Figure - available from: Frontiers in Neuroscience
This content is subject to copyright.
A quantitative summary of the change in hematoma and edema volume in a post-ICH pig brain. Panels (A–C) illustrate a representative MRI image showing outlined boundaries of intracranial volume, perihematoma, and hematoma at days 1, 7, and 14, respectively. Panels (D,E) show Perihematoma edema (D) and hematoma (E) volumes. A double asterisk (∗∗) denotes the significant temporal ipsilesional difference between the time point (p < 0.05). The error bars represent standard error in the mean.
Source publication
Purpose
Perihematomal edema (PHE) occurs in patients with intracerebral hemorrhage (ICH) and is often used as surrogate of secondary brain injury. PHE resolves over time, but little is known about the functional integrity of the tissues that recover from edema. In a pig ICH model, we aimed to assess metabolic integrity of perihematoma tissues by us...
Citations
... A multicenter study evaluated the subtypes of nontraumatic ICH and pointed out that hypertensive angiopathy (HA) is the most common cause of ICH, followed by undetermined ICH, cerebral amyloid angiopathy (CAA), structural vascular lesions, medication, and systemic disease [13]. ICH pathogenesis consists of primary injury related to the rupture of blood vessels, physical compression, and disruption of brain tissues by the expanding blood mass, as well as secondary injury, which is associated with hematoma toxicity, oxidative stress, neuroinflammation, blood-brain barrier (BBB) disruption, and consequent perihematomal edema (PHE) [14][15][16]. ...
Intracerebral hemorrhage (ICH) is a common subtype of stroke and places a great burden on the family and society with a high mortality and disability rate and a poor prognosis. Many findings from imaging and pathologic studies have suggested that cerebral ischemic lesions visualized on diffusion-weighted imaging (DWI) in patients with ICH are not rare and are generally considered to be associated with poor outcome, increased risk of recurrent (ischemic and hemorrhagic) stroke, cognitive impairment, and death. In this review, we describe the changes in cerebral blood flow (CBF) and DWI lesions after ICH and discuss the risk factors and possible mechanisms related to the occurrence of DWI lesions, such as cerebral microangiopathy, cerebral atherosclerosis, aggressive early blood pressure lowering, hyperglycemia, and inflammatory response. We also point out that a better understanding of cerebral DWI lesions will be a key step toward potential therapeutic interventions to improve long-term recovery for patients with ICH.
... Therefore, it is critical to better understand the reliability of PHE quantification methods and the clinical significance of PHE after ICH. So far, we know that PHE develops and progresses in several stages, each of which has significant morphological differences along with the corresponding molecular changes [13][14][15][16][17]. Evidence indicates that cerebral edema, predominantly neuronal cytotoxic edema, is not irreversible in its early phase after stroke [18,19]. Before we can establish the causal relationship between the severity of PHE and the functional outcomes of ICH, more studies are needed to investigate the mechanism of PHE to identify therapeutic targets. ...
Acute intracerebral hemorrhage (ICH) is a devastating type of stroke worldwide. Neuronal destruction involved in the brain damage process caused by ICH includes a primary injury formed by the mass effect of the hematoma and a secondary injury induced by the degradation products of a blood clot. Additionally, factors in the coagulation cascade and complement activation process also contribute to secondary brain injury by promoting the disruption of the blood-brain barrier and neuronal cell degeneration by enhancing the inflammatory response, oxidative stress, etc. Although treatment options for direct damage are limited, various strategies have been proposed to treat secondary injury post-ICH. Perihematomal edema (PHE) is a potential surrogate marker for secondary injury and may contribute to poor outcomes after ICH. Therefore, it is essential to investigate the underlying pathological mechanism, evolution, and potential therapeutic strategies to treat PHE. Here, we review the pathophysiology and imaging characteristics of PHE at different stages after acute ICH. As illustrated in preclinical and clinical studies, we discussed the merits and limitations of varying PHE quantification protocols, including absolute PHE volume, relative PHE volume, and extension distance calculated with images and other techniques. Importantly, this review summarizes the factors that affect PHE by focusing on traditional variables, the cerebral venous drainage system, and the brain lymphatic drainage system. Finally, to facilitate translational research, we analyze why the relationship between PHE and the functional outcome of ICH is currently controversial. We also emphasize promising therapeutic approaches that modulate multiple targets to alleviate PHE and promote neurologic recovery after acute ICH.
... The PHE expansion has been considered a novel neuroimaging marker of poor prognosis, and a recent study reviewed the impact of PHE on ICH prognosis (25). The preclinical research on magnetic resonance spectroscopy revealed that the recovery of N-acetylaspartate, choline, and creatine was faster in the PHE area than in the non-PHE area (31), suggesting that the PHE may provide a protective buffer against irreversible impairment. Nevertheless, real-world research showed that patients with absolute (15,32,33) and relative PHE expansion (5, 16) have a higher risk of developing poor neurological outcomes. ...
We attempt to generate a definition of delayed perihematomal edema expansion (DPE) and analyze its time course, risk factors, and clinical outcomes. A multi-cohort data was derived from the Chinese Intracranial Hemorrhage Image Database (CICHID). A non-contrast computed tomography (NCCT) -based deep learning model was constructed for fully automated segmentation hematoma and perihematomal edema (PHE). Time course of hematoma and PHE evolution correlated to initial hematoma volume was volumetrically assessed. Predictive values for DPE were calculated through receiver operating characteristic curve analysis and were tested in an independent cohort. Logistic regression analysis was utilized to identify risk factors for DPE formation and poor outcomes. The test cohort’s Dice scores of lesion segmentation were 0.877 and 0.642 for hematoma and PHE, respectively. Overall, 1201 patients were enrolled for time-course analysis of ICH evolution. A total of 312 patients were further selected for DPE analysis. Time course analysis showed the growth peak of PHE approximately concentrates in 14 days after onset. The best cutoff for DPE to predict poor outcome was 3.34 mL of absolute PHE expansion from 4-7 days to 8-14 days (AUC=0.784, sensitivity=72.2%, specificity=81.2%), and 3.78 mL of absolute PHE expansion from 8-14 days to 15-21 days (AUC=0.682, sensitivity=59.3%, specificity=92.1%) in the derivation sample. Patients with DPE was associated with worse outcome (OR: 12.340, 95%CI: 6.378-23.873, P<0.01), and the larger initial hematoma volume (OR: 1.021, 95%CI: 1.000-1.043, P=0.049) was the significant risk factor for DPE formation. This study constructed a well-performance deep learning model for automatic segmentations of hematoma and PHE. A new definition of DPE was generated and is confirmed to be related to poor outcomes in ICH. Patients with larger initial hematoma volume have a higher risk of developing DPE formation.
... The complicated pathophysiological processes involved in ICH are associated with primary and secondary brain injuries [3][4][5]. A primary injury is characterized by physical compression, hematoma volume and disruption of brain tissues [6]. A secondary injury is triggered by hematoma toxicity, acute inflammation and oxidative stress. ...
Intracerebral hemorrhage (ICH) is a devastating cerebrovascular disease with a high mortality rate affecting individuals worldwide. After ICH, persistent inflammation results in the death of brain cells, as well as the promotion of secondary brain injury. Verbascoside (VB), an active component in herbal medicine, possesses antioxidant, anti-inflammatory and neuroprotective properties. Furthermore, previous studies have shown that VB improves recovery of neuronal function after spinal cord injury in rats. In this study, we investigated whether VB limited inflammation induced by ICH through the targeting of NLRP3, which is associated with acute inflammation and apoptosis. Administration of VB reduced neurological impairment and pathological abnormalities associated with ICH, while increasing cell viability of neurons. This was achieved through NLRP3 inhibition and microglial activation. VB treatment decreased neuronal damage when co-cultured with microglia. Furthermore, knockout of NLRP3 eliminated the ability of VB to inhibit inflammation, cell death or protect neurons. Taken together, VB suppressed the inflammatory response following ICH by inhibiting NLRP3.
... Further, mobile stroke units may not only help in the early diagnosis of ischemic stroke but also add to rapid diagnosis of ICH and to correctly triaging these patients to the appropriate hospital, which may especially be important in rural areas [74][75][76]. The use of advanced imaging techniques such as MRspectroscopy promises to provide new insights into the diagnosis and pathophysiology of hemorrhage, the course of cerebral recovery, and the response to putative therapies not only of the ICH itself but also the surrounding edematous tissue [77,78]. ...
Intracerebral hemorrhage (ICH) accounts for 10% to 20% of all strokes worldwide and is associated with high morbidity and mortality. Neuroimaging is clinically important for the rapid diagnosis of ICH and underlying etiologies, but also for identification of ICH expansion, often as-sociated with an increased risk for poor outcome. In this context, rapid assessment of early hema-toma expansion risk is both an opportunity for therapeutic intervention and a potential hazard for hematoma evacuation surgery. In this review, we provide an overview of the current literature surrounding the use of multimodal neuroimaging of ICH for etiological diagnosis, prediction of early hematoma expansion, and prognostication of neurological outcome. Specifically, we discuss standard imaging using computed tomography, the value of different vascular imaging modalities to identify underlying causes and present recent advances in magnetic resonance imaging and computed tomography perfusion.
... Further, mobile stroke units may not only help in the early diagnosis of ischemic stroke but also add to rapid diagnosis of ICH and to correctly triaging these patients to the appropriate hospital, which may especially be important in rural areas [74][75][76]. The use of advanced imaging techniques such as MRspectroscopy promises to provide new insights into the diagnosis and pathophysiology of hemorrhage, the course of cerebral recovery, and the response to putative therapies not only of the ICH itself but also the surrounding edematous tissue [77,78]. ...
... In a recent study, injection of blood to the target region of the brain was performed after a craniotomy, but this was only performed to apply focused ultrasounds to liquefy induced intracerebral blood clots [165]. However, the main method remains to be the surgical access to the target area and direct injection of the blood through a catheter or needle [158,159,[187][188][189][190][191][192][193][194]197,[199][200][201][202][203][204][205][206][207][208][209][210][211][212]. ...
In the search of animal stroke models providing translational advantages for biomedical research, pigs are large mammals with interesting brain characteristics and wide social acceptance. Compared to rodents, pigs have human-like highly gyrencephalic brains. In addition, increasingly through phylogeny, animals have more sophisticated white matter connectivity; thus, ratios of white-to-gray matter in humans and pigs are higher than in rodents. Swine models provide the opportunity to study the effect of stroke with emphasis on white matter damage and neuroanatomical changes in connectivity, and their pathophysiological correlate. In addition, the subarachnoid space surrounding the swine brain resembles that of humans. This allows the accumulation of blood and clots in subarachnoid hemorrhage models mimicking the clinical condition. The clot accumulation has been reported to mediate pathological mechanisms known to contribute to infarct progression and final damage in stroke patients. Importantly, swine allows trustworthy tracking of brain damage evolution using the same non-invasive multimodal imaging sequences used in the clinical practice. Moreover, several models of comorbidities and pathologies usually found in stroke patients have recently been established in swine. We review here ischemic and hemorrhagic stroke models reported so far in pigs. The advantages and limitations of each model are also discussed.
... Specifically, the structural and functional disruption of neurovascular unit (NVU) may be critically involved in the pathogenesis [17]. NVU is structurally related to neuronal and neuroglial cells, as well as microvascular endothelial cells, smooth muscle cells, pericytes and the extracellular matrix [18][19][20][21][22]. Thus, through tightly regulated multidirectional molecular signaling, the NVU is considered to be involved in many key processes critical for functional neurovascular coupling, including via a response of angiogenesis. ...
Background
Cerebral stroke occurs following ischemic and hemorrhagic lesions in the brain. Survival and recovery of stroke patients depend on the severity of the initial injury but also the therapeutic approaches applied for emergent lifesaving and continuing post-stroke management. Dl-3-n-Butylphthalide (NBP), an active compound derived from Chinese celery seeds, has shown clinical efficacy in the treatment of ischemic cerebral stroke.
Results
In the present study we explored the therapeutic effect of NBP in a rat model of intracerebral hemorrhage (ICH), focusing on its potential role in promoting neovascularization in the perihemorrhagic zone. ICH was induced in male Sprague-Dawley rats by unilateral injection of autologous blood into the globus pallidus, with sham-operated (Sham group), vehicle-treated (ICH) and NBP-treated (at 10 and 25 mg/kg/Bid, p.o., ICH + NBP10 and ICH + NBP25, respectively) groups examined behaviorally, macroscopically, histologically and biochemically at 1, 3, 7 and 15 days (d) post operation. Rats in the ICH + NBP10 and ICH + NBP25 groups showed reduced Longa’s motor scores relative to the ICH groups at the 3 and 7d time points, while the hematoma volume was comparable in the two NBP relative to the ICH groups as measured at 7d and 15d. In the perihemorrhagic zone, the numeric density of blood vessels immunolabeled by CD34, an angiogenic marker, was greater in the ICH + NBP10 and ICH + NBP25 than ICH groups, more so in the higher dosage group, at 1, 3, 7 and 15d. Levels of the vascular endothelial growth factor (VEGF) and angiopoietins-2 (Ang-2) proteins were elevated in the NBP groups relative to the sham and vehicle controls in immunoblotting of tissue lysates from the injection region.
Conclusion
These results suggest that NBP can alleviate neurological defects following experimentally induced local brain hemorrhage, which is associated with a potential role of this drug in promoting neovascularization surrounding the bleeding loci.
Swimming training (ST) can mitigate functional disorders in neurological diseases, but the effect and mechanism of ST in improving the neurological function of intracerebral haemorrhage (ICH) have not been reported. Our study aimed to explore the protective effect of early ST on ICH mice and its relationship with the serine-threonine kinase (Akt)/glycogen synthase kinase 3β (GSK3β) pathway. Our findings showed that the ICH model mice had poor behavioural manifestations in the Y maze test and open field test compared to the ST group and sham group. The modified neurological severity score was increased in the ICH mice, and 7 days of ST intervention significantly attenuated the neurological deficits. The ratios of myo-inositol/creatine, lactate/creatine and glutamate/creatine were decreased, and the ratios of N-acetylaspartate/creatine and choline/creatine were increased in the ICH mice with ST intervention. ST intervention decreased the expression of Iba1 and GFAP. Seven days of ST significantly increased the expression of p-Akt/Akt compared to that in the ICH mice. Furthermore, the Akt kinase inhibitor GSK690693 exacerbated neurological impairment, increased the expression of Iba1, GFAP and Bax/Bcl-2, and reversed the anti-apoptotic effects and anti-glia activation of ST, which was associated with the inhibition of p-Akt/Akt and p-GSK3β/GSK3β expression. These results indicated that the protective role of ST in ICH was mediated via the Akt/GSK3β pathway. In conclusion, ST displayed neuroprotection by inhibiting apoptosis and glial activation in ICH mice by activating the Akt/GSK3β signalling pathway.
Objectives
To explore whether radiomic features of perihematomal tissue can improve the forecasting accuracy for the prognosis of patients with an intracerebral hemorrhage (ICH).
Materials and methods
In total, 118 ICH patients were retrospectively studied that had a clinical and radiological diagnosis of spontaneous ICH. The functional outcome 3 months after ictus was measured using the modified Rankin Scale (mRS), which was divided into good (mRS ≤ 2) and poor outcomes (mRS > 2). A total of 2260 radiomics features were obtained from non-contrast computer tomography (NCCT) images, with 1130 features extracted from the hematoma and the hematoma plus perihematoma. The high-dimensional data was modeled by a logistic regression algorithm and the accuracy of the model was verified by five-fold cross-validation. The predictive performance of radiomics models was assessed by the area under the receiver operating characteristic (ROC) curve.
Results
In the test set, the mean ROC area under the curve (AUC) of the hematoma set to predict the prognosis of ICH was 0.83, and the specificity and sensitivity were 78% and 81%, respectively. When the hematoma and perihematomal tissue were combined, the mean AUC increased to 0.88, and the specificity and sensitivity reached 85% and 84%, respectively. The hematoma plus perihematoma model showed a significantly higher AUC and specificity.
Conclusions
Analysis of the hematoma and perihematomal tissue NCCT-based radiomics could potentially identify the progression of a hematoma more accurately and could be a valuable clinical target to enhance the prediction of outcomes in patients with ICH.
