Utilizing RNA sequencing to identify gene expression markers of stroke-causing thrombi origin: A pilot study.

INTRODUCTION: Stroke embolic source have an unknown origin in 30-40% of cases. Mechanical thrombectomy for acute large vessel occlusion stroke has provided us with a method to directly retrieve the thrombi from patients for analysis. By collecting stroke-causing thrombi from known sources, we can then use high-throughput RNA sequencing (RNAseq) technology to directly measure the gene expression signatures of these clots. This may allow us to identify genetic markers to predict the cause of cryptogenic embolism. METHODS: This is a prospective study in which RNAseq was used to analyze cerebral thrombi retrieved by mechanical thrombectomy devices in acute ischemic stroke patients. Samples were separated into two groups based on known stroke thrombus etiology, including Carotid group (patients with ipsilateral >70% carotid stenosis) and Atrial fibrillation (AF) group (patients with atrial fibrillation). Gene expression was compared by RNAseq analysis between the groups. RESULTS: From October 2016 to September 2017, 8 thrombi (4 in Carotid group, 4 in Afib group) were included in this study. There were 131 genes that were significantly up- or down-regulated between the two groups defined as a false discovery rate ≤ 0.05 and a fold change ≥ 2. Twenty-six genes were selected as candidate gene biomarkers based on the criteria in the methods section. Candidate genes HSPA1B, which encodes a heatshock protein, and GPRC5B, which encodes a G-protein, showed the greatest fold differences in expression between the two groups. CONCLUSION: This study has shown that RNA sequencing of acute ischemic stroke thrombi is feasible and indentified potential novel biomarkers for identifying stroke-causing thrombi origin, especially in cryptogenic stroke.

Stroke and stroke prevention in sickle cell anemia in developed and selected developing countries.

This comprehensive review provides an insight into the pathophysiology, epidemiology, evaluation, and treatment of sickle cell anemia (SCA)-related stroke in developed and developing countries. Vascular injury, hypercoagulability and vaso-occlusion play a role in the pathophysiology of stroke in SCA. Transcranial Doppler ultrasound (TCD) has lowered the incidence of ischemic stroke from 11% to 1% as TCD identifies children who are at risk for stroke, providing opportunities for interventions to reduce this risk. Whereas blood exchange is indicated in acute stroke, chronic transfusions (either simple or exchange on a monthly basis) are used for primary as well as secondary stroke prevention in developed countries. Children with abnormally high TCD velocities (≥ 200 cm/s) are at high risk of stroke and might benefit from hydroxyurea or hydroxycarbamide (HU) after a period of a successful transition from chronic transfusions. Hematopoietic stem cell transplant presents a cure for SCA. Gene therapy is currently investigated and may be offered to patients with SCA who had a stroke or who are at high risk of stroke if proven efficacious and safe. However, gene therapy is not likely to be implemented in low-income countries due to cost. Alternatively, HU is utilized for primary and secondary stroke prevention in developing countries. Further expansion of TCD implementation should be a priority in those settings.

Evaluation of Balloon Test Occlusion Before Therapeutic Carotid Artery Occlusion: Flat Detector Computed Tomography Cerebral Blood Volume Imaging versus Single-Photon Emission Computed Tomography.

OBJECTIVE: We aimed to compare flat detector computed tomography cerebral blood volume (FD-CBV) imaging to single-photon emission computed tomography (SPECT) as an adjunctive technique during balloon test occlusion (BTO) in patients with intracranial aneurysms or tumors. METHODS: Twelve patients who underwent SPECT (99mTc-ethyl cysteinate dimer) and FD-CBV imaging during BTO were enrolled. Color-coded cerebral blood flow (CBF) images and color-coded FD-CBV images were generated and visually inspected whether there were asymmetries between the ipsilateral and contralateral cerebral hemispheres. Region of interest measurements were performed on the color-coded images at the same locations for both modalities. The mean interhemispheric region of interest ratios were calculated, and the ratio between these were estimated using linear regression models. RESULTS: Ten patients had no symptoms during BTO. Two patients developed subtle but inconclusive neurologic changes approximately 10 minutes after balloon inflation; their images showed asymmetric color-coded images with decreased CBF and FD-CBV in the ipsilateral hemisphere. The mean interhemispheric ratio of CBF was significantly smaller in patients with subtle changes than in those without (0.84 vs. 0.98; P < 0.001). Similarly, the mean interhemispheric ratio of FD-CBV was significantly smaller in patients with subtle changes than in those without (0.88 vs. 1.06; P = 0.01). No patient showed increased CBF or FD-CBV in the ipsilateral hemisphere. CONCLUSIONS: The patients with decreased CBF on SPECT also showed decreased FD-CBV in the ipsilateral hemisphere. FD-CBV imaging may be useful as an adjunctive technique for BTO before potential therapeutic carotid artery occlusion.

Mesenchymal Stem Cell Therapy in Ischemic Stroke: A Meta-analysis of Preclinical Studies.

Numerous preclinical studies have been carried out using mesenchymal stem cells (MSCs) therapy for ischemic stroke. The purpose of the present meta-analysis is to review the quality of preclinical studies. In all, 4,361 articles were identified, out of which 64 studies were included (excluding in vitro studies). The results were obtained across species, route, and time of administration, immunogenicity, and doses. The median quality score 4.90/10, confidence interval 95%, and large effect size were observed, which strongly supports the translation potential of MSC therapy for ischemic stroke.

Variability of hemodynamic parameters using the common viscosity assumption in a computational fluid dynamics analysis of intracranial aneurysms.

BACKGROUND: In most simulations of intracranial aneurysm hemodynamics, blood is assumed to be a Newtonian fluid. However, it is a non-Newtonian fluid, and its viscosity profile differs among individuals. Therefore, the common viscosity assumption may not be valid for all patients. OBJECTIVE: This study aims to test the suitability of the common viscosity assumption. METHODS: Blood viscosity datasets were obtained from two healthy volunteers. Three simulations were performed for three different-sized aneurysms, two using measured value-based non-Newtonian models and one using a Newtonian model. The parameters proposed to predict an aneurysmal rupture obtained using the non-Newtonian models were compared with those obtained using the Newtonian model. RESULTS: The largest difference (25%) in the normalized wall shear stress (NWSS) was observed in the smallest aneurysm. Comparing the difference ratio to the NWSS with the Newtonian model between the two Non-Newtonian models, the difference of the ratio was 17.3%. CONCLUSIONS: Irrespective of the aneurysmal size, computational fluid dynamics simulations with either the common Newtonian or non-Newtonian viscosity assumption could lead to values different from those of the patient-specific viscosity model for hemodynamic parameters such as NWSS.

Large animal canine endovascular ischemic stroke models: A review.

BACKGROUND: Stroke is one of the leading causes of death and long-term disability worldwide. Recent exciting developments in the field with endovascular treatments have shown excellent outcomes in acute ischemic stroke. Prior to translating these treatments to human populations, a large-animal ischemic stroke model is needed. With the advent of new technologies in digital subtraction angiography, less invasive endovascular stroke models have been developed. Canines have gyrencephalic brain similar to human brain and accessible neurovascular anatomy for stroke model creation. Canine stroke model can be widely utilized to understand the disease process of stroke and to develop novel treatment. Less invasive endovascular internal carotid emboli injection and coil embolization methods can be used to simulate transient or permanent middle cerebral artery occlusion. Major restriction includes the extensive collateral circulation of canine cerebral arteries that can limit the stroke size. Transient internal carotid artery occlusion can decrease collateral circulation and increase stroke size to some degree. Additional method of manipulating the extent of collateral circulation needs to be studied. Other types of canine stroke models, including vertebral artery occlusion and basilar artery occlusion, can also be accomplished by endovascular thrombi injection. CONCLUSIONS: We extensively review the literature on endovascular technique of creating canine ischemic stroke models and their application in finding new therapies for ischemic stroke.

Treatment of unruptured intracranial aneurysms: a review.

INTRODUCTION: Unruptured brain aneurysms (UIAs) present a challenge due to the lack of definitive understanding of their natural history and treatment outcomes. As the treatment of UIAs is aimed at preventing the possibility of rupture, the immediate risk of treatment must be weighed against the risk of rupture in the future. As such, treatment for a large proportion of UIAs is currently individualized. AREAS COVERED: In this article, we discuss the important natural history studies of UIAs and discuss the existing scientific evidence and recent advances that help identify the rupture risk guide management of UIAs. We also address the recent advances in pharmacological therapy of UIAs. Expert commentary: In the recent years, there have been great advances in understanding the pathophysiology of UIAs and determining the rupture risk going beyond the traditional parameter of aneurysm size. Aneurysm morphology and hemodynamics play a pivotal role in growth and rupture. A true randomized trial for the management of UIAs is the need of the hour.

Determining the Presence of Thin-Walled Regions at High-Pressure Areas in Unruptured Cerebral Aneurysms by Using Computational Fluid Dynamics.

BACKGROUND: Thin-walled regions (TWRs) of cerebral aneurysms are at high risk of rupture, and careful attention should be paid during surgical procedures. Despite this, an optimal imaging technique to estimate TWRs has not been established. Previously, pressure elevation at TWRs was reported with computational fluid dynamics (CFD) but not fully evaluated. OBJECTIVE: To investigate the possibility of predicting aneurysmal TWRs at high-pressure areas with CFD. METHODS: Fifty unruptured middle cerebral artery aneurysms were analyzed. Spatial and temporal maximum pressure (Pmax) areas were determined with a fluid-flow formula under pulsatile blood flow conditions. Intraoperatively, TWRs of aneurysm domes were identified as reddish areas relative to the healthy normal middle cerebral arteries; 5 neurosurgeons evaluated and divided these regions according to Pmax area and TWR correspondence. Pressure difference (PD) was defined as the degree of pressure elevation on the aneurysmal wall at Pmax and was calculated by subtracting the average pressure from the Pmax and dividing by the dynamic pressure at the aneurysm inlet side for normalization. RESULTS: In 41 of the 50 cases (82.0%), the Pmax areas and TWRs corresponded. PD values were significantly higher in the correspondence group than in the noncorrespondence group (P = .008). A receiver-operating characteristic curve demonstrated that PD accurately predicted TWRs at Pmax areas (area under the curve, 0.764; 95% confidence interval, 0.574-0.955; cutoff value, 0.607; sensitivity, 66.7%; specificity, 82.9%). CONCLUSION: A high PD may be a key parameter for predicting TWRs in unruptured cerebral aneurysms. ABBREVIATIONS: CFD, computational fluid dynamicsMCA, middle cerebral arteryPave, average pressurePD, pressure differencePmax, maximum pressureTWR, thin-walled regionWSS, wall shear stress.

Intra-arterial delivery of mesenchymal stem cells.

While treatments have been developed to combat stroke, such as intravenous recombinant tissue plasminogen activator and endovascular recanalization therapies, their ability to decrease the long-term disability that accompanies stroke is limited. Currently, stem cell research focused on mesenchymal stem cells (MSCs). MSCs are multipotent, nonhematopoietic stem cells found in the stromal fraction of the bone marrow, along with the connective tissue of most organs. MSCs are an increasingly appealing cell source due to the relative ease in which they can be retrieved, developed, and handled in vitro. Despite the fact that numerous paths of stem cell transport to the brain in acute ischemic stroke (AIS) exist, the intra-arterial (IA) route of stem cell transport is most attractive. This is due to its great potential for clinical translation, especially considering the growing clinical application of endovascular treatment for AIS. Here, we evaluate research examining IA delivery of MSCs to the stroke region. The results of the study revealed the maximum tolerated dose and that the optimal time for administration was 24 h, following cerebral ischemia. It is important that future translational studies are performed to establish IA administration of MSCs as a widely used treatment for AIS.

Fluid structure interaction analysis reveals facial nerve palsy caused by vertebral-posterior inferior cerebellar artery aneurysm.

Cranial nerve palsy caused by aneurysmal compression has not been fully evaluated. The main causes of symptoms are considered to be direct mechanical compression and aneurysm pulsations. Recent studies indicate that nerve dysfunction is mainly induced by pulsation rather than by direct compression, and successful cases of endovascular surgery have been reported. We describe a patient with an unruptured vertebral artery-posterior inferior cerebellar artery (VA-PICA) aneurysm compressing the facial nerve at the root exit zone (REZ). The patient presented with peripheral facial nerve palsy but not hemifacial spasm and was successfully treated by coil embolization. To investigate the mechanisms underlying peripheral facial nerve palsy, fluid structure interaction (FSI) analysis can approximate displacement and the magnitude of aneurysmal wall motion due to hemodynamic forces. In our case, maximum mesh displacement was observed at the aneurysmal wall attached to the facial nerve inside the pons rather than the REZ, which explains the clinical manifestation of facial nerve palsy in the absence of hemifacial spasm. This preliminary report demonstrates the utility of FSI analysis for investigating cranial nerve neuropathy.

[A Case of Foix-Alajouanine Syndrome due to Perimedullary AVF: Remission and Aggravation Mechanism Considered by an Open Surgical Biopsy and Intraoperative ICG Angiography].

Foix-Alajouanine syndrome (FAS), also known as congestive myelopathy due to spinal vascular malformations, presents with paraplegia, sensory disturbance of lower limbs, and dysfunction of the bladder and rectum. Although FAS is characterized by a subacute onset of neurological symptoms that may wax and wane over a few years, the progression mechanism remains unclear. We report a case of FAS due to an angiographically occult arteriovenous fistula (AVF) that was diagnosed by an open surgical biopsy and intraoperative indocyanine green (ICG) angiography. The patient was a 74-year-old female who presented with a one-year history of gradually progressive gait disturbance, weakness, and decreased sensation in her legs associated with bladder and rectum dysfunction. MRI showed intramedullary T1 hypointensity, T2 hyperintensity at level Th4-12, and intramedullary enhancing with a Gd-DTPA lesion at level Th8-12. A true-FISP image of the MRI revealed an abnormal tortuous vessel in the dorsal spinal subarachnoid space, but digital subtraction angiography of the spine at the C1-L5 level showed no abnormality. The patient also underwent Th8-12 laminectomy for open biopsy. ICG angiography revealed blood flow stagnation in an abnormally enlarged posterior spinal vein. Histological findings indicated necrotizing myelopathy and stenosis with wall thickening of the posterior spinal vein. We hypothesized that the progression mechanism in the present case may have resulted from histological changes in the draining veins of an AVF. Intraoperative ICG angiography may be a valuable method, not only for diagnosing AVFs but also for determining the existence and pathological characteristics of FAS.

[Transient charles bonnet syndrome after excision of a right occipital meningioma: a case report].

Charles Bonnet syndrome is a condition characterized by visual hallucinations. These simple or complex visual hallucinations are more common in elderly individuals with impaired peripheral vision. The current report describes a case of transient Charles Bonnet syndrome appearing after the removal of a meningioma. The patient was a 61-year-old man who already had impaired visual acuity due to diabetic retinopathy. Brain MRI revealed a cystic tumor severely compressing the right occipital lobe. Starting on day 2 postoperatively, the patient was troubled by recurring visual hallucinations involving people, flowers, pictures, and familiar settings(the train and a coffee shop). These continued for 3.5 months. This period roughly coincided with the time for the occipital lobe to recover from the compression caused by the tumor, a fact that was confirmed by several MRI scans. ¹²³I-IMP SPECT performed 1 month after the surgical operation showed an area of hypoperfusion in the right parieto-occipital lobe. Based on the patient's clinical course and MRI findings, the mechanism of onset of visual hallucinations in this patient was put forward. The release of pressure in the brain by tumor removal and subsequent recovery changed the blood flow to the brain. This triggered visual hallucinations in the patient, who was already predisposed to developing Charles Bonnet syndrome because of diabetic retinopathy. This case is interesting since it indicates that central neurological factors, as well as visual deficits, may induce the appearance of visual hallucinations in Charles Bonnet syndrome.

Long-term follow-up of growth hormone-producing pituitary carcinoma with multiple spinal metastases following multiple surgeries: case report.

This report describes a rare case of a patient with growth hormone (GH)-secreting pituitary adenoma with malignant transformation resulting in multiple metastases to the dura mater of the cerebral convexity and high cervical spine. The patient was a 60-year-old man with a previous history of pituitary adenoma with suprasellar extension who had undergone transsphenoidal surgery, craniotomy for a convexity tumor, and suboccipital craniotomy for a cerebellar tumor. Thirteen years after the initial surgery, suboccipital craniotomy for a cervicomedullary junction tumor and cervicospinal surgery for a metastatic tumor was performed. Histologic findings of resected specimens demonstrated that the primary pituitary tumor was typical adenoma (similar to specimens from the initial surgery) but that the cerebellar and the dural tumor from the high cervical spine had a high incidence of mitotic figures, and cellular anaplasia with nuclear polymorphism and necrosis. In addition, the serum levels of GH were noted to have decreased with recurrence of the tumor. It was concluded that patients with pituitary adenoma, even when benign, must be carefully followed for signs of malignant transformation, and spinal or distant metastases.

Cerebellar hemorrhage secondary to cerebellopontine angle metastasis from thyroid papillary carcinoma.

A 63-year-old woman presented with a metastatic focus of papillary thyroid carcinoma in the cerebellopontine angle manifesting as lateral gazing nystagmus and slurred speech. Computed tomography demonstrated massive hemorrhage in the left cerebellar hemisphere. She was treated conservatively. Her symptoms resolved completely, but she experienced progressive deterioration in auditory acuity and ataxia over the next 6 months. Magnetic resonance imaging with gadolinium demonstrated an enhanced mass in the left cerebellopontine angle, and she was scheduled for elective resection of the tumor. Left retrosigmoid craniotomy was performed, and the tumor was subtotally removed except for a small amount at the junction of the trigeminal nerve and the pons. Histological examination confirmed a diagnosis of metastatic papillary thyroid carcinoma. The patient then underwent adjuvant gamma knife radiosurgery. Her clinical course was unremarkable, and her hypoacusis and ataxia resolved completely. Postoperative gallium scintigraphy revealed no residual tumor and no other systemic metastases. Hemorrhagic cerebellar metastasis from papillary thyroid carcinoma is extremely rare, but early recognition of metastatic cerebellar tumor should prompt immediate treatment to avoid the development of hearing loss, ataxia, and tonsillar herniation.

Combined unilateral hemilaminectomy and thoracoscopic resection of the dumbbell-shaped thoracic neurinoma: a case report.

A 41-year-old woman complained of chest pain when coughing. Computed tomography and magnetic resonance imaging disclosed a homogenously enhanced tumor occupying the spinal canal at the Th7 level and extending into the right paravertebral space through the intervertebral foramen between Th7 and Th8. The tumor was successfully removed via a posterolateral approach using unilateral hemilaminectomy followed by thoracoscopic surgery. Since the tumor had a dumbbell shape, a combined approach was considered essential. The histological diagnosis was a thoracic neurinoma. Combined hemilaminectomy and thoracoscopic surgery may be a good alternative for the management of thoracic dumbbell-shaped tumors.

Multiple Pulmonary Metastases following Total Removal of a Bilateral Parasagittal Meningioma with Complete Occlusion of the Superior Sagittal Sinus: Report of a Case.

Pulmonary metastases of benign meningiomas are extremely rare. The case of a 34-year-old man with bilateral parasagittal meningioma who developed pulmonary metastases is described. The meningioma was an enormous hypervascular tumor with invasion of the superior sagittal sinus. The tumor was resected completely and histologically diagnosed as transitional meningioma. The Ki-67 labeling index was 5%. Four months after operation, the patient subsequently developed bilateral multiple lung lesions later identified as metastases. The lung lesions were partially removed surgically and histologically diagnosed as meningothelial meningioma WHO grade I. The Ki-67 labeling index was 2%. The histological findings demonstrated that the tumor occupied the arterial lumen and the perivascular space, suggesting that pulmonary tumors might metastasize via the vascular route. The histopathological features and mechanisms of metastasizing meningiomas are reviewed and discussed.