Pathophysiology of Subarachnoid Hemorrhage, Early Brain Injury, and Delayed Cerebral Ischemia

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke associated with high mortality and morbidity. The blood-brain-barrier (BBB) is a structure consisting primarily of cerebral microvascular endothelial cells, end feet of astrocytes, extracellular matrix, and pericytes. Post-SAH pathophysiology included early brain injury and delayed cerebral ischemia. BBB disruption was a critical mechanism of early brain injury and was associated with other pathophysiological events. These pathophysiological events may propel the development of secondary brain injury, known as delayed cerebral ischemia. Imaging advancements to measure BBB after SAH primarily focused on exploring innovative methods to predict clinical outcome, delayed cerebral ischemia, and delayed infarction related to delayed cerebral ischemia in acute periods. These predictions are based on detecting abnormal changes in BBB permeability. The parameters of BBB permeability are described by changes in computed tomography (CT) perfusion and magnetic resonance imaging (MRI). Kep seems to be a stable and sensitive indicator in CT perfusion, whereas Ktrans is a reliable parameter for dynamic contrast-enhanced MRI. Future prediction models that utilize both the volume of BBB disruption and stable parameters of BBB may be a promising direction to develop practical clinical tools. These tools could provide greater accuracy in predicting clinical outcome and risk of deterioration. Therapeutic interventional exploration targeting BBB disruption is also promising, considering the extended duration of post-SAH BBB disruption.

Download Full-text

Abstract 192: The Relationship of Platelet-leukocyte Aggregates and Early Brain Injury After Subarachnoid Hemorrhage

Stroke ◽

10.1161/str.48.suppl_1.192 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Jennifer A Frontera ◽

Vladimir Katyshev ◽

Thomas M McIntyre ◽

Fatima A Sehba ◽

Jonathan M Weimer ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Delayed Cerebral Ischemia ◽

Early Brain Injury ◽

Aneurysm Rupture ◽

Acute Brain Injury ◽

Unruptured Aneurysms ◽

Major Predictor ◽

A Prospective Study ◽

And Control

Introduction: Acute brain injury incurred after aneurysm rupture in subarachnoid hemorrhage (SAH) is a major predictor of poor functional outcome. We hypothesize that platelet-leukocyte aggregates (PLA) form early after SAH and contribute to acute brain injury. Methods: A prospective study of antiplatelet-naive SAH patients and controls (patients with unruptured aneurysms undergoing repair) was conducted from 3/2014-3/2016. Platelet-monocyte, platelet-lymphocyte and platelet-neutrophil aggregates in whole blood were measured with and without exposure to a platelet agonist (Thrombin receptor activating peptide [TRAP]) using flow cytometry. PLA within 24h and averaged over 72h from ictus (prior to the onset of delayed cerebral ischemia/vasospasm) were compared between patients with mild (admission Hunt-Hess [HH] 1-3) versus severe early brain injury (EBI; HH 4-5). Results: We enrolled 60 SAH patients and 13 controls. PLA were significantly lower in those with severe EBI compared to those with mild EBI (Platelet-monocyte-aggregates 36% versus 53%, P=0.011; Platelet-neutrophil-aggregates 15.2 versus 23.1%, P=0.002) within 24h of ictus and prior to aneurysm repair and remained significantly lower over 72h (both P<0.05). Platelet-monocyte, platelet-neutrophil and platelet-lymphocyte aggregates were also significantly lower in those with severe EBI compared to controls (all P<0.05). The ability of platelets to be stimulated/activated by TRAP to form PLA was also lower in severe EBI patients compared to mild EBI and control patients over 72h (platelet-neutrophil-aggregates 79.7, 88.2 and 92.7%, respectively, P=0.003; platelet-lymphocyte aggregates 9.2, 11.0 and 14.6%, respectively, P=0.022), consistent with prior platelet activation/degranulation. Conclusions: PLA are lower, and respond less to stimulation in patients with severe EBI after SAH compared to those with mild EBI and controls. These data suggest that in severe EBI: PLA may form earlier and are cleared, are adherent to endothelium and not shed in the blood, or have migrated into the parenchyma. These hypotheses bear further study.

Download Full-text

Early Brain Injury: A Common Mechanism in Subarachnoid Hemorrhage and Global Cerebral Ischemia

Stroke Research and Treatment ◽

10.1155/2013/394036 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 26

Author(s):

Mohammed Sabri ◽

Elliot Lass ◽

R. Loch Macdonald

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Cerebral Ischemia ◽

Early Brain Injury ◽

Cerebral Hypoperfusion ◽

Global Cerebral Ischemia ◽

Common Mechanism ◽

Common Denominator ◽

Transient Ischemia

Early brain injury (EBI) has become an area of extreme interest in the recent years and seems to be a common denominator in the pathophysiology of global transient ischemia and subarachnoid hemorrhage (SAH). In this paper, we highlight the importance of cerebral hypoperfusion and other mechanisms that occur in tandem in both pathologies and underline their possible roles in triggering brain injury after hemorrhagic or ischemic strokes.

Download Full-text

Assessment of tissue permeability by early CT perfusion as a surrogate parameter for early brain injury after subarachnoid hemorrhage

Journal of Neurosurgery ◽

10.3171/2019.5.jns19765 ◽

2020 ◽

Vol 133 (3) ◽

pp. 808-813 ◽

Cited By ~ 1

Author(s):

Vesna Malinova ◽

Bogdan Iliev ◽

Ioannis Tsogkas ◽

Veit Rohde ◽

Marios-Nikos Psychogios ◽

...

Keyword(s):

Logistic Regression ◽

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Predictive Value ◽

Time Course ◽

Ct Perfusion ◽

Delayed Cerebral Ischemia ◽

Early Brain Injury ◽

Tissue Permeability ◽

Perfusion Deficits

OBJECTIVEThe severity of early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (aSAH) correlates with delayed cerebral ischemia (DCI) and outcome. A disruption of the blood-brain barrier is part of EBI pathophysiology. The aim of this study was to assess tissue permeability (PMB) by CT perfusion (CTP) in the acute phase after aSAH and its impact on DCI and outcome.METHODSCTP was performed on day 3 after aSAH. Qualitative and quantitative analyses of all CTP parameters, including PMB, were performed. The areas with increased PMB were documented. The value of an early PMB increase as a predictor of DCI and outcome according to the modified Rankin Scale (mRS) grade 3 to 24 months after aSAH was assessed. Possible associations of increased PMB with the Subarachnoid Hemorrhage Early Brain Edema Score (SEBES) and with early perfusion deficits, as radiographic EBI markers, were evaluated.RESULTSA total of 69 patients were enrolled in the study. An increased PMB on early CTP was detected in 10.1% (7/69) of all patients. A favorable outcome (mRS grade ≤ 2) occurred in 40.6% (28/69) of all patients. DCI was detected in 25% (17/69) of all patients. An increased PMB was a predictor of DCI (logistic regression, p = 0.03) but not of outcome (logistic regression, p = 0.40). The detection of increased PMB predicted DCI with a sensitivity of 25%, a specificity of 94%, a positive predictive value of 57%, and a negative predictive value of 79% (chi-square test p = 0.03). Early perfusion deficits were seen in 68.1% (47/69) of the patients, a finding that correlated with DCI (p = 0.005) but not with the outcome. No correlation was found between the SEBES and increased PMB.CONCLUSIONSChanges in PMB can be detected by early CTP after aSAH, which correlates with DCI. Future studies are needed to evaluate the time course of PMB changes and their interaction with therapeutic measures.

Download Full-text

Role of Damage Associated Molecular Pattern Molecules (DAMPs) in Aneurysmal Subarachnoid Hemorrhage (aSAH)

International Journal of Molecular Sciences ◽

10.3390/ijms19072035 ◽

2018 ◽

Vol 19 (7) ◽

pp. 2035 ◽

Cited By ~ 20

Author(s):

Shafqat Chaudhry ◽

Ahmad Hafez ◽

Behnam Rezai Jahromi ◽

Thomas Kinfe ◽

Alf Lamprecht ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Therapy Monitoring ◽

Delayed Cerebral Ischemia ◽

Early Brain Injury ◽

Neurological Deficits ◽

Endovascular Coiling ◽

Molecular Pattern ◽

Extracellular Matrix Components

Aneurysmal subarachnoid hemorrhage (aSAH) represents only a small portion of all strokes, but accounts for almost half of the deaths caused by stroke worldwide. Neurosurgical clipping and endovascular coiling can successfully obliterate the bleeding aneurysms, but ensuing complications such as cerebral vasospasm, acute and chronic hydrocephalus, seizures, cortical spreading depression, delayed ischemic neurological deficits, and delayed cerebral ischemia lead to poor clinical outcomes. The mechanisms leading to these complications are complex and poorly understood. Early brain injury resulting from transient global ischemia can release molecules that may be critical to initiate and sustain inflammatory response. Hence, the events during early brain injury can influence the occurrence of delayed brain injury. Since the damage associated molecular pattern molecules (DAMPs) might be the initiators of inflammation in the pathophysiology of aSAH, so the aim of this review is to highlight their role in the context of aSAH from diagnostic, prognostic, therapeutic, and drug therapy monitoring perspectives. DAMPs represent a diverse and a heterogenous group of molecules derived from different compartments of cells upon injury. Here, we have reviewed the most important DAMPs molecules including high mobility group box-1 (HMGB1), S100B, hemoglobin and its derivatives, extracellular matrix components, IL-1α, IL-33, and mitochondrial DNA in the context of aSAH and their role in post-aSAH complications and clinical outcome after aSAH.

Download Full-text

Measuring the Impact of Delayed Cerebral Ischemia on Neuropsychological Outcome After Aneurysmal Subarachnoid Hemorrhage—Protocol of a Swiss Nationwide Observational Study (MoCA–DCI Study)

Neurosurgery ◽

10.1093/neuros/nyy155 ◽

2018 ◽

Vol 84 (5) ◽

pp. 1124-1132 ◽

Cited By ~ 5

Author(s):

Martin N Stienen ◽

Christian Fung ◽

Philippe Bijlenga ◽

Daniel W Zumofen ◽

Rodolfo Maduri ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Cerebral Ischemia ◽

Observational Study ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Patient Specific ◽

Neuropsychological Outcome ◽

The Relationship ◽

Baseline Examination

AbstractBACKGROUNDThe exact relationship between delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) and neuropsychological impairment remains unknown, as previous studies lacked a baseline examination after aneurysm occlusion but before the DCI-period. Neuropsychological evaluation of acutely ill patients is often applied in a busy intensive care unit (ICU), where distraction represents a bias to the obtained results.OBJECTIVETo evaluate the relationship between DCI and neuropsychological outcome after aSAH by comparing the Montreal Cognitive Assessment (MoCA) results in aSAH patients with and without DCI at 3 mo with a baseline examination before the DCI-period (part 1). To determine the reliability of the MoCA, when applied in an ICU setting (part 2).METHODSProspective, multicenter, and observational study performed at all Swiss neurovascular centers. For part 1, n = 240 consecutive aSAH patients and for part 2, n = 50 patients with acute brain injury are recruited.EXPECTED OUTCOMESPart 1: Effect size of the relationship between DCI and neuropsychological outcome (MoCA). Part 2: Reliability measures for the MoCA.DISCUSSIONThe institutional review boards approved this study on July 4, 2017 under case number BASEC 2017-00103. After completion, the results will be offered to an international scientific journal for peer-reviewed publication. This study determines the exact impact of DCI on the neuropsychological outcome after aSAH, unbiased by confounding factors such as early brain injury or patient-specific characteristics. The study provides unique insights in the neuropsychological state of patients in the early period after aSAH.

Download Full-text

Automated Quantification of Reduced Sulcal Volume Identifies Early Brain Injury After Aneurysmal Subarachnoid Hemorrhage

Stroke ◽

10.1161/strokeaha.120.032001 ◽

2021 ◽

Author(s):

Jane Y. Yuan ◽

Yasheng Chen ◽

Atul Kumar ◽

Zach Zlepper ◽

Keshav Jayaraman ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Characteristic Curve ◽

Delayed Cerebral Ischemia ◽

Early Brain Injury ◽

Younger Patients ◽

Poor Outcome ◽

Dependent Relationship ◽

Relationship Of

Background and Purpose: Early brain injury may be a more significant contributor to poor outcome after aneurysmal subarachnoid hemorrhage (aSAH) than vasospasm and delayed cerebral ischemia. However, studying this process has been hampered by lack of a means of quantifying the spectrum of injury. Global cerebral edema (GCE) is the most widely accepted manifestation of early brain injury but is currently assessed only through subjective, qualitative or semi-quantitative means. Selective sulcal volume (SSV), the CSF volume above the lateral ventricles, has been proposed as a quantitative biomarker of GCE, but is time-consuming to measure manually. Here we implement an automated algorithm to extract SSV and evaluate the age-dependent relationship of reduced SSV on early outcomes after aSAH. Methods: We selected all adults with aSAH admitted to a single institution with imaging within 72 hours of ictus. Scans were assessed for qualitative presence of GCE. SSV was automatically segmented from serial CTs using a deep learning-based approach. Early SSV was the lowest SSV from all early scans. Modified Rankin Scale score of 4 to 6 at hospital discharge was classified as a poor outcome. Results: Two hundred forty-four patients with aSAH were included. Sixty-five (27%) had GCE on admission while 24 developed it subsequently within 72 hours. Median SSV on admission was 10.7 mL but frequently decreased, with minimum early SSV being 3.0 mL (interquartile range, 0.3–11.9). Early SSV below 5 mL was highly predictive of qualitative GCE (area under receiver-operating-characteristic curve, 0.90). Reduced early SSV was an independent predictor of poor outcome, with a stronger effect in younger patients. Conclusions: Automated assessment of SSV provides an objective biomarker of GCE that can be leveraged to quantify early brain injury and dissect its impact on outcomes after aSAH. Such quantitative analysis suggests that GCE may be more impactful to younger patients with SAH.

Download Full-text

The Role of the Glycocalyx in the Pathophysiology of Subarachnoid Hemorrhage-Induced Delayed Cerebral Ischemia

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.731641 ◽

2021 ◽

Vol 9 ◽

Author(s):

Hanna Schenck ◽

Eliisa Netti ◽

Onno Teernstra ◽

Inger De Ridder ◽

Jim Dings ◽

...

Keyword(s):

Oxidative Stress ◽

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Brain Damage ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Neurovascular Unit ◽

Delayed Cerebral Ischemia ◽

Treatment Strategies ◽

Early Brain Injury

The glycocalyx is an important constituent of blood vessels located between the bloodstream and the endothelium. It plays a pivotal role in intercellular interactions in neuroinflammation, reduction of vascular oxidative stress, and provides a barrier regulating vascular permeability. In the brain, the glycocalyx is closely related to functions of the blood-brain barrier and neurovascular unit, both responsible for adequate neurovascular responses to potential threats to cerebral homeostasis. An aneurysmal subarachnoid hemorrhage (aSAH) occurs following rupture of an intracranial aneurysm and leads to immediate brain damage (early brain injury). In some cases, this can result in secondary brain damage, also known as delayed cerebral ischemia (DCI). DCI is a life-threatening condition that affects up to 30% of all aSAH patients. As such, it is associated with substantial societal and healthcare-related costs. Causes of DCI are multifactorial and thought to involve neuroinflammation, oxidative stress, neuroinflammation, thrombosis, and neurovascular uncoupling. To date, prediction of DCI is limited, and preventive and effective treatment strategies of DCI are scarce. There is increasing evidence that the glycocalyx is disrupted following an aSAH, and that glycocalyx disruption could precipitate or aggravate DCI. This review explores the potential role of the glycocalyx in the pathophysiological mechanisms contributing to DCI following aSAH. Understanding the role of the glycocalyx in DCI could advance the development of improved methods to predict DCI or identify patients at risk for DCI. This knowledge may also alter the methods and timing of preventive and treatment strategies of DCI. To this end, we review the potential and limitations of methods currently used to evaluate the glycocalyx, and strategies to restore or prevent glycocalyx shedding.

Download Full-text