Successful administration of clazosentan in subarachnoid hemorrhage patient with severe heart failure.

Background: Clazosentan, an endothelin receptor antagonist, has been shown to prevent cerebral vasospasms following subarachnoid hemorrhage (SAH) effectively. However, clazosentan-induced pulmonary edema is a frequently reported adverse effect and a primary reason for discontinuing treatment. The presence of preexisting heart conditions predisposes patients to severe pulmonary edema; thus, the administration of clazosentan is generally contraindicated. Case Description: We report the successful administration of clazosentan in a 58-year-old female patient with SAH and severe heart failure (Takotsubo cardiomyopathy). The patient initially presented with a ruptured left internal carotid posterior communicating artery aneurysm, leading to SAH. She successfully underwent neck clipping, and postoperative treatment to prevent cerebral vasospasm, including clazosentan, was initiated. Following the emergency surgical intervention, she exhibited pulmonary edema and diffused left ventricular hypokinesis with an ejection fraction of 10-20%. Although drug-induced pulmonary edema emerged after the administration of clazosentan, tailored fluid management based on daily cardiac function and ventilator management in response to pulmonary edema enabled the completion of a 2-week clazosentan therapy regimen. This approach guaranteed the patient's stability throughout the treatment period. Neither cerebral vasospasm nor cardiopulmonary complications were observed. Conclusion: This case highlights the importance of a multidisciplinary approach in managing complex patients with severe cardiac comorbidities undergoing clazosentan therapy.

A Case of Scurvy Associated With Intracerebral Hemorrhage in a Patient With Alcohol Use Disorder.

Vitamin C deficiency, also known as scurvy, causes abnormalities in connective tissues and varied symptoms. We describe a patient with putaminal hemorrhage, a very rare presentation of scurvy. A 39-year-old man presented with weakness in the left arm and left leg. Right putaminal hemorrhage was initially diagnosed, and he underwent evacuation of the intracerebral hemorrhage. Scurvy was suspected when repeated physical examinations revealed a bleeding tendency and multiple untreated dental caries, missing teeth, and gingivitis. A diagnosis of scurvy was further supported by the patient's history of smoking, alcohol use disorder, poor diet, and low plasma vitamin C concentration. After receiving oral nutritional supplementation including vitamin C, the bleeding tendency quickly improved. This case highlights the importance of including scurvy in a differential diagnosis for patients with bleeding tendencies, especially those with a poor diet or unknown dietary history. Empirical administration of vitamin C is a reasonable treatment.

Retrospective Observational Study of Patients With Subdural Hematoma Treated With Idarucizumab.

Use of anticoagulants is increasing with the aging of societies. The safe first-line drug is likely to be a direct oral anticoagulant (DOAC), but outcomes of treatment of traumatic brain injury (TBI) with anticoagulants are uncertain. Therefore, we examined the clinical effect of idarucizumab as reversal therapy in elderly patients with TBI who were treated with dabigatran. A retrospective multi-center observational study was performed in patients ≥65 years of age who developed acute traumatic subdural hematoma during treatment with dabigatran and underwent reversal therapy with idarucizumab. The items examined included patient background, neurological and imaging findings at arrival, course after admission, complications, and outcomes. A total of 23 patients were enrolled in the study. The patients had a mean age of 78.9 years. Cause of TBI was fall in 60.9% of the subjects. Mean Glasgow Coma Scale score at arrival was 8.7; anisocoria was present in 31.8% of cases. Exacerbation of consciousness was found in 30.4%, but only in 13.3% of subjects treated with idarucizumab before consciousness and imaging findings worsened. Dabigatran was discontinued in 81.8% of cases after hematoma development, with a mean withdrawal period of 12.1 days. The favorable outcome rate was 21.7%, and mortality was 39.1%. In multi-variate analysis, timing of idarucizumab administration was associated with a favorable outcome. There were ischemic complications in 3 cases (13.1%), and all three events occurred ≥7 days after administration of idarucizumab. These findings suggest that in cases that develop hematoma during treatment with dabigatran, it is important to administer idarucizumab early and restart dabigatran after conditions stabilize.

Evaluation of Brain Tumors Using Amide Proton Transfer Imaging: A Comparison of Normal Amide Proton Transfer Signal With Abnormal Amide Proton Transfer Signal Value.

OBJECTIVE: The aim of the study was to evaluate the relationship of amide proton transfer (APT) signal characteristics in brain tumors and uninvolved brain tissue for patients with glioblastoma and those with brain metastases. METHODS: Using the mDIXON 3D-APT sequence of the fast spin echo method, an APT image was obtained. The mean APT signal values of tumor core, peritumor edema, ipsilateral normal-appearing white matter (INAWM), and contralateral normal white matter (CNAWM) were obtained and compared between glioblastoma and brain metastases. Receiver operating characteristic curves were used to evaluate parameters for distinguishing between glioblastoma and brain metastases. In addition, the difference and change rate in APT signal values between tumor core and peritumoral edema (PE) and CNAWM were evaluated, respectively. RESULTS: The APT signal values of glioblastoma were the highest in tumor core (3.41% ± 0.49%), followed by PE (2.24% ± 0.29%), INAWM (1.35% ± 0.15%), and CNAWM (1.26% ± 0.12%, P < 0.001). The APT signal value of brain metastases was the highest in tumor core (2.74% ± 0.34%), followed by PE (1.86% ± 0.35%), INAWM (1.17% ± 0.13%), and CNAWM (1.2% ± 0.09%, P < 0.01). The APT change rate (between PE and CNAWM) was not significantly different at 78% and 56% for glioblastoma and brain metastases, respectively ( P > 0.05). CONCLUSIONS: Performing APT imaging under the same parameters used in this study may aid in the identification of brain tumors.

Cerebral Venous Thrombosis as an Initial Presentation of Ulcerative Colitis.

Cerebral venous thrombosis (CVT) is a rare complication of ulcerative colitis (UC) that is potentially fatal once it occurs. This report describes a case of CVT that led to a diagnosis of UC. A 48-year-old woman was diagnosed with CVT due to paresthesia and weakness and was hospitalized for treatment. She developed bloody diarrhea on admission and was further diagnosed with UC based on endoscopic and pathologic findings. Treatment of UC with steroids and sulfasalazine was administered immediately. Her condition improved significantly within several days following treatment. After discharge, the patient experienced no recurrence of either CVT or UC flare-up over the last five years. This report describes CVT as an initial presentation of UC. This is also the first report of a long-term follow-up following successful treatment of CVT with concomitant UC.

Quantitative Analysis of Mobile Proteins in Normal Brain Tissue by Amide Proton Transfer Imaging: Age Dependence and Sex Differences.

PURPOSE: The aims of this study were to evaluate the relationship between age change and amide proton transfer (APT) signal in each region of the whole brain and to derive the standard value of APT signal in each brain region of normal adults. MATERIALS AND METHODS: Using the mDIXON 3-dimensional-APT sequence of the fast spin echo method, an APT image was obtained. In total, 60 patients (mean age, 49.8 ± 16.9 years) with no abnormal findings on magnetic resonance imaging data were included. For image analysis, registration parameters were created using the FMRIB Software Library 5.0.11, and then a region of interest was set in the Montreal Neurological Institute structural atlas for analysis. Statistical analyses were performed using the age-dependent and sex differences in APT signals from each brain region. RESULTS: No significant correlation was seen between APT signal and age and sex in all brain regions. CONCLUSION: Under the APT imaging parameter conditions used in this study, local brain APT signals in healthy adults are independent of age and sex.

Carotid Artery Stenting for Symptomatic Carotid Artery Dissection Developing from Stanford Type A Aortic Dissection: A Report of Two Cases.

Objective: Stanford type A acute aortic dissection (AAD) is associated with carotid artery dissections (CADs). We report two cases of carotid artery stenting (CAS) for symptomatic CAD after ascending aortic replacement (AAR) for AAD. Case Presentation: Case 1: A 51-year-old man with AAD was transferred to our institute. He had no notable paralysis symptoms on initial presentation. However, after AAR for AAD was performed, left paralysis developed within a few hours. Emergency angiography revealed right CAD and pseudo-occlusion. CAS was performed successfully using intravascular ultrasound (IVUS). He was transferred to a rehabilitation hospital with a modified Rankin Scale (mRS) score of 2.Case 2: A 55-year-old man underwent AAR for AAD, but asymptomatic left CAD remained. Two weeks after the operation, he presented with slight signs of aphasia. Aspirin was prescribed and follow-up was performed, but his symptoms did not improve. He underwent magnetic resonance imaging in our department, which revealed acute cerebral infarction on the left pars opercularis and an artery-to-artery embolism from CAD. CAS was performed via the retrograde approach with direct puncture of the normal left common carotid artery using IVUS. He was discharged with no complications and a mRS score of 1. Conclusion: IVUS can be useful for CAS to confirm the true lumen and extension of long CAD lesions developing from AAD.

Reverse takotsubo cardiomyopathy caused by patent foramen ovale-related cryptogenic stroke: a case report.

BACKGROUND: Reverse takotsubo cardiomyopathy (rTTC) is recognized as an atypical type of TTC. It has been suggested that neurological events are typical trigger of rTTC, especially in young individuals. CASE SUMMARY: In this case report, we describe a 16-year-girl who presented with neurological deficits due to embolic stroke and acute heart failure. Transthoracic echocardiography on admission revealed a severely reduced left ventricular (LV) function with akinesis of basal to mid LV, but normal contraction in apex. Coronary computed tomography angiography confirmed unobstructed coronary arteries. Two weeks later, her LV wall motion and ejection fraction were completely normalized. Transthoracic echocardiography and transoesophageal echocardiography demonstrated no evidence of intracardiac thrombus but showed a patent foramen ovale (PFO) with large shunt. After thorough work-up and brain-heart team discussion, we concluded that the patient developed rTTC due to cryptogenic stroke related with her PFO. She underwent percutaneous PFO closure for secondary prevention with good clinical course. DISCUSSION: Reverse TTC is a rare condition. It should be considered in stroke patients with acute heart failure. Quick diagnosis and management with brain-heart team is crucial for better prognosis.

Spontaneous Subclavian Artery Dissection Causing Ischemia of the Medulla Oblongata and Cerebellum.

BACKGROUND: Spontaneous subclavian artery dissection is a rare etiology. Spontaneous artery dissection causing brain ischemia is rare in all ischemic strokes. However, in young to middle-aged patients with brain ischemia, spontaneous carotid or vertebral artery dissection causing ischemic stroke accounts for 10-25%. CASE REPORT: A 58-year-old man with a history of hypertension presented to the Emergency Department with a sudden onset of left-arm paresthesia and numbness followed by symptoms of vertigo and vomiting. A neurological examination showed left-arm paresthesia, horizontal-rotational nystagmus, and left-side dysmetria according to a finger-to-nose test. Contrast-enhanced computed tomography showed left subclavian artery dissection. Diffusion-weighted imaging demonstrated hyperintensity in the left medulla oblongata and inferior part of the cerebellum. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Spontaneous artery dissection is an important etiology of ischemic stroke among young patients. Cervical magnetic resonance angiography is the gold standard for the diagnosis of arterial dissection. Cervical disc disease is a common etiology in a patient with neck and shoulder pain without cause or neurologic symptoms, when cervical MRI is negative, however, spontaneous subclavian artery dissection should be considered in the differential diagnosis when a patient, especially in a case of younger patient, presents with acute new-onset neck and shoulder pain followed by the onset of neurological symptoms.

Cerebral hyperperfusion syndrome after endovascular covered stent grafting for a giant extracranial aneurysm of the internal carotid artery.

Symptomatic giant extracranial internal carotid artery (ICA) aneurysm is a rare and surgically intractable disease. Several authors have described successful treatments for extracranial ICA aneurysm. None, however, have described a perioperative evaluation of cerebral perfusion or a postoperative complication of cerebral hyperperfusion syndrome (CHS). We present a rare case of CHS after endovascular covered stent grafting for a giant extracranial ICA aneurysm. The CHS was successfully managed on the basis of hemodynamic monitoring. CHS can appear after endovascular reconstruction of an extracranial ICA aneurysm, and perioperative repeated evaluation of cerebral perfusion allows safe and effective management of CHS.

A molecular screening approach to identify and characterize inhibitors of glioblastoma stem cells.

Glioblastoma (GBM) is among the most lethal of all cancers. GBM consist of a heterogeneous population of tumor cells among which a tumor-initiating and treatment-resistant subpopulation, here termed GBM stem cells, have been identified as primary therapeutic targets. Here, we describe a high-throughput small molecule screening approach that enables the identification and characterization of chemical compounds that are effective against GBM stem cells. The paradigm uses a tissue culture model to enrich for GBM stem cells derived from human GBM resections and combines a phenotype-based screen with gene target-specific screens for compound identification. We used 31,624 small molecules from 7 chemical libraries that we characterized and ranked based on their effect on a panel of GBM stem cell-enriched cultures and their effect on the expression of a module of genes whose expression negatively correlates with clinical outcome: MELK, ASPM, TOP2A, and FOXM1b. Of the 11 compounds meeting criteria for exerting differential effects across cell types used, 4 compounds showed selectivity by inhibiting multiple GBM stem cells-enriched cultures compared with nonenriched cultures: emetine, n-arachidonoyl dopamine, n-oleoyldopamine (OLDA), and n-palmitoyl dopamine. ChemBridge compounds #5560509 and #5256360 inhibited the expression of the 4 mitotic module genes. OLDA, emetine, and compounds #5560509 and #5256360 were chosen for more detailed study and inhibited GBM stem cells in self-renewal assays in vitro and in a xenograft model in vivo. These studies show that our screening strategy provides potential candidates and a blueprint for lead compound identification in larger scale screens or screens involving other cancer types.

Siomycin A targets brain tumor stem cells partially through a MELK-mediated pathway.

Glioblastoma multiforme (GBM) is a devastating disease, and the current therapies have only palliative effect. Evidence is mounting to indicate that brain tumor stem cells (BTSCs) are a minority of tumor cells that are responsible for cancer initiation, propagation, and maintenance. Therapies that fail to eradicate BTSCs may ultimately lead to regrowth of residual BTSCs. However, BTSCs are relatively resistant to the current treatments. Development of novel therapeutic strategies that effectively eradicate BTSC are, therefore, essential. In a previous study, we used patient-derived GBM sphere cells (stemlike GBM cells) to enrich for BTSC and identified maternal embryonic leucine-zipper kinase (MELK) as a key regulator of survival of stemlike GBM cells in vitro. Here, we demonstrate that a thiazole antibiotic, siomycin A, potently reduced MELK expression and inhibited tumor growth in vivo. Treatment of stemlike GBM cells with siomycin A resulted in arrested self-renewal, decreased invasion, and induced apoptosis but had little effect on growth of the nonstem cells of matched tumors or normal neural stem/progenitor cells. MELK overexpression partially rescued the phenotype of siomycin A-treated stemlike GBM cells. In vivo, siomycin A pretreatment abraded the sizes of stemlike GBM cell-derived tumors in immunodeficient mice. Treatment with siomycin A of mice harboring intracranial tumors significantly prolonged their survival period compared with the control mice. Together, this study may be the first model to partially target stemlike GBM cells through a MELK-mediated pathway with siomycin A to pave the way for effective treatment of GBM.

BMPing off glioma stem cells.

Brain tumor stem cells (BTSC) bear some similarities to neural stem cells (NSC). Bone morphogenetic proteins (BMPs) have a proproliferative effect on early embryonic NSC, and a prodifferentiative effect on postnatal NSC. In this issue of Cancer Cell, Lee et al. demonstrate that BMPs have differing effects on different BTSC lines, either promoting or inhibiting an astrocytic-like differentiation program. This latter effect is the result of epigenetic silencing of the BMP receptor 1B (BMPR1B). These findings document the importance of the BMP signaling system in BTSC as well as that of taking heterogeneity into account when studying BTSC as potential targets for therapy.

Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells.

Emerging evidence suggests that neural stem cells and brain tumors regulate their proliferation via similar pathways. In a previous study, we demonstrated that maternal embryonic leucine zipper kinase (Melk) is highly expressed in murine neural stem cells and regulates their proliferation. Here we describe how MELK expression is correlated with pathologic grade of brain tumors, and its expression levels are significantly correlated with shorter survival, particularly in younger glioblastoma patients. In normal human astrocytes, MELK is only faintly expressed, and MELK knockdown does not significantly influence their growth, whereas Ras and Akt overexpressing astrocytes have up-regulated MELK expression, and the effect of MELK knockdown is more prominent in these transformed astrocytes. In primary cultures from human glioblastoma and medulloblastoma, MELK knockdown by siRNA results in inhibition of the proliferation and survival of these tumors. Furthermore, we show that MELK siRNA dramatically inhibits proliferation and, to some extent, survival of stem cells isolated from glioblastoma in vitro. These results demonstrate a critical role for MELK in the proliferation of brain tumors, including their stem cells, and suggest that MELK may be a compelling molecular target for treatment of high-grade brain tumors.

Overexpressed Skp2 within 5p amplification detected by array-based comparative genomic hybridization is associated with poor prognosis of glioblastomas.

To better understand the pathogenesis of glioblastoma multiforme (GBM) and to increase the accuracy of predicting outcomes for patients with this disease, we performed genome-wide screening for DNA copy-number aberrations in 22 glioma-derived cell lines using a custom-made comparative genomic hybridization-array. Copy-number gains were frequently detected at 3q, 7p, 7q, 20q, Xp and Xq, and losses at 4q, 9p, 10p, 10q, 11q, 13q, 14q, 18q, and 22q. Among several non-random chromosomal aberrations, the gain/amplification of DNA at 5p, which has never been reported before in GBM, was detected with a relatively high ratio (log2 ratio = 0.41-1.19) in four cell lines. Amplification and subsequent overexpression of SKP2, a possible target of amplification within 5p, were detected in four of the 22 cell lines. We also investigated the expression of the gene product in primary GBM by immunohistochemistry, which revealed increased levels of Skp2 in 11 of the 35 tumors examined (31.4%). Heightened expression of Skp2 was associated with shorter overall survival (P = 0.001, logrank test), especially in patients younger than 65 years. These results suggest that overexpression of Skp2 through gene amplification may contribute to the pathogenesis of GBM, and that overabundance of the protein might be a useful prognostic tool in patients with this disease.

[Benign intracranial hypertension resulting from corticosteroid withdrawal: case report].

We report a case of benign intracranial hypertension (BIH) resulting from corticosteroid withdrawal. A 36-year-old woman was admitted to hospital because of an intractable headache. A neurological examination on admission showed no abnormalities other than a headache and nausea. CT, MRI, and angiogram examinations showed no abnormalities. Hematological and laboratory data were also normal. Continuous monitoring of her cerebrospinal fluid (CSF) pressure showed a value of over 25 mmHg during sleep, but papilledema was not observed. A diagnosis of BIH was made, with corticosteroid withdrawal considered to be the most probable cause. The patient was given isosorbide solution for 3 months. However, her clinical condition continued to deteriorate; she eventually began to develop visual loss, photopsia, and memory disturbances. She underwent lumboperitoneal shunt surgery, which immediately eliminated the headache, photopsia, and memory disturbances. She regained her vision over a five-month period. BIH should be considered as a differential diagnosis when an intractable headache develops after corticosteroid withdrawal, especially in young women.