Ischemic Neurological Deficits Research Articles

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

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. 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. 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. 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.

Appropriate Blood Pressure in Cerebral Aneurysm Clipping for Prevention of Delayed Ischemic Neurologic Deficits.

Background Delayed ischemic neurologic deficit (DNID) is a problem after cerebral aneurysm clipping. Intraoperative hypotension seems to be indicated as a risk factor, but it remains a controversial issue with varying low-blood pressure levels accepted. Methods A retrospective, hospital-based, case-control study was performed with patients who received general anesthesia for cerebral aneurysm clipping. 42 medical record charts were randomly selected and matched 1 : 2 (1 case with DNID : 2 controls without DNID) based on the type of general anesthetic techniques and severity of subarachnoid hemorrhage. The optimal cutoff points of hemodynamic response were calculated by the area under the curve. Results Data suggested that the optimal cutoff points for lowest blood pressure for prevention of DNID should be systolic blood pressure (SBP) of 95 mmHg (sensitivity of 78.6%; specificity of 53.6%), diastolic blood pressure (DBP) of 50 mmHg (sensitivity of 71.4%; specificity of 67.9%), and mean arterial pressure (MAP) of 61.7 mmHg (sensitivity of 85.7%; specificity of 35.7%). Furthermore, the optimal cutoff point mean difference baseline blood pressure was recommended as Δ SBP of 36 mmHg (sensitivity of 85.7%; specificity of 60.7%), Δ DBP of 27 mmHg (sensitivity of 92.9%; specificity of 71.4%), and Δ MAP of 32 mmHg (sensitivity of 92.9%; specificity of 85.7%). No significant difference between DNID and non-DNID groups was found for end-tidal carbon dioxide (ETCO2) and has poor diagnostic value for predicting DNID. Conclusion To prevent DNID, we recommend that optimal blood pressure should not be lower than 95 for SBP, 50 for DBP, and 61.7 mmHg for MAP. Additionally, we suggest that Δ SBP, Δ DBP, and Δ MAP should be less than 36, 27, and 32 mmHg, respectively.

Endothelin Receptor Antagonists: Status Quo and Future Perspectives for Targeted Therapy.

The endothelin axis, recognized for its vasoconstrictive action, plays a central role in the pathology of pulmonary arterial hypertension (PAH). Treatment with approved endothelin receptor antagonists (ERAs), such as bosentan, ambrisentan, or macitentan, slow down PAH progression and relieves symptoms. Several findings have indicated that endothelin is further involved in the pathogenesis of certain other diseases, making ERAs potentially beneficial in the treatment of various conditions. In addition to PAH, this review summarizes the use and perspectives of ERAs in cancer, renal disease, fibrotic disorders, systemic scleroderma, vasospasm, and pain management. Bosentan has proven to be effective in systemic sclerosis PAH and in decreasing the development of vasospasm-related digital ulcers. The selective ERA clazosentan has been shown to be effective in preventing cerebral vasospasm and delaying ischemic neurological deficits and new infarcts. Furthermore, in the SONAR (Study Of Diabetic Nephropathy With Atrasentan) trial, the selective ERA atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease. These data suggest atrasentan as a new therapy in the treatment of diabetic nephropathy and possibly other renal diseases. Preclinical studies regarding heart failure, cancer, and fibrotic diseases have demonstrated promising effects, but clinical trials have not yet produced measurable results. Nevertheless, the potential benefits of ERAs may not be fully realized.

Transcranial Doppler Sonography Defined Vasospasm, Ischemic Brain Lesions, and Delayed Ischemic Neurological Deficit in Younger and Elderly Patients after Aneurysmal Subarachnoid Hemorrhage

Vasospasm, delayed ischemic neurologic deficit (DIND), and ischemic brain lesions after acute subarachnoid hemorrhage (SAH) are associated with increased morbidity and mortality. The purpose of this study was to analyze age cutoffs for vasospasm, DIND, and ischemic brain lesions after SAH. This study included 292 aneurysmal SAH patients from January 2005 to December 2015. Patients' data were extracted from a prospective database with measurements of transcranial Doppler sonography. Any vasospasm was defined as a maximum mean flow velocity (MMFV) >120 cm/sec. Severe vasospasms were defined as at least 2 measurements of MMFVs >200 cm/sec or an increase of MMFV >50 cm/sec/24 hours over 2 consecutive days or a new neurologic deficit. All MMFVs >120 cm/sec in absence of severe vasospasm criteria were defined as mild vasospasm. Age-related cutoff values were calculated using receiver operating curve analysis. Any vasospasms occurred in 142 patients and thereof mild vasospasm in 86/142 (60.6%) patients and severe vasospasm in 56/142 patients (39.4%). Significantly higher incidences of any vasospasm (P = 0.005), severe vasospasm (P = 0.003), DIND (P = 0.031), and ischemic brain lesions (P = 0.04) were observed in patients aged <50 years. According to receiver operating curve analysis, the optimal age cutoff was 50 years for the presence of overall vasospasms, severe vasospasms, DIND, and ischemic brain lesions and 65 years for mild vasospasms. Higher incidences of any vasospasms, severe vasospasms, DIND, and ischemic brain lesions were observed in younger SAH patients.

FasL-PDPK1 Pathway Promotes the Cytotoxicity of CD8+ T Cells During Ischemic Stroke.

CD8+ T cells are recognized as key players in exacerbation of ischemic stroke; however, the underlying mechanism in modulating the function of CD8+ T cells has not been completely elucidated. Here, we uncovered that FasL enhanced the cytotoxicity of CD8+ T cells to neurons after ischemic stroke. Inactivation of FasL specific on CD8+ T cells protected against brain damage and neuron loss. Proteomic analysis identified that PDPK1 functioned downstream of FasL signaling and inhibition of PDPK1 effectively reduced cytotoxicity of CD8+ T cells and improved ischemic neurological deficits. Taken together, these results highlight an intrinsic FasL-PDPK1 pathway regulating the cytotoxicity of CD8+ T cells in ischemic stroke.

Atorvastatin reduces cerebral vasospasm and infarction after aneurysmal subarachnoid hemorrhage in elderly Chinese adults.

We explored whether acute atorvastatin treatment would improve clinical outcomes and reduce the incidence of cerebral vasospasm after aneurysmal subarachnoid hemorrhage in elderly Chinese adults. Patients (60 to 90 years old) were admitted to intensive care units after surgery to clip or embolize their aneurysms. We assessed 592 patients and assigned 159 to receive atorvastatin (20 mg/day) and 158 to receive placebo once daily for up to 14 days. The primary outcome was the Glasgow outcome scale at 6 months, and secondary outcomes were cerebral vasospasm, 30-days all-cause mortality, cerebral infarction, and delayed ischemic neurological deficit. The incidence of postoperative cerebral vasospasm (39.3% vs 56%, P =0.004) and cerebral infarction (18.7% vs 27.3%, P=0.027) were significantly lower in the atorvastatin group. The study did not detect benefits in the use of atorvastatin for 6 months clinical outcome or 30-day all-cause mortality, but it suggests that atorvastatin together with nimodipine can reduce cerebral vasospasm and cerebral infarction after subarachnoid hemorrhage.

A Case Report of Cerebral Vasospasm Following Elective Clipping of Unruptured Aneurysm: Pathogenetic Theories and Clinical Features of a Dangerous Underestimated Event

Background and Importance: Angiographic-proven and clinically-evident cerebral vasospasm (CVS) after uneventful elective clipping of unruptured intracranial aneurysm (UIA) is a very rare and often underestimated event. To date, the knowledge of risk factors, pathophysiology, and demographic characteristics of these conditions are solely relegated to few case reports. With the aim of better characterize shared features and mechanism that could be involved in such event we also performed a review of the present literature and analyzed aneurysm’s features, surgical factors, treatments, recovery and of all reported cases of CVS after elective clipping. Clinical Presentation: We report a case of a cerebral vasospasm following elective clipping of a middle cerebral artery (MCA) bifurcation aneurysm in a 59-year-old woman who smoked next days after treatment, despite medical advice. We found ten cases comparable to ours with angiographic-proven and clinically evident cerebral vasospasm after uneventful elective clipping. Conclusion: Classic mechanisms of CVS following SAH have been widely studied. In all the cases we analyzed, no subarachnoid bleeding occurred, as demonstrated in pre and postoperative CT scans and intraoperatively. Various theories on the possible mechanism have been advanced. It seems reasonable that CVS following elective clipping of unruptured aneurysm is a multifactorial phenomenon. Although its pathogenesis is unclear, clinicians should keep in mind the existence of this event, that is rare, but it could be seen in the clinical practice of every neurosurgery ward. In our opinion, it’s worth to know this possible post-operative complication because, when suspected clinical signs and symptoms of delayed ischemic neurological deficit (DIND) arise after elective clipping, it’s important to make an early diagnosis of CVS owing to early treatments are critical to improve clinical outcome

Can we improve the prediction of complications and outcome in aneurysmal subarachnoid hemorrhage? The clinical implications of serum proteomics.

Aneurysmal subarachnoid hemorrhage is a devastating condition, often leading to a debilitating outcome. Delayed ischemic neurological deficits are considered the feared sequelae. Proteomics is a large-scale study of proteins incorporating structural and functional properties in complex biological fluids. Analysis of proteomes has led to identifying relevant complex proteins related to specific pathophysiological processes reflecting the severity and extent of diseases. Proteomics has evolved in the past few years; more biomarkers are deemed clinically relevant to diagnose, monitor, and define prognosis in patients with aneurysmal subarachnoid hemorrhage. Despite the absence of candidate biomarkers in the clinical routine, many have shown promising results. The complexity of proteins implicated in aneurysmal subarachnoid hemorrhage rendered these biomarkers' clinical use paved with various pitfalls and technical difficulties, especially when data about the perfect timing and values are lacking. We review the latest literature concerning serum proteomics and their clinical utility regarding the prediction of cerebral vasospasm and other complications of aneurysmal subarachnoid hemorrhage, as well as the clinical outcome. Future prospective studies will allow changing the disease's course, label patients according to their prognosis to provide earlier and better management and improve outcomes.

Anti-miR-223-5p Ameliorates Ischemic Damage and Improves Neurological Function by Preventing NCKX2 Downregulation after Ischemia in Rats

It has been demonstrated that the K+-dependent Na+/Ca2+ exchanger, NCKX2, is a new promising stroke neuroprotective target. However, because no pharmacological activator of NCKX2 is still available, microRNA (miRNA) may represent an alternative method to modulate NCKX2 expression. In particular, by bioinformatics analysis, miR-223-5p emerged as a possible modulator of NCKX2 expression. In the light of these premises, the aims of the present study were: (1) to evaluate miR-223-5p and NCKX2 expression in the temporoparietal cortex and striatum of rats subjected to transient middle cerebral artery occlusion; (2) to evaluate whether miR-223-5p targets the 3′ UTR of the NCKX2 transcript; and (3) to evaluate the effect of miR-223-5p modulation on brain ischemic volume and neurological deficits. Our results showed that miR-223-5p expression increased in a time-dependent manner in the striatum of ischemic rats in parallel with NCKX2 downregulation, and that the transfection of cortical neurons with miR-223-5p induced a reduction of NCKX2 expression. Moreover, a luciferase assay showed that miR-223-5p specifically interacts with the NCKX2 3′ UTR subregion (+7037 to +8697), thus repressing NCKX2 translation. More interestingly, intracerebroventricular infusion of anti-miR-223-5p prevented NCKX2 downregulation after ischemia, thus promoting neuroprotection. The present findings support the idea that blocking miR-223-5p by antimiRNA is a reasonable strategy to reduce the neurodetrimental effect induced by NCKX2 downregulation during brain ischemia.

Management of cerebral vasospasm in subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) has been shown to result in cerebral vasospasm at day 4 to day 14, which is the main cause of mortality and morbidity after SAH. Outcome after SAH depends on many factors, including the severity of the event, medical management, and prevention of several serious complications. The principal goal in management of vasospasm after SAH is to prevent delayed ischemic neurological deficit (DIND) by decreasing intracranial pressure (ICP), optimizing cerebral oxygen demand rate and improving cerebral blood flow (CBF). Therapeutic management has been applied to prevent or treat vasospasm, including hemodynamic therapy, and endovascular therapy. Endovascular therapies, including mechanical angioplasty and chemical angioplasty with administration of intra-arterial (IA) vasodilator, have been widely used and given a good outcome. The purpose of this article is to describe the management of vasospasm including medical management and endovascular treatment. This review will describe the treatment modalities and management strategies to treat vasospasm.Abbreviations: SAH – subarachnoid hemorrhage; aSAH – aneurysmal subarachnoid hemorrhage; TCD – transcranial Doppler; ROS – reactive oxygen species; ICAM – intercellular adhesion molecule; VCAM – vascular cell adhesion molecule; IL – interleukin; CTA – computed tomography angiography; MRA – magnetic resonance angiography; CBF – cerebral blood flow; DIND – delayed ischemic neurological deficit; RCT - randomized controlled trialsCitation: Prahaztuti D, Hidayati HB, Sani AF. Management of cerebral vasospasm in subarachnoid hemorrhage. Anaesth Pain &amp; Intensive Care 2018;22(3 Suppl 1):S58-S66.Received: 19 Oct 2018 Reviewed: 4, 11 Nov 2018 Accepted: 12 Nov 2018

Haptoglobin administration into the subarachnoid space prevents hemoglobin-induced cerebral vasospasm

Delayed ischemic neurological deficit (DIND) is a major driver of adverse outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH), defining an unmet need for therapeutic development. Cell-free hemoglobin that is released from erythrocytes into the cerebrospinal fluid (CSF) is suggested to cause vasoconstriction and neuronal toxicity, and correlates with the occurrence of DIND. Cell-free hemoglobin in the CSF of patients with aSAH disrupted dilatory NO signaling ex vivo in cerebral arteries, which shifted vascular tone balance from dilation to constriction. We found that selective removal of hemoglobin from patient CSF with a haptoglobin-affinity column or its sequestration in a soluble hemoglobin-haptoglobin complex was sufficient to restore physiological vascular responses. In a sheep model, administration of haptoglobin into the CSF inhibited hemoglobin-induced cerebral vasospasm and preserved vascular NO signaling. We identified 2 pathways of hemoglobin delocalization from CSF into the brain parenchyma and into the NO-sensitive compartment of small cerebral arteries. Both pathways were critical for hemoglobin toxicity and were interrupted by the large hemoglobin-haptoglobin complex that inhibited spatial requirements for hemoglobin reactions with NO in tissues. Collectively, our data show that compartmentalization of hemoglobin by haptoglobin provides a novel framework for innovation aimed at reducing hemoglobin-driven neurological damage after subarachnoid bleeding.

Delayed Ischemic Neurologic Deficit after Aneurysmal Subarachnoid Hemorrhage.

Delayed ischemic neurologic deficit (DIND) is the main preventable cause of poor outcomes in aneurysmal subarachnoid hemorrhage (SAH) patients. Of 50% of survivors from a SAH, approximately 30% of patients will present clinical vasospasm (VS). The cornerstone of the DIND management comprises prevention and early identification. Several diagnostic methods have been proposed differing in efficacy, invasiveness, and costs. Serial neurological examination is the most reliable method to detect a new neurological deficit. On the other hand, comatose patients require advanced monitoring methods which identify changes in the microcirculatory environment, brain autoregulation, and spreading depolarization. Multimodality monitoring with continuous electroencephalography, microdialysis, and intracranial pressure monitoring represents altogether the current state-of-art technology for the intensive care of SAH patients. Moreover, advances in genetic biomarkers to predict clinical VS have shown consistent accuracy which may in the near future allow the early prediction of DIND through a simple blood test. Several clinical trials have tested drugs with theoretical effects on DIND prevention or treatment. Nevertheless, nimodipine remains the Holy Grail in the prevention of clinical VS. Among rescue therapies, the endovascular treatment through intra-arterial vasodilator (verapamil or nicardipine) infusion is the most employed method for DIND reversal; however, there is no good quality evidence comparing results of intra-arterial infusion of vasodilators versus balloon angioplasty. Although we have addressed the most refined technology in the management of SAH and DIND, the clinical experience and strict follow-up in neurointensive care will be determinant for favorable long-term outcomes.

#48 Use of metformin during pregnancy and risk of major congenital malformations: Preliminary findings of a systematic review and meta-analysis

Clazosentan, an endothelin receptor antagonist, reduced vasospasm and delayed ischemic neurologic deficit (DIND) but did not improve outcome after subarachnoid hemorrhage (SAH) in clinical trials. However, a lack of dose-dependent analysis and potential overestimation of clazosentan's effect are concerning. We used stratified analysis and trial sequential analysis (TSA) of existing data to investigate the effects of clazosentan on SAH outcome.Studies from PubMed, Embase, and Cochrane were reviewed for eligibility. Primary outcomes were DIND requiring rescue therapy, all-cause mortality, and vasospasm-related morbidity at 6 weeks. Secondary outcomes were moderate-to-severe angiographic vasospasm, new cerebral infarction, and poor clinical outcome at 3 months. TSA was performed to assess the required information size and the α-spending monitoring boundary effect of relative risk (RR) reduction. A stratified analysis of clazosentan dosage was performed.Five studies (N = 2317) were included. Clazosentan significantly reduced the risk of DIND requiring rescue therapy (RR, 0.625; 95% confidence interval [CI], 0.462–0.846) and vasospasm (RR, 0.543; 95% CI, 0.464–0.635), but did not significantly affect mortality or vasospasm-related morbidity (RR, 0.775; 95% CI, 0.578–1.039), new cerebral infarction (RR, 0.604; 95% CI, 0.383–0.952), or outcome (RR, 1.131; 95% CI, 0.959–1.334). TSA revealed that the studies were underpowered to evaluate the effects of clazosentan on mortality and vasospasm-associated morbidity. We found 10–15 mg/h of clazosentan administration was associated with lower rates of vasospasm and new cerebral infarctions compared with 5 mg/h.Clazosentan reduced the risk of DIND requiring rescue therapy and moderate-to-severe vasospasm. Further meta-analyses based on individual patient data with different clazosentan doses and more refined outcome measures are necessary to clarify clazosentan's efficacy in improving post-SAH outcome.

Nitric Oxide-Based Treatment of Poor-Grade Patients After Severe Aneurysmal Subarachnoid Hemorrhage

BackgroundPatients with aneurysmal subarachnoid hemorrhage (aSAH) require close treatment in neuro intensive care units (NICUs). The treatments available to counteract secondary deterioration and delayed ischemic events remain restricted; moreover, available neuro-monitoring of comatose patients is undependable. In comatose patients, clinical signs are hidden, and timing interventions to prevent the evolution of a perfusion disorder in response to fixed ischemic brain damage remain a challenge for NICU teams. Consequently, comatose patients often suffer secondary brain infarctions. The outcomes for long-term intubated patients w/wo pupil dilatation are the worst, with only 10% surviving. We previously added two nitroxide (NO) donors to the standard treatment: continuous intravenous administration of Molsidomine in patients with mild-to-moderate aSAH and, if required as a supplement, intraventricular boluses of sodium nitroprusside (SNP) in high-risk patients to overcome the so-called NO-sink effect, which leads to vasospasm and perfusion disorders. NO boluses were guided by clinical status and promptly reversed recurrent episodes of delayed ischemic neurological deficit. In this study, we tried to translate this concept, the initiation of intraventricular NO application on top of continuous Molsidomine infusion, from awake to comatose patients who lack neurological–clinical monitoring but are primarily monitored using frequently applied transcranial Doppler (TCD).MethodsIn this observational, retrospective, nonrandomized feasibility study, 18 consecutive aSAH comatose/intubated patients (Hunt and Hess IV/V with/without pupil dilatation) whose poor clinical status precluded clinical monitoring received standard neuro-intensive care, frequent TCD monitoring, continuous intravenous Molsidomine plus intraventricular SNP boluses after TCD-confirmed macrospasm during the daytime and on a fixed nighttime schedule.ResultsVery likely associated with the application of SNP, which is a matter of further investigation, vasospasm-related TCD findings promptly and reliably reversed or substantially weakened (p < 0.0001) afterward. Delayed cerebral ischemia (DCI) occurred only during loose, low-dose or interrupted treatment (17% vs. an estimated 65% with secondary infarctions) in 17 responders. However, despite their worse initial condition, 29.4% of the responders survived (expected 10%) and four achieved Glasgow Outcome Scale Extended (GOSE) 8–6, modified Rankin Scale (mRS) 0–1 or National Institutes of Health Stroke Scale (NIHSS) 0–2.ConclusionsEven in comatose/intubated patients, TCD-guided dual-compartment administration of NO donors probably could reverse macrospasm and seems to be feasible. The number of DCI was much lower than expected in this specific subgroup, indicating that this treatment possibly provides a positive impact on outcomes. A randomized trial should verify or falsify our results.

Dental Pulp Stem Cell-Derived Factors Alleviate Subarachnoid Hemorrhage-Induced Neuroinflammation and Ischemic Neurological Deficits.

Aneurysmal subarachnoid hemorrhage (aSAH), characterized by the extravasation of blood into the subarachnoid space caused by an intracranial aneurysm rupture, may lead to neurocognitive impairments and permanent disability and usually carries poor outcome. Dental or gingiva-derived stem cells have been shown to contribute to immune modulation and neuroregeneration, but the underlying mechanisms are unclear. In the present study, we sought to investigate whether dental pulp stem cells (DPSCs) secrete certain factor(s) that can ameliorate the neural damage and other manifestations in a rat aSAH model. Twenty-four hours after the induction of aSAH, microthrombosis, cortical vasoconstriction, and the decrease in microcirculation and tissue oxygen pressure were detected. Intrathecal administration of DPSC-derived conditioned media (DPSC-CM) ameliorated aSAH-induced vasoconstriction, neuroinflammation, and improved the oxygenation in the injured brain. Rotarod test revealed that the aSAH-induced cognitive and motor impairments were significantly improved by this DPSC-CM administration. Cytokine array indicated the major constituent of DPSC-CM was predominantly insulin growth factor-1 (IGF-1). Immunohistochemistry staining of injured brain tissue revealed the robust increase in Iba1-positive cells that were also ameliorated by DPSC-CM administration. Antibody-mediated neutralization of IGF-1 moderately deteriorated the rescuing effect of DPSC-CM on microcirculation, Iba1-positive cells in the injured brain area, and the cognitive/motor impairments. Taken together, the DPSC-derived secretory factors showed prominent therapeutic potential for aSAH. This therapeutic efficacy may include improvement of microcirculation, alleviation of neuroinflammation, and microglial activation; partially through IGF-1-dependent mechanisms.

Compartmentalisation of the inflammatory response following aneurysmal subarachnoid haemorrhage

There is some evidence to suggest that a systemic and central nervous system (CNS) inflammatory response occurs following aneurysmal subarachnoid haemorrhage (aSAH) which may be related to the pathophysiology of early brain injury and delayed ischaemic neurological deficit (DIND). The aim of this study was to measure inflammatory mediator levels in plasma and cerebrospinal fluid (CSF) in the days following aSAH and to determine their association with aSAH, DIND and clinical outcome. Plasma and CSF samples were obtained prospectively from patients with aSAH on days 1-3, 5, 7 and 9 and profiled for interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-8, IL-10, IL-15, IL-17, IL-18, macrophage chemotactic protein (MCP)-1, vascular endothelial growth factor (VEGF) and tumour necrosis factor (TNF)-α. Plasma and CSF samples from non-aSAH patients undergoing spinal anaesthesia were used as controls. The CSF levels of all cytokines investigated except for IL-1α were significantly higher in aSAH compared to controls in the first seven days of ictus. CSF levels of IL-1α (p = 0.014), IL-18 (p = 0.016), IL-6 (p = 0.0006) and IL-8 (p = 0.006) showed significant increases in the days following aSAH. Conversely IL-17 demonstrated a decrease. In particular, IL-4 was higher in the CSF of patients who had DIND at all time-points (p = 0.032). Plasma IL-6 and IL-8 levels were higher, and IL-1α levels lower, than controls at most time-points. All mediators demonstrated persistent elevation in the CSF compared to plasma apart from IL-1α and IL-18 which followed the opposite trend. Day 3 plasma IL-6 levels predicted poor outcome at six months (Exp(B) 1.12 1.03-1.22, P = 0.012), although this association was lost in the second analysis incorporating Fisher grade, WFNS grade and age. The post aSAH inflammatory response peaks on days 5-7 post ictus and remains largely compartmentalised within the CNS. IL-4 may have a particular association with DIND although its precise role in the pathophysiology of the disorder remains unclear. IL-6 predicted poor outcome but not independently of clinical grade, suggesting that it may be a surrogate marker of early brain injury.

Efficacy of Statins in Cerebral Vasospasm, Mortality, and Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Aneurysmal subarachnoid hemorrhage (aSAH) is an acute cerebrovascular disease with frequent cerebral vasospasm and delayed cerebral ischemia (DCI). The use of statins for patients with aSAH is controversial. The present study evaluated the efficacy of statins in aSAH-induced vasospasm, DCI, delayed ischemic neurological deficit (DIND), mortality, and other outcomes. A literature search was performed in PubMed, EMBASE, and the Cochrane Library. English reports of patients with aSAH who had been treated with statins without combination were included. The outcomes, including cerebral vasospasm, DIND, DCI, mortality, disability, and creatine kinase/alanine aminotransferase/aspartic transaminase elevation, were extracted for meta-analysis. A total of 13 studies, with 776 versus 821 patients treated with statins versus placebo, were retained for the statistical meta-analysis. The results showed that statin administration significantly reduced the frequency of vasospasm (relative risk [RR], 0.76; 95% confidence interval [CI], 0.63-0.91; P= 0.003), DIND (RR, 0.76; 95% CI, 0.63-0.91; P= 0.003), vasospasm-DCI (RR, 0.49; 95% CI, 0.32-0.74; P= 0.0008), and mortality (RR, 0.73; 95% CI, 0.54-0.98; P= 0.03). Statins showed insignificant efficacy in the prevention of disability (RR, 0.92; 95% CI, 0.71-1.20), a neurological poor prognosis (RR, 0.75; 95% CI, 0.45-1.27), and creatine kinase/alanine aminotransferase/aspartic transaminase elevation (RR, 1.90; 95% CI, 0.55-6.50). Statins significantly reduced the incidence of vasospasm, DIND, DCI, and mortality in individuals with aSAH, suggesting its efficacy in aSAH.

Moderate Protein Restriction Protects Against Focal Cerebral Ischemia in Mice by Mechanisms Involving Anti-inflammatory and Anti-oxidant Responses

Food composition influences stroke risk, but its effects on ischemic injury and neurological deficits are poorly examined. While severe reduction of protein content was found to aggravate neurological impairment and brain injury as a consequence of combined energy-protein malnutrition, moderate protein restriction not resulting in energy deprivation was recently suggested to protect against perinatal hypoxia-ischemia. Male C57BL6/j mice were exposed to moderate protein restriction by providing a normocaloric diet containing 8% protein (control: 20% protein) for 7, 14, or 30 days. Intraluminal middle cerebral artery occlusion was then induced. Mice were sacrificed 24 h later. Irrespective of the duration of food modification (that is, 7–30 days), protein restriction reduced neurological impairment of ischemic mice revealed by a global and focal deficit score. Prolonged protein restriction over 30 days also reduced infarct volume, brain edema, and blood-brain barrier permeability and increased the survival of NeuN+ neurons in the core of the stroke (i.e., striatum). Neuroprotection by prolonged protein restriction went along with reduced brain infiltration of CD45+ leukocytes and reduced expression of inducible NO synthase and interleukin-1β. As potential mechanisms, increased levels of the NAD-dependent deacetylase sirtuin-1 and anti-oxidant glutathione peroxidase-3 were noted in ischemic brain tissue. Irrespective of the protein restriction duration, a shift from pro-oxidant oxidative stress markers (NADPH oxidase-4) to anti-oxidant markers (superoxide dismutase-1/2, glutathione peroxidase-3 and catalase) was found in the liver. Moderate protein restriction protects against ischemia in the adult brain. Accordingly, dietary modifications may be efficacious strategies promoting stroke outcome.

Propentdyopents as Heme Degradation Intermediates Constrict Mouse Cerebral Arterioles and Are Present in the Cerebrospinal Fluid of Patients With Subarachnoid Hemorrhage.

Delayed ischemic neurological deficit is the most common cause of neurological impairment and unfavorable prognosis in patients with subarachnoid hemorrhage (SAH). Despite the existence of neuroimaging modalities that depict the onset of the accompanying cerebral vasospasm, preventive and therapeutic options are limited and fail to improve outcome owing to an insufficient pathomechanistic understanding of the delayed perfusion deficit. Previous studies have suggested that BOXes (bilirubin oxidation end products), originating from released heme surrounding ruptured blood vessels, are involved in arterial vasoconstriction. Recently, isolated intermediates of oxidative bilirubin degradation, known as PDPs (propentdyopents), have been considered as potential additional effectors in the development of arterial vasoconstriction. To investigate whether PDPs and BOXes are present in hemorrhagic cerebrospinal fluid and involved in the vasoconstriction of cerebral arterioles. Via liquid chromatography/mass spectrometry, we measured increased PDP and BOX concentrations in cerebrospinal fluid of SAH patients compared with control subjects. Using differential interference contrast microscopy, we analyzed the vasoactivity of PDP isomers in vitro by monitoring the arteriolar diameter in mouse acute brain slices. We found an arteriolar constriction on application of PDPs in the concentration range that occurs in the cerebrospinal fluid of patients with SAH. By imaging arteriolar diameter changes using 2-photon microscopy in vivo, we demonstrated a short-onset vasoconstriction after intrathecal injection of either PDPs or BOXes. Using magnetic resonance imaging, we observed a long-term PDP-induced delay in cerebral perfusion. For all conditions, the arteriolar narrowing was dependent on functional big conductance potassium channels and was absent in big conductance potassium channels knockout mice. For the first time, we have quantified significantly higher concentrations of PDP and BOX isomers in the cerebrospinal fluid of patients with SAH compared to controls. The vasoconstrictive effect caused by PDPs in vitro and in vivo suggests a hitherto unrecognized pathway contributing to the pathogenesis of delayed ischemic deficit in patients with SAH.

Haptoglobin genotype and aneurysmal subarachnoid hemorrhage: Individual patient data analysis.

To perform an individual patient-level data (IPLD) analysis and to determine the relationship between haptoglobin (HP) genotype and outcomes after aneurysmal subarachnoid hemorrhage (aSAH). The primary outcome was favorable outcome on the modified Rankin Scale or Glasgow Outcome Scale up to 12 months after ictus. The secondary outcomes were occurrence of delayed ischemic neurologic deficit, radiologic infarction, angiographic vasospasm, and transcranial Doppler evidence of vasospasm. World Federation of Neurological Surgeons (WFNS) scale, Fisher grade, age, and aneurysmal treatment modality were covariates for both primary and secondary outcomes. As preplanned, a 2-stage IPLD analysis was conducted, followed by these sensitivity analyses: (1) unadjusted; (2) exclusion of unpublished studies; (3) all permutations of HP genotypes; (4) sliding dichotomy; (5) ordinal regression; (6) 1-stage analysis; (7) exclusion of studies not in Hardy-Weinberg equilibrium (HWE); (8) inclusion of studies without the essential covariates; (9) inclusion of additional covariates; and (10) including only covariates significant in univariate analysis. Eleven studies (5 published, 6 unpublished) totaling 939 patients were included. Overall, the study population was in HWE. Follow-up times were 1, 3, and 6 months for 355, 516, and 438 patients. HP genotype was not associated with any primary or secondary outcome. No trends were observed. When taken through the same analysis, higher age and WFNS scale were associated with an unfavorable outcome as expected. This comprehensive IPLD analysis, carefully controlling for covariates, refutes previous studies showing that HP1-1 associates with better outcome after aSAH.