A case of a pilocytic astrocytoma with histological features of anaplasia and unprecedent genetic alterations.

We report a case of pediatric glioma with uncommon imaging, morphological, and genetic features. A one-year-old boy incidentally presented with a tumor in the fourth ventricle. The tumor was completely resected surgically and investigated pathologically. The mostly circumscribed tumor had piloid features but primitive and anaplastic histology, such as increasing cellularity and mitosis. The Ki-67 staining index was 25% at the hotspot. KIAA1549::BRAF fusion and KIAA1549 partial deletions were detected by direct PCR, supported by Sanger sequencing. To the best of our knowledge, this is the first report of a glioma with both deletion of KIAA1549 p.P1771_P1899 and fusion of KIAA1549::BRAF. The tumor could not be classified using DNA methylome analysis. The present tumor fell into the category of pilocytic astrocytoma with histological features of anaplasia (aPA). Further studies are needed to establish pediatric aPA.

Intratumoral thrombosis as a histological biomarker for predicting epidermal growth factor receptor alteration and poor prognosis in patients with glioblastomas.

PURPOSE: Intratumoral thrombosis is a specific finding in glioblastomas and considered the origin of palisading necrosis. Its distribution and contribution to the glioblastoma pathophysiology and systemic thrombosis are obscure, although deep vein thrombosis is a common complication in glioblastoma cases. METHODS: Clinicopathological and genetic analyses were performed on 97 glioblastoma tissue specimens to elucidate the role of thrombotic events and associated molecular abnormalities. RESULTS: Morphologically, intratumoral thrombosis was observed more frequently in vessels composed of single-layered CD34-positive endothelium and/or αSMA-positive pericytes in the tumor periphery, compared to microvascular proliferation with multi-channeled and pericyte-proliferating vessels in the tumor center. Intratumoral thrombosis was significantly correlated with the female sex, high preoperative D-dimer levels, and epidermal growth factor receptor (EGFR) amplification. The presence of one or more thrombi in 20 high-power fields was a predictive marker of EGFR amplification, with a sensitivity of 81.5% and specificity of 52.6%. RNA sequencing demonstrated that the group with many thrombi had higher EGFR gene expression levels than the group with few thrombi. The tumor cells invading along the vessels in the tumor periphery were positive for wild-type EGFR but negative for EGFRvIII, whereas the cells around the microvascular proliferation (MVP) in the tumor center were positive for both wild-type EGFR and EGFRvIII. Intratumoral thrombosis is an independent poor prognostic factor. CONCLUSIONS: Aberrant but exquisitely regulated EGFR can induce thrombosis in non-MVP vessels in the tumor invasion area and then promote palisading necrosis, followed by hypoxia, abnormal angiogenesis, and further tumor cell invasion.

Visual Outcomes and Surgical Approach Selection Focusing on Active Optic Canal Decompression and Maximum Safe Resection for Suprasellar Meningiomas.

The goal of treating patients with suprasellar meningioma is improving or preserving visual function while achieving long-term tumor control. We retrospectively examined patient and tumor characteristics and surgical and visual outcomes in 30 patients with a suprasellar meningioma who underwent resection via an endoscopic endonasal (15 patients), sub-frontal (8 patients), or anterior interhemispheric (7 patients) approach. Approach selection was based on the presence of optic canal invasion, vascular encasement, and tumor extension. Optic canal decompression and exploration were performed as key surgical procedures. Simpson grade 1 to 3 resection was achieved in 80% of cases. Among the 26 patients with pre-existing visual dysfunction, vision at discharge improved in 18 patients (69.2%), remained unchanged in six (23.1%), and deteriorated in two (7.7%). Further gradual visual recovery and/or maintenance of useful vision were also observed during follow-up. We propose an algorithm for selecting the appropriate surgical approach to a suprasellar meningioma based on preoperative radiologic tumor characteristics. The algorithm focuses on effective optic canal decompression and maximum safe resection, possibly contributing to favorable visual outcomes.

Clinicopathologic analysis of pineal parenchymal tumors of intermediate differentiation: a multi-institutional cohort study by the Kyushu Neuro-Oncology Study Group.

PURPOSE: Pineal parenchymal tumors of intermediate differentiation (PPTIDs), which were recognized in the 2007 World Health Organization (WHO) classification, are rare, accounting for less than 1% of all central nervous system tumors. This rarity and novelty complicate the diagnosis and treatments of PPTID. We therefore aimed to evaluate the clinicopathological significance of this tumor. METHODS: At 11 institutions participating in the Kyushu Neuro-Oncology Study Group, data for patients diagnosed with PPTID were collected. Central pathology review and KBTBD4 mutation analysis were applied to attain the diagnostically accurate cohort. RESULTS: PPTID was officially diagnosed in 28 patients: 11 (39%) with WHO grade 2 and 17 (61%) with WHO grade 3 tumors. Median age was 49 years, and the male:female ratio was 1:2.1. Surgery was attempted in all 28 patients, and gross total resection (GTR) was achieved in 46% (13/28). Adjuvant radiotherapy and chemotherapy were administered to, respectively, 82% (23/28) and 46% (13/28). The 5-year progression-free survival (PFS) and overall survival rates were 64.9% and 70.4% respectively. Female sex (p = 0.018) and GTR (p < 0.01) were found to be independent prognostic factors for PFS and female sex (p = 0.019) was that for OS. Initial and second recurrences were most often leptomeningeal (67% and 100% respectively). 80% (20/25) of patients harbored a KBTBD4 mutation. CONCLUSIONS: Female sex and GTR were independent prognostic factors in our patients with PPTID. Leptomeningeal recurrence was observed to be particularly characteristic of this tumor. The rate of KBTBD4 mutation observed in our cohort was acceptable and this could prove the accuracy of our PPTID cohort.

Effects of Microvascular Decompression on Pain Relief and Quality of Life in Late Elderly Patients with Trigeminal Neuralgia.

Pharmacotherapy is frequently selected over surgical interventions for late elderly patients with trigeminal neuralgia (TN). However, medication may affect these patients' activities of daily living (ADL). Hence, we investigated the effect of the surgical treatment of TN on ADL in older patients. This study included 11 late elderly patients >75 years old and 26 nonlate elderly patients who underwent microvascular decompression (MVD) for TN at our hospital from June 2017 to August 2021. We evaluated pre- and postsurgical ADL using the Barthel Index (BI) score, side effects of antineuralgic drugs, the BNI pain intensity score, and perioperative medication. The BI score of late elderly patients significantly improved postoperatively, particularly in transfer (pre: 10.5; post: 13.2), mobility (pre: 10; post: 12.7), and feeding (pre: 5.9 points; post: 10 points). Additionally, antineuralgic drugs caused preoperative disturbances of transfer and mobility. Trends of a longer disease duration and frequent occurrence of side effects were observed in all patients in the elderly group, compared to only 9 out of 26 patients in the younger group (100% vs. 35%, p = 0.0002). In addition, drowsiness was observed more frequently in the late elderly group (73% vs. 23%, p = 0.0084). However, the change in scores indicating improvement after surgery was significantly greater in the late elderly group, although both pre- and postoperative scores were higher in the nonlate elderly group (11.4 ± 1.9 vs. 6.9 ± 0.7, p = 0.027). Surgical treatment can improve older patients' ADL because it relieves pain and facilitates discontinuation of antineuralgic drugs. Consequently, MVD can be positively recommended for older patients with TN if general anesthesia is acceptable.

Endoscopic aqueductal membrane fenestration was effective for intractable hydrocephalus after removal of a nongerminomatous germ cell tumor exhibiting growing teratoma syndrome: a case report.

BACKGROUND: Primary central nervous system (CNS) germ cell tumors (GCTs) are rare neoplasms predominantly observed in the pediatric and young adult populations. A mixed GCT including immature teratoma exhibiting growing teratoma syndrome is presented. The pathogenesis of growing teratoma syndrome remains unclear, and its treatment strategy has not been established. GCTs are often located within the ventricles, causing hydrocephalus, which sometimes improves after removal of the tumor due to restoration of cerebrospinal fluid (CSF) flow. On the other hand, even if the flow route of CSF from the third ventricle to arachnoid granulations on the brain surface quadrigeminal cistern is restored after removal of the tumor, hydrocephalus may not improve. CASE PRESENTATION: A case whose intractable hydrocephalus improved after penetrating the aqueductal membrane via endoscopy is described. An 11-year-old boy was treated for pineal intracranial growing teratoma syndrome (IGTS). The tumor grew rapidly in a short period, and hydrocephalus progressed despite endoscopic third ventriculostomy (ETV). Although the obstruction was removed by radiation, chemotherapy, and total tumor resection, the hydrocephalus did not improve. Endoscopic membrane perforation was performed because a membrane-like structure was seen at the entrance of the cerebral aqueduct on magnetic resonance imaging. The hydrocephalus improved immediately after the operation, and the patient's consciousness disturbance also improved significantly. CONCLUSION: The purpose of this report is to update the current knowledge and standards of management for patients with growing teratoma syndrome, as well as to drive future translational and clinical studies by recognizing the unmet needs concerning hydrocephalus.

Profiling chromosomal-level variations in gastric malignancies.

Aneuploidy arises from persistent chromosome segregation errors, or chromosomal instability. Although it has long been known as a hallmark of cancer cells, reduced cellular fitness upon induced ploidy alterations hinders the understanding of how aneuploidy relates to cancer development in the body. In this study, we used FISH analysis targeting centromeres to indicate ploidy changes, and quantitatively evaluated the ploidy statuses of gastric tumors derived from a total of 214 patients, ranging from early to advanced disease. We found that cancer cells reveal a marked elevation of aneuploid population, increasingly in cases diagnosed in advanced stages. The expansion of the aneuploid population is well associated with p53 deficiency, consistent with its essential role in genome maintenance. Comparisons among multiple locations within the tumor, or between the primary and metastatic tumors, indicated that cancer cells mostly retain their ploidy alterations throughout primary tumors, but metastatic tumors may consist of cells with either increased or decreased levels of aneuploidy. We also found that a notable proportion of polyploid cells are often already present in chronic gastritis epithelia. These observations underscore that chromosome-level variations are widespread in gastric cancers, shaping their genetic heterogeneity and malignant properties.

Necessity for craniospinal irradiation of germinoma with positive cytology without spinal lesion on MR imaging-A controversy.

BACKGROUND: Cerebrospinal fluid (CSF) cytology and spinal MR imaging are routinely performed for staging before treatment of intracranial germinoma. However, the interpretation of the results of CSF cytology poses 2 unresolved clinical questions: (1) Does positive CSF cytology correlate with the presence of spinal lesion before treatment? and (2) Is craniospinal irradiation (CSI) necessary for patients with positive CSF cytology in the absence of spinal lesion? METHODS: Multicenter retrospective analyses were performed based on a questionnaire on clinical features, spinal MR imaging finding, results of CSF cytology, treatments, and outcomes which was sent to 86 neurosurgical and 35 pediatrics departments in Japan. Pretreatment frequencies of spinal lesion on MR imaging were compared between the patients with positive and negative cytology. Progression-free survival (PFS) rates were compared between patients with positive CSF cytology without spinal lesion on MR imaging treated with CSI and with whole brain or whole ventricular irradiation (non-CSI). RESULTS: A total of 92 germinoma patients from 45 institutes were evaluated by both CSF cytology and spinal MR images, but 26 patients were excluded because of tumor markers, the timing of CSF sampling or incomplete estimation of spinal lesion. Of the remaining 66 germinoma patients, spinal lesions were equally identified in patients with negative CSF cytology and positive cytology (4.9% and 8.0%, respectively). Eleven patients treated with non-CSI had excellent PFS comparable to 11 patients treated with CSI. CONCLUSION: CSI is unnecessary for germinoma patients with positive CSF cytology without spinal lesions on MR imaging.

Efficacy of a Novel Prophylactic Barbiturate Therapy for Severe Traumatic Brain Injuries: Step-down Infusion of a Barbiturate with Normothermia.

This study aimed to examine the beneficial effects of a novel prophylactic barbiturate therapy, step-down infusion of barbiturates, using thiamylal with normothermia (NOR+sdB), on the poor outcome in the patients with severe traumatic brain injuries (sTBI), in comparison with mild hypothermia (MD-HYPO). From January 2000 to March 2019, 4133 patients with TBI were admitted to our hospital. The inclusion criteria were: a Glasgow coma scale (GCS) score of ≤8 on admission, age between 20 and 80 years, intracranial hematoma requiring surgical evacuation of the hematoma with craniotomy and/or external decompression, and patients who underwent management of body temperature and assessed their outcome at 6-12 months. Finally, 43 patients were included in the MD-HYPO (n = 29) and NOR+sdB (n = 14) groups. sdB was initiated intraoperatively or immediately after the surgical treatment. There were no significant differences in patient characteristics, including age, sex, past medical history, GCS on admission, type of intracranial hematoma, and length of hospitalization between the two groups. Although NOR+sdB could not improve the patient's poor outcome either at discharge from the intensive care unit (ICU) or at 6-12 months after admission, the treatment inhibited composite death at discharge from the ICU. The mean value of the maximum intracranial pressure (ICP) in the NOR+sdB group was <20 mmHg throughout the first 120 h. NOR+sdB prevented composite death in the ICU in patients with sTBI, and we may obtain novel insights into the beneficial role of prophylactic barbiturate therapy from suppression of the elevated ICP during the first 120 h.

A novel step-down infusion method of barbiturate therapy: Its safety and effectiveness for intracranial pressure control.

Intracranial pressure (ICP) has to be maintained quite constant, because increased ICP caused by cerebrovascular disease and head trauma is fatal. Although controlling ICP is clinically critical, only few therapeutic methods are currently available. Barbiturates, a group of sedative-hypnotic drugs, are recognized as secondary treatment for controlling ICP. We proposed a novel "step-down infusion" method, administrating barbiturate (thiamylal) after different time point from the start of treatment under normothermia, at doses of 3.0 (0-24 h), 2.0 (24-48 h), 1.5 (48-72 h), and 1.0 mg/kg/h (72-96 h), and evaluated its safety and effectiveness in clinical. In 22 patients with severe traumatic brain injury or severe cerebrovascular disease (Glasgow coma scale ≤8), thiamylal concentrations and ICP were monitored. The step-down infusion method under normothermia maintained stable thiamylal concentrations (<26.1 µg/ml) without any abnormal accumulation/elevation, and could successfully keep ICP <20 mmHg (targeted management value: ICP <20 mmHg) in all patients. Moreover the mean value of cerebral perfusion pressure (CPP) was also maintained over 65 mmHg during all time course (targeted management value: CPP >65 mmHg), and no threatening changes in serum potassium or any hemodynamic instability were observed. Our novel "step-down infusion" method under normothermia enabled to maintain stable, safe thiamylal concentrations to ensure both ICP reduction and CPP maintenance without any serious side effects, may provide a novel and clinically effective treatment option for patients with increased ICP.

So-called bifocal tumors with diabetes insipidus and negative tumor markers: are they all germinoma?

BACKGROUND: The Delphi consensus statements on the management of germ cell tumors (GCTs) failed to reach agreements on the statement that the cases with (i) pineal and neurohypophyseal bifocal lesion, (ii) with diabetes insipidus, and (iii) with negative tumor markers can be diagnosed as germinoma without histological verification. To answer this, multicenter retrospective analysis was performed. METHODS: A questionnaire on clinical findings, histological diagnosis, and details of surgical procedures was sent to 86 neurosurgical and 35 pediatrics departments in Japan. RESULTS: Fifty-one institutes reported 132 cases that fulfilled the 3 criteria. Tissue sampling was performed in 91 cases from pineal (n = 44), neurohypophyseal (n = 32), both (n = 6), and distant (n = 9) lesions. Histological diagnosis was established in 89 cases: pure germinoma or germinoma with syncytiotrophoblastic giant cells in 82 (92.1%) cases, germinoma and mature teratoma in 2 cases, and granulomatous inflammation in 2 cases. Histological diagnosis was not established in 2 cases. Although no tumors other than GCTs were identified, 3 (3.4%) patients had non-germinomatous GCTs (NGGCTs). None of the patients developed permanent complications after endoscopic or stereotactic biopsy. Thirty-nine patients underwent simultaneous procedure for acute hydrocephalus without permanent complications, and hydrocephalus was controlled in 94.9% of them. CONCLUSION: All patients who fulfilled the 3 criteria had GCTs or granulomatous inflammation, but not other types of tumors. However, no fewer than 3.4% of the patients had NGGCTs. Considering the safety and the effects of simultaneous procedures for acute hydrocephalus, biopsy was recommended in such patients.

Endoscopic third ventriculostomy for myelomeningocele-related hydrocephalus after shunt failure: Long-term outcome in a series of 8 patients.

OBJECTIVE: Endoscopic third ventriculostomy (ETV) has now become an accepted mode of hydrocephalus treatment. However, the long-term effects of ETV for myelomeningocele-related hydrocephalus (MMC-rH) after shunt malfunction remains unclear. We aimed to assess the long-term outcome and the factors associated with the success of ETV for MMC-rH after shunt malfunction. METHODS: We performed a retrospective analysis of data collected between 2001 and 2018 from 8 patients with MMC-rH after shunt malfunction, who underwent ETV at the Kurume University Hospital and were followed up for at least 5 years. We extracted data regarding age, sex, clinical symptoms, radiological imaging, intraoperative findings, and outcomes. RESULTS: The overall success rate was 62.5% and their ETV success score is 67.5. The most frequent clinical symptom was intracranial hypertension symptoms (100 %), followed by Chiari type II symptoms (87.5 %). In preoperative MRI scans, we observed aqueduct stenosis in 6 cases, Chiari type II malformations in 7 cases, four patients had a narrow prepontine cistern, five patients had an absent septum pellucidum, and three presented with stenosis of the foramen of Monro. All cases in the failure group had the above 5 symptoms. Based on intraoperative findings, a thick third ventricle floor was found in 5 patients. Two patients had a thin hypothalamic adhesion in the third ventricle floor. They had no major complications. CONCLUSION: ETV for MMC-rH after shunt malfunction is an effective treatment option. However, we recommend that a neurosurgeon with extensive experience in neuroendoscopy perform ETV because MMC patients more often had intraventricular malformations than those with other hydrocephalus diseases.

Long-term outcomes of endoscopic third ventriculostomy for Blake's pouch cyst in adults.

OBJECTIVE: The optimal treatment method for persistent Blake's pouch cyst (BPC) remains unclear owing to its low prevalence. We aimed to characterize a patient population with adult BPC and to identify the risk factors associated with endoscopic third ventriculostomy (ETV) for BPC. This study reports the largest number of BPC cases in adults and is the first report to reveal the long-term outcomes of ETV in such patients. METHODS: We performed a retrospective analysis of data collected from seven adult patients with BPC between 2005 and 2019. They underwent ETV at the Kurume University Hospital and were followed up for five years or more. We extracted data regarding patient age, sex, clinical symptoms, radiological imaging, intraoperative findings and outcomes. RESULTS: The ages of the patients ranged between 30 and 60 years (45 ±â€¯12 years). The mean postoperative follow-up time was 92.1 ±â€¯13.5 months. The overall success rate was 71.4%. The most frequent symptom was headache (86%), followed by mild cognitive impairment (71%). The average cerebrospinal fluid pressure was slightly elevated (18.4 ±â€¯1.4 cmH2O). A decrease in ventricular size (Evans' index) detected early after ETV was associated with satisfactory clinical outcomes (p = 0.02). The incidence of prepontine scarring was observed in all cases of the ETV failure group. A significant risk factor for ETV was the to-and-fro movements of the third ventricle floor after ETV (p = 0.048). CONCLUSIONS: ETV could be a safe and effective treatment option for adult patients with BPC. It is important that prepontine scarring and the to-and-fro movements of the third ventricle after ETV should be confirmed carefully when performing ETV on adult patients with BPC.

Sagittal diffusion-weighted imaging in preventing the false-negative diagnosis of acute brainstem infarction: Confirmation of the benefit by anatomical characterization of false-negative lesions.

BACKGROUND: In some cases of acute brainstem infarction (BI), standard axial diffusion-weighted imaging (DWI) does not show a lesion, leading to false-negative (FN) diagnoses. It is important to recognize acute BI accurately and promptly to initiate therapy as soon as possible. METHODS: Of the 171 patients with acute cerebral infarctions in our institution who were examined, 16 were diagnosed with true-positive BI (TP-BI) and six with FN-BI. We evaluated the effectiveness of sagittal DWI in accurately diagnosing acute BI and sought to find the cause of its effectiveness by the anatomical characterization of FN-BIs. RESULTS: Considering the direction of the brainstem perforating arteries, we supposed that sagittal DWI might more effectively detect BIs than axial DWI. We found that sagittal DWI detected all FN-BIs more clearly than axial DWI. The mean time between the onset of symptoms and initial DWI was significantly longer in the TP group (17.6 ± 5.5 h) than in the FN group (5.0 ± 1.2 h; P < 0.0001). The lesion volumes were much smaller in FN-BIs (259 ± 82 mm3) than in TP-BIs (2779 ± 767 mm3; P = 0.0007). FN-BIs had a significant inverse correlation with the ventrodorsal length of infarcts (FN 3.5 ± 1.1 mm, TP 11.4 ± 3.6 mm; P < 0.0004) and no correlation with other size parameters such as rostrocaudal thickness and lateral width. CONCLUSION: Anatomical characterization clearly confirmed that the addition of sagittal DWI to the initial axial DWI in suspected cases of BI ensures its accurate diagnosis and improves the patient's prognosis.

Gamma knife surgery-induced aneurysm rupture associated with tissue plasminogen activator injection: A case report and literature review.

BACKGROUND: Cases involving delayed development of intracranial aneurysms related to gamma knife surgery (GKS) have been recently reported. Here, we present a rare case of GKS-induced aneurysm rupture after intravenous injection of tissue plasminogen activator (t-PA) for occlusion of the middle cerebral artery (MCA). To the best of our knowledge, this is the first case in which t-PA-induced rupture of a GKS-related unruptured aneurysm. CASE DESCRIPTION: A 56-year-old woman underwent GKS for left trigeminal neuralgia. Eighteen years later, she suddenly experienced MCA occlusion with consciousness disturbance and right hemiparesis. She received an intravenous injection of t-PA and then was transferred to our hospital. We confirmed residual thrombus, and she underwent mechanical thrombectomy successfully. A postthrombectomy brain computed tomography scan revealed subarachnoid hemorrhage with a hematoma in the left cerebellar hemisphere. Cerebral angiography revealed a small irregular-shaped aneurysm at the branching site of the left circumflex branch at the distal position of the anterior inferior cerebellar artery, which was not detected on initial imaging. Coil embolization was performed. One month after the ischemic attack, she was transferred to a rehabilitation hospital, with a modified Rankin Scale score of 5. CONCLUSIONS: The tendency to rupture is greater for GKS-induced aneurysms than for intrinsic unruptured aneurysms, according to previous reports. When performing acute treatment for cerebral infarction in patients with a history of GKS, the presence of aneurysms should be evaluated and we should keep in mind that GKS aneurysms are very small and tend to rupture.

Leptomeningeal Carcinomatosis After Neoplastic Cerebral Aneurysm Rupture.

BACKGROUND: Several possible mechanisms exist for the spread of a primary tumor to the leptomeninges in leptomeningeal carcinomatosis. This report describes a case caused by direct bleeding in the subarachnoid space from a neoplastic cerebral aneurysm rupture. CASE DESCRIPTION: A 48-year-old Japanese woman, who was diagnosed with breast carcinoma (pT3 pN2 M0) at the age of 45 years and underwent mastectomy and chemotherapy, was admitted in a coma following a sudden-onset severe headache. Computed tomography revealed diffuse hemorrhage in the subarachnoid space, and angiography revealed an aneurysm at the distal middle cerebral artery. Superficial temporal artery-middle cerebral artery bypass, aneurysmal trapping, and aneurysm resection were performed within 24 hours of admission. Staining for AE1/AE3 revealed accumulation of atypical cells with a high nuclear-cytoplasmic ratio in the aneurysmal wall. After showing initial improvement, she developed disturbed consciousness due to complicated ventricular enlargement on day 45. Although the cerebrospinal fluid in the acute phase had no atypical cells, subsequent testing revealed atypical cells, which supported a diagnosis of leptomeningeal carcinomatosis due to breast cancer dissemination. The patient died on day 78 after receiving standard endocrine therapy and radiation therapy. CONCLUSIONS: Tumor cells reach the leptomeninges via hematogenous spread or direct extension from preexisting lesions and can undergo neuraxis dissemination via the cerebrospinal fluid. Subarachnoid hemorrhage and leptomeningeal carcinomatosis are both devastating conditions with extremely poor prognoses. This patient experienced delayed disturbed consciousness leptomeningeal carcinomatosis with decreased performance status, which made it difficult to justify aggressive treatment on the basis of her poor prognosis.

Neuroprotective effects of a novel carnosine-hydrazide derivative on hippocampal CA1 damage after transient cerebral ischemia.

Ischemia-reperfusion injuries produce reactive oxygen species that promote the peroxide lipid oxidation process resulting in the production of an endogenic lipid peroxide, 4-hydroxy-trans-2-nonenal (4-HNE), a highly cytotoxic aldehyde that induces cell death. We synthesized a novel 4-HNE scavenger - a carnosine-hydrazide derivative, l-carnosine hydrazide (CNN) - and examined its neuroprotective effect in a model of transient ischemia. PC-12 cells were pre-incubated with various doses (0-50 mmol/L) of CNN for 30 min, followed by incubation with 4-HNE (250 µM). An MTT assay was performed 24 h later to examine cell survival. Transient ischemia was induced by bilateral common carotid artery occlusion (BCCO) in the Mongolian gerbil. Animals were assigned to sham-operated (n = 6), placebo-treated (n = 12), CNN pre-treated (20 mg/kg; n = 12), CNN post-treated (100 mg/kg; n = 11), and histidyl hydrazide (a previously known 4-HNE scavenger) post-treated (100 mg/kg; n = 7) groups. Heat shock protein 70 immunoreactivity in the hippocampal CA1 region was evaluated 24 h later, while delayed neuronal death using 4-HNE staining was evaluated 7 days later. Pre-incubation with 30 mmol/L CNN completely inhibited 4-HNE-induced cell toxicity. CNN prevented delayed neuronal death by >60% in the pre-treated group (p < 0.001) and by >40% in the post-treated group (p < 0.01). Histidyl hydrazide post-treatment elicited no protective effect. CNN pre-treatment resulted in high heat shock protein 70 and low 4-HNE immunoreactivity in CA1 pyramidal neurons. Higher 4-HNE immunoreactivity was also found in the placebo-treated animals than in the CNN pre-treated animals. Our novel compound, CNN, elicited highly effective 4-HNE scavenging activity in vitro. Furthermore, CNN administration both pre- and post-BCCO remarkably reduced delayed neuronal death in the hippocampal CA1 region via its induction of heat shock protein 70 and scavenging of 4-HNE.

Stenotic changes of the posterior cerebral artery are a major contributing factor for cerebral infarction in moyamoya disease.

BACKGROUND: Some patients with moyamoya disease (MMD) show broad infarction with moderate internal carotid artery (ICA) stenosis, whereas others with complete ICA occlusion show no infarction. This suggests that other factors contribute to the occurrence of infarction. Contributing factors predictive of cerebral infarcts must be identified for the prevention of infarction and the consequent neurological deficits. METHODS: We examined data from 93 patients with confirmed MMD for the presence of infarction (n = 72), transient ischemic attack (TIA, n = 41), asymptomatic presentation (n = 51), or hemorrhage (n = 22) in 186 bilateral cerebral hemispheres. We analyzed the relationship between the occurrence of infarction and several clinical factors, such as steno-occlusive status or the site of the ICA and posterior cerebral artery (PCA). RESULTS: The incidence of PCA steno-occlusive lesions was significantly higher in infarcted (77.8%) than in non-infarcted hemispheres (TIA, 14.6%; asymptomatic, 9.8%; hemorrhagic 9.1%; P < 0.01). The steno-occlusive site of ICA was also a significant factor (P < 0.05). There was no significant correlation between the occurrence of infarction and the steno-occlusive status of the ICA or grade of the moyamoya vessels. Multivariate statistical analysis demonstrated that the PCA steno-occlusive changes were an important contributing factor for infarction (P < 0.0001). CONCLUSIONS: This is the multivariate statistical analysis study identifying PCA steno-occlusive lesions as the most important independent factor that is predictive to cerebral infarction in moyamoya patients. The prediction and inhibition of PCA steno-occlusive changes may help to prevent cerebral infarction.