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Susanna Bacigaluppi,1– 3 Nicola L Bragazzi,4 Federico Ivaldi,1 Federica Benvenuto,1 Antonio Uccelli,1,5,* Gianluigi Zona1,2,* 1DINOGMI, University of Genoa, Genoa, Italy; 2Department of Neurosurgery and Neurotraumatology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy; 3Department of Neurosurgery, E.O. Ospedali Galliera, Genoa, Italy; 4DISSAL-University of Genoa, Genoa, Italy; 5Department of Neurology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy*These authors contributed equally to this workCorrespondence: Susanna Bacigaluppi, Department of Neurosurgery and Neurotraumatology, DINOGMI, University of Genoa, IRCCS Policlinico San Martino, Largo Rosanna Benzi 10, Genoa, 16132, Italy, Email susanna.bacigaluppi@unige.itObjective: It is well known that spontaneous non-aneurysmal subarachnoid hemorrhage (SAH), also known as sine materia SAH (smSAH), has usually a better course and prognosis than its aneurysmal counterpart (aSAH). This might depend on different inflammatory mechanisms initiated by bleeding events of different origins. The aim of the present study was to explore the systemic inflammatory response in spontaneous SAH, comparing aSAH and smSAH.Methods: We performed a prospective observational study over a consecutive series of patients with SAH. For these patients, we collected all clinical data and, furthermore, performed venous blood sampling over six time points to analyze blood cells. We further performed the analysis of lymphocytes and monocytes by means of flow cytometry to quantify common subtypes. Statistical analysis included a t-student test, Chi-square test, multivariate logistic regression, and ROC analysis.Results: 48 patients were included: six (12.5%) with a diagnosis of spontaneous smSAH, and forty-two patients (87.5%) with aSAH. Significant differences on Day 0 were found for neutrophils and a systemic neuro-inflammatory index, namely, systemic inflammatory response index (SIRI). At the ROC analysis, neut

Background and aim Cerebral ischemia is characterized by both acute and delayed neuronal injuries. Neuro-protection is a major issue that should be properly addressed from a pharmacological point of view, and cell-based treatment approaches are of interest due to their potential pleiotropic effects. Endothelial progenitor cells have the advantage of being mobilized from the bone marrow into the circulation, but have been less studied than other stem cells, such as mesenchymal stem cells. Therefore, the comparison between human endothelial progenitor cells (hEPC) and human mesenchymal progenitor cells (hMSC) in terms of efficacy in rescuing neurons from cell death after transitory ischemia is the aim of the current study, in the effort to address further directions. Materials and methods In vitro model of oxygen-glucose deprivation (OGD) on a primary culture of rodent cortical neurons was set up with different durations of exposure: 1, 2 and 3 hrs with assessment of neuron survival. The 2 hrs OGD was chosen for the subsequent experiments. After 2 hrs OGD neurons were either placed in indirect co-culture with hMSC or hEPC or cultured in hMSC or hEPC conditioned medium and cell viability was evaluated by MTT assay. Results At day 2 after 2 hrs OGD exposure, mean neuronal survival was 47.9 ± 24.2%. In contrast, after treatment with hEPC and hMSC indirect co-culture was 74.1 ± 27.3%; and 69.4 ± 18.8%, respectively. In contrast, treatment with conditioned medium did not provide any advantage in terms of survival to OGD neurons Conclusion The study shows the efficacy of hEPC in indirect co-culture to rescue neurons from cell death after OGD, comparable to that of hMSC. hEPC deserve further studies given their potential interest for ischemia.

Oxygen and glucose deprivation (OGD) due to ischemic events or trauma in the brain result in neuronal loss. The therapeutic approaches available for the treatment of these conditions are not and often the outcome is unfavorable for the patient or at least unpredictable. Stem cells could be useful for the treatment of OGD injured-neurons. Mesenchymal Stem Cells (MSCs), isolated from bone marrow as well as from various tissues, have poor immunogenicity and neuroprotective properties being able to alleviate ischemic brain injuries in animal models. The Endothelial Progenitor Cells (EPCs) are present at low frequencies both in the bone marrow and in the peripheral blood and can be mobilized by the administration of drugs such as statins. They are thought to play a role in the recovery of cerebrovasculature integrity after stroke. In the present study we evaluated the potential neuroprotective effect of human MSC and human EPCs on rat embryonic cortical neurons injured by OGD. OGD was induced by incubating the cortical neurons in a hypoxia chamber in a 95% N2 + 5% CO2 atmosphere at 37°C without glucose for periods ranging from 30 minutes and 6 hours. When the neurons were returned in normoxic atmosphere they were 1) co-cultured with either MSCs or EPCs seeded on a cell culture avoiding neurons and MSCs or EPCs direct contact while sharing the same medium, or 2) cultured in a medium previously conditioned by either MSCs or EPCs. Neuronal survival was evaluated by MTT assay and viable cellular counting. Also neuronal morphology was taken into account to evaluate the potential MSCs and EPCs neuroprotective effect. Both MSCs and EPCs increased neuronal survival after ODG. This effect was observed in absence of a direct contact between MSCs or EPCs and the injured neurons, suggesting that the release of soluble factors may be the main mechanism of action. In conclusion both MSCs and EPCs could represent a potential therapeutic approach for the treatment of brain ischemic inju

Cerebral cavernous malformations (CCMs) are a diffuse cerebrovascular disease affecting approximately 0.5% of the population. A CCM is characterized by abnormally enlarged and leaky capillaries arranged in mulberry-like structures with no clear flow pattern. The lesion might predispose to seizures, focal neurological deficits or fatal intracerebral hemorrhage. However, a CCM can also remain neurologically silent. It might either occur sporadically or as an inherited disorder with incomplete penetrance and variable expressivity. Due to advances in imaging techniques, the incidence of CCM diagnoses are increasing, and the patient must be managed on a multidisciplinary basis: genetic counselling, treatment if needed, and follow-up. Advances have been made using radiological and pathological correlates of CCM lesions adding to the accumulated knowledge of this disease, although management of these patients is very variable among centers. This review is aimed at providing an update in genetic and molecular insights of this condition. Included are implications for genetic counselling, and possible approaches to prevention and treatment that derive from the understanding of pathogenetic mechanisms

Cerebral aneurysm formation is the result of a complex interplay of systemic and local factors. Among the latter, the role of the geometry of the vessel hosting an aneurysm, of the upstream vasculature and the induced hemodynamics still need to be carefully investigated. In this paper we combine computational fluid dynamics analysis and morphological characterization and carry out the statistical investigation of the features of the internal carotid artery (ICA) of 52 patients affected by a cerebral aneurysm. The functional principal component analysis performed on the geometric and fluid dynamics features of the patients reveals correlations with the location of the aneurysm in the cerebral circulation and its rupture status. This allows a clustering of the patients that is anticipated to contribute to the design of an index for the rupture risk. In particular, ICA featuring a pronounced WSS peak are statistically inclined to hosting ruptured aneurysms. Moreover, our statistical results suggest that patients with a double-bend siphons (S-class) are less prone to the development of cerebral aneurysms

Background: Standard endovascular therapy has shown little success in treatment of very large and giant ophthalmic segment aneurysms. We hypothesize that surgical treatment of these aneurysms yields better results in terms of visual function and aneurysm obliteration. Methods: The Toronto Brain Vascular Malformation Study Group database was analyzed to retrieve patients treated surgically for very large (>15 mm) and giant aneurysms of the ophthalmic segment of the carotid artery. Preoperative data and postoperative long-term outcomes with specific consideration for visual function and aneurysm obliteration were evaluated. Results: Of the 257 patients with ophthalmic and paraophthalmic aneurysms, 38 patients had very large or giant aneurysms. Twenty-one underwent surgical treatment; 19 had direct clipping; 1 had trapping, and 1 underwent trapping and bypass. Fifteen patients had unruptured and six had ruptured aneurysms. The mean follow-up period was 88 months. Six (28%) aneurysms had a small residual neck remnant. Of the 12 patients with documented preoperative visual deficit, 9 (75%) improved, 2 (16%) remained stable, and 1 (8%) worsened. Two patients had mild to moderate new visual deficit. Thus, the surgery-related visual complications were 14%. Eighteen patients (86%) had a good or excellent outcome (GOS IV and V). Presentation with prior visual deficit and poor neurological function were predictors of worse visual and clinical outcome, respectively (P = 0.02 and 0.01). Conclusions: There is considerable surgery-related risk for optic pathways during treatment of very large and giant ophthalmic segment aneurysms. Surgery, however, seems to be the treatment of choice in terms of overall visual outcome and aneurysm obliteration as compared to the current endovascular results in this subset of patients

Objective: To describe the application of intraoperative monitoring techniques during aneurysm surgery and to discuss the advantages and limitations of these techniques in prevention of postoperative neurologic deficits. Methods: Articles found in the literature through PubMed for the time frame 1980-2011 and the authors' personal files were reviewed. Results: Various techniques for detection of vascular insufficiency are available, including direct methods to measure cerebral blood flow and indirect methods to evaluate the integrity of neurologic pathways. Conclusions: The choice of monitoring modality should be governed by the vessel and by the vascular territory most at risk during the planned procedure with proper awareness of the potential limits related to each technique. Aneurysm surgery monitoring should help to address issues of continuity and provide a morphologic and functional assessment. Although the use of monitoring devices is still not routine in aneurysm surgery and no standards have been established, combining different monitoring techniques is crucial to optimize aneurysm surgery and avoid or minimize complications. © 2012 Elsevier Inc. All rights reserved.

Title: Role and potential of endothelial progenitor cells in cerebral vasospasm Abstract: Background and aim: Despite many treatment approaches, cerebral vasospasm and delayed ischemic neuronal damage (DIND) still represent a serious threat to patients with subarachnoid haemorrhage (SAH). Endothelial progenitor cells (EPC) have been involved as prognostic indicators in several vascular diseases and mesenchymal stem cells already have shown some benefits in ischemic injury. Aim of this study was to investigate the therapeutic potential of endothelial progenitor cells (EPC) and mesenchymal stem cells (MSC) in attenuating or preventing vasospasm and DIND in patients with SAH. Methods: Given the emergent role of DIND as a result of multifactorial hypoperfusion stress in the outcome of SAH patients, the efficacy of EPC and MSC in reducing neuronal damage has been evaluated in an in vitro model of ischemia, namely the oxygen glucose deprivation (OGD), on primary rat cortical neuronal cultures. Further, we tested in a clinical observational study SAH patients with and without vasospasm for different recruitment patterns of circulating EPC. To this purpose arterial blood samples were collected at various timepoints from admission to discharge of the patients. On these samples real-time quantitative PCR (RT-qPCR) was performed to detect gene expression relative to EPCs, since cytofluorimetric analysis appeared not sensitive enough to detect this rare cell population. Results: Though present results need further confirmation, in vitro it was observed that both MSC and EPC treatment through conditioned medium or co-culture in transwell- although with some differences - mediate a survival advantage for OGD stressed neurons. Furthermore stem cell mediated treatment showed efficacy even when applied 24 hours after OGD stress induction. RT-qPCR results from a small sample of SAH patients might indicate an early mobilization of EPC related gene expression in subjects that do not de

BACKGROUND: Intracranial aneurysm development and rupture may be associated to the morphology of the parent vessel. OBJECTIVE: To quantitatively characterize the geometry of the internal carotid artery (ICA) in relation to the location and orientation of lateral aneurysms and to identify recurrent patterns associated with their rupture status. METHODS: The geometry of 54 ICAs hosting lateral aneurysms was analyzed by means of computational geometry techniques. The ICA was split into individual bends, and the bend hosting the aneurysm was described in terms of curvature, torsion, length, and radius. Aneurysm position and orientation with respect to the parent vessel and specifically the hosting bend were characterized, as well as angles between the portions of the parent artery immediately upstream of and downstream from the aneurysm and the aneurysm ostium. Differences in geometric parameters with respect to rupture status and their performance as classifiers were evaluated. RESULTS: ICA bends hosting ruptured aneurysms were shorter with a smaller radius, lower maximum curvature, and lower proximal torsion compared with those hosting unruptured lesions. Ruptured aneurysms occurred in more distal portions of the ICA, along the outer wall of the vessel, and closer to the curvature peak within the hosting bend than unruptured ones. The proximal portions of ICAs hosting ruptured aneurysms approached the ostium region at a smaller angle. CONCLUSION: Geometric factors relative to the ICA were associated with the distribution of aneurysms and their rupture status. The present work has potential implications in the quest for hemodynamic factors contributing to the development, progression, and rupture of intracranial aneurysms. Copyright © 2011 by the Congress of Neurological Surgeons.