Percutaneous Trigeminal Nerve Stimulation Induces Cerebral Vasodilation in a Dose-Dependent Manner.

BACKGROUND: The trigeminal nerve directly innervates key vascular structures both centrally and peripherally. Centrally, it is known to innervate the brainstem and cavernous sinus, whereas peripherally the trigemino-cerebrovascular network innervates the majority of the cerebral vasculature. Upon stimulation, it permits direct modulation of cerebral blood flow (CBF), making the trigeminal nerve a promising target for the management of cerebral vasospasm. However, trigeminally mediated cerebral vasodilation has not been applied to the treatment of vasospasm. OBJECTIVE: To determine the effect of percutaneous electrical stimulation of the infraorbital branch of the trigeminal nerve (pTNS) on the cerebral vasculature. METHODS: In order to determine the stimulus-response function of pTNS on cerebral vasodilation, CBF, arterial blood pressure, cerebrovascular resistance, intracranial pressure, cerebral perfusion pressure, cerebrospinal fluid calcitonin gene-related peptide (CGRP) concentrations, and the diameter of cerebral vessels were measured in healthy and subarachnoid hemorrhage (SAH) rats. RESULTS: The present study demonstrates, for the first time, that pTNS increases brain CGRP concentrations in a dose-dependent manner, thereby producing controllable cerebral vasodilation. This vasodilatory response appears to be independent of the pressor response induced by pTNS, as it is maintained even after transection of the spinal cord at the C5-C6 level and shown to be confined to the infraorbital nerve by administration of lidocaine or destroying it. Furthermore, such pTNS-induced vasodilatory response of cerebral vessels is retained after SAH-induced vasospasm. CONCLUSION: Our study demonstrates that pTNS is a promising vasodilator and increases CBF, cerebral perfusion, and CGRP concentration both in normal and vasoconstrictive conditions.

Vitamin D-A New Perspective in Treatment of Cerebral Vasospasm.

BACKGROUND: Cerebral vasospasm (CVS) is a frequent complication after subarachnoid hemorrhage (SAH), with no sufficient therapy and a complex pathophysiology. OBJECTIVE: To explore the vitamin D system as a potential treatment for CVS. METHODS: 25-vitamin D3 levels tested between 2007 and 2015 and data of SAH patients admitted during the months with a peak vs nadir of VitD3 values were analyzed, retrospectively. We prospectively correlated VitD3 and vasospasm/outcome data in SAH patients admitted in 2017. An experimental mice SAH model and cell culture model were used to investigate the effect of 1,25-dihydroxyvitamin D3 (1,25-VitD3). Additionally, the mediators acting in the VitD mechanism were researched and detected. RESULTS: Based on the retrospective analysis demonstrating an increased frequency of vasospasm in SAH patients during the low vitamin D period in winter, we started basic research experiments. Active 1,25-VitD3 hormone attenuated CVS, neurological deficit, and inflammation after intrathecal blood injection in mice. Deletion of the vitamin D receptor in the endothelium or in myeloid cells decreased the protective 1,25-VitD3 effect. Co-culture experiments of myeloid and endothelial cells with blood confirmed the anti-inflammatory 1,25-VitD3 effect but also revealed an induction of stroma-cell-derived factor 1α (SDF1α), vascular endothelial growth factor, and endothelial nitric oxide synthase by 1,25-VitD3. In mice, SDF1α mimicked the protective effect of 1,25-VitD3 against CVS. From bench to bedside, CVS severity was inversely correlated with vitamin D plasma level, prospectively. Patients with more severe CVS exhibited attenuated expression of SDF1α and 1,25-VitD3-responsive genes on circulating myeloid cells. CONCLUSION: 1,25-VitD3 attenuates CVS after SAH by inducing SDF1α. However, VitD administration should be tested as optional treatment to prevent CVS.

PD-1+ Monocytes Mediate Cerebral Vasospasm Following Subarachnoid Hemorrhage.

BACKGROUND: Cerebral vasospasm is a major source of morbidity and mortality following aneurysm rupture and has limited treatment options. OBJECTIVE: To evaluate the role of programmed death-1 (PD-1) in cerebral vasospasm. METHODS: Endovascular internal carotid artery perforation (ICAp) was used to induce cerebral vasospasm in mice. To evaluate the therapeutic potential of targeting PD-1, programmed death ligand-1 (PD-L1) was administered 1 h after ICAp and vasospasm was measured histologically at the level of the ICA bifurcation bilaterally. PD-1 expressing immune cell populations were evaluated by flow cytometry. To correlate these findings to patients and evaluate the potential of PD-1 as a biomarker, monocytes were isolated from the peripheral blood and analyzed by flow cytometry in a cohort of patients with ruptured cerebral aneurysms. The daily frequency of PD-1+ monocytes in the peripheral blood was correlated to transcranial Doppler velocities as well as clinical and radiographic vasospasm. RESULTS: We found that PD-L1 administration prevented cerebral vasospasm by inhibiting ingress of activated Ly6c+ and CCR2+ monocytes into the brain. Human correlative studies confirmed the presence of PD-1+ monocytes in the peripheral blood of patients with ruptured aneurysms and the frequency of these cells corresponded with cerebral blood flow velocities and clinical vasospasm. CONCLUSION: Our results identify PD-1+ monocytes as mediators of cerebral vasospasm and support PD-1 agonism as a novel therapeutic strategy.

Relationship Between Vasospasm and Serum Chromogranin A Levels in an Experimental Subarachnoid Hemorrhage Model.

AIM: To analyze Chromogranin A levels on vasospasm in an experimental subarachnoid heamorrhage (SAH) model. MATERIAL AND METHODS: Sixteen Wistar Albino male rats were used in study. Two groups are formed; first was consisting of 8 rats that experimental SAH was performed on them, second group was control group that nothing was done. Animals were sacrified fourtyeight hours later subarachnoid heamorrhage was occured. Peripheral venous blood samples were taken from the experimental group before SAH formation, 15 minutes, 75 minutes after experimental SAH formation and 48 hours as peak of vasospasm. Simultaneous peripheral venous blood samples were also collected from the control group. Blood samples were biochemically evaluated after centrifugation and serum Chromogranin A levels were studied. RESULTS: Serum chromogranin A levels increased statistically significant (p < 0.05) at the 15th minute after SAH, as the samples obtained from the experimental and control groups were anticipated as a result of the statistical analysis of the data after the biochemical examinations. CONCLUSION: In all these findings, we concluded that Chromogranin A could be used as a marker for the investigation of endocrine stress in the early period of post-SAH vasospasm and it could be proved by more studies.

Low total cholesterol and high density lipoprotein are independent predictors of poor outcomes following aneurysmal subarachnoid hemorrhage: A preliminary report.

INTRODUCTION: Aneurysmal subarachnoid hemorrhage (aSAH) is devastating, with delayed cerebral ischemia (DCI) significantly contributing to the high morbidity and mortality rates. Cholesterol has been studied as a measure of nutritional status in other neurological pathologies, but reports examining cholesterol's effects on aSAH outcomes are sparse. This study aimed to elucidate the effect of low total cholesterol (TC) and high density lipoprotein (HDL) on mortality and DCI following aSAH. METHODS: We performed a retrospective cohort study at a quaternary academic medical center between June 2014 and July 2018. All patients had aSAH confirmed by digital subtraction angiography and had TC measured on admission. Primary outcomes were mortality and DCI. Secondary outcome was radiographic vasospasm. Univariate and multivariate logistic regressions were performed. RESULTS: There were 75 aSAH patients, with an average age of 58.7 ±â€¯1.7 (range: 14-89) and Hunt & Hess score of 2.8 ±â€¯0.1, included for analysis. Those with a low TC < 160 mg/dL had 3 times increased odds of DCI (OR = 3.4; 95 %CI: 1.3-9.0; p = 0.0175) and a nearly 5 times increased odds of death (OR = 4.9; 95 %CI: 1.1-18.3; p = 0.0339). Low HDL < 40 mg/dL was associated with 12 times increased odds of DCI (OR = 12.3; 95 %CI: 2.7-56.4; p = 0.0003) but no significant differences in death (p = 0.2205). In multivariate analysis, low TC was an independent risk factor for increased mortality (OR = 5.6; 95 %CI: 1.2-27.6; p = 0.0335) while low HDL was associated with increased risk for DCI (OR = 17.9; 95 %CI: 3.1-104.4; p = 0.0013). There was no effect of TC or HDL on radiographic vasospasm. CONCLUSIONS: Low TC and HDL are independent predictors of increased mortality and DCI, respectively, following aSAH. Low TC and HDL may be markers of poor overall health, in addition to having some pathophysiological effect on cerebral vasculature. These results may have practical implications for the improvement of aSAH prognostication and management.

Thick and diffuse cisternal clot independently predicts vasospasm-related morbidity and poor outcome after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with significant morbidity and mortality. The presence of thick, diffuse subarachnoid blood may portend a worse clinical course and outcome, independently of other known prognostic factors such as age, aneurysm size, and initial clinical grade. METHODS: In this post hoc analysis, patients with aSAH undergoing surgical clipping (n = 383) or endovascular coiling (n = 189) were pooled from the placebo arms of the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS)-2 and CONSCIOUS-3 randomized, double-blind, placebo-controlled phase 3 studies, respectively. Patients without and with thick, diffuse SAH (≥ 4 mm thick and involving ≥ 3 basal cisterns) on admission CT scans were compared. Clot size was centrally adjudicated. All-cause mortality and vasospasm-related morbidity at 6 weeks and Glasgow Outcome Scale-Extended (GOSE) scores at 12 weeks after aSAH were assessed. The effect of the thick and diffuse cisternal aSAH on vasospasm-related morbidity and mortality, and on poor clinical outcome at 12 weeks, was evaluated using logistic regression models. RESULTS: Overall, 294 patients (51.4%) had thick and diffuse aSAH. Compared to patients with less hemorrhage burden, these patients were older (median age 55 vs 50 years) and more often had World Federation of Neurosurgical Societies (WFNS) grade III-V SAH at admission (24.1% vs 16.5%). At 6 weeks, all-cause mortality and vasospasm-related morbidity occurred in 36.1% (95% CI 30.6%-41.8%) of patients with thick, diffuse SAH and in 14.7% (95% CI 10.8%-19.5%) of those without thick, diffuse SAH. Individual event rates were 7.5% versus 2.5% for all-cause death, 19.4% versus 6.8% for new cerebral infarct, 28.2% versus 9.4% for delayed ischemic neurological deficit, and 24.8% versus 10.8% for rescue therapy due to cerebral vasospasm, respectively. Poor clinical outcome (GOSE score ≥ 4) was observed in 32.7% (95% CI 27.3%-38.3%) and 16.2% (95% CI 12.1%-21.1%) of patients with and without thick, diffuse SAH, respectively. CONCLUSIONS: In a large, centrally adjudicated population of patients with aSAH, WFNS grade at admission and thick, diffuse SAH independently predicted vasospasm-related morbidity and poor 12-week clinical outcome. Patients with thick, diffuse cisternal SAH may be an important cohort to target in future clinical trials of treatment for vasospasm.

Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage - Serum D-dimer and C-reactive Protein as Early Markers.

BACKGROUND: Identifying patients at risk for delayed cerebral ischemia after an aneurysmal subarachnoid hemorrhage remains challenging and both delayed treatment and over-treatment are reasonable concerns. OBJECTIVE: To evaluate the role of the serum markers C-reactive protein, white blood count, and d-dimer as prognostic factors for the occurrence of delayed cerebral ischemia. METHODS: All patients admitted within 24 hours after an aneurysmal subarachnoid hemorrhage were included over a 6-year period. The World Federation of Neurosurgery and Fisher grading scales as well as the extended Glasgow Outcome Scale were documented at discharge and after a 3-to-6-month follow-up period. C-reactive protein, d-dimer, white blood count, and procalcitonin were assessed on admission, day 1, day 4, day 9, day 14, and at discharge. Radiologically confirmed delayed cerebral ischemia before discharge was the primary endpoint. Severe angiographic vasospasm and outcome were used as secondary endpoints. RESULTS: Delayed cerebral ischemia occurred in 19.6% of the 138 patients included. Delayed cerebral ischemia correlated with severe vasospasm and with a worse outcome. Serum C-reactive protein levels were higher in patients with severe vasospasm during the period of vasospasm. D-dimer levels on admission correlated with Fisher grades. Delayed cerebral ischemia occurred more frequently in patients with Fisher grade IV hemorrhage, if d-dimer levels were higher on admission. The cut-off was .445 µg/ml. CONCLUSION: Our observations support a multifactorial genesis for delayed cerebral ischemia, including vasospasm and microthrombotic and inflammatory processes. Serum d-dimer levels greater than .445 µg/ml might be a predictor for the occurrence of delayed cerebral ischemia in patients with a Fisher grade IV aneurysmal subarachnoid hemorrhage.

Is Admission Lipoprotein-Associated Phospholipase A2 a Novel Predictor of Vasospasm and Outcome in Patients With Aneurysmal Subarachnoid Hemorrhage?

BACKGROUND: The relationships between lipoprotein-associated phospholipase A2 (Lp-PLA2) level, vasospasm, and clinical outcome of patients with aneurysmal subarachnoid hemorrhage (aSAH) are still unclear. OBJECTIVE: To identify the associations between admission Lp-PLA2 and vasospasm following subarachnoid hemorrhage and the clinical outcome of aSAH. METHODS: A total of 103 aSAH patients who had Lp-PLA2 level obtained within 24 h postbleeding were included. The relationships between Lp-PLA2 level, vasospasm, and clinical outcome were analyzed. RESULTS: Vasospasm was observed in 52 patients (50.49%). Patients with vasospasm had significantly higher Lp-PLA2 level than those without (P < .001). Both modified Fisher grade (P = .014) and Lp-PLA2 level (P < .001) were significant predictors associated with vasospasm. The Z test revealed that power of Lp-PLA2 was significantly higher than that of modified Fisher grade in predicting vasospasm (Z = 2.499, P = .012). At 6-mo follow-up, 44 patients (42.72%) had unfavorable outcome and 36 patients (34.95%) died. The World Federation of Neurosurgical Societies (WFNS) grade and Lp-PLA2 level were both significant predictors associated with 6-mo unfavorable outcome and mortality (all P < .001). The predictive values of Lp-PLA2 for unfavorable outcome and mortality at 6-mo tended to be lower than those of the WFNS grade, but the differences were not statistically significant (P = .366 and 0.115, respectively). Poor-grade patients having Lp-PLA2 > 200 µg/L had significantly worse 6-mo survival rate than poor-grade patients having Lp-PLA2 ≤ 200 µg/L (P = .001). CONCLUSION: The Lp-PLA2 might be useful as a novel predictor in aSAH patients. A total of 30 poor-grade patients; those with elevated Lp-PLA2 level have higher risk of 6-mo mortality compared to those without.

Plasma Levels of IL-6, IL-8, IL-10, ICAM-1, VCAM-1, IFNγ, and TNFα are not Associated with Delayed Cerebral Ischemia, Cerebral Vasospasm, or Clinical Outcome in Patients with Subarachnoid Hemorrhage.

BACKGROUND: Delayed cerebral ischemia (DCI) is a serious and frequent complication following subarachnoid hemorrhage (SAH). The pathophysiology behind DCI remains poorly understood, but inflammation has been proposed to play a significant role. This study investigated the relationship between plasma levels of some of the most important inflammatory markers and DCI, cerebral vasospasm, and functional outcome in patients with SAH. METHODS: In 90 patients with SAH, interleukin-6, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, high sensitivity C-reactive protein (HsCRP), interleukin-8, interleukin-10, interferon gamma, and tumor necrosis factor alpha were measured in peripheral blood day 3 and day 8 after SAH. Any occurrence of DCI or infection was recorded, and computed tomography angiography was performed on day 8. Clinical outcome was assessed after 3 months. RESULTS: HsCRP on day 3 was higher in patients with angiographic vasospasm (P = 0.003), and HsCRP on day 8 was higher in patients with poor outcome (P = 0.014). No association with DCI, vasospasm, or outcome was found for any of the remaining analyzed substances. CONCLUSIONS: High plasma levels of HsCRP were significantly associated with angiographic vasospasm and clinical outcome. Plasma levels of interleukin-6, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, interleukin-8, interleukin-10, interferon gamma, and tumor necrosis factor alpha were not associated with DCI, angiographic vasospasm, or clinical outcome at 3 months.

Serum Glucose and Potassium Ratio as Risk Factors for Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: Cerebral vasospasm is associated with poor prognosis in patients with aneurysmal subarachnoid hemorrhage (SAH), and biomarkers for predicting poor prognosis have not yet been established. We attempted to clarify the relationship between serum glucose/potassium ratio and cerebral vasospasm in patients with aneurysmal SAH. METHODS: We studied 333 of 535 aneurysmal SAH patients treated between 2006 and 2016 (123 males, 210 females; mean age 59.7 years; range 24-93). We retrospectively analyzed the relationship between cerebral vasospasm grade and clinical risk factors, including serum glucose/potassium ratio. RESULTS: Postoperative angiography revealed cerebral vasospasm in 112 patients (33.6%). Significant correlations existed between the ischemic complication due to cerebral vasospasm and glucose/potassium ratio (P < .0001), glucose (P = .016), and potassium (P = .0017). Serum glucose/potassium ratio was elevated in the cerebral vasospasm grade dependent manner (Spearman's r = 0.1207, P = .0279). According to the Glasgow Outcome Scale (GOS) score at discharge, 185 patients (55.5%) had a poor outcome (GOS scores 1-3). Serum glucose/potassium ratio was significantly correlated between poor outcome (GOS scores 1-3) and age (P < .0001), serum glucose/potassium ratio (P < .0001), glucose (P < .0001), potassium (P = .0004), white blood cell count (P = .0012), and cerebral infarction due to cerebral vasospasm (P < .0001). Multivariate logistic regression analyzes showed significant correlations between cerebral infarction due to cerebral vasospasm and serum glucose/potassium ratio (P = .018), glucose (P = .027), and potassium (P = .052). CONCLUSIONS: Serum glucose/potassium ratio in cases of aneurysmal SAH was significantly associated with cerebral infarction due to cerebral vasospasm and GOS at discharge. Therefore, this factor was useful to predict prognosis in patients with cerebral vasospasm and aneurysmal SAH.

Serum Alkaline Phosphatase Level is Associated with Angiographic Vasospasm, Delayed Cerebral Ischemia-Caused Clinical Deterioration, and Functional Outcome After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Alkaline phosphatase (ALP) has been implicated to be associated with poor outcome in ischemic stroke patients, yet its role in aneurysmal subarachnoid hemorrhage (aSAH) patients is unknown. The current study aimed to investigate the on-admission and short-term variation trend of ALP levels in aSAH patients as well as its associations with vasospasm, delayed cerebral ischemia (DCI), and outcome after aSAH. METHODS: Between January 2014 and May 2018, all consecutive aSAH patients were prospectively enrolled. Blood samples from patients and 78 healthy individuals were obtained. Baseline information, clinical data, and radiologic data were collected, and serum ALP levels during hospitalization were measured. Patients were followed up for 6 months. RESULTS: One hundred and ninety-six aSAH patients were included. The serum ALP levels in aSAH patients were significantly higher compared to controls (71 vs. 61 U/L, p = 0.0002), yet did not differ significantly between patients with severe (WFNS 4-5) and mild clinical condition (72 vs. 63 U/L, p = 0.3362). However, ALP was significantly higher in patients with severe radiologic status (modified Fisher 3-4) compared to those with mild radiologic status (77 vs. 61.5 U/L, p = 0.0005). A significant correlation emerged between modified Fisher score and ALP level (r = 0.246, p = 0.001). Multivariable analysis found that higher ALP level was associated with angiographic vasospasm (OR 1.019, 95% CI 1.002-1.036, p = 0.026) and DCI-caused clinical deterioration (OR 1.019, 95% CI 1.001-1.037, p = 0.037), while higher WFNS score, modified Fisher score, and ALP level were independently associated with unfavorable outcome (serum ALP level, OR 1.083, 95% CI 1.041-1.127, p < 0.001). Trend analysis of ALP level based on 103 patients' data revealed a significant decrease in ALP level on post-admission day 7-9 (median; on-admission day vs. post-admission day 7-9, 72 vs. 60 U/L, p = 0.0012; post-admission day 3-5 vs. day 7-9, 70 vs. 60 U/L, p = 0.0052) and subsequent increase in ALP level on post-admission day 12-14 (median, 84 U/L, p < 0.0001). Higher ALP levels were observed in patients with unfavorable outcome on on-admission day, post-admission day 3-5, and 12-14 (median; unfavorable vs. favorable; on-admission day, 86 vs. 67 U/L, p = 0.0122; post-admission day 3-5, 80 vs. 64 U/L, p = 0.0044; post-admission day 7-9, 75 vs. 53.5 U/L, p < 0.0001) but not on post-admission day 12-14. CONCLUSIONS: Elevated serum ALP level is associated with vasospasm, DCI-caused clinical deterioration, and functional outcome after aSAH. Further studies are required to examine the potential role of serum ALP as an outcome predictor for aSAH patients.

Whole-Blood miRNA Sequencing Profiling for Vasospasm in Patients With Aneurysmal Subarachnoid Hemorrhage.

Background and Purpose- Arterial vasospasm is a well-known delayed complication of aneurysmal subarachnoid hemorrhage (aSAH). However, no validated biomarker exists to help clinicians discriminating patients with aSAH who will develop vasospasm (VSP+) and identifying those who then deserve aggressive preventive therapy. We hypothesized that whole-blood miRNAs could be a source of candidate biomarkers for vasospasm. Methods- Using a next-generation sequencing approach, we performed whole-blood miRNA profiling between VSP+patients with aSAH and patients who did not develop vasospasm (VSP-) in a prospective cohort of 32 patients. Profiling was performed on the admission day and 3 days before vasospasm. Results- Four hundred forty-two miRNAs were highly expressed in whole blood of patients with aSAH. Among them, hsa-miR-3177-3p demonstrated significant ( P=5.9×10-5; PBonferronicorrected=0.03) lower levels in VSP- compared with VSP+ patients. Looking for whole-blood mRNA correlates of hsa-miR-3177-3p, we observed some evidence that the decrease in hsa-miR-3177-3p levels after aSAH was associated with an increase in LDHA mRNA levels in VSP- ( P<10-3) but not in VSP+ ( P=0.66) patients. Conclusions- Whole-blood miRNA levels of hsa-miR-3177-3p could serve as a biomarker for vasospasm. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01779713.

[Disturbances of the hemostatic system in patients with aneurysmal subarachnoid hemorrhage]. / Narusheniia sistemy gemostaza u patsientov s anevrizmaticheskim subarakhnoidal'nym krovoizliianiem.

Subarachnoid hemorrhages due to rupture of cerebral aneurysms are characterized by high mortality. More than 25% of patients who have survived the first hours after aneurysmal SAH (aSAH) develop delayed cerebral ischemia that is one of the main causes of disability. The mechanisms underlying delayed ischemia have not yet been fully understood. Previously, the development of vasospasm was believed to be the only cause for development of delayed ischemia. In recent years, there has been evidence that hemostatic system disorders typical of this category of patients are the cause of cerebral artery thrombosis, which is one of the main pathophysiological mechanisms for the development of delayed cerebral ischemia. This review presents an analysis of published papers on hemostasis disturbances in patients with aSAH, their pathophysiological mechanisms, and their role in the development of cerebral ischemia.

Systemic High-Mobility Group Box-1: A Novel Predictive Biomarker for Cerebral Vasospasm in Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVES: To investigate the release of proinflammatory damage-associated molecular pattern molecule "high-mobility group box-1" in the serum of patients after aneurysmal subarachnoid hemorrhage and its association with cerebral vasospasm. DESIGN: Retrospective observational study. SETTING: University hospital. PATIENTS: Aneurysmal subarachnoid hemorrhage patients admitted within 24 hours of ictus. INTERVENTIONS: Standard subarachnoid hemorrhage treatment after clipping or coiling of aneurysm. MEASUREMENTS AND MAIN RESULTS: We enrolled 53 aneurysmal subarachnoid hemorrhage patients from which peripheral venous blood was withdrawn on days 1, 3, 5, 7, 9, 11, and 13 and once from the controls to obtain the serum. Serum high-mobility group box-1 concentration was quantified by enzyme-linked immunosorbent assay. Serum interleukin-6 and peripheral blood leukocytes were also determined over the first 2 weeks after subarachnoid hemorrhage. Patients' data were recorded prospectively. Serum high-mobility group box-1 was significantly elevated in subarachnoid hemorrhage patients from day 1 to day 13 when compared with nonsubarachnoid hemorrhage patients (p < 0.05). Patients with cerebral vasospasm showed significantly higher high-mobility group box-1 starting from day 1 to day 13 when compared with patients without cerebral vasospasm. Cumulative levels of high-mobility group box-1 showed significant correlation with peripheral blood leukocytes and interleukin-6 levels (p < 0.05). Receiver operating characteristic curve analysis showed that serum high-mobility group box-1 level at admission may be a predictive biomarker for cerebral vasospasm with a sensitivity of 59% and a specificity of 82% at a cutoff value of 5.6 ng/mL. CONCLUSIONS: Serum high-mobility group box-1 is differentially elevated after subarachnoid hemorrhage. Serum high-mobility group box-1 levels were elevated early after subarachnoid hemorrhage (day 1) and remained significantly high until day 13 in patients who developed cerebral vasospasm. Our data suggest that serum high-mobility group box-1 may be a predictive biomarker for the detection of CVS.

Influence of ABO blood type on the outcome after non-aneurysmal subarachnoid hemorrhage.

BACKGROUND: In patients with non-aneurysmal subarachnoid hemorrhage (NA-SAH), the etiology is unknown and the bleeding source remains unidentified. However, the ABO blood type system has a profound role in patient's hemostasis and thrombosis. To date, the aspect of ABO blood type in incidence, clinical course, and outcome after NA-SAH has not been investigated. METHODS: In this retrospective analysis, 81 patients with non-traumatic and non-aneurysmal subarachnoid hemorrhage treated between 2010 and 2014 at the author's institution were included. WFNS admission status, cerebral vasospasm, delayed infarction, ventriculoperitoneal shunt necessity, the Fisher grade, and the modified Rankin Scale were analyzed for their association with ABO blood type. Four hundred seventy patients with aneurysmal subarachnoid hemorrhage served as a control group. RESULTS: The AB blood type is more frequent in NA-SAH compared to aneurysmal patients and the German population (OR 2.45, p ≤ 0.05). Furthermore, NA-SAH with AB blood type showed a similar sequelae compared to aneurysmal patients in terms of shunt necessity (OR 2.00, p ≥ 0.05), cerebral vasospasm (OR 1.66, p ≥ 0.05), and delayed infarctions (OR 1.07, p ≥ 0.05). CONCLUSION: The clinical course of NA-SAH AB blood type patients shows similar severity as of aneurysmal subarachnoid hemorrhage. Therefore, patients with AB blood type should be under intensified observation.

Reversible cerebral vasoconstriction syndrome secondary to caffeine withdrawal.

We describe a 39-year-old man who developed thunderclap headaches during a hospital admission for accidental superficial burns. His magnetic resonance brain imaging was normal expect for diffuse segmental vasoconstriction. Prior to admission, he was consuming excessive amounts of caffeine which was restarted and slowly tapered and stopped over weeks. Repeat magnetic resonance angiogram showed resolution of segmental vasoconstriction. The implications of prescribed and non-prescribed drugs on cerebral vasculature have been discussed.

Comparison of plasma copeptin and multiple biomarkers for assessing prognosis of patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND: Increased plasma copeptin concentrations are related to poor prognosis after aneurysmal subarachnoid hemorrhage (aSAH). The aim of this study was to assess prognostic significance of plasma copeptin detection compared with glial fibrillary astrocyte protein, myelin basic protein, S100B, phosphorylated axonal neurofilament subunit H, neuron-specific enolase, tau and ubiquitin carboxyl-terminal hydrolase L1 in aSAH. METHODS: We detected plasma concentrations of the aforementioned biomarkers in 105 healthy controls using ELISA. Their predictive ability for symptomatic cerebral vasospasm and 6-month poor outcome (Glasgow Outcome Scale score of 1-3) were compared. RESULTS: Plasma concentrations of the preceding biomarkers were highly correlated with World Federation of Neurological Surgeons subarachnoid hemorrhage scale (WFNS) scores as well as were significantly higher in patients with symptomatic cerebral vasospasm than in those without symptomatic cerebral vasospasm and in patients with poor outcome than in those with good outcome. In terms of area under receiver operating characteristic curve, their predictive value for symptomatic cerebral vasospasm and 6-month poor outcome was in the range of WFNS scores. Plasma copeptin concentration, but not plasma concentrations of other biomarkers, statistically significantly improved the predictive performance of WFNS scores. CONCLUSIONS: Copeptin in plasma might have the potential to be a useful prognostic biomarker for aSAH.

Expression and significance of vWF, GMP-140 and ADAMTS13 in patients with aneurysmal subarachnoid hemorrhage.

OBJECTIVE: The aim of this study was to investigate the role of the von Willebrand factor (vWF) in patients with aneurysmal subarachnoid hemorrhage (aSAH), platelet membrane glycoprotein-140 (GMP-140). The aim is also to discover the expression and clinical significance of von Willebrand factor (vWF) cleaving protease (ADAMTS13). PATIENTS AND METHODS: 83 patients with aSAH were selected from January 2014 to December 2016. The patients were divided into cerebral vasospasm group (CVS group) (n = 37) and no convulsion group (non-CVS group) (n = 46); delayed cerebral ischemia group (DCI group) (n = 31) and non-delayed cerebral ischemia group (non-DCI group) (n = 52). Also, the different aneurysm diameter group included 43 patients in < 5 mm group, 29 patients in 5-10 mm group, 11 patients in > 10 mm group. The number of patients in the good prognosis group and the poor prognosis group were 49 and 34, respectively. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of vWF, GMP-140, and ADAMTS13 in plasma of aSAH patients, and the correlation between the indexes was analyzed. RESULTS: The repeated measures analysis of variance showed that there was no significant difference in plasma vWF, GMP-140, and ADAMTS13 levels in each group of the aSAH patients (p < 0.05). The vWF level of the CVS group was higher than that of the non-CVS group on day 4 and day 10. The GMP-140 level of the CVS group was higher than that of the non-CVS group on day 1, day 4 and day 10. And the ADAMTS13 level was lower than that of the non-CVS group on day 1 and day 10. The difference was statistically significant (p < 0.05). The plasma vWF level of DCI group was higher than that of the non-DCI group on day 1 and day 4. The plasma GMP-140 level at day 4 was higher than that of the non-DCI group. The plasma ADAMTS13 level at day 1 was lower than that in the non-DCI group. The difference was significant (p < 0.05). The plasma vWF level in > 10 mm group was higher than that in < 5 mm group and 5-10 mm group at day 1 and day 4. The plasma vWF level in 5-10 mm group was higher than that in < 5 mm group at day 4. The plasma GMP-140 levels in > 10 mm group were higher than that in < 5 mm group and 5-10 mm group at day 1 and d ay 4. The plasma GMP-140 level in 5-10 mm group was higher than that in < 5 mm group at day 1. The plasma ADAMTS13 level in > 10 mm group was lower than that in < 5 mm group and 5-10 mm group on day 1. Moreover, the plasma ADAMTS13 level in 5-10 mm group was lower than that in < 5 mm group: p < 0.05. The plasma vWF level in the good prognosis group was lower than that in the poor prognosis group on day 4 and day 10. On day 1, day 4, and day 10, the level of GMP-140 was lower than that of the poor prognosis group. The ADAMTS13 level on day 1 and day 4 was higher than that in the poor prognosis group. The difference was statistically significant (p < 0.05). Pearson product moment correlation analysis showed that the plasma vWF level was positively correlated with GMP-140 at day 1 (r = 0.334, p < 0.05), negatively correlated with ADAMTS13 (r = -0.426, p < 0.05), and GMP-140 was negatively correlated with ADAMTS13 (r = -0.398, p < 0.05). At day 4, plasma vWF was positively correlated with GMP-140 (r = 0.278, p < 0.05), negatively correlated with ADAMTS13 (r = -0.311, p < 0.05), and GMP-140 was negatively correlated with ADAMTS13 (r = -0.235, p < 0.05). At day 10, there was no significant correlation between vWF, GMP-140, and ADAMTS13 (p > 0.05). CONCLUSIONS: VWF, GMP-140, and ADAMTS13 were correlated with the diameters and prognoses of CVS, DCI, aneurysms. Combined detection can help to evaluate the condition of patients with aSAH, so as to provide a guide for clinical treatment and prognosis.

Decreased serum sodium levels predict symptomatic vasospasm in patients with subarachnoid hemorrhage.

BACKGROUND: Symptomatic vasospasm is a major cause of morbidity and mortality in subarachnoid hemorrhage patients. Hyponatremia and dehydration due to natriuresis after subarachnoid hemorrhage are related to symptomatic vasospasm. Therefore, most institutions are currently targeting euvolemia and eunatremia in subarachnoid hemorrhage patients to avoid complications. We retrospectively investigated the predictors of symptomatic vasospasm with respect to water and sodium homeostasis, while maintaining euvolemia and eunatremia after subarachnoid hemorrhage. METHODS: We monitored changes in serum sodium levels, serum osmolarity, daily sodium intake, daily urine volume, and daily water balance for 14days after subarachnoid hemorrhage. Outcomes were assessed using the modified Rankin scale at 1month after subarachnoid hemorrhage. RESULTS: Among 97 patients, 27 (27.8%) had symptomatic vasospasm. Patients with symptomatic vasospasm were older than those without symptomatic vasospasm; the occurrence of symptomatic vasospasm affected outcomes. Serum sodium levels were sequentially significantly decreased, but within the normal range from 1day before the occurrence of symptomatic vasospasm. Serum osmolarity of the spasm group was lower than that of the non-spasm group. CONCLUSIONS: Symptomatic vasospasm occurs more often in older patients and affects outcomes. A decrease in serum sodium levels occurs a day before symptomatic vasospasm. This observation may help predict symptomatic vasospasm.

High Prolactin Level as a Predictor of Vasospasm in Aneurysmal Subarachnoidal Hemorrhage.

BACKGROUND Aneurysmal subarachnoid hemorrhage (aSAH) is a destructive syndrome with a mortality rate of 50%. Recent studies have also suggested a high pervasiveness of hypothalamic-pituitary insufficiency in up to 45% of patients after aSAH. Prolactin has been associated with the pathogenesis of hypertensive irregularities that are linked to pregnancy. MATERIAL AND METHODS We identified a group of 141 patients with spontaneous SAH due to a ruptured cerebral aneurysm; these patients were operated on at our institution's Neurosurgery and Interventional Radiology Department between 2011 and June 2015. All of the data were obtained retrospectively from medical records. RESULTS The hormonal abnormalities observed in the initial 24 h after ictus in subjects with subarachnoid SAH were caused by stressful stimulation aggravated by intracranial bleeding. CONCLUSIONS The elevated prolactin levels that occur in patients with aSAH can be used in conjunction with other auxiliary factors that we believe may be beneficial to vasospasm.