Therapeutic potential of stem cells in subarachnoid hemorrhage

Aneurysm rupture can result in subarachnoid hemorrhage,a condition with potentially severe consequences,such as disability and death.In the acute stage,early brain injury manifests as intracranial pressure elevation,global cerebral ischemia,acute hydrocephalus,and direct blood–brain contact due to aneurysm rupture.This may subsequently cause delayed cerebral infarction,often with cerebral vasospasm,significantly affecting patient outcomes.Chronic complications such as brain volume loss and chronic hydrocephalus can further impact outcomes.Investigating the mechanisms of subarachnoid hemorrhage-induced brain injury is paramount for identifying effective treatments.Stem cell therapy,with its multipotent differentiation capacity and anti-inflammatory effects,has emerged as a promising approach for treating previously deemed incurable conditions.This review focuses on the potential application of stem cells in subarachnoid hemorrhage pathology and explores their role in neurogenesis and as a therapeutic intervention in preclinical and clinical subarachnoid hemorrhage studies.

Cerebral venous sinus thrombosis presenting with subarachnoid hemorrhage and intracerebral hemorrhage:a case report

Objective:To explore the clinical and pathological characteristics of cerebral venous sinus thrombosis(CVST)with subarachnoid hemorrhage(SAH)and intracerebral hemorrhage(ICH),and to investigate the diagnosis,radiographic changes,and prognosis over the course of treatment.Methods:The clinical data and radiographic findings of a young male CVST patient,who presented with initial symptoms of SAH and ICH,were collected and analyzed.The relevant literature was also reviewed.Results:The patient had no specific clinical symptoms except for headache.The brain computed tomography(CT)scan revealed SAH,a high-density shadow in the right posterior fossa and cerebellar hemisphere,and ICH in the left frontal lobe.Magnetic resonance venography(MRV)further revealed bilateral thrombosis in the transverse and sigmoid sinuses.Conclusion:CVST with SAH and ICH is rare and difficult to diagnose.Careful radiological study and clinical analysis are important for the correct and early diagnosis of this condition.Anticoagulation therapy is considered the primary treatment for CVST.

Inhibitory effects of lidocaine on cerebral vasospasm in a rabbit model of subarachnoid hemorrhage

Following subarachnoid hemorrhage, vasoconstrictor substances, cellular apoptosis, blood coagulation, and vascular cell proliferation affect the onset of cerebral vasospasm. Previous studies from our laboratory have revealed that injection of lidocaine （2 mg） into the cisterna magna reduces cerebral vasospasm and nerve functional impairment in an animal model of subarachnoid hemorrhage. The present study determined the optimal lidocaine dose for vasospasm and brain injury by injecting different doses of lidocaine into the cisterna magna in a rabbit model of subarachnoid hemorrhage. Results showed that endothelin, tumor necrosis factor-a, and interleukin-6 levels significantly increased in plasma, and calcitonin gene-related peptide levels significantly decreased in plasma （P 〈 0.05）. The number of neurons was decreased, the number of cells expressing c-Fos increased in the hippocampus, and cross-sections and diameters of basilar arteries were reduced （P 〈 0.05）. These changes significantly improved following injection of lidocaine （1,2, 4, and 6 mg） into the cisterna magna. A dose of 6 mg lidocaine into the cisterna magna resulted in optimal effects on cerebral vasospasm and brain injury following subarachnoid hemorrhage.

Cerebral venous thrombosis presenting with headache only and misdiagnosed as subarachnoid hemorrhage

Patients with headache constitute up to 4.5% of emergency department （ED） visits.~11 Cerebral venous thrombosis （CVT） is an important cause of the headache that is more common than once suspected. The diagnosis of CVT is often missed or delayed because of non- specific clinical manifestations, and brain computerized tomography （CT） may easily be misinterpreted.

Whole-brain CT Perfusion at Admission and During Delayed Time-window Detects the Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage

Objective To evaluate the utility of computed tomography perfusion(CTP)both at admission and during delayed cerebral ischemia time-window(DCITW)in the detection of delayed cerebral ischemia(DCI)and the change in CTP parameters from admission to DCITW following aneurysmal subarachnoid hemorrhage.Methods Eighty patients underwent CTP at admission and during DCITW.The mean and extreme values of all CTP parameters at admission and during DCITW were compared between the DCI group and non-DCI group,and comparisons were also made between admission and DCITW within each group.The qualitative color-coded perfusion maps were recorded.Finally,the relationship between CTP parameters and DCI was assessed by receiver operating characteristic(ROC)analyses.Results With the exception of cerebral blood volume(P=0.295,admission;P=0.682,DCITW),there were significant differences in the mean quantitative CTP parameters between DCI and non-DCI patients both at admission and during DCITW.In the DCI group,the extreme parameters were significantly different between admission and DCITW.The DCI group also showed a deteriorative trend in the qualitative color-coded perfusion maps.For the detection of DCI,mean transit time to the center of the impulse response function(Tmax)at admission and mean time to start(TTS)during DCITW had the largest area under curve(AUC),0.698 and 0.789,respectively.Conclusion Whole-brain CTP can predict the occurrence of DCI at admission and diagnose DCI during DCITW.The extreme quantitative parameters and qualitative color-coded perfusion maps can better reflect the perfusion changes of patients with DCI from admission to DCITW.

Establishment of a new symptomatic cerebral vasospasm model following subarachnoid hemorrhage in rabbit

Objective To establish an experimental model of symptomatic cerebral vasospasm(CVS) after subarachnoid hemorrhage(SAH)in rabbits. Method 2 weeks after the ligation of bilateral common carotid arteries, We induced CVS by injecting arterial blood twice via a cranial hole 2 mm×2 mm and then neurological symptoms ,cerebral blood flow(rCBF) and food intake were evaluated. Results Food intake and rCBF decreased and neurological disorders were observed. Conclusion An experimental rabbit model of symptomatic CVS can be established by injecting blood via a cranial hole after bilateral common carotid arteries ligation.

Rhino-orbito-cerebral mucormycosis complicated with an ophthalmic artery occlusion followed by subarachnoid hemorrhage

A 70-year-old female with poorly controlled diabetes developed sudden visual loss, ptosis and complete ophthalmoplegia of the right eye. Funduscopic examination showed the pale retina and the cherry red spot in the right eye. Fluorescein angiography and indocyanine green angiography demonstrated the absence of retinal arterial filling and choroidal perfusion in the right eye even 20 minutes after injecting the dye. The patient was diagnosed with right ophthalmic artery occlusion. Computed tomography (CT) showed diffuse mucosal thickening in the right ethmoidal sinus. Based on the clinical findings and endoscopic biopsy result, mucormycosis was confirmed. Amphotericin B (40 mg/day) and ceftriaxone (2 g/day) were intravenously administered. Despite the improvement of the right ethmoidal sinusitis and the right proptosis, the patient deteriorated into a comatose state after 19 days of systemic amphotericin B therapy. Although the previous CT showed no cerebral aneurysm, a repeated CT showed newly developed posterior communicating artery aneurysm and the subarachnoid hemorrhage. Despite the amphotericin B treatment and the improvement of the sinusitis, mucormycosis could cause sudden cerebral aneurysm rupture and subarachnoid hemorrhage resulting in coma.

Studies of the antagonistic effect of BQ-123 on cerebral vasospasm induced by intracisternal injection of endothelin-1 and subarachnoid hemorrhage

To clarify whether the endothelin A (ETA)-receptor antagonist BQ-123 can prevent the development of cerebral vasospasm (CVS) induced by endothelin (ET-1) and subarachnoid hemorrhage (SAH), which has been controversia11y reported by various authors. We have performed investigations in anesthetized Sprague-Dawley rats- Intracisternal injection (i. c. ) of ET-l (10-11, 10-10, 10-9 mol/kg) could induce acute dose-dependent CVS, furthermore, the highest dose of ET-l (lO-’ mo1/kg) had a biphasic response in CVS of a 24-hour duration. However, the CVS by ET-1 (10-9 mol/kg) could be prevented effectively by previous i. c. of BQ-123 in a dose-dependent manner (10-9, 10-8, 10-7 mol/kg), of which the i. c- of BQ-123 (10-7mol/kg) could abolish the CVS completely. i. c. of BQ-123 (10-7 mol/kg) before SAH induced by a single i. c, of 150 pl autologous fresh blood directly to the Willis circle cou1d prevent the following CVS largely, which was a biphasic response and long-lasting (duration of 72 h). We conclude that subarachnoid application of ETA-receptor antagonist can effecti vely prevent CVS induced by ET-1 and SAH, and ET-1 may be the major mediator responsible for the CVS following SAH.

Clinical characteristics of asymptomatic Terson syndrome in the patients with aneurysmal subarachnoid hemorrhage

●AIM:To investigate clinical characteristics of asymptomatic Terson syndrome and its clinical impact in patients with aneurysmal subarachnoid hemorrhage(SAH).●METHODS:This retrospective,interventional study included 31 patients with aneurysmal SAH,and the medical records were reviewed.In addition to baseline characteristics of the study population such as age,sex,and underlying medical history,multi-modal imaging analysis,including fluorescein angiography(FA),spectral domain optical coherence tomography(SD-OCT),were also reviewed.Glasgow Coma Scale(GCS),Hunt-Hess(HH)grade,and Fisher scale at the time of admission,and functional outcome by using modified Rankin Scale(mRS)at 6 mo were compared.●RESULTS:Of the 31 patients,10 patients(32.3%)were diagnosed with Terson syndrome.All the patients with Terson syndrome did not report visual symptoms at the time of ophthalmologic screening.FA showed microvascular changes of retinal capillaries and varying degrees of disc leakage.SD-OCT allowed intuitive anatomical localization of multi-layered retinal hemorrhages and assessment of ellipsoid zone integrity.The patients with Terson syndrome showed significantly worse GCS(P=0.047)and HH grade(P=0.025)than those without,except Ficher scale(P=0.385).There was no significant difference in the mRS(P=0.250)at 6 mo.Among baseline factors,the HH grade was the only significant factor associated with Terson syndrome(B=1.079,P=0.016).●CONCLUSION:In our study,32.3%of the patients have Terson syndrome without visual symptoms.The baseline HH grade is significantly correlated with Terson syndrome,and there is no significant difference in the functional outcome between the patients with and without Terson syndrome.Terson syndrome may develop without any visual symptoms as shown in our study,and ophthalmologic screening may be recommended to prevent further visual deterioration especially in the patients with poor HH grade at the time of aneurysmal SAH.

In vivo observation of cerebral microcirculation after experimental subarachnoid hemorrhage in mice

Acute brain injury caused by subarachnoid hemorrhage is the major cause of poor prognosis. The pathology of subarachnoid hemorrhage likely involves major morphological changes in the microcirculation. However, previous studies primarily used fixed tissue or delayed injury models. Therefore, in the present study, we used in vivo imaging to observe the dynamic changes in cerebral microcirculation after subarachnoid hemorrhage. Subarachnoid hemorrhage was induced by perforation of the bifurcation of the middle cerebral and anterior cerebral arteries in male C57/BL6 mice. The diameter of pial arterioles and venules was measured by in vivo fluorescence microscopy at different time points within 180 minutes after subarachnoid hemorrhage. Cerebral blood flow was examined and leukocyte adhesion/albumin extravasation was determined at different time points before and after subarachnoid hemorrhage. Cerebral pial microcirculation was abnormal and cerebral blood flow was reduced after subarachnoid hemorrhage. Acute vasoconstriction occurred predominantly in the arterioles instead of the venules. A progressive increase in the number of adherent leukocytes in venules and substantial albumin extravasation were observed between 10 and 180 minutes after subarachnoid hemorrhage. These results show that major changes in microcirculation occur in the early stage of subarachnoid hemorrhage. Our findings may promote the development of novel therapeutic strategies for the early treatment of subarachnoid hemorrhage.

Toll-like receptor 4 as a possible therapeutic target for delayed brain injuries after aneurysmal subarachnoid hemorrhage

Neuroinflammation is a well-recognized consequence of subarachnoid hemorrhage（SAH）, and Toll-like receptor（TLR） 4 may be an important therapeutic target for post-SAH neuroinflammation. Of the TLR family members, TLR4 is expressed in various cell types in the central nervous system, and is unique in that it can signal through both the myeloid differentiation primary-response protein 88-dependent and the toll receptor associated activator of interferon-dependent cascades to coordinate the maximal inflammatory response. TLR4 can be activated by many endogenous ligands having damage-associated molecular patterns including heme and fibrinogen at the rupture of an intracranial aneurysm, and the resultant inflammatory reaction and thereby tissue damages may furthermore activate TLR4. It is widely accepted that the excreted products of TLR4 signaling alter neuronal functions. Previous studies have focused on the pathway through nuclear factor（NF）-κΒ signaling among TLR4 signaling pathways as to the development of early brain injury（EBI） such as neuronal apoptosis and blood-brain barrier disruption, and cerebral vasospasm. However, many findings suggest that both pathways via NF-κΒ and mitogen-activated protein kinases may be involved in EBI and cerebral vasospasm development. To overcome EBI and cerebral vasospasm is important to improve outcomes after SAH, because both EBI and vasopasm are responsible for delayed brain injuries or delayed cerebral ischemia, the most important preventable cause of poor outcomes after SAH. Increasing evidence has shown that TLR4 signaling plays an important role in SAH-induced brain injuries. Better understanding of the roles of TLR4 signaling in SAH will facilitate development of new treatments.

Encephalic hemodynamic phases in subarachnoid hemorrhage:how to improve the protective effect in patient prognoses

Subarachnoid hemorrhage is frequently associated with poor prognoses. Three different hemo- dynamic phases were identified during subarachnoid hemorrhage： oligemia, hyperemia, and vasospasm. Each phase is associated with brain metabolic changes. In this review, we correlated the hemodynamic phases with brain metabolism and potential treatment options in the hopes of improving patient prognoses.

Hydrocephalus after subarachnoid hemorrhage:A metaanalytic comparison of aneurysm treatments

AIM： To compare two treatments for ruptured cerebral aneurysm with reference to the relative risk of develop-ing hydrocephalus.METHODS： We reviewed the English language litera-ture on the risk of developing hydrocephalus after an-eurysm treatment. Data were divided by type of study （randomized controlled trial, cohort trial, nonrandomized comparison, prospectively- and retrospectively-collected observational study）. They were also divided by type of aneurysm treatment （microvascular - clipping, or endo-vascular - coiling）. Additional predictive variables collected for each publication were average age, gender distribu-tion, measures of hemorrhage volume and subarachnoid hemorrhage severity, aneurysm locations, time to treat-ment, duration of follow-up and date of publication. Weemployed meta-analysis to calculate pooled risk ratios of developing hydrocephalus in cases receiving aneurysm clipping vs those receiving coiling. Meta-regression was used to correct pooled results for covariates.RESULTS： Because indications for the two treatments are different, there is little clinical equipoise for treat-ing most cases. The single randomized, controlled trial dealt with a small subset of ruptured aneurysms. Nei-ther this nor pooled values from other studies which compared the two treatments had the power to dem-onstrate signifcant differences between the two treat-ments. Nor was there an apparent difference when observational data were meta-analytically pooled. How-ever, when meta-regression was used to correct for predictive variables known to differ between the two treatment groups, a highly-significant difference ap-peared. Coiling is used more commonly in older, sicker patients with aneurysms in certain locations. These cases are more likely to develop hydrocephalus. When corrected for these covariates, the risk of hydrocepha-lus was found to be significantly lower in coiled vsclipped cases （P = 0.014）.CONCLUSION： Pooled observational data were nec-essary to demonstrate that coiling ruptured cerebral aneurysms is associated with a lower risk of developing hydrocephalus than is clipping.

Diffuse coronary artery vasospasm in a patient with subarachnoid hemorrhage: A case report

BACKGROUND Coronary artery vasospasm(CAV)is a reversible,transient form of vasoconstriction with clinical manifestations ranging from stable angina to acute coronary syndromes(ACS).Vasospasm of epicardial coronary arteries or associated micro-vasculature can lead to total or subtotal occlusion and has been demonstrated in nearly 50%of patients undergoing angiography for suspected ACS.The mechanism for CAV has been described in literature,but in a subgroup of patients presenting with intracranial hemorrhage,it appears to be multifactorial.These patients tend to have electrocardiographic changes,elevation of cardiac biomarkers of injury and neurogenic stress cardiomyopathy.CASE SUMMARY A 44-year-old woman presented with severe headaches and tonic-clonic seizures.She was found to have diffuse subarachnoid hemorrhage(SAH)requiring ventricular drain placement,coil embolization and induced hypertension.She subsequently developed chest pain with ST elevations in anterior precordial leads,elevated cardiac enzymes and apical ballooning with left ventricular ejection fraction of 35%on transthoracic echocardiogram.Coronary angiogram revealed severe diffuse triple vessel stenoses secondary to CAV seen distally.Subsequent cardiac MRI notable for apical non-viability and scar formation.CONCLUSION This case highlights a unique etiology of acute myocardial infarction in a patient with SAH leading to ST elevations,diffuse triple vessel CAV and apical scar.

A prospective cohort study on serum A20 as a prognostic biomarker of aneurysmal subarachnoid hemorrhage

BACKGROUND:A20 may be a neuroprotective factor.Herein,we aimed to investigate whether serum A20 levels were associated with disease severity,delayed cerebral ischemia(DCI),and outcome after aneurysmal subarachnoid hemorrhage(aSAH).METHODS:In this prospective cohort study containing 112 aSAH patients and 112 controls,serum A20 levels were quantified.At 90 d poststroke,Modified Rankin Scale(MRS) scores≥3 were defined as a poor outcome.All correlations and associations were assessed using multivariate analysis.RESULTS:Compared with controls,there was a significant elevation of serum A20 levels in patients(median 123.7 pg/mL vs.25.8 pg/mL;P<0.001).Serum A20 levels were independently correlated with Hunt-Hess scores(β 9.854;95% confidence interval [95% CI] 2.481-17.227,P=0.009) and modified Fisher scores(β 10.349,95% CI 1.273-19.424,P=0.026).Independent associations were found between serum A20 levels and poor outcome(odds ratio [OR] 1.015,95%CI 1.000-1.031,P=0.047) and DCI(OR 1.018,95% CI 1.001-1.035,P=0.042).Areas under the curve for predicting poor outcome and DCI were 0.771(95% CI 0.682-0.845) and 0.777(95% CI 0.688-0.850),respectively.Serum A20 levels ≥128.15 pg/mL predicted poor outcome,with a sensitivity of 73.9% and specificity of 74.2%,and A20 levels ≥160.55 pg/mL distinguished the risk of DCI with65.5% sensitivity and 89.2% specificity.Its ability to predict poor outcome and DCI was similar to those of Hunt-Hess scores and modified Fisher scores(both P>0.05).CONCLUSION:Enhanced serum A20 levels are significantly associated with stroke severity and poor clinical outcome after aSAH,implying that serum A20 may be a potential prognostic biomarker for aSAH.

Role of endothelin in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage

A model of cerebral vasospasm (CVS) associated with subarachnoid hemorrhage (SAH) was prepared on male Sprague-Dawley rats by a single intracisternal injection (i. c.) of 150 μl autologous fresh blood directly to Willis circle.The process of CVS was monit

Research on the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage

目的 :进一步研究脑血管痉挛的发生机理 ,为临床治疗服务。方法 :采用 1 4只成年家犬 ,实验组 9只 ,对照组 5只 ,通过 2次枕大池注血法建立蛛网膜下腔出血 (SAH)模型。观察痉挛血管的自由基变化、血管活性、血管造影像、超微结构变化。另外 2 0只犬用来观察血管扩张剂的作用。结果 :实验组较对照组自由基含量高 ,血管活性降低 ,血管狭窄 ,管壁损害重。结论 :尼莫地平对急性痉挛有效 ,对慢性痉挛无效 ;慢性血管痉挛是以管壁结构性狭窄为特点。

Mitigation effect of atorvastatin on cerebral vasospasm after subarachnoid hemorrhage in rats and its effect on expression of Mitofusin-2 and BDNF

Objective:To investigate the mitigation effect of atorvastatin on cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) in rats and its effect on mitochondrial fusion protein 2 (Mitofusin-2) and brain-derived neurotrophic factor (BDNF), which provides an experimental basis and a new method for the prevention and treatment of CVS after SAH.Methods:30 male SD rats were randomly divided into the sham operation group, the model group and the treatment group, with 10 rats in each group. In the model group and the treatment group, the subarachnoid hemorrhage model was made by the double injection of blood in the occipital cistern, and the sham operation group was injected with physiological saline in the same manner. The treatment group was given atorvastatin 20 mg/kg, which was dissolved in 2 mL of distilled water. The sham operation group and the model group were given 2 mL of distilled water. The body weight, mortality, neurological deficit, basilar artery inner diameter, wall thickness and smooth muscle cell apoptosis were observed in the rats 5 d after intervention. The expression levels of Mitofusin-2 and BDNF in each group were observed.Results:The body weight of the three groups was from low to high in the sham operation group, the treatment group and the model group, and the difference was statistically significant. One rat died in the sham operation group and the treatment group, respectively, 2 rats died in the model group and there was no significant difference in mortality between the three groups. The scores of the three groups of neurological function were from low to high among the model group, treatment group and sham operation group, and the difference was statistically significant. The diameter of the three groups of blood vessels was from small to large among the model group, treatment group and sham operation group, and the difference was statistically significant. The apoptotic rate of the three groups of vascular endothelial cells was from small to large among the model group, treatment group and sham operation group, and the difference was statistically significant. The expression levels of Mitofusin-2 were from low to high among the sham operation group, model group and treatment group, respectively.Conclusion:Atorvastatin can alleviate the occurrence of CVS after SAH and alleviate brain tissue damage, and its mechanism may be related to up-regulation of Mitofusin-2 expression.

Use of Color Doppler Ultrasound for the Diagnosis of Subarachnoid Hemorrhage in Asymptomatic Full-Term Neonate:A Case Report

Cerebral hemorrhages are fairly common in full-term neonates with no history of traumatic birth, mostly limited, and with benign evolution. We report a case of a full-term neonate from vaginal birth with caput succedaneum in the right parietal area. The neonate underwent cranial ultrasonography and color Doppler which showed extra-axial blood effusion. Color Doppler showed vessels crossing the collection area, which allowed the diagnosis of subarachnoid hematoma.

Correlation of calcitonin gene-related peptide and endothelin receptor A with subarachnoid hemorrhage

Numerous studies have demonstrated that endothelin-1 combines with endothelin receptor A, resulting in intense vasoconstriction. Although calcitonin gene-related peptide （CGRP） suppresses endothelin-1, CGRP and endothelin receptor A exhibit direct biological effects on brain tissue. The present study analyzed CGRP and endothelin receptor A expression following subarachnoid hemorrhage in rabbits using immunohistochemistry. CGRP expression was significant at 5 days after model establishment, and endothelin receptor A expression was significant at 3 days after model induction. The perimeter of the basilar artery was measured to determine the amount of cerebral vasospasm. Analytical results revealed a significantly shortened basilar artery perimeter following subarachnoid hemorrhage. Changes in the basilar artery perimeter were negatively associated with endothelin receptor A expression, but positively correlated with CGRP expression in vessels. These results suggest that following subarachnoid hemorrhage, CGRP and endothelin receptor A expressions dynamically changed in brain vessels and tissues, although these changes were not synchronous. Changes in endothelin receptor A expression exhibited a significant effect on the occurrence and development of delayed cerebral vasospasm and delayed neuronal death, while CGRP relaxed vessels and protected nerves.