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.

Intraoperative hematoma volume can predict chronic subdural hematoma recurrence.

BACKGROUND: We routinely measured the exact chronic subdural hematoma (CSDH) volume during single burr hole surgery. To date, several risk factors have been reported for CSDH recurrence, including sex, hematoma volume and degree of midline shift calculated from computed tomography, use of anticoagulants or antiplatelet medications, and alcohol consumption habits. The aim of this study was to clarify whether hematoma volume, in conjunction with other factors, can predict recurrence. METHODS: We retrospectively reviewed the clinical data of 194 consecutive patients with CSDH who underwent single burr hole surgery. The risk factors for recurrence were analyzed based on patients' sex, age, bilaterality, existence of apparent trauma history, exact intraoperative hematoma volume, and various clinical factors, including preoperative anticoagulant/antiplatelet intake. RESULTS: Recurrence occurred in 22 patients (11.3%). Multivariate logistic regression analysis revealed that intraoperative hematoma volume was an independent risk factor for CSDH recurrence (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.01-1.02, P < 0.001), in addition to sex (male) (OR 9.25; 95% CI, 1.00-84.8; P = 0.049) and diabetes mellitus (DM) (OR: 3.97, 95% CI, 1.34-11.7, P = 0.013). Based on receiver operating characteristics analysis, the cutoff value of the hematoma volume predicting CSDH recurrence was 150 ml (sensitivity and specificity of 72.7% and 72.1%, respectively; area under the curve: 0.7664, 95% CI: 0.654-0.879, P < 0.001). Of these, a hematoma volume ≥150 mL was the strongest independent risk factor for recurrence according to multiple regression (OR: 8.98, 95% CI: 2.73-29.6, P < 0.001) and Cox regression analysis (hazard ratio: 3.05, 95% CI: 1.18-7.87, log-rank P = 0.0046, P = 0.021). Follow-up periods after surgery were significantly longer for cases with recurrence than for non-recurrence cases (24.8 ± 11.5 vs. 15.9 ± 9.7 days), and the recurrence prediction cutoff value was 17 days, with a sensitivity and specificity of 83.1% and 68.2%, respectively (AUC: 0.7707, 95% CI: 0.6695-0.8720, P < 0.001). CONCLUSION: Intraoperative hematoma volume could be a predictive value for CSDH recurrence.

Analysis of twisted internal carotid arteries in carotid endarterectomy.

BACKGROUND: The twisted carotid artery is a variant, in which the internal carotid artery (ICA) courses medially to the external carotid artery. Due to the sparse descriptions in the literature, we, here, report our experience with cases of carotid endarterectomy (CEA) for twisted carotid artery and its clinical features. METHODS: Fifty-seven consecutive CEA-treated patients were evaluated, and the twist angle was measured on the source images of axial slices of computed tomography angiography (CTA). RESULTS: Eight male patients (14.2%) demonstrated a twisted right ICA (mean age, 77.0 ± 2.6 years; and mean stenosis, 66.9% ± 19.9%). The mean twist angle was 30.1° ± 17.9°, while the normal ICA is angled at -23.0° ± 12.3°. No statistical differences in the distribution of coexisting diseases were found between the normal and twisted ICA cases. CEA was successfully performed with the correction of the carotid position in all cases; however, significant position correction was not observed in the postoperative evaluation. Right-side dominancy (P = 0.045) and prolonged clamping time (P = 0.053) were observed in the twisted cases. CONCLUSION: Twisted ICA was preferentially found in the right ICA and men. CEA of the twisted ICA was safely performed with appropriate head rotation and wider longitudinal skin incision than usual without a significant increase in the operative time. CTA is useful for preoperative evaluation. This specific variation should be considered by the neurosurgeon involved in the evaluation and treatment of carotid stenoses.

Surgical Site Infection due to a Preauricular Sinus: A Rare Complication after Craniotomy.

SUMMARY: Wound infection due to a preauricular sinus after craniotomy has not been previously reported. A 71-year-old woman visited our institute with subarachnoid hemorrhage. The aneurysm was surgically clipped with external decompression. Sixteen days after surgery, a focal erythema and discharging were observed at the inferior end of the skin incision. Careful inspection revealed a small pit there, which was diagnosed as a preauricular sinus. After the infection subsided, the sinus was completely excised. Neurosurgeons must be aware of this rare condition and must opt for complete excision to prevent infectious sequelae even if the preauricular sinus is asymptomatic.

Progression of intracranial meningioma during luteinizing hormone-releasing hormone agonist treatment for prostate cancer: case report.

The authors describe a male patient who developed a large intracranial meningioma during the hormone therapy for pre-existing prostate cancer. A 70-year-old man received a brain check-up, and no intracranial abnormality was detected. Five months later, prostate cancer was diagnosed, and he underwent prostatectomy. Leuprorelin acetate, a luteinizing hormone-releasing hormone (LH-RH) agonist, was subsequently administered to the patient once a month for 3 years. After that he presented with a large parasagittal mass, which was excised. The tumor was histologically diagnosed as meningothelial meningioma, and LH-RH receptors were verified immunohistochemically in the cytoplasm of the tumor cells. Leuprorelin acetate may accelerate the rapid growth of meningioma in this patient.

Angiotensin II AT1 receptor blocker candesartan prevents the fast up-regulation of cerebrocortical benzodiazepine-1 receptors induced by acute inflammatory and restraint stress.

Centrally acting Angiotensin II AT(1) receptor blockers (ARBs) protect from stress-induced disorders and decrease anxiety in a model of inflammatory stress, the systemic injection of bacterial endotoxin lipopolysaccharide (LPS). In order to better understand the anxiolytic effect of ARBs, we treated rats with LPS (50 µg/kg) with or without 3 days of pretreatment with the ARB candesartan (1mg/kg/day), and studied cortical benzodiazepine (BZ) and corticotrophin-releasing factor (CRF) receptors. We compared the cortical BZ and CRF receptors expression pattern induced by LPS with that produced in restraint stress. Inflammation stress produced a generalized increase in cortical BZ(1) receptors and reduced mRNA expression of the GABA(A) receptor γ(2) subunit in cingulate cortex; changes were prevented by candesartan pretreatment. Moreover, restraint stress produced similar increases in cortical BZ(1) receptor binding, and candesartan prevented these changes. Treatment with candesartan alone increased cortical BZ(1) binding, and decreased γ(2) subunit mRNA expression in the cingulate cortex. Conversely, we did not find changes in CRF(1) receptor expression in any of the cortical areas studied, either after inflammation or restraint stress. Cortical CRF(2) receptor binding was undetectable, but CRF(2) mRNA expression was decreased by inflammation stress, a change prevented by candesartan. We conclude that stress promotes rapid and widespread changes in cortical BZ(1) receptor expression; and that the stress-induced BZ(1) receptor expression is under the control of AT(1) receptor activity. The results suggest that the anti-anxiety effect of ARBs may be associated with their capacity to regulate stress-induced alterations in cortical BZ(1) receptors.

Angiotensin II AT1 receptor blockade ameliorates brain inflammation.

Brain inflammation has a critical role in the pathophysiology of brain diseases of high prevalence and economic impact, such as major depression, schizophrenia, post-traumatic stress disorder, Parkinson's and Alzheimer's disease, and traumatic brain injury. Our results demonstrate that systemic administration of the centrally acting angiotensin II AT(1) receptor blocker (ARB) candesartan to normotensive rats decreases the acute brain inflammatory response to administration of the bacterial endotoxin lipopolysaccharide (LPS), a model of brain inflammation. The broad anti-inflammatory effects of candesartan were seen across the entire inflammatory cascade, including decreased production and release to the circulation of centrally acting proinflammatory cytokines, repression of nuclear transcription factors activation in the brain, reduction of gene expression of brain proinflammatory cytokines, cytokine and prostanoid receptors, adhesion molecules, proinflammatory inducible enzymes, and reduced microglia activation. These effects are widespread, occurring not only in well-known brain target areas for circulating proinflammatory factors and LPS, that is, hypothalamic paraventricular nucleus and the subfornical organ, but also in the prefrontal cortex, hippocampus, and amygdala. Candesartan reduced the associated anorexic effects, and ameliorated associated body weight loss and anxiety. Direct anti-inflammatory effects of candesartan were also documented in cultured rat microglia, cerebellar granule cells, and cerebral microvascular endothelial cells. ARBs are widely used in the treatment of hypertension and stroke, and their anti-inflammatory effects contribute to reduce renal and cardiac failure. Our results indicate that these compounds may offer a novel and safe therapeutic approach for the treatment of brain disorders.

Synthesis, structures, and electronic properties of [8Fe-7S] cluster complexes modeling the nitrogenase P-cluster.

High-yield synthesis of the iron-sulfur cluster [{N(SiMe(3))(2)}{SC(NMe(2))(2)}Fe(4)S(3)](2)(mu(6)-S) {mu-N(SiMe(3))(2)}(2) (1), which reproduces the [8Fe-7S] core structure of the nitrogenase P(N)-cluster, has been achieved via two pathways: (1) Fe{N(SiMe(3))(2)}(2) + HSTip (Tip = 2,4,6-(i)Pr(3)C(6)H(2)) + tetramethylthiourea (SC(NMe(2))(2)) + elemental sulfur (S(8)); and (2) Fe(3){N(SiMe(3))(2)}(2)(mu-STip)(4) (2) + HSTip + SC(NMe(2))(2) + S(8). The thiourea and terminal amide ligands of 1 were found to be replaceable by thiolate ligands upon treatment with thiolate anions and thiols at -40 degrees C, respectively, and a series of [8Fe-7S] clusters bearing two to four thiolate ligands have been synthesized and their structures were determined by X-ray analysis. The structures of these model [8Fe-7S] clusters all closely resemble that of the reduced form of P-cluster (P(N)) having 8Fe(II) centers, while their 6Fe(II)-2Fe(III) oxidation states correspond to the oxidized form of P-cluster (P(OX)). The cyclic voltammograms of the [8Fe-7S] clusters reveal two quasi-reversible one-electron reduction processes, leading to the 8Fe(II) state that is the same as the P(N)-cluster, and the synthetic models demonstrate the redox behavior between the two major oxidation states of the native P-cluster. Replacement of the SC(NMe(2))(2) ligands in 1 with thiolate anions led to more negative reduction potentials, while a slight positive shift occurred upon replacement of the terminal amide ligands with thiolates. The clusters 1, (NEt(4))(2)[{N(SiMe(3))(2)}(SC(6)H(4)-4-Me)Fe(4)S(3)](2)(mu(6)-S){mu-N(SiMe(3))(2)}(2) (3a), and [(SBtp){SC(NMe(2))(2)}Fe(4)S(3)](2)(mu(6)-S){mu-N(SiMe(3))(2)}(2) (5; Btp = 2,6-(SiMe(3))(2)C(6)H(3)) are EPR silent at 4-100 K, and their temperature-dependent magnetic moments indicate a singlet ground state with antiferromagnetic couplings among the iron centers. The (57)Fe Mössbauer spectra of these clusters are consistent with the 6Fe(II)-2Fe(III) oxidation state, each exhibiting two doublets with an intensity ratio of ca. 1:3, which are assignable to Fe(III) and Fe(II), respectively. Comparison of the quadrupole splittings for 1, 3a, and 5 has led to the conclusion that two Fe(III) sites of the clusters are the peripheral iron atoms.

An intracranial pseudoaneurysm in the distal middle cerebral artery in a child.

Intracranial pseudoaneurysms are rare, particularly in children and adolescents. They are characterized by the presence of organizing hematoma and fibrosis without true vascular elements. Most pseudoaneurysms result from events such as major trauma or infectious illness, and the development of pseudoaneurysm without a preceding incident is rare. We here describe a patient with a large pseudoaneurysm arising in the distal middle cerebral artery. A 10-year-old boy experienced a sudden onset of headache, nausea, and vomiting followed by loss of consciousness and was referred to our medical center. Brain computed tomography showed massive subcortical hemorrhage in the left temporal lobe. Digital cerebral angiography revealed a huge aneurysmal dilatation of the distal left M1 segment of the middle cerebral artery, with delayed filling and emptying of contrast media. Surgical resection of the aneurysm with evacuation of the hematoma yielded restoration of consciousness. Although the cause of aneurysm in this case is uncertain, this type of patient is seldom encountered; its etiology and mechanisms of onset are discussed with reference to the literature.

Intracranial internal carotid artery stenosis with vulnerable plaques successfully treated by stenting under cerebral protection.

Percutaneous transluminal angioplasty with stenting (PTA/stenting) for intracranial atherosclerotic stenoses is usually performed without any protection devices. We report a unique case of atherothrombotic stenosis with the vulnerable plaque in the cavernous portion of the internal carotid artery (ICA), which was successfully treated by PTA/stenting under cerebral protection with the flow reversal system. A 68-year-old woman presented repetitive transient ischemic attacks in the right ICA territory. Cerebral angiography revealed 80% stenosis in the cavernous portion of the right ICA. High-resolution magnetic resonance imaging (HR-MRI) demonstrated lipid-rich plaques at this lesion. PTA/stenting was performed with a proximal protection device under flow reversal. A filter device captured much amount of atherothrombotic debris with lipid-rich macrophages and leukocytes, which was consistent with HR-MRI findings. Some selected cases of intracranial atherothrombotic ICA stenoses may need endovascular treatment with cerebral protection system. HR-MRI is useful to evaluate plaque characteristics even in the cavernous portion of the ICA.

Tissue plasminogen activator enhances the hypoxia/reoxygenation-induced impairment of the blood-brain barrier in a primary culture of rat brain endothelial cells.

Hemorrhagic transformation is a major complication associated with tissue plasminogen activator (tPA) therapy for ischemic stroke. We studied the effect of tPA on the blood-brain barrier (BBB) function with our in vitro monolayer model generated using rat brain microvascular endothelial cells subjected either to normoxia or to hypoxia/reoxygenation (H/R) with or without the administration of tPA. The barrier function was evaluated by the transendothelial electrical resistance (TEER), the permeability of sodium fluorescein and Evans' blue-albumin (EBA), and the uptake of lucifer yellow (LY). The permeability of sodium fluorescein and EBA was used as an index of paracellular and transcellular transport, respectively. The administration of tPA increased the permeability of EBA and the uptake of LY under normoxia. It enhanced the increase in the permeability of both sodium fluorescein and EBA, the decrease in the TEER, and the disruption in the expression of ZO-1 under H/R conditions. Administration of tPA could cause an increase in the transcellular transport under normoxia, and both the transcellular and paracellular transport of the BBB under H/R conditions in vitro. Even in humans, tPA may lead to an opening of the BBB under non-ischemic conditions and have an additional effect on the ischemia-induced BBB disruption.

Pericytes from brain microvessels strengthen the barrier integrity in primary cultures of rat brain endothelial cells.

(1) The blood-brain barrier (BBB) characteristics of cerebral endothelial cells are induced by organ-specific local signals. Brain endothelial cells lose their phenotype in cultures without cross-talk with neighboring cells. (2) In contrast to astrocytes, pericytes, another neighboring cell of endothelial cells in brain capillaries, are rarely used in BBB co-culture systems. (3) Seven different types of BBB models, mono-culture, double and triple co-cultures, were constructed from primary rat brain endothelial cells, astrocytes and pericytes on culture inserts. The barrier integrity of the models were compared by measurement of transendothelial electrical resistance and permeability for the small molecular weight marker fluorescein. (4) We could confirm that brain endothelial monolayers in mono-culture do not form tight barrier. Pericytes induced higher electrical resistance and lower permeability for fluorescein than type I astrocytes in co-culture conditions. In triple co-culture models the tightest barrier was observed when endothelial cells and pericytes were positioned on the two sides of the porous filter membrane of the inserts and astrocytes at the bottom of the culture dish. (5) For the first time a rat primary culture based syngeneic triple co-culture BBB model has been constructed using brain pericytes beside brain endothelial cells and astrocytes. This model, mimicking closely the anatomical position of the cells at the BBB in vivo, was superior to the other BBB models tested. (6) The influence of pericytes on the BBB properties of brain endothelial cells may be as important as that of astrocytes and could be exploited in the construction of better BBB models.

High-resolution magnetic resonance imaging using gadolinium-based contrast agent for atherosclerotic carotid plaque.

BACKGROUND: Early detection of vulnerable plaques at risk of causing thromboembolic events is very important, and many investigators report the usefulness of high-resolution MRI. The purpose of this study was to determine whether the detection of atherosclerotic carotid plaques can be enhanced after administration of contrast agents and, if so, to evaluate the potential for functional information. METHODS: We studied 9 patients (10 subjects) who underwent a high-resolution MRI examination using a gadolinium-based contrast agent before CEA. Pre- and postcontrast-enhanced T1-weighted images were reviewed, and their histopathologic characteristics evaluated in the corresponding tissue slices. RESULTS: Strong contrast enhancement patterns were found in 6 of 10 subjects. For 5 of 6 subjects, many microvessels with inflammatory cells or intraplaque hemorrhages were demonstrated in their corresponding tissue slices. Contrast enhancement patterns were noted to be focal, diffuse, and along the luminal surface or the vessel adventitial boundary. Moreover, some plaques were clearly demonstrated by using contrast agent, and others were clearly divided into fibrous and lipid regions. CONCLUSION: Gadolinium-based contrast agent can penetrate human atherosclerotic carotid plaques. The extent or size of neovascularization and the endothelial permeability are likely related to the mechanism of enhancement, and contrast-enhanced MRI may be essential for the identification of plaque neovascularization which is an important factor of vulnerable plaques. In addition to morphologic information, with the functional information provided using various contrast agents, we may expect a more correct diagnosis of carotid plaques at risk of causing thromboembolic events.

Asymptomatic carotid artery plaques: use of magnetic resonance imaging to characterize vulnerable plaques in 6 cases.

BACKGROUND: Echography is a convenient and noninvasive method of characterizing carotid artery plaques. However, recent reports suggest that multisequential MR imaging may yield better data regarding the instability of asymptomatic carotid artery plaques. Therefore, the goal of the present study was to show the useful information for asymptomatic carotid artery plaque. METHODS: A total of 6 patients (5 men, 1 woman; age range, 62-76 years; mean age, 69.2 years) with carotid artery plaques, which were detected during medical check-up using carotid MR angiography and/or echography, underwent MR imaging. Two-dimensional TOF MR angiography, T1WI, and fat-suppressed, cardiac-gated, black-blood proton density image, and T2WI were obtained with a 1.5-T MR imager. All plaques underwent carotid endarterectomy and histological examination. RESULTS: The MR imaging demonstrated high signals in at least one modality in 4 of 7 plaques. In the remaining 3 patients, MR imaging detected partial-high signals, which corresponded to histologically confirmed partial lipid core or hemorrhagic components in the fibrous tissues The TOF MR imaging showed 2 cases of thin fibrous caps, and MR imaging also showed a large mural thrombus in 1 patient. CONCLUSIONS: Magnetic resonance imaging was useful in characterizing factors associated with plaque instability in patients with asymptomatic carotid artery plaques and may help guide therapeutic strategies for asymptomatic carotid artery plaques.

Quantification of the regional cerebral blood flow and vascular reserve in moyamoya disease using split-dose iodoamphetamine I 123 single-photon emission computed tomography.

OBJECTIVES: We quantified the rCBF and regional vascular reserve (CVR) in adult patients with moyamoya disease before and after surgery using IMP I 123 SPECT. METHODS: The patient population included 5 adult patients with ages at presentation ranging between 23 and 42 years. One patient had stroke, whereas 4 patients had transient ischemic attacks. RESULTS: Before surgery, the mean resting rCBF and mean CVR in the frontal, parietal, and temporal lobes of the surgically treated hemisphere were 40.09, 39.50, and 36.9 mL/100 g per minute and 15.39%, 27.09%, and 28.92%, respectively. After surgery, the rCBF increased significantly (P = .0002, .0005, and .0062), but in a CVR evaluation, only the frontal lobe increased significantly (P = .0055). In the unaffected hemispheres, the mean resting rCBF significantly increased only in the frontal lobe (P = 038) and no significant increase in the CVR was observed after surgery. In 2 patients who showed steal phenomenon induced by acetazolamide administration, CVR significantly increased not only in the frontal lobe but also in the parietal and temporal lobe after surgery, although the CVR in these areas significantly decreased both before and after surgery in comparison to the mean CVR in all patients. CONCLUSIONS: The frontal lobe showed severe hemodynamic ischemia. The cerebral hemodynamics in patients with moyamoya disease improved after surgical intervention, especially in severely damaged patients. Split-dose (123)I-IMP SPECT was therefore found to be a useful diagnostic modality for quantifying the hemodynamics of moyamoya disease.