Cerebrospinal Fluid Refill Test as a Novel Diagnostic Tool for Cerebrospinal Fluid Hypovolemia: Preliminary Result.

OBJECTIVE: Cerebrospinal fluid (CSF) hypovolemia presents with orthostatic headaches due to CSF leakage. However, a direct association between the lack of CSF and clinical symptoms has not been found. CSF hypovolemia can be improved by refilling CSF. Therefore, we assessed the validity of a CSF refill test. METHODS: From November 2019 to August 2021, we included 10 patients (≥18 years old) with potential CSF hypovolemia, clear orthostatic headaches, and a CSF opening pressure <10 cmH2O. In the CSF refill test, 10 mL of artificial CSF was injected intrathecally. The primary outcome was improvement in orthostatic headache assessed using a visual analog scale (VAS), while the secondary outcomes were the 10-m walk time and adverse events. When the symptoms temporarily improved after intrathecal injection, the patients underwent radiologic imaging to identify the CSF leak, and an epidural blood patch was proposed accordingly. RESULTS: All patients showed post-test improvements in the VAS score (median [interquartile range], pretest 63.0 [50.3-74.3] vs. post-test 1.5 [0.0-26.0]). The 10-m walk time also significantly improved (9.5 [8.5-10.2] s vs. 8.2 [7.9-8.7] s). One patient experienced temporary right leg numbness associated with a lumbar puncture. After radiologic investigation, 9 patients underwent epidural blood patches, of which 6 were completely cured, and 3 revealed partial improvement. CONCLUSIONS: The cerebrospinal fluid (CSF) refill test was safe and effective in demonstrating the direct association between the lack of CSF and clinical symptoms and may help predict the outcome of an epidural blood patch.

The Cervical Spine as a Predominant Site of Cerebrospinal Fluid Leak: Preliminary Results Using the Overflow Leak Test.

BACKGROUND: Cerebrospinal fluid (CSF) hypovolemia is usually treated via an epidural blood patch (EBP). Accurate placement of the EBP at the site of CSF leakage is required for successful treatment of CSF hypovolemia. The thoracolumbar spine is evidently a common site of leakage, but because rates of detection of the leakage site via conventional imaging have historically not been high, there may be other common leakage sites. In this study, CSF leakage sites were identified via a combination of conventional imaging, a new method called the overflow leak test, and patient interviews. METHODS: CSF leakage sites were identified using computed tomography myelography, radioisotope cisternography, and the overflow leak test in 14 patients with CSF hypovolemia. The patients were also asked about their history with regard to potential trauma. EBP was performed, and the accuracy of leakage site identification was assessed. RESULTS: Conventional imaging identified a leakage site in 7 of 14 patients, and in most cases it was in the lumbar spine. In the remaining 7 cases, the overflow leak test and ascertaining a history of trauma facilitated identification of the cervical spine as a leakage site. The site of the EBP was the cervical spine in 10 patients and the lumbar spine in 4 patients. Complete recovery was observed in 13 of 14 patients. CONCLUSIONS: The cervical spine was a common leakage site in this study. Leakage in the cervical spine was undetectable via conventional imaging, suggesting that many cases of cervical spine leakage may remain undetected.

Acute Deterioration in a Patient with Bilateral Chronic Subdural Hematomas Associated with Intracranial Hypotension Treated with an Epidural Blood Patch.

BACKGROUND: Intracranial hypotension due to cerebrospinal fluid (CSF) leak is often associated with secondary chronic subdural hematoma (CSDH). Although epidural blood patch (EBP) treatment for the CSF leak site has been reported to result in spontaneous regression of the CSDH in most cases, it is still debatable whether blocking CSF leak first in the patients with intracranial hematoma is always safe. CASE DESCRIPTION: A 72-year-old woman presented with orthostatic headache after a head injury and was diagnosed with intracranial hypotension. Computed tomography myelography and radioisotope cisternography failed to reveal the CSF leak point. The overflow leak test, a novel diagnostic method for intracranial hypotension, revealed a leakage at the cervical spine. Bilateral CSDHs were also observed by a computed tomography scan of the head. We performed EBP at the cervical spine and anticipated subsequent regression of the CSDH by normalizing intrathecal pressure. However, the patient became delirious the morning after EBP, and an emergency burr hole trepanation was performed. The patient's consciousness fully recovered, and her orthostatic headache improved as well. CONCLUSIONS: This case presentation demonstrated that in the case of intracranial hypotension with secondary CSDH, performing EBP and waiting for subsequent spontaneous regression of CSDH are not necessarily safe. Immediate burr hole trepanation should be prepared for the subsequent rapid symptomatic change of the CSDH after EBP.

[Preliminary Experience of a Biplane Flat Panel and Tailor-made Operating Table-equipped Hybrid Operating Room].

A hybrid operating room(Hybrid OR), where operative equipment and flat panel angiography are both available, is becoming common for complex cerebrovascular surgery. However, the current Hybrid OR remains suboptimal as it is not cost-effective and contains uncomfortable operating beds, and a single-plane flat panel. Therefore, we introduced a novel Hybrid OR system, which has a biplane flat panel detector and three mutually exchangeable tailor-made operating beds. In this article, we report our preliminary experience of this novel Hybrid OR, focusing on improved cost-effectiveness by the availability of diagnostic angiography and standard endovascular surgery, optimal selection of three different types of operating beds, and procedural workflow in individual hybrid cerebrovascular surgery.

[Recurrent High-grade Astroblastoma Treated with Stereotactic Radiotherapy:A Case Report].

INTRODUCTION: Astroblastoma is a rare, supratentorial glial tumor, occurring predominantly in children and young adults. However, treatment strategies have not yet been established for this rare disease. CASE PRESENTATION: A 6-year-old boy presented with headache and nausea. CT and MRI revealed a left frontal mass lesion with slight edema and macrocalcifications. Gross tumor resection was performed. Histological examination found neoplastic cells with astroblastic characteristics, and a striking perivascular array of pseudorosettes. The final diagnosis was high-grade astroblastoma. MRI 13 months after surgery suggested local recurrence, and an enlargement was found 3 months later. Stereotactic radiotherapy(SRT)was performed. MRI after SRT showed enhanced cyst formation around the tumor bed, suggesting tumor recurrence. However, 11C-methionine positron emission tomography(PET)revealed radiation necrosis. The last follow-up MRI 15 months after SRT showed no further recurrence. CONCLUSION: Astroblastoma is rare, therefore, no optimal management is known. SRT may be effective to treat recurrent astroblastomas. 11C-methionine PET/CT was useful to differentiate metastatic disease from radiation necrosis.

Use of fat-suppressed T2 -weighted sagittal images after infusion of excess saline into the subarachnoid space as a new diagnostic modality for cerebrospinal fluid hypovolemia: technical note.

The diagnosis of CSF hypovolemia remains controversial. The primary diagnostic factor relies on confirmation of leakage of the CSF based on reduced spinal fluid pressure. Determining the specific leakage site is the most important issue for effective treatment but remains a difficult task. Although CT myelography, radioisotope cisternography, and MRI are commonly performed in the diagnosis of CSF hypovolemia, these techniques can rarely identify the precise leakage site. Therefore, an epidural blood patch is performed in the lumbar spine in many cases. This study reports a new diagnostic modality that can help to confirm the leakage site. Fat-suppressed T2-weighted sagittal images were compared before and after the infusion of 20 ml of saline into the subarachnoid space of the lumbar region to detect the specific leakage site with high probability. Three patients were successfully treated by the epidural blood patch based on data obtained with the new diagnostic modality. Two patients were treated in the cervical region and 1 in the lumbar region. The use of fat-suppressed T2-weighted sagittal images after saline infusion could be a relevant diagnostic modality compared with images obtained by CT myelography, radioisotope cisternography, and ordinary MRI to achieve accurate diagnosis and effective treatment of patients with CSF hypovolemia.

Elevated cell invasion in a tumor sphere culture of RSV-M mouse glioma cells.

Cancer stem cells (CSCs) are the sole population possessing high self-renewal activity in tumors, with their existence affecting tumor recurrence. However, the invasive activity of CSCs has yet to be fully understood. In this article, we established a tumor sphere culture of RSV-M mouse glioma cells (RSV-M-TS) and evaluated their migration and invasion activities. Histological analysis of a tumor formed by cranial injection of the RSV-M-TS cells showed highly invasive properties and similarities with human malignant glioma tissues. When the migration activity of both RSV-M and RSV-M-TS cells were compared by intracranial injection, rapid migration of RSV-M-TS cells was observed. To confirm the invasive capabilities of RSV-M-TS cells, a three-dimensional collagen invasion assay was performed in vitro using RSV-M, RSV-M-TS, and RSV-M-TS cells cultured with medium containing serum. RSV-M and RSV-M-TS cultured with medium containing serum for 8 days indicated low migration activity, while moderate invasion activity was observed in RSV-M-TS cells. This activity was further enhanced by incubation with medium containing serum overnight. To identify the genes involved in this invasion activity, we performed quantitative polymerase chain reaction (PCR) array analysis of RSV-M and RSV-M-TS cells. Of 84 cancer metastasis-related genes, up-regulation was observed in 24 genes, while 4 genes appeared to be down-regulated in RSV-M-TS cells. These results suggest that the enhanced invasive activity of glioma sphere cells correlates with a number of tumor metastasis-related genes and plays a role in the dissemination and invasion of glioma cells.

Evaluation of two- and three-dimensional visualization for endoscopic endonasal surgery using a novel stereoendoscopic system in a novice: a comparison on a dry laboratory model.

BACKGROUND: Three-dimensional (3-D) stereoscopic vision is theoretically superior to two-dimensional (2-D) vision in endoscopic endonasal surgery. However, only few reports have quantitatively compared endoscopic performance under the two visual conditions. We introduced a newly designed stereoendoscopic system with a "dual-lens and single camera" for endoscopic endonasal surgery and objectively compared the performances under 3-D and high-definition 2-D visualizations on a dry laboratory model. METHODS: Thirty subjects without experience performing endoscopic surgery, computer-simulated training or any 3-D video system were recruited and divided into two groups (Group A and Group B) for performing two different tasks. The novel 4.7-mm-diameter stereoendoscope provided high-definition (HD) images. In Task 1, Group A started the task under the 3-D condition followed by the 2-D condition, and Group B vice versa. In Task 2, Group A started the task under the 2-D condition followed by the 3-D condition, and Group B vice versa. The performance accuracy and speed under the two visual conditions were analyzed. RESULTS: Significant improvement in performance accuracy and speed was seen under 3-D conditions in the both "3-D first" and "2-D first" subgroups during both tasks (P < .001). Regardless of order, the inaccuracy rate and performance time under 3-D conditions was significantly lower than that under 2-D conditions in each subject. CONCLUSIONS: We demonstrated the advantage of 3-D visualization over 2-D visualization for inexperienced subjects. Further quantitative clinical studies are required to confirm whether stereoendoscopy actually provides benefits in clinical settings.

Preoperative surgical approach planning for metastatic pituitary stalk tumor using multimodal fusion imaging in a neuronavigation system--case report.

A 72-year-old woman presented with a metastatic brain tumor around the pituitary stalk compressing the chiasm anteriorly and upward. After tumor resection by a left pterional approach failed, a three-dimensional (3D) image of the area of interest was reconstructed using the Vecter Vision navigation system and iPlan Cranial planning software version 2.5. Preoperative 3D computed tomography and magnetic resonance imaging data were fused to demonstrate the anatomical relationship between vessels, nerves, and tumor. Clearer demonstration of the optic nerves utilized thin slice axial and sagittal views along the nerves. The 3D reconstructed image demonstrated the spatial relationship of the tumor and surrounding tissue, and suggested the necessity of a right orbitozygomatic approach to create adequate working space for tumor resection. Second surgery according to this preoperative planning was successful. High quality multimodal fusion images in a navigation system has distinct advantages in preoperative assessment of essential structural relationships allowing adequate exposure of certain lesions and surrounding structures in individual patients by defining specific surgical approaches.

Enhanced expression of cancer testis antigen genes in glioma stem cells.

Cancer stem cells are an important target for effective therapy, since they show tumorigenicity, chemoresistance, and radioresistance. We isolated cancer stem cells from glioma cell lines and tissues and examined the expression of cancer testis antigen (CTA) genes as potential target molecules for cancer vaccine therapy. CTA genes were highly and frequently expressed in cancer stem cells compared with differentiated cells. In addition, histone acetylation levels in the promoter regions of CTA genes were high in cancer stem cells and low in differentiated cells, while DNA methylation analysis of the promoter regions revealed hypomethylation in cancer stem cells. This epigenetic difference between cells leads to heterogeneous expression of CTA genes in the tumor mass, which consists of cells at various levels of differentiation. Moreover, the expression level of HLA class I antigens was not affected by the differentiation status, suggesting that CTA genes may present as surface antigens in cancer stem cells. Taken together, these findings suggest that CTA genes may be attractive candidates for targeted vaccine therapy against cancer stem cells in glioma patients.

Enhanced MDR1 expression and chemoresistance of cancer stem cells derived from glioblastoma.

We established a cancer stem (CS) cell line, U87CS, by means of spheroid culture of U87MG cells derived from glioblastoma (GBM) in neuronal stem cell medium. U87CS cells presented positive immunohistochemical staining for multidrug resistance (MDR)1 and CD133, a marker for a subset of leukemia and GBM CS cells. The gene expression of MDR1 and CD133 on U87CS cells increased by an average of 8.51 and 47.18 times, respectively, compared to the levels on U87MG cells by real-time quantitative RT-PCR. U87CS cells possessed stronger drug-resistance to conventional anti-cancer drugs, such as doxorubicin (Dox), etoposide (VP-16), carboplastin, and BCNU than U87MG cells. Double immunofluoresence staining showed co-expression of MDR1 and CD133 on U87CS cells transplanted into nude mice brains. In addition, we identified the crossreactivity of CD133 and MDR1 in a surgical specimen of GBM. Our results suggest that CS cells may be resistant to current chemotherapy and represent a novel target for GBM therapeutics.

Synthesis and evaluation of 2-{[2-(4-hydroxyphenyl)-ethyl]amino}pyrimidine-5-carboxamide derivatives as novel STAT6 inhibitors.

The STAT6 (signal transducers and activators of transcription 6) protein is activated by interleukin (IL)-4 and IL-13, and plays an important role in T-helper cell 2 (Th2) differentiation. STAT6 might therefore be an excellent therapeutic target for various allergic conditions, including asthma and atopic diseases. We synthesized a series of 2-{[2-(4-hydroxyphenyl)ethyl]amino}pyrimidine-5-carboxamide derivatives and evaluated their STAT6 inhibitory activities. Among these compounds, 4-(benzylamino)-2-{[2-(3-chloro-4-hydroxyphenyl)ethyl]amino}pyrimidine-5-carboxamide (2t, AS1517499) showed potent STAT6 inhibition with an IC(50) value of 21 nM, and also inhibited IL-4-induced Th2 differentiation of mouse spleen T cells with an IC(50) value of 2.3 nM and without influencing T-helper cell 1 (Th1) differentiation induced by IL-12.

A rapidly enlarging nocardial brain abscess mimicking malignant glioma.

Nocardial brain abscesses are uncommon and are not preceded by clear infectious symptoms in most cases. Delayed identification of the bacteria is responsible for a high mortality rate. A 58-year-old afebrile woman was admitted to our hospital because of progressive right hemiparesis and aphasia. Magnetic resonance imaging (MRI) showed a single ring-enhanced lesion in the left frontal lobe. It was extremely difficult to establish the diagnosis of brain abscess, because the laboratory data provided little evidence of bacterial infection, (201)TlCl-scintigraphy revealed definite accumulation of thallium in the lesion, and follow-up MRI demonstrated rapid enlargement of the lesion. Total resection was performed because of the possibility of a malignant brain tumor, but brain abscess was finally diagnosed with histological examination. A nocardial species was detected through microscopic examination of the pus obtained at surgery, and this precise diagnosis of nocardial brain abscess in the early stage enabled the administration of appropriate antibiotics and the patient's quick recovery. Nocardial brain abscesses are often misdiagnosed as malignant brain tumors, and a definitive diagnosis may not be possible without detecting bacteria from the lesion. Total excision of the abscess can produce good results when the abscess is large and located superficially, but incomplete aspiration and drainage of a lesion is associated with a high chance of relapse.

Characterization of microglia induced from mouse embryonic stem cells and their migration into the brain parenchyma.

We derived microglia from mouse embryonic stem cells (ES cells) at very high density. Using the markers Mac1(+)/CD45(low) and Mac1(+)/CD45(high) to define microglia and macrophages, respectively, we show that Mac1(+) cells are induced by GM-CSF stimulation following neuronal differentiation of mouse ES cells using a five-step method. CD45(low) expression was high and CD45(high) expression was low on induced cells. We used a density gradient method to obtain a large amount of microglia-like cells, approximately 90% of Mac1(+) cells. Microglia-like cells expressed MHC class I, class II, CD40, CD80, CD86, and IFN-gammaR. The expression level of these molecules on microglia-like cells was barely enhanced by IFN-gamma. Intravenously transferred GFP(+) microglia derived from GFP(+) ES cells selectively accumulated in brain but not in peripheral tissues such as spleen and lymph node. GFP(+) cells were detected mainly in corpus callosum and hippocampus but were rarely seen in cerebral cortex, where Iba1, another marker of microglia, is primarily expressed. Furthermore, both GFP(+) and Iba1(+) cells exhibited a ramified morphology characteristic of mature microglia. These studies suggest that ES cell-derived microglia-like cells obtained using our protocol are functional and migrate selectively into the brain but not into peripheral tissues after intravenous transplantation.

Primitive neuroectodermal tumor (PNET) treated with interferon-beta after surgical removal and irradiation: case report.

This case report describes an 11-year-old boy with primitive neuroectodermal tumor (PNET), which remains the pediatric brain tumor with the worst prognosis despite combination treatment with surgery, irradiation and anti-cancer drugs. The boy was successfully treated with intratumoral administration of interferon-beta (IFN-beta) following surgical resection and irradiation. Two million units of IFN-beta were locally administered into the post-operative cavity through the Ommaya's reservoir every two weeks after discharge. He was managed as an outpatient without serious side-effects to IFN. The patient has shown no tumor recurrence, mental retardation, or neuroendocrine impairment for over three years and has lived a normal school life with a full Karnofsky Performance Status score. The local administration of IFN-beta may be warranted for maintenance therapy in children with PNET.