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The pathophysiology of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) is incompletely understood. Intrathecal activation of inflammatory immune cells is suspected to play a major role for the induction of DCI. The aim of this study is to identify immune cell subsets and mediators involved in the pathogenesis of DCI. We prospectively collected blood and CSF from 25 patients with aSAH at early and late time points. We performed multicolor flow cytometry of peripheral blood and CSF, analyzing immune cell activation and pro-inflammatory cyto- and chemokines. In addition to the primary immune analysis, we retrospectively analyzed immune cell dynamics in the CSF of all our SAH patients. Our results show an increased monocyte infiltration secondary to aneurysm rupture in patients with DCI. Infiltrating monocytes are defined by a non-classical (CD14 dim CD16 + ) phenotype at early stages. The infiltration is most likely triggered by the intrathecal immune activation. Here, high levels of pro-inflammatory chemokines, such as CXCL1, CXCL9, CXCL10, and CXCL11, are detected. The intrathecal cellular activation profile of monocytes was defined by upregulation of CD163 and CD86 on monocytes and a presumable later differentiation into antigen-presenting plasmacytoid dendritic cells (pDCs) and hemosiderophages. Peripheral immune activation was reflected by CD69 upregulation on T cells. Analysis of DCI prevalence, Hunt and Hess grade, and clinical outcome correlated with the degree of immune activation. We demonstrate that monocytes and T cells are activated intrathecally after aSAH and mediate a local inflammatory response which is presumably driven by chemokines. Our data shows that the distinct pattern of immune activation correlates with the prevalence of DCI, indicating a pathophysiological connection to the incidence of vasospasm.

Background: Cerebral aneurysm surgery has significant mortality and morbidity rate. Inflammation plays a key role in the pathogenesis of intracranial aneurysms, their rupture, subarachnoid hemorrhage and neurologic complications. Proinflammatory cytokine level in blood and cerebrospinal fluid (CSF) is an indicator of inflammatory response. Cytokines contribute to secondary brain injury and can worsen the outcome of the treatment. Lidocaine is local anesthetic that can be applied in neurosurgery as regional anesthesia of the scalp and as topical anesthesia of the throat before direct laryngoscopy and endotracheal intubation. Besides analgesic, lidocaine has systemic anti-inflammatory and neuroprotective effect.Primary aim of this trial is to determine the influence of local anesthesia with lidocaine on the perioperative levels of pro-inflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor-α in plasma and CSF in cerebral aneurysm patients., Methods: We will conduct prospective randomized clinical trial among patients undergoing craniotomy and cerebral aneurysm clipping surgery in general anesthesia. Patients included in the trial will be randomly assigned to the lidocaine group (Group L) or to the control group (Group C). Patients in Group L, following general anesthesia induction, will receive topical anesthesia of the throat before endotracheal intubation and also regional anesthesia of the scalp before Mayfield frame placement, both done with lidocaine. Patients in Group C will have general anesthesia only without any lidocaine administration. The primary outcomes are concentrations of cytokines interleukin-1β, interleukin-6 and tumor necrosis factor-α in plasma and CSF, measured at specific timepoints perioperatively. Secondary outcome is incidence of major neurological and infectious complications, as well as treatment outcome in both groups., Discussion: Results of the trial could provide insight into influence of lidocaine on local and systemic inflammatory response in cerebrovascular surgery, and might improve future anesthesia practice and treatment outcome. TRIAL IS REGISTERED AT CLINICALTRIALS.GOV:: NCT03823482.

Cerebral vasospasm (CVS) is a major contributor to the high morbidity and mortality of aneurysmal subarachnoid hemorrhage (aSAH) patients. We measured histidine-rich glycoprotein (HRG), a new biomarker of aSAH, in cerebrospinal fluid (CSF) to investigate whether HRG might be an early predictor of CVS. A total of seven controls and 14 aSAH patients (8 males, 6 females aged 53.4±15.4 years) were enrolled, and serial CSF and serum samples were taken. We allocated these samples to three phases (T1-T3) and measured HRG, interleukin (IL)-6, fibrinopeptide A (FpA), and 8-hydroxy-2'-deoxyguanosine (8OHdG) in the CSF, and the HRG in serum. We also examined the release of HRG in rat blood incubated in artificial CSF. In contrast to the other biomarkers examined, the change in the CSF HRG concentration was significantly different between the nonspasm and spasm groups (p<0.01). The rat blood/CSF model revealed a time course similar to that of the human CSF samples in the non-spasm group. HRG thus appears to have the potential to become an early predictor of CVS. In addition, the interaction of HRG with IL-6, FpA, and 8OHdG may form the pathology of CVS., Competing Interests: No potential conflict of interest relevant to this article was reported.

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is often complicated by the occurrence of delayed ischemic neurologic deficits (DIND), which impairs the clinical outcome of patients. The release of oxyhemoglobin (oxyHb) from lysing erythrocytes into cerebrospinal fluid (CSF) may critically contribute to the development of DIND., Methods: Ventricular CSF of 18 high-grade (Fisher 3 and 4) aSAH patients was sampled daily from external ventricular drains between days 0 and 14 after bleeding. CSF was spectrophotometrically analyzed with precise quantification of cell-free oxyHb levels., Results: OxyHb levels in CSF showed a delayed peak reaching the highest levels in the high-risk period for developing of DIND between days 3 and 14 after aneurysm rupture. Patients with DIND had a significantly higher cumulative oxyHb exposure within the first week after bleeding., Conclusions: OxyHb levels in CSF may be useful as a biomarker to predict DIND in aSAH patients. The contribution of oxyHb in CSF to the pathogenesis of DIND should be further investigated as a potential therapeutic target., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background:  Subarachnoid hemorrhage (SAH) is a severe condition associated with high mortality. Early brain injury (EBI) plays an important role in the pathophysiology of SAH, and inflammation is a major contributor to EBI. Inflammation is a widely studied topic in both experimental and clinical conditions; however, just a few clinical studies have focused primarily on the early inflammatory response after SAH, and detailed information about the association between the dynamics of early inflammatory response with main clinical characteristics is lacking. This study analyzes the early dynamics of inflammatory response after SAH and evaluates the possible associations between the markers of early inflammatory response and main clinical characteristics., Patients and Methods:  A total of 47 patients with a diagnosis of aneurysmal SAH within the last 24 hours were enrolled in the study. All treatments, including treatment of aneurysm (surgery/coiling) and implantation of a drainage system (external ventricular drainage/lumbar catheter), were conducted in the same way as in other patients with this diagnosis. Blood and cerebrospinal fluid (CSF) samples were collected three times a day for 4 days. The dynamics of proinflammatory cytokines were assessed, and associations between levels of the proinflammatory cytokines interleukin (IL)-6, IL-1β, or tumor necrosis factor (TNF)α and main clinical characteristics were evaluated using linear mixed-effect models., Results:  The CSF levels of IL-6 were massively increased initially after SAH (up to 72 hours) with an additional increase in later phases (after 72 hours), but there was high variability in IL-6 levels. A significant association was noted between the Glasgow Outcome Scale score and both overall levels of IL-6 ( p  = 0.0095) and their dynamics ( p  = 0.0208); the effect of the Hunt and Hess scale was borderline ( p  = 0.0887). No association was found between IL-6 levels and Fisher grade, modality of treatment (surgery, coiling, no treatment), and later development of cerebral vasospasm. Plasmatic levels of IL-6 increased slightly, but no significant association was found. The levels of IL-1β and TNFα were within the physiologic range in both CSF and plasma., Conclusions:  Early dynamics of IL-6 in CSF are associated with a patient́s outcome. But it is difficult to use IL-6 alone for outcome prediction due to its high variability. The question is whether the dynamics of IL-6 could be used in combination with other early markers associated with brain injury. More detailed research is required to answer this question., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: The aim of this paper was to determine the diagnostic value of cerebrospinal fluid (CSF) analysis in the setting of aneurysmal subarachnoid hemorrhage (aSAH), hypothesizing that CSF analysis is only critical in confirming suspected infection and may be useful in predicting and/or detecting delayed cerebral ischemia (DCI)., Methods: Retrospective review of consecutive adult patients diagnosed with aSAH from 1/2000 to 12/2013 at Mayo Clinic, Rochester, MN, USA with cerebral aneurysm(s) identified by vascular imaging, and CSF drawn within 14 days of the date of hemorrhage., Results: We identified 741 patients during the study period, 167 met inclusion criteria and 356 samples were collected. First Median CSF samples were taken 5 (4-8) days postbleed. Multiple samples were taken in 94 (54.5%) patients and the mean number of samples per patient was 2.1. Ventriculitis, confirmed by growth of organism from CSF culture was present in 2 (1.2%) patients and one patient (0.6%) developed meningitis. CSF WBC count remained elevated throughout the 14 days, even when corrected for red blood cell count (RBC). Peak CSF RBCs occurred 2-4 days post bleed, and then gradually normalized. Maximum CSF RBCs did not correlate with modified Fisher grades (P=0.422). Delayed cerebral ischemia (DCI) was present in 86 (51.5%) patients and there was no difference in the CSF profile of patients with DCI compared with those without., Conclusions: Routine CSF sampling for cell count and chemistry in the setting of temporary diversion following aSAH appears to have little clinical benefit beyond the evaluation for infection.

Receptors for advanced glycation end-products (RAGE) mediate the inflammatory reaction that follows aneurysmal subarachnoid haemorrhage. Soluble RAGE (sRAGE) may function as a decoy receptor. The significance of this endogenous anti-inflammatory mechanism in subarachnoid haemorrhage (SAH) remains unknown. The present study aims to analyse sRAGE levels in the cerebrospinal fluid (CSF) of SAH patients. sRAGE levels were assayed by ELISA kit in 47 CSF samples collected on post-SAH days 0-3, 5-7, and 10-14 from 27 SAH patients with acute hydrocephalus. CSF levels of sRAGE were compared with a control group and correlated with other monitored parameters. In the control group, the CSF contained only a trace amount of sRAGE. By contrast, the CSF of 20 SAH patients collected on post-SAH days 0-3 was found to contain statistically significant higher levels of sRAGE (mean concentration 3.91 pg/mL, p < 0.001). The most pronounced difference in CSF sRAGE levels between good and poor outcome patients was found on days 0-3 post-SAH but did not reach the significance threshold ( p = 0.234). CSF sRAGE levels did not change significantly during hospitalisation ( p = 0.868) and correlated poorly with treatment outcome, systemic inflammatory markers, and other monitored parameters. Our study revealed an early and constant increase of sRAGE level in the CSF of SAH patients.

BACKGROUND Delayed cerebral vasospasm (DCVS) following aneurismal subarachnoid hemorrhage (SAH) is a leading cause of poor prognosis and death in SAH patients. Effective management to reduce DCVS is needed. A prospective controlled trial was conducted to determine if massive cerebrospinal fluid (CSF) replacement (CR) could reduce DCVS occurrence and improve the clinical outcome after aneurysmal SAH treated with endovascular coiling. MATERIAL AND METHODS Patients treated with endovascular coiling after aneurysmal SAH were randomly divided into a control group receiving regular therapy alone (C group, n=42) and a CSF replacement group receiving an additional massive CSF replacement with saline (CR group, n=45). CSF examination, head CT, DCVS occurrence, cerebral infarction incidence, Glasgow Outcome Scale prognostic score, and 1-month mortality were recorded. RESULTS The occurrence of DCVS was 30.9% in the C group and 4.4% in the CR group (P<0.005). The cerebral infarction incidences in the C and CR groups were 19.0% and 2.2% (P<0.05), respectively, 1 month after the treatments. Mortality was not significantly different between the 2 groups during the follow-up period. CONCLUSIONS Massive CR after embolization surgery for aneurysmal SAH can significantly reduce DCVS occurrence and effectively improve the outcomes.

Background: Recent evidence suggests a link between the magnitude and distribution of hemodynamic factors and the formation and rupture of intracranial aneurysms. However, there are many conflicting results., Objective: To quantify the effect of hemodynamic factors on aneurysm formation and their association with ruptured aneurysms., Methods: We performed a systematic review and meta-analysis through October 2014. Analysis of the effects of hemodynamic factors on aneurysm formation was performed by pooling the results of studies that compared geometrical models of intracranial aneurysms and "preaneurysm" models where the aneurysm was artificially removed. Furthermore, we calculated pooled standardized mean differences between ruptured and unruptured aneurysms to quantify the association of hemodynamic factors with ruptured aneurysms. Standard PRISMA guidelines were followed., Results: The hemodynamic factors that showed high positive correlations with location of aneurysm formation were high wall shear stress (WSS) and high gradient oscillatory number, with pooled proportions of 78.8% and 85.7%, respectively. Positive correlations were largely seen in bifurcation aneurysms, whereas negative correlations were seen in sidewall aneurysms. Mean and normalized WSS were significantly lower and low shear area significantly higher in ruptured aneurysms., Conclusion: Pooled analyses of computational fluid dynamics models suggest that an increase in WSS and gradient oscillatory number may contribute to aneurysm formation, whereas low WSS is associated with ruptured aneurysms. The location of the aneurysm at the bifurcation or sidewall may influence the correlation of these hemodynamic factors.

Diagostic approach to aneurysmal subarachnoid hemorrhage (aSAH) is based on computer tomography (CT) imaging, although a lumbar puncture and subsequent cerebrospinal fluid analysis is sometimes necessary. Identification of the ruptured aneurysm is done using angiography. Despite of modern imaging techniques, diagnostic definition of aSAH is still occasionally challenging. We describe three cases in which the diagnosis of aSAH has been delayed, in spite of positive imaging or lumbar puncture findings.

Introduction: Intracranial aneurysms (IAs) remain a devastating clinical challenge, and the pathogenesis of IA formation and progression continues to be unclear. Biomarker analysis can help us understand IA development. The authors performed a systematic review of current literature on genetic and serum biomarkers for IAs in an attempt to identify diagnostic/prognostic factors for ruptured and unruptured aneurysms., Methods: All relevant studies on PubMed that reported blood/cerebrospinal fluid (CSF) biomarkers and genes that regulate biomarker levels for IAs were assessed for whether the biomarkers/genes studied correlated with IA formation and rupture., Results: Thirty-three studies were reviewed. IAs are associated with an increase in levels of immunologic markers, particularly complement C3 and C9, immunoglobulins IgG and IgM, M1/M2 macrophages, monocytes, and B and T lymphocytes; increase in blood and CSF levels of adhesion molecules; selectins found on vascular endothelium, platelets, and leukocytes; doubled ratios of elastase-to-alpha-1-antitrypsin as controls; elevated levels of neurofilament heavy chain SM135 and S-100 post rupture; and locus 19q13 with many candidate genes., Conclusion: Though the pathophysiology of the disease remains unclear, the current literature supports the role of inflammatory and cell adhesion molecules, enzymes and hormones that effect cerebral vasculature, and other cerebral proteins related to brain and vascular damage in both the formation and progression to rupture of IAs. Future investigations are needed to validate results from previous studies and identify new diagnostic/prognostic biomarkers of IAs., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Recently proposed cutoff criteria for cerebrospinal fluid (CSF) analyses might safely exclude a diagnosis of aneurysmal subarachnoid hemorrhage (aSAH)., Objective: The objective of this study was to examine the sensitivity of a CSF red blood cell (RBC) count greater than 2000 × 10(6)/L (ie, 2000 RBCs per microliter) or the presence of visible CSF xanthochromia in identifying patients with aSAH., Methods: We identified a retrospective case series of patients diagnosed with aSAH after lumbar puncture (LP) in an integrated health delivery system between January 2000 and June 2013 by chart review. All identified patients had at least 1 cerebral aneurysm that was treated with a neurosurgical or endovascular intervention during the index hospitalization. The lowest CSF RBC count was used for validation analysis. Cerebrospinal fluid color was determined by visual inspection. Xanthochromia was defined as pink, orange, or yellow pigmentation of CSF supernatant., Results: Sixty-four patients met study inclusion criteria. Of these, 17 (33%) of 52 underwent LP within 12 hours of headache onset, and 49 (84%) of 58 exhibited CSF xanthochromia. The median CSF RBC count was 63250 × 10(6)/L. The sensitivity of a CSF RBC count of greater than 2000 × 10(6)/L in identifying aSAH was 96.9% (95% confidence interval, 89.3%-99.1%). Additional consideration of CSF xanthochromia resulted in a sensitivity of 100% (95% confidence interval, 94.3%-100%)., Conclusions: All patients in this case series of patients with aSAH had either a CSF RBC count greater than 2000 × 10(6)/L or visible CSF xanthochromia, increasing the likelihood that this proposed cutoff strategy may safely identify patients who warrant further investigation for an aneurysmal cause of subarachnoid hemorrhage., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Locally administered tissue plasminogen activator (TPA) accelerates clearance of intraventricular hemorrhage (IVH), but its impact on neurologic outcomes remains unclear and preclinical research suggests it may have pro-inflammatory effects. We randomly allocated patients with ruptured cerebral aneurysms and IVH, treated with endovascular coiling and ventricular drainage, to receive either 2-mg intraventricular TPA or placebo every 12 hours. Cerebrospinal fluid (CSF) and serum cytokine and white blood cell (WBC) concentrations were measured before drug administration and daily for 72 hours. Cerebrospinal fluid D-dimer levels were assessed 6 and 12 hours after administration to quantify fibrinolysis. Six patients were randomized to each group. Patients treated with TPA developed higher CSF cytokine concentrations compared with placebo-treated patients (P<0.05 for tumor necrosis factor-α, interferon-γ, interleukin (IL)-1α, IL-1β, IL-2, IL-4, and IL-6), as well as higher CSF WBC counts (P=0.03). Differences were greatest after 24 hours and decreased over 48 to 72 hours. The magnitude of the inflammatory response was significantly associated with peak CSF D-dimer concentration and extent of IVH clearance. We conclude that intraventricular TPA administration produces a transient local inflammatory response, the severity of which is strongly associated with the degree of fibrinolysis, suggesting it may be induced by release of hematoma breakdown products, rather than the drug itself.

Subarachnoid hemorrhage (SAH) carries a 50% mortality rate. The extravasated erythrocytes that surround the brain contain heme, which, when released from damaged red blood cells, functions as a potent danger molecule that induces sterile tissue injury and organ dysfunction. Free heme is metabolized by heme oxygenase (HO), resulting in the generation of carbon monoxide (CO), a bioactive gas with potent immunomodulatory capabilities. Here, using a murine model of SAH, we demonstrated that expression of the inducible HO isoform (HO-1, encoded by Hmox1) in microglia is necessary to attenuate neuronal cell death, vasospasm, impaired cognitive function, and clearance of cerebral blood burden. Initiation of CO inhalation after SAH rescued the absence of microglial HO-1 and reduced injury by enhancing erythrophagocytosis. Evaluation of correlative human data revealed that patients with SAH have markedly higher HO-1 activity in cerebrospinal fluid (CSF) compared with that in patients with unruptured cerebral aneurysms. Furthermore, cisternal hematoma volume correlated with HO-1 activity and cytokine expression in the CSF of these patients. Collectively, we found that microglial HO-1 and the generation of CO are essential for effective elimination of blood and heme after SAH that otherwise leads to neuronal injury and cognitive dysfunction. Administration of CO may have potential as a therapeutic modality in patients with ruptured cerebral aneurysms.

Objectives: To describe the findings in cerebrospinal fluid from patients with acute headache that could distinguish subarachnoid hemorrhage from the effects of a traumatic lumbar puncture., Design: A substudy of a prospective multicenter cohort study., Setting: 12 Canadian academic emergency departments, from November 2000 to December 2009., Participants: Alert patients aged over 15 with an acute non-traumatic headache who underwent lumbar puncture to rule out subarachnoid hemorrhage., Main Outcome Measure: Aneurysmal subarachnoid hemorrhage requiring intervention or resulting in death., Results: Of the 1739 patients enrolled, 641 (36.9%) had abnormal results on cerebrospinal fluid analysis with >1 × 10(6)/L red blood cells in the final tube of cerebrospinal fluid and/or xanthochromia in one or more tubes. There were 15 (0.9%) patients with aneurysmal subarachnoid hemorrhage based on abnormal results of a lumbar puncture. The presence of fewer than 2000 × 10(6)/L red blood cells in addition to no xanthochromia excluded the diagnosis of aneurysmal subarachnoid hemorrhage, with a sensitivity of 100% (95% confidence interval 74.7% to 100%) and specificity of 91.2% (88.6% to 93.3%)., Conclusion: No xanthochromia and red blood cell count <2000 × 10(6)/L reasonably excludes the diagnosis of aneurysmal subarachnoid hemorrhage. Most patients with acute headache who meet this cut off will need no further investigations and aneurysmal subarachnoid hemorrhage can be excluded as a cause of their headache., (© Perry et al 2015.)

Preclinical studies show that epoxyeicosatrienoic acids (EETs) regulate cerebrovascular tone and protect against cerebral ischemia. We investigated the relationship between polymorphic genes involved in EET biosynthesis/metabolism, cytochrome P450 (CYP) eicosanoid levels, and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage (aSAH). Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid (DHET) cerebrospinal fluid (CSF) levels, as well as acute outcomes defined by delayed cerebral ischemia (DCI) or clinical neurologic deterioration (CND), were assessed over 14 days. Long-term outcomes were defined by Modified Rankin Scale (MRS) at 3 and 12 months. CYP2C8*4 allele carriers had 44% and 36% lower mean EET and DHET CSF levels (P=0.003 and P=0.007) and were 2.2- and 2.5-fold more likely to develop DCI and CND (P=0.039 and P=0.041), respectively. EPHX2 55Arg, CYP2J2*7, CYP2C8*1B, and CYP2C8 g.36785A allele carriers had lower EET and DHET CSF levels. CYP2C8 g.25369T and CYP2C8 g.36755A allele carriers had higher EET levels. Patients with CYP2C8*2C and EPHX2 404del variants had worse long-term outcomes while those with EPHX2 287Gln, CYP2J2*7, and CYP2C9 g.816G variants had favorable outcomes. Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3-month outcomes. Dihydroxyeicosatetraenoic acids were not associated with outcomes. No associations passed Bonferroni multiple testing correction. These are the first clinical data demonstrating the association between the EET biosynthesis/metabolic pathway and the pathophysiology of aSAH.

Remote intraparenchymal hemorrhage after clipping of a ruptured aneurysm is rare. The pathogenesis is variable, and the therapeutic strategies remain controversial, because the natural history is unclear. Here we report a woman with subarachnoid hemorrhage (SAH), who had an aneurysm of the anterior communicating artery identified by computed tomography angiography (CTA). A 51-year-old women, who was in a good preoperative condition without movement disorders before operation, went on to exhibit left hemiparesis after aneurysmal clipping as she recovered from anesthesia in the operating room. CT images performed immediately after surgery showed that two intraparenchymal hemorrhages were present contralateral to the site of the operation. After conservative treatment, the patient recovered, but still displayed a movement disorder in the left limb. SAH induced-vasospasm, defective vascular autoregulation, excessive drainage of the cerebrospinal fluid, a change in the intracranial pressure after craniotomy, and brain shift may contribute to the pathogenesis of remote hemorrhage after surgery.

Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is the second major protein in human cerebrospinal fluid (CSF) and belongs to the lipocalin superfamily composed of various secretory lipophilic ligand transporter proteins. However, the endogenous ligand of L-PGDS has not yet been elucidated. In this study, we purified L-PGDS from the CSF of aneurysmal subarachnoid hemorrhage (SAH) patients. Lipocalin-type PG D synthase showed absorbance spectra with major peaks at 280 and 392 nm and a minor peak at around 660 nm. The absorbance at 392 nm of L-PGDS increased from 1 to 9 days and almost disappeared at 2 months after SAH, whereas the L-PGDS activity decreased from 1 to 7 days and recovered to normal at 2 months after SAH. These results indicate that some chromophore had accumulated in the CSF after SAH and bound to L-PGDS, thus inactivating it. Matrix assisted laser desorption ionization time-of-flight mass spectrometry of L-PGDS after digestion of it with endoproteinase Lys-C revealed that L-PGDS had covalently bound biliverdin, a by-product of heme breakdown. These results suggest that L-PGDS acted as a scavenger of biliverdin, which is a molecule not found in normal CSF. This is the first report of identification of a pathophysiologically important endogenous ligand for this lipocalin superfamily protein in humans.

Background and Purpose: Red blood cell transfusion (RBCT) may increase the risk of thrombotic events (TE) in patients with subarachnoid hemorrhage (SAH) through changes induced by storage coupled with SAH-related hypercoagulability. We sought to investigate the association between RBCT and the risk of TE in patients with SAH., Methods: 205 consecutive patients with acute, aneurysmal SAH admitted to the neurovascular intensive care unit of a tertiary care, academic medical center between 3/2008 and 7/2009 were enrolled in a retrospective, observational cohort study. TE were defined as the composite of venous thromboembolism (VTE), myocardial infarction (MI), and cerebral infarction noted on brain CT scan. Secondary endpoints included the risk of VTE, poor outcome (modified Rankin score 3-6 at discharge), and in-hospital mortality., Results: 86/205 (42 %) received RBCT. Eighty-eight (43 %) had a thrombotic complication. Forty (34 %) of 119 non-transfused and 48/86 (56 %) transfused patients had a TE (p = 0.002). In multivariate analysis, RBCT was associated with more TE by [OR 2.4; 95 % CI (1.2, 4.6); p = 0.01], VTE [OR 2.3; 95 % CI (1.0, 5.2); p = 0.04], and poor outcome [OR 5.0; 95 % CI (1.9, 12.8); p < 0.01]. The risk of TE increased by 55 % per unit transfused when controlling for univariate variables. Neither mean nor maximum age of blood was significantly associated with thrombotic risk., Conclusions: RBCT is associated with an increased risk of TE and VTE in SAH patients. A dose-dependent relationship exists between number of units transfused and thrombosis. Age of blood does not appear to play a role.

Aim: External ventricular drainage (EVD) and lumbar drainage (LD) are the most widely used procedures for continued bloody cerebrospinal fluid drainage. Each has his own advantages and disadvantages. Here, we compared complications and clinical outcomes in patients with World Federation of Neurosurgical Societies (WFNS) grade III aneurysmal subarachnoid hemorrhage (aSAH) who underwent coil placement followed by EVD or LD., Material and Methods: In this prospective, controlled study, all patients with aSAH classified as WFNS grade III who underwent coil placement at our institution were divided randomly into 2 groups: the EVD group and the LD group. The ratios of intracerebral hemorrhage, vasospasm, infection, duration of catheter placement, hydrocephalus, and Glasgow outcome scale (GOS) after 2 months of onset were analyzed between the 2 groups., Results: A total of 148 patients (mean age 56.8 years) were enrolled in this study. Seventy-six patients were assigned to the EVD group, and 72 patients were assigned to the LD group. The average time interval from stroke onset to surgery was 35.1 h. Compared with the EVD group, the LD group had a lower incidence of intracerebral hemorrhage, slightly higher rates of infection and hydrocephalus, and similar vasospasm and chronic hydrocephalus rates, durations of catheter placement, and GOS scores at 2 months after onset., Conclusion: In order to improve the clinical outcomes of patients with aSAH, we suggest that LD is better than EVD for patients with WFNS grade III aSAH who underwent coil placement.

Aim: To investigate the changes of cerebrospinal fluid (CSF) cystatin C (CC) levels associated with the postoperative ischemic conditions and prognostic outcome in patients with aneurysmal subarachnoid hemorrhage (SAH)., Material and Methods: The study group consisted of 40 patients with microsurgically clipped intracranial aneurysms (IA's) and 22 control CSF samples. In patients, CSF samples were taken from the lumbar intrathecal catheter for CC measurement, at the beginning of operation, immediately after the operation (early postoperative), and the first postoperative day (late postoperative)., Results: CC levels in three periods were significantly higher in patients with Hunt-Hess scores of 4, 5 than 1, 2, 3. There was a significant difference between the CC concentrations on the first postoperative day and controls. In patients who developed focal cerebral ischemia, CC levels at early and late postoperative periods were significantly higher than the group without ischemia. In addition, patients with poor prognostic outcome (GOS score of 1, 2, 3) had significantly higher levels of CC in all three periods than that of patients with good outcome (GOS score of 4, 5)., Conclusion: The raised CSF CC concentrations appear to be associated with the severity of bleeding, intraoperative ischemic events and poor prognostic outcome in patients with aneurysmal SAH.

Object: Fenestration of the lamina terminalis (FLT) during aneurysm surgery for subarachnoid hemorrhage can, in theory, improve CSF circulation from the lateral and third ventricles to the cortical subarachnoid space, which may, in turn, decrease the incidence of hydrocephalus and vasospasm. However, the actual effects of FLT on CSF circulation have been difficult to determine, due to confounding factors. In addition, it is unclear whether the lamina terminalis remains functionally patent when the brain resumes its normal position. The goal of this study was to assess the functional patency of the fenestrated lamina terminalis in patients who underwent surgery for ruptured aneurysms., Methods: This prospective study included 15 patients who underwent surgical clipping of ruptured anterior circulation aneurysms, with FLT performed during surgery. On postoperative Day 1, the external ventricular drain of each patient was closed, and 1 ml of Omnipaque 300, an iodine based contrast agent, was injected intraventricularly, accompanied by cranial maneuvering designed to position the contrast agent adjacent to the lamina terminalis. Three to 5 minutes after cranial maneuvering, the flow of contrast agent into the basal cisterns was assessed with CT imaging. Flow was verified by an increase in Hounsfield units in a prespecified "region of interest" within the basal cisterns on the CT scan. This procedure was performed using a standardized protocol designed in consultation with the Department of Radiology and approved by the institutional review board. One patient who underwent endoscopic third ventriculostomy was recruited as a positive control to validate the technique, and 1 patient who underwent aneurysm clipping but not FLT was recruited as a negative control., Results: Seventeen patients consented to study participation. In the 15 patients who underwent aneurysm clipping and FLT, and the negative control patient who underwent aneurysm clipping but not FLT, the contrast agent followed the normal ventricular pathway from the lateral ventricles into the fourth ventricle, and did not appear in the basal cisterns. In the positive control patient, the contrast agent robustly and immediately filled the basal cisterns., Conclusions: Fenestration of the lamina terminalis did not result in functional patency of the lamina terminalis when performed as part of surgical clipping for ruptured aneurysms.

Introduction: Sympathetic activation promotes hemostasis, and subarachnoid hemorrhage (SAH) is associated with pronounced sympathetic activation. This investigation will assess whether catecholaminergic activity relates to venous thrombotic events in patients with acute SAH., Methods: Observational study of consecutive SAH grade 3-5 patients requiring ventriculostomy insertion who did not undergo open surgical treatment of cerebral aneurysm. Cerebrospinal fluid (CSF) samples were obtained within 48 h of hemorrhage for assay of catecholamines, which were related to occurrence of deep venous thrombosis (DVT) and pulmonary embolization (PE)., Results: Of the 92 subjects, mean age was 57 years, 76% were female, and 57% Caucasian; 11% experienced lower extremity (LE) DVT, 12% developed upper extremity (UE) or LE DVT, and 23% developed any DVT/PE. Mean time to occurrence of UE/LE DVT was 7.8 days (+/-5.9 days), and mean time to development of PE was 8.8 days (+/-5.4 days). In hazards analysis models, independent predictors of LE DVT included neurogenic cardiomyopathy (NC) [HR 4.97 (95%CI 1.32-18.7)], norepinephrine/3,4-dihydroxyphenylglycol ratio (NE/DHPG) [3.81 (2.04-7.14)], NE [5.91 (2.14-16.3)], and dopamine (DA) [2.27 (1.38-3.72)]. Predictors of UE/LE DVT included NC [5.78 (1.70-19.7)], cerebral infarction [4.01 (1.18-13.7)], NE [3.58 (1.40-9.19)], NE/DHPG [3.38 (1.80-6.33)] and DA [2.01 (1.20-3.35)]. Predictors of DVT/PE included Hunt-Hess grade (H/H) [3.02 (1.19-7.66)], NE [2.56 (1.23-5.37)] and 3,4-dihydroxyphenylalanine (DOPA) [3.49 (1.01-12.0)]., Conclusions: In severe SAH, central sympathetic activity and clinical manifestations of (nor)adrenergic activity relate to the development of venous thromboemboli. Catecholamine activation may promote hemostasis, or may represent a biomarker for venous thromboses.

In patients with sudden severe headache and a negative computed tomography (CT) scan, a lumbar puncture (LP) is performed to rule in or out a subarachnoid haemorrhage (SAH), but this procedure is under debate. In a hospital-based series of 30 patients with sudden headache, a negative CT scan but a positive LP (defined as detection of bilirubin >0.05 at wavelength 458 nm), we studied the chance of harbouring an aneurysm and the clinical outcome. Aneurysms were found in none of both patients who presented within 3 days, in 8 of the 18 (44%) who presented within 4-7 days and in 5 of the 10 (50%) who presented within 8-14 days. Of the 13 patients with an aneurysm, 3 (23%) had poor outcome. In patients who present late after sudden headache, the yield in terms of aneurysms is high in those who have a positive lumbar puncture. In patients with an aneurysm as cause of the positive lumbar puncture, outcome is in the same range as in SAH patients admitted in good clinical condition.

To better understand the development of hydrocephalus of different origins, we evaluated cytokine and growth factor concentration in cerebrospinal fluid from patients with hydrocephalus. CSF was collected from patients developing hydrocephalus following hemorrhage (n = 15), patients with normal pressure hydrocephalus (n = 10), and following the embolization of unruptured intracranial aneurysms (n = 9). Myelography patients (n = 15) served as controls. Quantification of 11 molecules relating angiogenesis, inflammation, and wound healing in the CSF was performed using ELISA. All three hydrocephalus groups had decreased concentration of TIMP-4 compared to the normal group. The hemorrhage group showed increased concentration of IL-6, IL-8, MCP-1, MMP-9, and TIMP-1 compared to the control group. The unruptured aneurysm group had increased concentration of IL-6 and decreased concentration of TIMP-2 compared to the control group. Compared to the normal patients, increased concentrations of wound healing molecules were evident in all three groups. Increased inflammation was evident in the hemorrhage and unruptured aneurysm groups.

The biological mechanisms associated with the development and rupture of intracranial aneurysms are not fully understood. To clarify the role of VEGF and the related receptors in the pathophysiology of aneurysm, immunostaining for VEGF, VEGFR1 and VEGFR2 was performed on specimens from six unruptured aneurysms and on two specimens of normal arteries wall as a control. The results were correlated with NO concentration of CSF collected during surgery from 8 patients affected by unruptured aneurysms and in 11 control patients. The immunohistochemical data showed a different pattern of VEGF/VEGFR1/VEGFR2 in aneurysms when compared with control. The results of this preliminary study suggest an imbalance of VEGF, VEGFR1 and VEGFR2, and the interaction of VEGF and NO in the pathophysiology of unruptured aneurysms. Our data support the hypothesis of aneurysm formation associated with a loss of expression of VEGFR1, moderate expression of VEGFR2 and high concentration of nitrate.

The diagnostic investigation of CT-negative subarachnoid haemorrhage (SAH) is a particular challenge in clinical neurology. Cerebrospinal fluid (CSF) analysis via lumbar puncture is the method of choice. The diagnosis of SAH in CSF is based on a bloody or xanthochromic discoloration of the CSF as well as on findings in non-automated CSF cytology including the detection of erythrophages and siderophages. The automated determination of CSF ferritin concentrations or spectrophotometric detection of xanthochromia may contribute to the diagnosis but are only useful with regard to the overall clinical picture. Generally, the knowledge of the time flow of CSF changes associated with SAH is essential for a correct interpretation of CSF findings.

The aim of this study is to determine effective biochemical markers and optimal sampling timing for prediction of neurological prognosis in post-surgical aneurysmal subarachnoid hemorrhage (SAH) patients. Subjects were a sequential group of SAH patients admitted to our centre who underwent aneurysm clipping before Day 3 and who received a cerebrospinal fluid (CSF) drain. CSF samples from 32 patients were collected on Days 3, 7, and 14. Neurological outcome was assessed by neurosurgeons using the Glasgow outcome scale (GOS) at 6 months after onset. CSF levels of neuron-specific enolase (NSE), S100B, and glial fibrillary acidic protein (GFAP) were determined using enzyme-linked immunosorbent assay, and the CSF concentrations of malondialdehyde (MDA) were determined using spectrophotometric assay. In univariate analysis, S100B on Days 3 and 14, GFAP on Days 3 and 7, and MDA on Day 14 were significantly higher in the poor outcome group (GOS 1-4) than in the good outcome group (GOS 5). In multivariate analysis, only MDA on Day 14 was identified as a significant predictor of poor neurological outcome at 6 months after onset. The area under the receiver-operating characteristic (ROC) curve for MDA on Day 14 was 0.841. For a threshold of 0.3 microM, sensitivity and specificity were 0.875 and 0.750, respectively. Our findings suggest that these biochemical markers, especially MDA, show significant promise as predictors of neurological outcome in clinical practice.

Subarachnoid hemorrhage (SAH) is a devastating neurological injury associated with significant patient morbidity and death. Since the first demonstration of cerebral vasospasm nearly 60 years ago, the preponderance of research has focused on strategies to limit arterial narrowing and delayed cerebral ischemia following SAH. However, recent clinical and preclinical data indicate a functional dissociation between cerebral vasospasm and neurological outcome, signaling the need for a paradigm shift in the study of brain injury following SAH. Early brain injury may contribute to poor outcome and early death following SAH. However, elucidation of the complex cellular mechanisms underlying early brain injury remains a major challenge. The advent of modern neuroproteomics has rapidly advanced scientific discovery by allowing proteome-wide screening in an objective, nonbiased manner, providing novel mechanisms of brain physiology and injury. In the context of neurosurgery, proteomic analysis of patient-derived CSF will permit the identification of biomarkers and/or novel drug targets that may not be intuitively linked with any particular disease. In the present report, the authors discuss the utility of neuroproteomics with a focus on the roles for this technology in understanding SAH. The authors also provide data from our laboratory that identifies high-mobility group box protein-1 as a potential biomarker of neurological outcome following SAH in humans.

Objectives: To investigate the effect of early aneurysm surgery (<72 h) on outcome in patients with subarachnoid haemorrhage (SAH)., Materials and Methods: We studied two consecutive series of patients with aneurysmal SAH [postponed surgery (PS) cohort, n = 118, 1989-1992: surgery was planned on day 12 and early surgery (ES) cohort, n = 85, 1996-1998: ES was performed only in patients with Glasgow Coma Scale (GCS) >13]. We used multivariable logistic regression analysis to assess outcome at 3 months., Results: Favourable outcome (Glasgow Outcome Scale 4 or 5) was similar in both cohorts. Cerebral ischemia occurred significantly more often in the ES cohort. The occurrence of rebleeds was similar in both cohorts. External cerebrospinal fluid (CSF) drainage was performed more often in the ES cohort (51% vs 19%). Patients with cisternal sum score (CSS) of subarachnoid blood <15 on admission [adjusted odds ratio (OR) for favourable outcome: 6.4, 95% confidence interval (CI) 1.0-39.8] and patients with both CSS <15 and GCS > 12 on admission benefited from the strategy including ES (OR 10.5, 95% CI 1.1-99.4)., Conclusions: Our results support the widely adopted practice of ES in good-grade SAH patients.

Objective: To determine the sensitivity, specificity, and negative and positive predictive values of cerebrospinal fluid (CSF) xanthochromia for detection of ruptured cerebral aneurysms in patients with thunderclap headache (sudden and severe headache with maximal intensity at onset)., Patients and Methods: We identified patients who presented to our emergency department with symptoms of thunderclap headache between January 1, 1998, and January 1, 2008. Those with normal results on computed tomography (CT) of the head were selected for inclusion in the study. All consenting adult patients had undergone a lumbar puncture procedure for CSF analysis. Xanthochromia was assessed by visual inspection. All patients with a normal CT result were further evaluated by conventional 4-vessel catheter angiography. If no aneurysms were detected in the initial study, the procedure was performed again within 7 to 14 days. All patients were followed up clinically for a mean period of approximately 29 months., Results: A total of 152 patients were identified (mean +/- SD age, 44.7+/-15.8 years; 53 men). Cerebrospinal fluid xanthochromia was present in 18 patients (12%), 13 (72%) of whom were ultimately diagnosed as having aneurysmal subarachnoid hemorrhage. A single patient who tested negative for xanthochromia and had a normal CT result was subsequently found to have a ruptured middle cerebral artery aneurysm. The sensitivity, specificity, positive predictive value, and negative predictive value of CSF xanthochromia for detection of cerebral aneurysms were 93%, 95%, 72%, and 99%, respectively., Conclusion: Although not perfect, visual inspection of CSF in patients with a history suggestive of subarachnoid hemorrhage remains a highly valuable and simple test to detect a recently ruptured aneurysm.

We describe three cases of cerebral angiopathy with aneurysms caused by a meningeal varicella-zoster virus infection occurring during AIDS. The clinical picture was rather stereotyped: severe immunocompromission due to HIV infection, ongoing multifocal cerebrovascular disease with territorial infarcts, lymphocytic meningitis with normal glucose content (two cases) or hypoglycorrhachia (one case), multifocal cerebral vasculopathy with narrowings and aneurysms, healing with or without neurological sequelae after intravenous aciclovir treatment. The diagnosis of varicella-zoster virus-induced angiopathy was ascertained by the positive specific PCR in the CSF in the three cases and by the results of the cerebromeningeal biopsy in one case. Although, varicella-zoster virus is already known as a cause of cerebral angiopathy both in the immunocompetent and the immunocompromised, these three cases are the first ever described of a particular angiopathy with narrowings and ectasias complicating AIDS. The infectious treatable cause and the risk of aggravation without treatment require early active oriented investigations in case of a patient with cerebrovascular disease occurring during HIV infection, including a CSF study with varicella-zoster PCR, to allow specific antiviral treatment. In our three cases, aciclovir intravenous treatment (30mg/kg per day) enabled VZ virus clearing from the CSF and stopped the course of the vasculopathy.

Background: Adrenomedullin (AM), a vasorelaxant peptide, is secreted into the cerebrospinal fluid (CSF) from the choroid plexus and can exert natriuretic effects in the kidney. CSF AM concentration is elevated 7-10 days after the onset of aneurysmal subarachnoid hemorrhage (SAH). The aim of the present study was to determine whether CSF AM concentrations correlate with hyponatremia and delayed ischemic neurological deficits (DIND) after SAH., Methods: CSF and plasma concentrations of AM, brain natriuretic peptide, and atrial natriuretic peptide concentrations were measured in 32 patients with SAH who underwent aneurysmal clipping within 48 h of onset. CSF and blood samples were obtained from these patients during the early period (days 1-3, day 0 being regarded as the day of SAH onset) and the late period (days 8-10)., Results: In all patients, AM concentration during the early and late periods was significantly higher in the CSF than in the plasma (p = 0.0028 and p < 0.0001). In addition, CSF AM concentration was significantly higher during the late period than during the early period (p < 0.0001). Hyponatremia (plasma sodium <135 mmol/l) was present in 11 patients (34.4%) during the late period, and DIND developed in 6 patients (19%) between day 5 and day 13. Logistic regression analysis demonstrated that late-period CSF AM concentration correlated with hyponatremia and DIND (95% CI: 1.003-1.069, p = 0.0074 and 95% CI: 1.003-1.052, p = 0.0108)., Conclusions: The present study demonstrated that CSF AM during the late period following SAH correlates with hyponatremia and DIND., ((c) 2008 S. Karger AG, Basel.)

Background: The pathophysiology of ischemic cerebral lesions following aneurysmal subarachnoid hemorrhage (SAH) is poorly understood. There is growing evidence that inflammatory reactions could be involved in the pathogenesis of such delayed occurring ischemic lesions. The aim of this study was to evaluate adhesion molecules with regard to these lesions following SAH., Methods: Serum and cerebrospinal fluid (CSF) samples were taken daily from 15 patients up to day 9 after SAH and evaluated for intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1)., Results: CSF and serum samples correlated well during nearly the whole time course (p < 0.0001). A secondary increase in ICAM-1 and VCAM-1 in the serum and CSF correlated with an increase in flow velocity in the transcranial Doppler (p > 0.0001 and p < 0.007) but not to a delayed lesion in the CT scan., Conclusion: We believe that inflammatory processes are involved in the pathogenesis of cerebral vasospasm but they might only be a part of a multifactorial pathogenesis., (Copyright 2006 S. Karger AG, Basel.)

The goal of the present study was to determine concentrations of E-selectin in both cerebrospinal fluid (CSF) and serum of patients with aneurysmal subarachnoid hemorrhage (SAH) and to evaluate the correlation between the clinical parameters and E-selectin levels. Both CSF and serum samples obtained from 12 patients with aneurysmal SAH and 8 patients with hydrocephalus (control group) without any other known central nervous system disease were assayed for E-selectin by quantitative enzyme-linked immunosorbent assay and the results were compared between the two groups. Mean levels of soluble forms of E-selectin within the first 3 days and on the 5th and 7th days of SAH were 4.0 +/- 7.9, 2.8 +/- 5.2, and 3.1 +/- 4.9 ng/ml in the patient's CSF, and 33.7 +/- 9.2, 35.1 +/- 7.0, and 35.2 +/- 8.7 ng/ml in serum, respectively. In contrast, mean E-selectin levels were 0.1 +/- 0.2 ng/ml in CSF and 8.7 +/- 5.0 ng/ml in serum of control patients. The difference between groups was statistically significant regarding both CSF and serum E-selectin levels (P < 0.05). Thus, we have demonstrated a marked increase of E-selectin concentration in both CSF and serum of patients with aneurysmal SAH compared with control and suggest that blocking the interaction between E-selectin and vascular endothelium may have a beneficial effect on vasospasms.

Cerebral mycotic aneurysms are one of the most serious complications of bacterial endocarditis but the mechanism underlying cerebral aneurysms is unclear. We reported the cytokine levels in a cerebral mycotic aneurysm in a child with Down's syndrome. The patient was a 12-year-old female. She was diagnosed as having Down's syndrome and congenital heart disease consisting of an endocardial cushion defect at birth. She underwent a radical operation at 9 years but mitral valve regurgitation remained. She was hospitalized with high fever, vomiting, loss of activity and gait disturbance. Neurological examination revealed facial palsy and hemiparesis on the left side. Cytokines such as IL-6, TNF-alpha, sTNFR1 and sE-selectin were elevated in blood, and IL-6, TNF-alpha and sTNFR1 in cerebrospinal fluid. T2-weighted MRI disclosed a low intensity area in the right Sylvian sulcus. MR angiography showed an aneurysm of the right middle cerebral artery. We think that cytokines and the formation abnormality of collagen fibers are related to the production of aneurysms.

In the examination of a patient with acute headache in which subarachnoid haemorrhage is suspected, a CT scan of the brain should be performed without delay. If the CT scan does not confirm subarachnoid haemorrhage, the next step is a lumbar puncture. This should not take place before twelve hours have elapsed from the start of the headache, so as to allow for the formation of sufficient amounts of bilirubin to be detected in a possible subarachnoid haemorrhage. Bilirubin colours the spinal fluid characteristically yellow and is detectable for at least two weeks following a subarachnoid haemorrhage. Spectrophotometric detection of bilirubin in the spinal fluid is considered more sensitive than visual detection. We present a case in which the spectrophotometric detection of bilirubin in the spinal fluid was the only pathological test result in the examination of a patient with acute headache. The spectrophotometric detection revealed an intracranial aneurysm, for which the patient received subsequent lifesaving surgical treatment. Spectrophotometric examination of spinal fluid has a high sensitivity rate. The test is simple to perform, is not expensive, and is within the scope of most laboratories. We present our method for spectrophotometric investigation of spinal fluid, along with practical advice.

Few reports of temporary disruption of the blood-brain barrier (BBB) following neurointerventional procedures, presumably caused by nonionic radiographic contrast medium (CM), exist in the literature. We described such a case in a 72-year-old man presenting with acute subarachnoid hemorrhage, who underwent coil embolization of a ruptured anterior communicating artery complex aneurysm. At the time of his follow-up CT examination, a large amount of iodine was found in the cerebrospinal fluid (CSF). Because of this experience, the iodine concentration in the CSF of five other patients who also underwent an intracranial endovascular procedure was measured. It was concluded that this increased iodine might have been caused by temporary leakage or breakdown of the BBB. Even if the total amount of CM may not be excessive, the disproportionately high concentration injected into a single vascular territory may pose a unique set of variables increasing the risk of BBB disruption.

Background: This study assessed the concentration of rocuronium in the cerebrospinal fluid (CSF) of patients undergoing cerebral aneurysm clipping, and investigated whether the mode of administration (single bolus vs continuous infusion) influenced the CSF concentration., Methods: Twenty patients with subarachnoid haemorrhage were randomly allocated to receive a bolus dose (bolus group), or a bolus followed by a continuous infusion of rocuronium (infusion group) (n=10 for each group). Arterial blood and ventricular CSF were sampled 2 h after the rocuronium bolus. Samples were analysed by liquid chromatography electrospray ionization-tandem mass spectrometry., Results: Rocuronium could be detected in all the CSF samples. The mean (range) CSF concentration was 2.2 (0.9-4.6) ng x ml(-1) in the bolus group and 12.4 (2.4-34.6) ng x ml(-1) in the infusion group; P<0.01., Conclusions: This study demonstrated that rocuronium, normally not considered to cross the blood-brain barrier, is regularly found in the CSF of patients undergoing cerebral clipping; continuous infusion of the drug led to higher plasma and CSF concentrations than after a single bolus dose.

Cytokines play a key role in mutual influence of the immunological, endocrine and CNS systems. It has been proven that proinflammatory ILs may intensify the cascade of biochemical changes in ischemic brain damage. Vasospasm, which may accompany SAH and often coexists with symptoms of DINDs, is the cause of ischemic changes in the brain. It is thought that immunological mechanisms may be one of the causes of degenerative-productive changes in vessel walls, in delayed vasospasm following SAH, which lead to substantial vasospasm and in consequence too cerebral ischemia. In the randomly selected group of patients, who underwent surgical treatment after aneurysmal SAH, we determined the concentration of IL-1 beta and IL-6 in CSF in the periods between Days 0 to 3; 4 to 7; and 8 to 15 after the occurrence of SAH. The presence and dynamics of development of vasospasm were assessed on the basis of increasing DINDs as well as CT and cerebral angiography. We examined the concentrations of ILs in CSF using radioimmunological methods, applying commercially available tests for their assessment. We found that in the period between 8 and 15 days after SAH, in increasing delayed vasospasm and DINDs, here is a statistically significant increase concentration of IL-1 beta in CSF (105.4 +/- 46.9 pg x ml-1; p<0.005), and no significant changes in patients without vasospasm and neurological deficits. On the other hand, we noted a statistically significant increase concentration of IL-6 in CSF (4802 +/- 1170 ng x ml-1; p<0.05) only in the acute phase after SAH (Days 0-3) in patients in poor clinical condition, in whom delayed vasospasm and cerebral ischemia developed later. This increase of ILs level in CSF is probably related to the intensity of the SAH, and secondarily aggravates the vasospasm and ischemic changes in the brain.

Background: The pathogenesis of cerebral vasospasm is likely to be multifactorial. Exposure of the adventitia of large cerebral arteries to blood breakdown products initiates a cascade of changes in both morphology and vasomotor regulation of the exposed vessels. The role of nitric oxide (NO) in development of cerebral vasospasm process is controversial. Basal cerebral vascular tone requires the continuous release of NO, nevertheless NO is involved in free radical mediated injury of endothelial cell membrane. Concentrations of nitrate/nitrite (stabile endproducts of NO metabolism) were studied in cisternal cerebrospinal fluid (cCSF) in patients suffering from aneurysmal subarachnoid haemorrhage (SAH)., Method: 21 patients suffering from aneurysmal SAH were investigated. Treatment included aneurysm clipping, cisternal drainage of CSF and intravenous nimodipine in all patients as well as tripple H therapy when indicated. TCDS was performed on a daily basis. A mean flow velocity of more than 150 cm/sec and the development a delayed neurological deficit was defined as vasospasm. CSF samples were collected on the day of surgery and for the 7 days following. NO-M (nitrite and nitrate) were measured using a commercially available test kit., Findings: 5 of 21 patients developed clinically symptomatic vasospasm. There was a significant difference in NO levels between the groups. Patients with cerebral vasospasm showed significantly higher levels of NO-M in CSF than patients with a uncomplicated follow-up between day 2 and 8., Interpretation: Our preliminary results indicate that SAH leads to an increase in NO-M in CSF. This increase of NO-M significantly correlates with the flow velocities in TCDS measurement suggesting that NO plays an important role in the pathogenesis of cerebral vasospasm.

Background: The aim of this paper is to compare the propofol concentration in blood and cerebrospinal fluid (CSF) in patients scheduled for different neurosurgical procedures and anaesthetized using propofol as part of a total intravenous anaesthesia technique., Methods: Thirty-nine patients (ASA I-III) scheduled for elective intracranial procedures, were studied. Propofol was infused initially at 12 mg kg(-1) h(-1) and then reduced in steps to 9 and 6 mg kg(-1) h(-1). During anaesthesia, bolus doses of fentanyl and cis-atracurium were administered as necessary. After tracheal intubation the lungs were ventilated to achieve normocapnia with an oxygen-air mixture (FI(O(2))=0.33). Arterial blood and CSF samples for propofol examination were obtained simultaneously directly after intracranial drainage insertion and measured using high-performance liquid chromatography. The patients were divided into two groups depending on the type of neurosurgery. The Aneurysm group consisted of 13 patients who were surgically treated for ruptured intracranial aneurysm. The Tumour group was composed of 26 patients who were undergoing elective posterior fossa extra-axial tumour removal., Results: Blood propofol concentrations in both groups did not differ significantly (P>0.05). The propofol concentration in CSF was 86.62 (SD 37.99) ng ml(-1) in the Aneurysm group and 50.81 (26.10) ng ml(-1) in the Tumour group (P<0.005)., Conclusions: Intracranial pathology may influence CSF propofol concentration. However, the observed discrepancies may also result from quantitative differences in CSF composition and from restricted diffusion of the drug in the CSF.

Background: Cerebral vasospasm is a poor resulting outcome of a ruptured cerebral aneurysm; to clarify the mechanism of vasospasm it is important to improve this outcome. C-type natriuretic peptide (CNP) is present in the brain as a cerebral vasodilator; it is also an endothelium-derived relaxing factor produced via cGMP. We speculated that CNP might be an inhibitor of cerebral vasospasm after subarachnoid hemorrhage (SAH)., Methods: To clarify the role of CNP in cerebral vasospasm after SAH, we conducted 1 week monitoring of CNP concentrations in the plasma and cerebrospinal fluid (CSF) of 26 patients who had undergone clipping within 24 hours of the occurrence of SAH, and divided them into group A (positive for angiographic spasm) and group B (negative for angiographic spasm). We also examined CNP concentrations in the CSF of patients who were receiving spinal anesthesia for small orthopedic operations, as reference patients., Results: The CNP concentration in the CSF on day 1 was higher than in the reference patients and decreased in both test groups, but we did not observe any significant difference between the groups. CNP concentrations in the plasma did not change in either group., Conclusions: CNP concentrations in the CSF were high in the acute phase after SAH, whereas plasma CNP concentrations remained constant. However, our findings did not support our hypothesis because we did not find any relationship between vasospasm and changes in CNP concentrations in the CSF.

Objective: Many patients exhibit cognitive disturbances after aneurysmal subarachnoid hemorrhage (SAH). Structural and functional neuroimaging has failed to demonstrate any correlation with these complaints. This study was performed to investigate whether neuropeptide concentrations in cerebrospinal fluid could be related to cognitive disturbances after SAH., Methods: Lumbar cerebrospinal fluid was obtained, 3 to 6 months after surgery, from 17 patients who experienced good outcomes after aneurysmal SAH. The samples were analyzed for various neuropeptides using radioimmunoassays, and the peptide concentrations were evaluated in relation to scores on standardized neuropsychological tests., Results: The neuropsychological test results were normal for eight individuals, whereas the remaining nine patients exhibited various degrees of cognitive impairment. There was no correlation between the concentrations of arginine vasopressin or neuropeptide Y and test performance. However, significant correlations between cognitive impairment and elevated levels of beta-endorphins (P = 0.02), corticotropin-releasing factor (P = 0.004), and delta sleep-inducing peptide (P = 0.045) were noted., Conclusion: Patients with cognitive impairments after aneurysmal SAH exhibited higher cerebrospinal fluid concentrations of endorphins, corticotropin-releasing factor, and delta sleep-inducing peptide than did those with normal capacity. This is probably attributable to diffuse derangement of transmitter release in the brain, resulting from the insult or ensuing complications, although a secondary increase in corticotropin-releasing factor concentrations caused by increased stress during the testing because of reduced cognitive capacity cannot be excluded.

Endothelial cell dysfunction may contribute to cerebral vasospasm and aggravation of ischemic brain damage following subarachnoid hemorrhage (SAH). It has been suggested that oxyhemoglobin derived from subarachnoid blood clots might be a prime candidate for cerebral vasospasm. In this study, cisternal bloody cerebrospinal fluid (bCSF) was collected from SAH patients four and seven days after aneurysmal rupture, and the effects of bCSF on the cell growth and intracellular calcium ion ([Ca2+]i) dynamics were investigated in cultured human umbilical vein endothelial cells. CSF collected from patients undergoing other intracranial surgeries was used as a control. Pre-treatment with bCSF4 significantly facilitated cell proliferation and DNA synthesis in the cultured endothelial cells, and significantly enhanced histamine-induced [Ca2+]i increase, while acute treatment of the bCSF elicited no [Ca2+]i change. Pre-treatment with interleukin-1 beta showed a similar significant enhancement of the histamine-induced [Ca2+]i response, while pre-treatment with high concentrations of serum or interleukin-6 did not change the [Ca2+]i response. It is concluded that bCSF collected from SAH patients contains some substances which enhance endothelial cell proliferation and sensitivity to inflammatory mediator.

Object: Whereas the removal of subarachnoid blood is possible during early-stage aneurysm surgery, this cannot be achieved in aneurysms treated by endovascular means. The levels of potential spasmogens in the cerebrospinal fluid (CSF) in patients receiving endovascular treatment might therefore be higher, with the potential for more severe post-subarachnoid hemorrhage (SAH) vasospasm., Methods: Serum and CSF concentrations of big endothelin (ET)-1 were serially measured in patients with SAH receiving one of the following treatments: 1) early (within 72 hours of SAH) aneurysm surgical treatment (15 patients), 2) early endovascular treatment (17 patients), or 3) no intervention in the acute phase (12 patients). In patients suffering delayed infarctions higher levels of big ET-1 CSF were demonstrated than in those without infarctions (p = 0.01). In patients in whom surgery was performed in the acute phase lower big ET-1 CSF concentrations were demonstrated than in those who received embolization treatment or no treatment (p = 0.02). Subgroup analysis demonstrated that in patients receiving early endovascular treatment, higher big ET-1 CSF concentrations were revealed than in those undergoing early aneurysm surgery; this was true for patients with (microsurgerytreated, 1.84 +/- 0.83 pg/ml; and embolization-treated 2.19 +/- 0.54 pg/ml) and without (microsurgery-treated 1.76 +/- 0.61 pg/ml; and embolization-treated 2.01 +/- 0.48 pg/ml) delayed infarctions., Conclusions: Among patients with SAH who received treatment during the acute phase, those undergoing early aneurysm surgery were shown to have lower big ET-1 CSF levels than those receiving embolization and no treatment (that is, the nonsurgical treatment groups). The clinical significance of this finding remains to be established in future clinical trials, because in the present study the trend toward lower levels of big ET-1 CSF in the microsurgically treated group was not paralleled by a lower delayed stroke rate or an improvement in neurological outcome.