Soluble Toll-Like Receptors 2 and 4 in Cerebrospinal Fluid of Patients with Acute Hydrocephalus following Aneurysmal Subarachnoid Haemorrhage

BackgroundToll-like receptor (TLR) signalling begins early in subarachnoid haemorrhage (SAH), and plays a key role in inflammation following cerebral aneurysm rupture. Available studies suggest significance of endogenous first-line blockers of a TLR pathway—soluble TLR2 and 4.MethodsEighteen patients with SAH and acute hydrocephalus underwent endovascular coiling and ventriculostomy; sTLR2 and 4 levels were assayed in cerebrospinal fluid (CSF) collected on post-SAH days 0–3, 5, and 10–12. Release kinetics were defined. CSF levels of sTLR2 and 4 were compared with a control group and correlated with the clinical status on admission, the findings on imaging, the degree of systemic inflammation and the outcome following treatment.ResultsNone of study group showed detectable levels of sTLR2 and 4 on post-SAH day 0–3. 13 patients showed increased levels in subsequent samples. In five SAH patients sTLR2 and 4 levels remained undetectable; no distinctive features of this group were found. On post-SAH day 5 the strongest correlation was found between sTLR2 level and haemoglobin level on admission (cc = -0.498, P = 0.037). On post-SAH day 10–12 the strongest correlation was revealed between sTLR2 and treatment outcome (cc = -0.501, P = 0.076). Remaining correlations with treatment outcome, status at admission, imaging findings and inflammatory markers on post-SAH day 5 and 10–12 were negligible or low (-0.5 ≤ cc ≤ 0.5).ConclusionsIn the majority of cases, rupture of a cerebral aneurysm leads to delayed release of soluble TLR forms into CSF. sTLR2 and 4 seem to have minor role in human post-SAH inflammation due to delayed release kinetics and low levels of these protein.     

Differential Regulation of Matrix-Metalloproteinases and Their Tissue Inhibitors in Patients with Aneurysmal Subarachnoid Hemorrhage

Background

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in vascular remodeling, (neuro)inflammation, blood-brain barrier breakdown and neuronal apoptosis. Proinflammatory mechanisms are suggested to play an important role during early brain injury and cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). This study aimed to analyze MMP-3, MMP-9, TIMP-1 and TIMP-3 in patients with SAH and their respective association with cerebral vasospasm (CVS).

Methods

Blood samples were collected in 20 SAH patients on days 1 to 7, 9, 11, 13 and 15 and 20 healthy age and gender matched volunteers. Serum MMPs and TIMPs were analyzed using enzyme-linked immunosorbent assay. Doppler sonographic CVS was defined as a mean blood flow velocity above 120 cm/sec in the middle cerebral artery. When discharged from hospital and at 6 month follow-up neurological outcome was evaluated using the Glasgow Outcome Score and the modified Rankin Scale.

Results

MMP-9 was higher in SAH patients compared to healthy controls (p<0.001). Patients with CVS (n = 11) had elevated MMP-9 serum levels compared to patients without CVS (n = 9, p<0.05). Higher MMP-9 was observed in the presence of cerebral ischemia associated with cerebral vasospasm (p<0.05). TIMP-1 was increased in patients with SAH on day 4 (p<0.05). There was an imbalance of the MMP-9/TIMP-1 ratio in favor of MMP-9 in SAH patients, in particular those with CVS (p<0.001). MMP-3 and TIMP-3 were significantly lower in SAH patients throughout day 4 and day 7, respectively (p<0.05). We did not find an association between MMP-, TIMP levels and neurological outcome after 6 months.

Conclusions

MMP-3 and -9 are differentially regulated in SAH patients with both enzymes showing peak levels correlating with the development of CVS. The inhibitors TIMP-1 and -3 were low during the acute phase after SAH and increased later on which might suggest a preponderance of pro-inflammatory mechanisms.     

Kallikrein 6 as a Serum Prognostic Marker in Patients with Aneurysmal Subarachnoid Hemorrhage

Background

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating condition that frequently causes death or significant disabilities. Blood tests to predict possible early complications could be very useful aids for therapy. The aim of this study was to analyze serum levels of kallikrein 6 (KLK6) in individuals with aSAH to determine the relevance of this protease with the outcome of these patients.

Methodology/Principal Findings

A reference interval for KLK6 was established by using serum samples (n = 136) from an adult population. Additionally, serum samples (n = 326) from patients with aSAH (n = 13) were collected for 5 to 14 days, to study the concentration of KLK6 in this disease. The correlation between KLK6 and S100B, an existing brain damage biomarker, was analyzed in 8 of 13 patients. The reference interval for KLK6 was established to be 1.04 to 3.93 ng/mL. The mean levels in patients with aSAH within the first 56 hours ranged from 0.27 to 1.44 ng/mL, with lowest levels found in patients with worse outcome. There were significant differences between patients with good recovery or moderate disability (n = 8) and patients with severe disability or death (n = 5) (mean values of 1.03 ng/mL versus 0.47 ng/mL, respectively) (p<0.01). There was no significant correlation between KLK6 and S100B.

Conclusions/Significance

Decreased serum concentrations of KLK6 are found in patients with aSAH, with the lowest levels in patients who died.     

Comparison of Montreal Cognitive Assessment and Mini-Mental State Examination in Evaluating Cognitive Domain Deficit Following Aneurysmal Subarachnoid Haemorrhage

Objective

Cognitive deficits are common after aneurysmal subarachnoid haemorrhage (aSAH), and clinical evaluation is important for their management. Our hypothesis was that the Montreal Cognitive Assessment (MoCa) is superior to the Mini-Mental State Examination (MMSE) in screening for cognitive domain deficit in aSAH patients.

Methods

We carried out a prospective observational and diagnostic accuracy study on Hong Kong aSAH patients aged 21 to 75 years who had been admitted within 96 hours of ictus. The domain-specific neuropsychological assessment battery, the MoCA and MMSE were administered 2–4 weeks and 1 year after ictus. A cognitive domain deficit was defined as a cognitive domain z score <−1.65 (below the fifth percentile). Cognitive impairment was defined as two or more cognitive domain deficits. The study is registered at ClinicalTrials.gov of the US National Institutes of Health ({"type":"clinical-trial","attrs":{"text":"NCT01038193","term_id":"NCT01038193"}}NCT01038193).

Results

Both the MoCA and the MMSE were successful in differentiating between patients with and without cognitive domain deficits and cognitive impairment at both assessment periods. At 1 year post-ictus, the MoCA produced higher area under the curve scores for cognitive impairment than the MMSE (MoCA, 0.92; 95% CI, 0.83 to 0.97 versus MMSE, 0.77; 95% CI, 0.66 to 0.83, p = 0.009).

Interpretation

Cognitive domain deficits and cognitive impairment in patients with aSAH can be screened with the MoCA in both the subacute and chronic phases.     

Whole Blood Gene Expression Profiles of Patients with a Past Aneurysmal Subarachnoid Hemorrhage

BackgroundThe pathogenesis of development and rupture of intracranial aneurysms (IA) is largely unknown. Also, screening for IA to prevent aneurysmal subarachnoid hemorrhage (aSAH) is inefficient, as disease markers are lacking. We investigated gene expression profiles in blood of previous aSAH patients, who are still at risk for future IA, aiming to gain insight into the pathogenesis of IA and aSAH, and to make a first step towards improvement of aSAH risk prediction.ConclusionsNo gene expression differences were present in blood of previous aSAH patients compared to controls, besides one differentially co-expressed gene network without a clear relevant biological function. Our findings suggest that gene expression profiles, as detected in blood of previous aSAH patients, do not reveal the pathogenesis of IA and aSAH, and cannot be used for aSAH risk prediction.     

Cerebrospinal Fluid from Patients with Subarachnoid Haemorrhage and Vasospasm Enhances Endothelin Contraction in Rat Cerebral Arteries

Introduction

Previous studies have suggested that cerebrospinal fluid from patients with subarachnoid hemorrhage (SAH) leads to pronounced vasoconstriction in isolated arteries. We hypothesized that only cerebrospinal fluid from SAH patients with vasospasm would produce an enhanced contractile response to endothelin-1 in rat cerebral arteries, involving both endothelin ET_A and ET_B receptors.

Methods

Intact rat basilar arteries were incubated for 24 hours with cerebrospinal fluid from 1) SAH patients with vasospasm, 2) SAH patients without vasospasm, and 3) control patients. Arterial segments with and without endothelium were mounted in myographs and concentration-response curves for endothelin-1 were constructed in the absence and presence of selective and combined ET_A and ET_B receptor antagonists. Endothelin concentrations in culture medium and receptor expression were measured.

Results

Compared to the other groups, the following was observed in arteries exposed to cerebrospinal fluid from patients with vasospasm: 1) larger contractions at lower endothelin concentrations (p<0.05); 2) the increased endothelin contraction was absent in arteries without endothelium; 3) higher levels of endothelin secretion in the culture medium (p<0.05); 4) there was expression of ET_A receptors and new expression of ET_B receptors was apparent; 5) reduction in the enhanced response to endothelin after ET_B blockade in the low range and after ET_A blockade in the high range of endothelin concentrations; 6) after combined ET_A and ET_B blockade a complete inhibition of endothelin contraction was observed.

Conclusions

Our experimental findings showed that in intact rat basilar arteries exposed to cerebrospinal fluid from patients with vasospasm endothelin contraction was enhanced in an endothelium-dependent manner and was blocked by combined ET_A and ET_B receptor antagonism. Therefore we suggest that combined blockade of both receptors may play a role in counteracting vasospasm in patients with SAH.     

Effect of Clazosentan in Patients with Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis of Randomized Controlled Trials

Background

Cerebral vasospasm is the most important potentially treatable cause of mortality and morbidity following aneurysmal subarachnoid hemorrhage (aSAH). Clazosentan, a selective endothelinreceptor antagonist, has been suggested to help reduce the incidence of vasospasm in patients with aSAH. However, the results were controversial in previous trials. This meta-analysis attempts to assess the effect of clazosentan in patients with aSAH.

Methodology/Principal Findings

We systematically searched Pubmed, Embase, and the Cochrane Library from their inception until June, 2012. All randomized controlled trials (RCTs) related to the effect of clazosentan in aSAH were included. The primary outcomes included the incidence of angiographic vasospasm, new cerebral infarction (NCI), delayed ischemic neurological deficits (DIND), and vasospasm-related morbidity/mortality (M/M); the second outcomes included the occurrence of rescue therapy, all-cause-mortality, and poor outcome. 4 RCTs were included with a total of 2156 patients. The risk of angiographic vasospasm (relative risk [RR] = 0.58; 95% CI, 0.48 to 0.71), DIND (RR = 0.76; 95% CI, 0.62 to 0.92), and vasospasm-related M/M (RR = 0.80; 95% CI, 0.67 to 0.96) were statistically significantly reduced in the clazosentan group. Patients treated with clazosentan had a reduced occurrence of rescue therapy (RR = 0.62; 95% CI, 0.49 to 0.79). However, no statistically significant effects were observed in NCI (RR = 0.74; 95% CI, 0.52 to 1.04), mortality (RR = 1.03; 95% CI, 0.71 to 1.49), and poor outcome (RR = 1.12; 95% CI, 0.96 to 1.30).

Conclusions/Significance

Our pooling data supports that clazosentan is probably effective in preventing the occurrence of angiographic vasospasm, vasospasm-related DIND, vasospasm related M/M, and rescue therapy. However, no evidence lends significant supports to the benefits of clazosentan in decreasing the occurrence of NCI, mortality or improving the functional outcome.     

ECG Changes in Subarachnoid Haemorrhage: A Synopsis

Subarachnoid haemorrhage (SAH) is a neurological emergency with high mortality rates. It is mainly caused by rupture of an aneurysm (congenital/infectious/traumatic) or rupture of an arteriovenous malformation. Electrocardiograms (ECGs) done in patients with SAH have shown morphological changes as well as arrhythmias. Subarachnoid haemorrhage (SAH) patients have often been misdiagnosed to have cardiac abnormalities based on their ECGs when in many of those instances the ECG change had been the result of the SAH itself. They have led to unnecessary and wasteful investigations and therapies in many occasions. Hence the current article is an effort at consolidating the information available in an attempt to avoid possible errors in diagnosis by house staff and internists. There are two mechanisms that might mediate ECG changes in patients with SAH, i.e. autonomic neural stimulation from the hypothalamus or elevated levels of circulating catecholamine. Hypothalamic stimulation may cause ECG changes without associated myocardial damage whereas elevated catecholamine levels have been correlated with QT-interval prolongation and myocardial damage.     

The Association between Meteorological Parameters and Aneurysmal Subarachnoid Hemorrhage: A Nationwide Analysis

Prior research has suggested that regional weather patterns impact the risk of rupture of cerebral aneurysms, but the findings in the literature have been inconsistent. Furthermore, no nationwide analysis to date has examined the association between meteorological factors and the post-procedural outcomes of patients after the treatment for ruptured cerebral aneurysms. The purpose of this study was to use a nationwide sample to analyze the association between specific meteorological parameters—temperature, precipitation, sunlight, and humidity—and hospital admission rate for and outcome after aneurysmal subarachnoid hemorrhage. Patients were identified using the Nationwide Inpatient Sample (2001–2010): Those with an ICD-9 diagnosis code for subarachnoid hemorrhage and a procedural code for aneurysm repair were included. Climate data were obtained from the State of the Climate Report 2010 released by the National Climatic Data Center. Multivariate regression models were constructed to analyze the association between average state monthly temperature, precipitation, and percent possible sunlight, as well as relative morning humidity and both monthly hospital admission rate, adjusted for annual state population in millions, and in-hospital mortality. 16,970 admissions were included from 723 hospitals across 41 states. Decreased daily sunlight and lower relative humidity were associated with an increased rate of admission for ruptured cerebral aneurysms (p<0.001), but had no association with differential inpatient mortality. No significant changes in these observed associations were seen when multivariate analyses were constructed. This is the first nationwide study to suggest that decreased sunlight and lower relative humidity are associated with admission for ruptured cerebral aneurysms. While it has been postulated that external atmospheric factors may cause hormonal and homeostatic changes that impact the risk of rupture of cerebral aneurysms, additional research is needed to confirm and further understand these relationships.     

血清ANXA1、dickkopf-1与动脉瘤性蛛网膜下腔出血患者脑损伤程度和预后的关系

摘要 目的：探讨动脉瘤性蛛网膜下腔出血（aSAH）患者血清膜联蛋白AI（ANXA1）、dickkopf相关蛋白1（dickkopf-1）水平与脑损伤程度及与预后的关系。方法：选取中国人民解放军联勤保障部队第九〇一医院2018年11月-2021年5月收治的100例aSAH患者作为观察组,选取同期健康体检者101例作为对照组。检测两组血清ANXA1、dickkopf-1水平,比较两组血清ANXA1、dickkopf-1水平差异。分析血清ANXA1、dickkopf-1水平与aSAH患者脑损伤程度和手术治疗后预后的关系。结果：观察组血清ANXA1水平低于对照组（P<0.05）,dickkopf-1水平高于对照组（P<0.05）。Spearman相关性分析显示,血清ANXA1与Hunt-Hess评分、WFNS评分和改良Fisher评分呈负相关（P<0.05）;血清dickkopf-1与Hunt-Hess评分、WFNS评分和改良Fisher评分均呈正相关（P<0.05）。所有患者均随访半年,经统计术后预后不良患者有56例,预后不良发生率为56%。多因素Logistic回归分析显示,高ANXA1水平为aSAH患者预后不良的保护因素（P<0.05）;高dickkopf-1水平、高Hunt-Hess评分、高WFNS评分、高改良Fisher评分是aSAH患者预后不良的危险因素（P<0.05）。ROC曲线分析显示：联合血清ANXA1、dickkopf-1及Hunt-Hess评分、WFNS评分、改良Fisher评分对aSAH患者预后的评估价值最高,ROC-AUC（0.95CI）为0.843(0.748～0.942)。结论：aSAH患者血清ANXA1、dickkopf-1水平与脑损伤程度密切相关,是患者预后不良的影响因素。联合血清ANXA1、dickkopf-1与病情评分对aSAH患者预后具有较高的预测价值。     

GTP Cyclohydrolase I and Tyrosine Hydroxylase Gene Mutations in Familial and Sporadic Dopa-Responsive Dystonia Patients

Dopa-responsive dystonia (DRD) is a rare inherited dystonia that responds very well to levodopa treatment. Genetic mutations of GTP cyclohydrolase I (GCH1) or tyrosine hydroxylase (TH) are disease-causing mutations in DRD. To evaluate the genotype-phenotype correlations and diagnostic values of GCH1 and TH mutation screening in DRD patients, we carried out a combined study of familial and sporadic cases in Chinese Han subjects. We collected 23 subjects, 8 patients with DRD, 5 unaffected family members, and 10 sporadic cases. We used PCR to sequence all exons and splicing sites of the GCH1 and TH genes. Three novel heterozygous GCH1 mutations (Tyr75Cys, Ala98Val, and Ile135Thr) were identified in three DRD pedigrees. We failed to identify any GCH1 or TH mutation in two affected sisters. Three symptom-free male GCH1 mutation carriers were found in two DRD pedigrees. For those DRD siblings that shared the same GCH1 mutation, symptoms and age of onset varied. In 10 sporadic cases, only two heterozygous TH mutations (Ser19Cys and Gly397Arg) were found in two subjects with unknown pathogenicity. No GCH1 and TH mutation was found in 40 unrelated normal Han Chinese controls. GCH1 mutation is the main etiology of familial DRD. Three novel GCH1 mutations were identified in this study. Genetic heterogeneity and incomplete penetrance were quite common in DRD patients, especially in sporadic cases. Genetic screening may help establish the diagnosis of DRD; however, a negative GCH1 and TH mutation test would not exclude the diagnosis.     

动脉瘤性蛛网膜下腔出血患者vWF、GMP-140及ADAMTS13的表达水平及临床意义

目的:探讨动脉瘤性蛛网膜下腔出血(aSAH)患者中血管性假血友病因子(v WF)、血小板膜糖蛋白-140(GMP-140)、血管性血友病因子裂解蛋白酶(ADAMTS13)的表达水平及临床意义。方法:选取2014年1月至2016年12月我院神经外科收治的83例aSAH患者,分为脑血管痉挛(CVS)组37例和无CVS组46例;迟发性脑缺血(DCI)组31例和非DCI组52例;根据不同动脉瘤直径分为5 mm组43例,5-10 mm组29例,10 mm组11例;预后良好组49例和预后不良组34例,检测aSAH患者血浆v WF、GMP-140、ADAMTS13水平,并分析各指标之间的相关性。结果:CVS组患者第4 d、10 d血浆v WF水平高于非CVS组,第1 d、4 d、10 d血浆GMP-140水平高于非CVS组,第1 d、10 d血浆ADAMTS13水平低于非CVS组,差异均有统计学意义(P0.05)。DCI组患者第1 d血浆v WF水平高于非DCI组,ADAMTS13水平低于非DCI组,第4 d血浆v WF、GMP-140水平高于非DCI组,差异均有统计学意义(P0.05)。10 mm组患者第1 d、4 d血浆v WF、GMP-140水平高于5 mm组和5-10 mm组,且5-10 mm组第4d的血浆v WF水平、第1 d的血浆,水平均高于5 mm组,差异有统计学意义(P0.05);10 mm组患者第1d的血浆ADAMTS13水平低于5 mm组和5-10 mm组,且5-10 mm组低于5 mm组,差异有统计学意义(P0.05)。预后良好组患者第4 d、10 d血浆v WF水平低于预后不良组,第1 d、4 d、10 d血浆GMP-140水平低于预后不良组,第1 d、4 d血浆ADAMTS13水平高于预后不良组,差异均有统计学意义(P0.05)。Pearson相关分析结果显示,第1 d、4 d血浆v WF与GMP-140呈正相关,与ADAMTS13呈负相关,GMP-140与ADAMTS13呈负相关(r=0.334、-0.426、-0.398、0.278、-0.311、-0.235,P0.05),第10 d血浆v WF、GMP-140、ADAMTS13之间无明显相关性(P0.05)。结论:v WF、GMP-140、ADAMTS13与CVS、DCI、动脉瘤直径以及预后密切相关,联合检测有助于综合评估aSAH患者病情,改善预后,值得临床推广。     

前列地尔联合尼莫地平对动脉瘤性蛛网膜下腔出血后脑血管痉挛患者血管内皮功能及炎症因子水平的影响

目的:探讨前列地尔联合尼莫地平对动脉瘤性蛛网膜下腔出血(aSAH)后脑血管痉挛(CVS)患者血管内皮功能及炎症因子水平的影响。方法:选取76例于2015年3月～2017年8月间在中南大学湘雅医院住院治疗的aSAH后CVS患者为研究对象,按随机数字表法将患者分为对照组(n=38)及观察组(n=38)。对照组在常规治疗基础上采用尼莫地平治疗,观察组在对照组基础上加用前列地尔治疗。比较治疗前后两组患者的大脑前、后、中动脉平均血流速度,观察并比较两组患者血浆降钙素基因相关肽(CGRP)、内皮素-1(ET-1)水平以及血清血管内皮生长因子(VEGF)、白细胞介素-8(IL-8)、超敏C反应蛋白(hs-CRP)、肿瘤坏死因子-α(TNF-α)水平的变化情况,评价两组疗效并观察治疗过程中的不良反应发生情况。结果:与对照组比较,治疗后观察组大脑前、后、中动脉血流速度均明显降低(P0.05)。与治疗前比较,治疗后两组患者CGRP水平明显升高,与对照组比较,治疗后观察组CGRP水平明显升高(P0.05),而治疗后两组患者ET-1、VEGF水平明显下降,且观察组低于对照组(P0.05)。与治疗前比较,治疗后两组患者IL-8、hs-CRP、TNF-α水平均明显下降,且与对照组比较,观察组IL-8、hs-CRP、TNF-α水平均降低(P0.05)。观察组患者治疗的总有效率为92.11%,明显高于对照组的73.68%(P0.05)。观察组总不良反应发生率与对照组比较差异无统计学意义(P0.05)。结论:前列地尔与尼莫地平联合使用治疗aSAH后CVS能明显改善患者的血管内皮功能,降低炎症因子水平,且未增加用药的不良反应,治疗效果较好。