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Journal of Neuroinflammation Sep 2022Cerebral vasospasm (CV) can contribute to significant morbidity in subarachnoid hemorrhage (SAH) patients. A key unknown is how CV induction is triggered following SAH.
BACKGROUND
Cerebral vasospasm (CV) can contribute to significant morbidity in subarachnoid hemorrhage (SAH) patients. A key unknown is how CV induction is triggered following SAH.
METHODS
Human aneurysmal blood and cerebral spinal fluid were collected for evaluation. To confirm mechanism, c57/bl6 wild type and c57/bl6 IL-6 female knockout (KO) mice were utilized with groups: saline injected, SAH, SAH + IL-6 blockade, SAH IL-6 KO, SAH IL-6 KO + IL-6 administration, SAH + p-STAT3 inhibition. Dual-labeled microglia/myeloid mice were used to show myeloid diapedesis. For SAH, 50 μm blood was collected from tail puncture and administered into basal cisterns. IL-6 blockade was given at various time points. Various markers of neuroinflammation were measured with western blot and immunohistochemistry. Cerebral blood flow was also measured. Vasospasm was measured via cardiac injection of India ink/gelatin. Turning test and Garcia's modified SAH score were utilized. P < 0.05 was considered significant.
RESULTS
IL-6 expression peaked 3 days following SAH (p < 0.05). Human IL-6 was increased in aneurysmal blood (p < 0.05) and in cerebral spinal fluid (p < 0.01). Receptor upregulation was periventricular and perivascular. Microglia activation following SAH resulted in increased caveolin 3 and myeloid diapedesis. A significant increase in BBB markers endothelin 1 and occludin was noted following SAH, but reduced with IL-6 blockade (p < 0.01). CV occurred 5 days post-SAH, but was absent in IL-6 KO mice and mitigated with IL-6 blockade (p < 0.05). IL-6 blockade, and IL-6 KO mitigated effects of SAH on cerebral blood flow (p < 0.05). SAH mice had impaired performance on turn test and poor modified Garcia scores compared to saline and IL-6 blockade. A distinct microglia phenotype was noted day 5 in the SAH group (overlap coefficients r = 0.96 and r = 0.94) for Arg1 and iNOS, which was altered by IL-6 blockade. Day 7, a significant increase in toll-like receptor 4 and Stat3 was noted. This was mitigated by IL-6 blockade and IL-6 KO, which also reduced Caspase 3 (p < 0.05). To confirm the mechanism, we developed a p-STAT3 inhibitor that targets the IL-6 pathway and this reduced NFΚB, TLR4, and nitrotyrosine (p < 0.001). Ventricular dilation and increased Tunel positivity was noted day 9, but resolved by IL-6 blockade (p < 0.05).
CONCLUSION
Correlation between IL-6 and CV has been well documented. We show that a mechanistic connection exists via the p-STAT3 pathway, and IL-6 blockade provides benefit in reducing CV and its consequences mediated by myeloid cell origin diapedesis.
Topics: Animals; Caspase 3; Caveolin 3; Endothelin-1; Female; Gelatin; Humans; Interleukin-6; Mice; Mice, Knockout; Subarachnoid Hemorrhage; Toll-Like Receptor 4; Vasospasm, Intracranial
PubMed: 36114540
DOI: 10.1186/s12974-022-02592-x -
Neurocritical Care Jun 2022
Topics: Cortical Spreading Depression; Humans; Subarachnoid Hemorrhage; Vasospasm, Intracranial
PubMed: 34704217
DOI: 10.1007/s12028-021-01373-3 -
Cells Jan 2022A subarachnoid hemorrhage (SAH), leading to severe disability and high fatality in survivors, is a devastating disease. Neuro-inflammation, a critical mechanism of...
A subarachnoid hemorrhage (SAH), leading to severe disability and high fatality in survivors, is a devastating disease. Neuro-inflammation, a critical mechanism of cerebral vasospasm and brain injury from SAH, is tightly related to prognoses. Interestingly, studies indicate that 2-[(pyridine-2-ylmethyl)-amino]-phenol (2-PMAP) crosses the blood-brain barrier easily. Here, we investigated whether the vasodilatory and neuroprotective roles of 2-PMAP were observed in SAH rats. Rats were assigned to three groups: sham, SAH and SAH+2-PMAP. SAHs were induced by a cisterna magna injection. In the SAH+2-PMAP group, 5 mg/kg 2-PMAP was injected into the subarachnoid space before SAH induction. The administration of 2-PMAP markedly ameliorated cerebral vasospasm and decreased endothelial apoptosis 48 h after SAH. Meanwhile, 2-PMAP decreased the severity of neurological impairments and neuronal apoptosis after SAH. Furthermore, 2-PMAP decreased the activation of microglia and astrocytes, expressions of TLR-4 and p-NF-κB, inflammatory markers (TNF-α, IL-1β and IL-6) and reactive oxygen species. This study is the first to confirm that 2-PMAP has vasodilatory and neuroprotective effects in a rat model of SAH. Taken together, the experimental results indicate that 2-PMAP treatment attenuates neuro-inflammation, oxidative stress and cerebral vasospasm, in addition to ameliorating neurological deficits, and that these attenuating and ameliorating effects are conferred through the TLR-4/NF-κB pathway.
Topics: Animals; Apoptosis; Astrocytes; Behavior, Animal; Brain Injuries; Cytokines; Inflammation; Inflammation Mediators; Microglia; Models, Biological; Motor Activity; NF-kappa B; Neurons; Pyridines; Rats, Sprague-Dawley; Reactive Oxygen Species; Severity of Illness Index; Signal Transduction; Subarachnoid Hemorrhage; Toll-Like Receptor 4; Vasospasm, Intracranial; Rats
PubMed: 35053358
DOI: 10.3390/cells11020242 -
Journal of Neurosurgery May 2020Aneurysmal subarachnoid hemorrhage (aSAH) is associated with significant morbidity and mortality. The presence of thick, diffuse subarachnoid blood may portend a worse...
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.
Topics: Adolescent; Adult; Aged; Aneurysm, Ruptured; Anthropometry; Blood Coagulation; Brain Damage, Chronic; Clinical Trials, Phase III as Topic; Computed Tomography Angiography; Double-Blind Method; Embolization, Therapeutic; Endovascular Procedures; Female; Glasgow Outcome Scale; Humans; Intracranial Aneurysm; Male; Middle Aged; Prognosis; Randomized Controlled Trials as Topic; Risk; Subarachnoid Hemorrhage; Survival Analysis; Treatment Outcome; Vasospasm, Intracranial; Young Adult
PubMed: 32442971
DOI: 10.3171/2020.3.JNS193400 -
Journal of Neurointerventional Surgery Oct 2023Vasospasm following aneurysmal subarachnoid hemorrhage (SAH) contributes significant morbidity and mortality after brain aneurysm rupture. However, the association...
BACKGROUND
Vasospasm following aneurysmal subarachnoid hemorrhage (SAH) contributes significant morbidity and mortality after brain aneurysm rupture. However, the association between vascular territory of vasospasm and clinical outcome has not been studied. We present a hypothesis-generating study to determine whether the location of vasospasm within the intracranial circulation is associated with functional outcome after SAH.
METHODS
A retrospective analysis of a prospective, intention-to-treat trial for aneurysmal SAH was performed to supplement trial outcomes with in-hospital angiographic imaging and treatment variables regarding vasospasm. The location of vasospasm and the position on the vessel (distal vs proximal) were evaluated. Modified Rankin scale (mRS) outcomes were assessed at discharge and 6 months, and predictive models were constructed.
RESULTS
A total of 406 patients were included, 341 with follow-up data at 6 months. At discharge, left-sided vasospasm was associated with poor outcome (odds ratio (OR), 2.37; 95% CI, 1.25 to 4.66; P=0.01). At 6 months, anterior cerebral artery (ACA) vasospasm (OR, 3.87; 95% CI, 1.29 to 11.88; P=0.02) and basilar artery (BA) vasospasm (OR, 6.22; 95% CI, 1.54 to 27.11; P=0.01) were associated with poor outcome after adjustment. A model predicting 6-month mRS score and incorporating vasospasm variables achieved an area under the curve of 0.85 and a net improvement in reclassification of 13.2% (P<0.01) compared with a previously validated predictive model for aneurysmal SAH.
CONCLUSIONS
In aneurysmal SAH, left-sided vasospasm is associated with worse discharge functional status. At 6 months, both ACA and BA vasospasm are associated with unfavorable functional status.
Topics: Humans; Subarachnoid Hemorrhage; Retrospective Studies; Vasospasm, Intracranial; Prospective Studies; Intracranial Aneurysm
PubMed: 36379702
DOI: 10.1136/jnis-2022-019016 -
Neuro-Chirurgie Jul 2022Delayed cerebral ischemia (DCI) and angiographic vasospasm following subarachnoid hemorrhage (SAH) have been associated for more than 50years. We aimed to examine... (Review)
Review
BACKGROUND AND PURPOSE
Delayed cerebral ischemia (DCI) and angiographic vasospasm following subarachnoid hemorrhage (SAH) have been associated for more than 50years. We aimed to examine whether the knowledge gained by theoretical research on vasospasm has actually translated into better patient outcomes in practice.
METHODS
This is a narrative review of the concept of vasospasm as a cause of DCI after SAH. We discuss recent studies that have assessed the accuracy and reliability of the diagnostic tests (transcranial Doppler ultrasound [TCD], CT angiography, and catheter angiography), which are used to identify SAH patients at-risk of DCI.
RESULTS
Both the diagnostic accuracy of TCD and the reliability of CT angiography to identify patients in severe vasospasm are poor. For the gold standard catheter angiography, the repeatability of the diagnosis of vasospasm, made by multiple raters, is only fair. Interventions on angiographic vasospasm have never been proven to improve patient outcomes. A pragmatic trial integrating the meaning of the diagnosis of vasospasm into a study protocol that assesses the value of endovascular interventions in the prevention of DCI after SAH seems to be in order. Such a trial could provide a pragmatic definition of clinically meaningful vasospasm.
CONCLUSION
We must move beyond research conceived as an enterprise aiming to acquire theoretical knowledge to one where research is integrated into clinical practice to improve clinical outcomes in real time.
Topics: Brain Ischemia; Cerebral Angiography; Humans; Reproducibility of Results; Subarachnoid Hemorrhage; Vasospasm, Intracranial
PubMed: 34844761
DOI: 10.1016/j.neuchi.2021.10.001 -
BMJ Case Reports Jan 2023We present a case of recurrent vasospasm as an uncommon cause of ventricular fibrillation in a young female patient who was found to have a genetic mutation of unknown...
We present a case of recurrent vasospasm as an uncommon cause of ventricular fibrillation in a young female patient who was found to have a genetic mutation of unknown significance in the desmoplakin (DSP) gene and ultimately required an implantable cardiac defibrillator and percutaneous coronary intervention. Refractory vasospasm as a cause of chest pain and cardiac arrest may be under-recognised. In this manuscript, we highlight the natural history of refractory vasospasm, treatment considerations including medical therapy, implantable cardiac defibrillator and percutaneous coronary intervention. Lastly, we explore the potential correlation between the DSP mutation and her clinical presentation and the growing importance of genetic testing in unexplained cardiac arrest.
Topics: Humans; Female; Coronary Vasospasm; Electrocardiography; Heart Arrest; Arrhythmias, Cardiac; Ventricular Fibrillation; Defibrillators, Implantable
PubMed: 36631170
DOI: 10.1136/bcr-2022-253884 -
Revue Neurologique 2022Aneurysmal subarachnoid hemorrhage (SAH) is a rare event affecting relatively young patients therefore leading to a high social impact. The management of SAH follows a... (Review)
Review
Aneurysmal subarachnoid hemorrhage (SAH) is a rare event affecting relatively young patients therefore leading to a high social impact. The management of SAH follows a biphasic course with early brain injuries in the first 72 hours followed by a phase at risk of secondary deterioration due to delayed cerebral ischemia (DCI) in 20 to 30% patients. Cerebral infarction from DCI is the most preventable cause of mortality and morbidity after SAH. DCI prevention, early detection and treatment is therefore advocated. Formerly limited to the occurrence of vasospasm, DCI is now associated with multiple pathophysiological processes involving for instance the macrocirculation, the microcirculation, neurovascular units, and inflammation. Therefore, the therapeutic targets and management strategies are also evolving and are not only focused on proximal vasospasm. In this review, we describe the current knowledge of DCI pathophysiology. We then discuss the diagnosis strategies that may guide physicians at the bedside with a multimodal approach in the unconscious patient. We will present the prevention strategies that have proven efficient as well as future targets and present the therapeutic approach that is currently being developed when a DCI occurs.
Topics: Brain Ischemia; Cerebral Infarction; Humans; Microcirculation; Subarachnoid Hemorrhage; Vasospasm, Intracranial
PubMed: 34961603
DOI: 10.1016/j.neurol.2021.11.006 -
Neurosurgical Review Dec 2022Cerebral vasospasm is a life-threatening complication following aneurysmal subarachnoid hemorrhage (aSAH). While digital subtraction angiography (DSA) is the current...
Cerebral vasospasm is a life-threatening complication following aneurysmal subarachnoid hemorrhage (aSAH). While digital subtraction angiography (DSA) is the current gold standard for detection, the diagnostic performance of computed tomography angiography (CTA) and transcranial Doppler (TCD) remains controversial. We aimed to summarize the available evidence and provide recommendations for their use based on GRADE criteria. A literature search was conducted for studies comparing CTA or TCD to DSA for adults ≥ 18 years with aSAH for radiographic vasospasm detection. The DerSimonian-Laird random-effects model was used to pool sensitivity and specificity and their 95% confidence intervals (CI) and derive positive and negative pooled likelihood ratios (LR + /LR -). Out of 2070 studies, seven studies (1646 arterial segments) met inclusion criteria and were meta-analyzed. Compared to the gold standard (DSA), CTA had a pooled sensitivity of 82% (95%CI, 68-91%) and a specificity of 97% (95%CI, 93-98%), while TCD had lower sensitivity 38% (95%CI, 19-62%) and specificity of 91% (95%CI, 87-94%). Only the LR + for CTA (27.3) reached clinical significance to rule in diagnosis. LR - for CTA (0.19) and TCD (0.68) approached clinical significance (< 0.1) to rule out diagnosis. CTA showed higher LR + and lower LR - than TCD for diagnosing radiographic vasospasm, thereby achieving a strong recommendation for its use in ruling in or out vasospasm, based on the high quality of evidence. TCDs had very low LR + and a reasonably low LR - , thereby achieving a weak recommendation against its use in ruling in vasospasm and weak recommendation for its use in ruling out vasospasm.
Topics: Adult; Humans; Vasospasm, Intracranial; Subarachnoid Hemorrhage; Computed Tomography Angiography; Cerebral Angiography; Ultrasonography, Doppler, Transcranial; Angiography, Digital Subtraction
PubMed: 36471088
DOI: 10.1007/s10143-022-01913-1 -
Minerva Anestesiologica Dec 2020Delayed cerebral ischemia (DCI) is the leading cause of mortality and disability in patients who survived the initial bleed of subarachnoid hemorrhage. Currently... (Review)
Review
Delayed cerebral ischemia (DCI) is the leading cause of mortality and disability in patients who survived the initial bleed of subarachnoid hemorrhage. Currently available guidelines are based on expert opinions derived from small observational studies due to the lack of randomized controlled trials. In this review, we will review some of the available literature and describe our local protocols for prophylaxis, risk stratification, monitoring in patients at risk, including multimodal invasive monitoring, and interventions measures in patients with DCI. These protocols are largely in line with the current guidelines but are deemed to evolve as ongoing and future trials provide stronger evidence to support interventions.
Topics: Brain Ischemia; Humans; Subarachnoid Hemorrhage; Vasospasm, Intracranial
PubMed: 32441086
DOI: 10.23736/S0375-9393.20.14507-3