H2 group will receive intra-cisternal magnesium sulfate infusion (2.5 mmol/L) at 20 mL/h for 14 days and intravenous hydrogen-rich fluid infusion (200 mL) twice a day for 14 days. Patients who are assigned to the Mg group will receive intra-cisternal magnesium sulfate infusion (2.5 mmol/L) at 20 mL/h for 14 days and intravenous normal glucose-electrolyte solution (200 mL) without added hydrogen twice a day for 14 days. Patients who are assigned to the control group will receive intra-cisternal Ringer solution without magnesium sulfate at 20 mL/h for 14 days and intravenous normal glucose-electrolyte solution (200 mL) without added hydrogen twice a day for 14 days. Primary outcome measures will be occurrence of delayed cerebral ischemia and cerebral vasospasm. Secondary outcome measures will be modified Rankin scale score at 3, 6, and 12 months and biochemical markers. DISCUSSION: The present protocol for a randomized, placebo-controlled study of intravenous hydrogen therapy with intra-cisternal magnesium infusion is expected to establish the efficacy and safety of this therapeutic strategy. TRIAL REGISTRATION UMIN-CTR: UMIN000014696.

Sulfasalazine and temozolomide with radiation therapy for newly diagnosed glioblastoma.

BACKGROUND: A recent phase 1/2 clinical trial argued for caution for the use of sulfasalazine in progressive glioblastoma (GBM). However, the study enrolled patients with recurrent or progressive high-grade glioma indicating that patients recruited probably had severe disease. Thus, the study may not accurately reflect the effectiveness of sulfasalazine for GBM and we hypothesized that earlier sulfasalazine administration may lead to anticancer effects. AIM: The aim of this study was to investigate whether sulfasalazine can improve the outcomes of patients with newly diagnosed GBM. SUBJECTS AND METHODS: A total of 12 patients were treated with temozolomide and sulfasalazine with radiation therapy after surgery. Twelve patients with primary GBM treated with temozolomide and radiation therapy formed the control group. Progression-free survival (PFS), overall survival (OS) and seizure-free survival (SFS) curves were obtained using the Kaplan-Meier method. The survival curves were compared using the log-rank test. RESULTS: The median OS, PFS and SFS did not differ between the groups. Grade 3 or 4 adverse events occurred over the duration of the study in nine (75%) patients. The median SFS was 12 months in nine patients who received sulfasalazine administration for more than 21 days, which was strongly but not significantly longer than the 3 months observed in the control group (P = 0.078). CONCLUSIONS: Sulfasalazine treatment with temozolomide plus radiotherapy for newly diagnosed primary GBM is associated with a high rate of discontinuation due to hematologic toxic effects. This treatment may have no effect on OS or PFS, although it may improve seizure control if an adequate dose can be administered.

Temporal profile of plasma adiponectin level and delayed cerebral ischemia in patients with subarachnoid hemorrhage.

Adiponectin affects nitric oxide production, and low plasma adiponectin levels are associated with impaired endothelium-dependent vasorelaxation. However, adiponectin pathophysiology in the acute phase after stroke, especially subarachnoid hemorrhage, is not well understood. The present study evaluated the changes in plasma adiponectin concentrations in patients with subarachnoid hemorrhage and investigated the relationship between plasma adiponectin and delayed cerebral ischemia. Serial plasma samples from 27 patients with subarachnoid hemorrhage were obtained on day 0 or 1 after hemorrhage, and days 3, 7, 10, 14, and 21. As a control, plasma samples were obtained from 26 healthy volunteers. Differences between patients with and without delayed cerebral ischemia were assessed to investigate the relationship between plasma adiponectin concentrations and the occurrence of delayed cerebral ischemia. There were no significant differences in the clinical characteristics of patients with and without delayed cerebral ischemia. The plasma adiponectin concentrations were significantly lower in patients on days 3 and 7 compared with controls. Plasma adiponectin concentrations in patients with delayed cerebral ischemia were significantly lower than in those without delayed cerebral ischemia on days 3, 7, 10, and 14. The present results indicate that low plasma adiponectin concentrations from day 3 to day 14 might be associated with the development of delayed cerebral ischemia.

"Reverse" bypass using a naturally formed "bonnet" superficial temporal artery in symptomatic common carotid artery occlusion: a case report.

We herein describe a patient with symptomatic common carotid artery occlusion who underwent a reverse superficial temporal artery (STA)-middle cerebral artery (MCA) single bypass using a naturally formed "bonnet" STA. The surgical procedure was performed without difficulty, and no further neurological deterioration was observed after surgery. In practice, this case highlights that the reverse STA-MCA bypass can be achieved safely and less invasively using a naturally formed "bonnet" STA.

Surgical resection of developmental venous anomaly causing massive intracerebral haemorrhage: a case report.

Abstract Cerebral developmental venous anomalies (DVAs) very rarely cause massive haematoma, but should be included in the differential diagnosis of atypical massive intracerebral haematoma (ICH). We describe a case of massive ICH caused only by a DVA and successfully treated by haematoma evacuation with surgical resection of the DVA.

A ruptured aneurysm located at a collateral artery that extended from the proximal A2 segment to the M1 segment, associated with an anomalous branch of the anterior choroidal artery and middle cerebral artery hypoplasia: case report.

We here describe the first case of a ruptured aneurysm located at a collateral artery that extended from the proximal A2 segment to the M1 segment, which was associated with an anomalous branch of the anterior choroidal artery and middle cerebral artery (MCA) hypoplasia. The aneurysm was revealed by angiograms and intraoperative findings. No previous accounts have been published of such an extremely rare vessel anomaly. In practice, this case highlights the urgent need to preoperatively recognize such vascular anomalies, as well as to better understand the collateral blood supply in cerebral ischemia associated with these MCA anomalies. Such knowledge will be helpful for planning optimal surgical procedures.

Adiponectin receptor 1 expression is associated with carotid plaque stability.

BACKGROUND: Adiponectin is a hormone secreted exclusively by adipose tissue, and is important in the regulation of tissue inflammation and insulin sensitivity. Adiponectin exerts its effects through two cell-surface receptors: Adiponectin receptor 1 (ADR1) and ADR2. However, the relationship between ADR1/2 expression and progression of atherosclerosis or plaque vulnerability remains unclear. AIMS: To investigate the relationship between ADR1/2 expression and plaque characteristics in patients with carotid artery atherosclerosis. MATERIALS AND METHODS: Forty-three patients who underwent carotid endarterectomy for treatment of carotid artery stenosis were reviewed. Immunohistochemical staining for ADR1 and ADR2 was performed in the specimens of carotid plaque. The relationships between ADR1/2 expression and clinical characteristics were analyzed statistically. RESULTS: Plaque was stable in 7 patients and vulnerable in 36 patients. ADR1 expression was considered weak in 29 patients and strong in 14 patients. The formation of vulnerable plaques was significantly correlated with weak ADR1 expression (P < 0.003). ADR2 expression was considered weak in 14 patients and strong in 29 patients. Rates of formation of vulnerable plaque did not differ between patients with weak and strong ADR2 expression. CONCLUSIONS: Based on previous and the present results, ADR1 may be strongly related to the stabilization of established atherosclerotic plaques via inactivating macrophages. Enhancement of ADR1 expression could serve as a therapeutic target for the prevention of the formation of vulnerable plaque.

Decrease in plasma adiponectin level and increase in adiponectin immunoreactivity in cortex and hippocampus after traumatic brain injury in rats.

AIM: Adiponectin plays an important role in the regulation of tissue inflammation. Recently, it has been reported that the plasma adiponectin levels in several acute illnesses decrease periodically, thus indicating that adiponectin may play a role in the inflammatory response in patients with acute illness. However, little is known about the effects of adiponectin following TBI. The aim of the present study was to examine the changes in the plasma adiponectin levels and the immunoreactivity of adiponectin in the brain after TBI. MATERIAL AND METHODS: Adult male Sprague-Dawley rats were subjected to lateral fluid percussion injury using the Dragonfly device. Plasma adiponectin levels were determined by ELISA kit. Immunohistochemistry and Western blot analysis were performed to assess the immunoreactivity of adiponectin. RESULTS: The plasma adiponectin levels gradually decreased and were significantly lower at 48 h and 72 h after injury than before injury. Immunohistochemistry and Western blot analysis showed that the adiponectin immunoreactivity was increased in the cerebral cortex at 24 hours after injury and in the hippocampus at 72 hours after injury. CONCLUSION: Our findings suggest that adiponectin might participate in the pathophysiological process occurring after TBI.

Safety of intravenous administration of hydrogen-enriched fluid in patients with acute cerebral ischemia: initial clinical studies.

BACKGROUND: Most of the results regarding hydrogen (H2) therapy for acute cerebral ischemia are derived from in vitro studies and animal experiments, with only a few obtained from human trials with a limited number of subjects. Thus, there is a paucity of information regarding both the beneficial therapeutic effects as well as the side effects of H2 on acute cerebral ischemia in humans. We designed a pilot study to investigate single dose intravenous H2-administration in combination with edaravone, aiming to provide an initial estimate of the possible risks and benefits in select patients presenting with acute ischemic stroke. METHODS: An open-label, prospective, non-randomized study of intravenous H2-administration was performed in 38 patients hospitalized for acute ischemic stroke. All patients received an H2-enriched intravenous solution in addition to edaravone immediately after the diagnosis of acute ischemic stroke. Acute stroke patients within 3 h of onset received intravenous tissue plasminogen activator (t-PA) (0.6 mg/kg) treatment, and patients receiving t-PA had to commence the administration of the H2-enriched intravenous solution and edaravone before or at the same time as the t-PA was infused. RESULTS: Complications were observed in 2 patients (5.3%), which consisted of diarrhea in 1 patient (2.6%) and cardiac failure in 1 patient (2.6%). No deterioration in laboratory tests, urinary tests, ECG, or chest X-ray radiograms occurred in any patient in this study. In all patients, the mean National Institutes of Health Stroke Scale (NIHSS) scores at baseline, and 7, 30, and 90 d after admission were 8.2 ± 7.5, 5.6 ± 7.1, 4.9 ± 6.5, and 4.5 ± 6.3, respectively. The early recanalization was identified in 4 of 11 patients (36.4%) who received intravenous t-PA administration. Hemorrhagic transformation was observed in 2 patients (18.2%). None of the patients in this study that were treated with t-PA developed symptomatic intracranial hemorrhage. CONCLUSIONS: Data from the current study indicate that an H2-enriched intravenous solution is safe for patients with acute cerebral infarction, including patients treated with t-PA.