Remote Ischemic Conditioning to Reduce Perihematoma Edema in Patients with Intracerebral Hemorrhage (RICOCHET): A Randomized Control Trial.

Background: Early perihematomal edema (PHE) growth is associated with worse functional outcomes at 90 days. Remote Ischemic conditioning (RIC) may reduce perihematomal inflammation if applied early to patients with intracerebral hemorrhage (ICH). We hypothesize that early RIC, delivered for seven days in patients with spontaneous ICH, may reduce PHE growth. Methods: ICH patients presenting within 6 h of symptom onset and hematoma volume < 60 milliliters (mL) were randomized to an RIC + standard care or standard care (SC) group. The primary outcome measure was calculated edema extension distance (EED), with the cm assessed on day seven. Results: Sixty patients were randomized with a mean ± SD age of 57.5 ± 10.8 years, and twenty-two (36.7%) were female. The relative baseline median PHE were similar (RIC group 0.75 (0.5-0.9) mL vs. SC group 0.91 (0.5-1.2) mL, p = 0.30). The median EEDs at baseline were similar (RIC group 0.58 (0.3-0.8) cm vs. SC group 0.51 (0.3-0.8) cm, p = 0.76). There was no difference in the median day 7 EED (RIC group 1.1 (0.6-1.2) cm vs. SC group 1 (0.9-1.2) cm, p = 0.75). Conclusions: Early RIC therapy delivered daily for seven days was feasible. However, no decrease in EED was noted with the intervention.

Clinical implications of Peri-hematomal edema microperfusion fraction in intracerebral hemorrhage intravoxel incoherent motion imaging - A pilot study.

BACKGROUND AND PURPOSE: Perihematomal edema (PHE) represents the secondary brain injury after intracerebral hemorrhage (ICH). However, neurobiological characteristics of post-ICH parenchymal injury other than PHE volume have not been fully characterized. Using intravoxel incoherent motion imaging (IVIM), we explored the clinical correlates of PHE diffusion and (micro)perfusion metrics in subacute ICH. MATERIALS AND METHODS: In 41 consecutive patients scanned 1-to-7 days after supratentorial ICH, we determined the mean diffusion (D), pseudo-diffusion (D*), and perfusion fraction (F) within manually segmented PHE. Using univariable and multivariable statistics, we evaluated the relationship of these IVIM metrics with 3-month outcome based on the modified Rankin Scale (mRS). RESULTS: In our cohort, the average (± standard deviation) age of patients was 68.6±15.6 years, median (interquartile) baseline National Institute of Health Stroke Scale (NIHSS) was 7 (3-13), 11 (27 %) patients had poor outcomes (mRS>3), and 4 (10 %) deceased during the follow-up period. In univariable analyses, admission NIHSS (p < 0.001), ICH volume (p = 0.019), ICH+PHE volume (p = 0.016), and average F of the PHE (p = 0.005) had significant correlation with 3-month mRS. In multivariable model, the admission NIHSS (p = 0.006) and average F perfusion fraction of the PHE (p = 0.003) were predictors of 3-month mRS. CONCLUSION: The IVIM perfusion fraction (F) maps represent the blood flow within microvasculature. Our pilot study shows that higher PHE microperfusion in subacute ICH is associated with worse outcomes. Once validated in larger cohorts, IVIM metrics may provide insight into neurobiology of post-ICH secondary brain injury and identify at-risk patients who may benefit from neuroprotective therapy.

Perihematomal edema-based CT-radiomics model to predict functional outcome in patients with intracerebral hemorrhage.

PURPOSE: The purpose of this study was to identify possible association between noncontrast computed tomography (NCCT)-based radiomics features of perihematomal edema (PHE) and poor functional outcome at 90 days after intracerebral hemorrhage (ICH) and to develop a NCCT-based radiomics-clinical nomogram to predict 90-day functional outcomes in patients with ICH. MATERIALS AND METHODS: In this multicenter retrospective study, 107 radiomics features were extracted from 1098 NCCT examinations obtained in 1098 patients with ICH. There were 652 men and 446 women with a mean age of 60 ± 12 (SD) years (range: 23-95 years). After harmonized and univariable and multivariable screening, seven of these radiomics features were closely associated with the 90-day functional outcome of patients with ICH. The radiomics score (Rad-score) was calculated based on the seven radiomics features. A clinical-radiomics nomogram was developed and validated in three cohorts. The model performance was evaluated using area under the curve analysis and decision and calibration curves. RESULTS: Of the 1098 patients with ICH, 395 had a good outcome at 90 days. Hematoma hypodensity sign and intraventricular and subarachnoid hemorrhages were identified as risk factors for poor outcomes (P < 0.001). Age, Glasgow coma scale score, and Rad-score were independently associated with outcome. The clinical-radiomics nomogram showed good predictive performance with AUCs of 0.882 (95% CI: 0.859-0.905), 0.834 (95% CI: 0.776-0.891) and 0.905 (95% CI: 0.839-0.970) in the three cohorts and clinical applicability. CONCLUSION: NCCT-based radiomics features from PHE are highly correlated with outcome. When combined with Rad-score, radiomics features from PHE can improve the predictive performance for 90-day poor outcome in patients with ICH.

Perihematomal edema: Implications for intracerebral hemorrhage research and therapeutic advances.

In humans, perihematomal edema (PHE) is considered to be a radiological marker of secondary injury following intracerebral hemorrhage (ICH). There is also evidence that PHE might contribute to poor outcome in ICH patients. Given the rising interest in secondary injury after ICH as a therapeutic target, PHE is becoming increasingly used as a proof-of-concept surrogate measure to assess the potential efficacy of various therapeutic interventions in clinical trials. We review the pathophysiology of PHE and its evolution, its prognostic significance and relationship to clinical outcomes, and variabilities in its detection and measurement methodologies to determine the advantages versus shortcomings of using PHE as a translational target or radiological marker to examine the efficacy of interventions aiming to mitigate secondary injury in ICH.

Decompressive Hemicraniectomy Associated With Ultrasound-Guided Minimally Invasive Puncture and Drainage Has Better Feasibility Than the Traditional Hematoma Evacuation for Deteriorating Spontaneous Intracranial Hemorrhage in the Basal Ganglia Region: A Retrospective Observational Cohort Study.

Objectives: Spontaneous intracerebral hemorrhage (ICH) is a devastating disease with higher mortality and disability rates; however, ideal surgical management is still to be determined for critical ICH. The purpose of this study was to prove the feasibility and unique clinical value of a novel combination, decompressive hemicraniectomy associated with ultrasound-guided minimally invasive puncture and drainage (DH + MIPD), for deteriorating ICH in the basal ganglia region. Methods: According to the enrollment criteria, 168 ICH patients were analyzed retrospectively, of which 86 patients received DH + MIPD and 82 patients received DH associated with traditional hematoma evacuation as the control group. The change process of three parameters, including hematoma size, peri-hematoma edema, and intracranial pressure (ICP), in a period of time after operation, as well as the short- and long-term therapeutic effect, was compared. Results: The DH + MIPD method could effectively achieve the evacuation rate of hematoma up to 87% at 5 days post-operation and had the significant advantages of minimal injury to cerebral tissue, less degree of edema, better effect of decreasing ICP, shorter operation time, less blood loss, and lower mortality compared with the control method. The DH + MIPD group had a significantly higher survival rate within 1 year post-operation (P = 0.007) and better functional outcome at 90 and 180 days post-operation (P = 0.004). A subgroup analysis pointed out that the DH + MIPD method had a definite survival advantage for critical ICH patients older than 60 years old and with hematoma located in the left dominant hemisphere. Conclusions: Our results proved the better feasibility of DH + MIPD on hematoma evacuation and implicated its significant advantages of reducing mortality and improving functional recovery. This method provides one more choice for the individualized therapy of ICH in the basal ganglia region.

Effects of Deferoxamine Mesylate on Hematoma and Perihematoma Edema after Traumatic Intracerebral Hemorrhage.

Deferoxamine mesylate can cross the blood-brain barrier and reduce iron accumulation in nervous tissue; moreover, it has a variety of neuroprotective functions in addition to complexing with iron ions. Such iron chelators are expected to become a new treatment option for intracerebral hemorrhage. This study evaluated the effects of deferoxamine mesylate on hematoma and edema absorption after traumatic intracerebral hemorrhage (TICH), and it provides clinical evidence for TICH treatment with deferoxamine mesylate. Patients with isolated TICH, confirmed by head computed tomography, were enrolled prospectively from January 2013 to December 2016. Patients were divided non-randomly into an experimental or control group as decided by the attending neurosurgeon. Patients in the experimental group received intravenous deferoxamine mesylate (20 mg/kg daily) from the day of admission for 5 consecutive days. We evaluated the impact of deferoxamine mesylate on the change in edema volume and the absorption of hematoma volume using a propensity score-matched analysis. In total, 190 patients were included. After matching, 94 patients were included in the final analysis (47 per group); no variable differed significantly between the two groups. The hematoma volume on the 7th day in the control group was higher than that at the same time-point in the experimental group (9.4 ± 7.2 vs. 5.2 ± 4.8 mL; p = 0.001). There was no difference in hematoma volume on Day 1 (12.6 ± 7.8 vs. 12.8 ± 6.4 mL; p = 0.896), Day 3 (12.4 ± 7.4 vs. 11.4 ± 4.9 mL; p = 0.442), and Day 14 (3.2 ± 3.0 vs. 2.5 ± 2.6 mL; p = 0.215) between the groups. The absorption of hematoma volume between the 1st and 3rd days and the 1st and 7th days in the experimental group was higher than that during the same periods in the control group. The edema volumes on the 3rd, 7th, and 14th days in the control group were higher than those at the same time-points in the experimental group. There was no difference in edema volume on the 1st day. The changes in edema volume between the 1st and 3rd days, the 1st and 7th days, and the 1st and 14th days in the control group were higher than those during the same periods in the experimental group. Deferoxamine mesylate may accelerate hematoma absorption and inhibit edema after TICH; however, further investigation is required to reach definitive conclusions.

Aggressive blood pressure treatment of hypertensive intracerebral hemorrhage may lead to global cerebral hypoperfusion: Case report and imaging perspective.

Hypoperfusion injury related to blood pressure decrease in acute hypertensive intracerebral hemorrhage continues to be a controversial topic. Aggressive treatment is provided with the intent to stop the ongoing bleeding. However, there may be additional factors, including autoregulation and increased intracranial pressure, that may limit this approach. We present here a case of acute hypertensive intracerebral hemorrhage, in which aggressive blood pressure management to levels within the normal range led to global cerebral ischemia within multiple border zones. Global cerebral ischemia may be of concern in the management of hypertensive hemorrhage in the presence of premorbid poorly controlled blood pressure and increased intracranial pressure.

After Intracerebral Hemorrhage, Oligodendrocyte Precursors Proliferate and Differentiate Inside White-Matter Tracts in the Rat Striatum.

Damage to myelinated axons contributes to neurological deficits after acute CNS injury, including ischemic and hemorrhagic stroke. Potential treatments to promote re-myelination will require fully differentiated oligodendrocytes, but almost nothing is known about their fate following intracerebral hemorrhage (ICH). Using a rat model of ICH in the striatum, we quantified survival, proliferation, and differentiation of oligodendrocyte precursor cells (OPCs) (at 1, 3, 7, 14, and 28 days) in the peri-hematoma region, surrounding striatum, and contralateral striatum. In the peri-hematoma, the density of Olig2(+) cells increased dramatically over the first 7 days, and this coincided with disorganization and fragmentation of myelinated axon bundles. Very little proliferation (Ki67(+)) of Olig2(+) cells was seen in the anterior subventricular zone from 1 to 28 days. However, by 3 days, many were proliferating in the peri-hematoma region, suggesting that local proliferation expands their population. By 14 days, the density of Olig2(+) cells declined in the peri-hematoma region, and, by 28 days, it reached the low level seen in the contralateral striatum. At these later times, many surviving axons were aligned into white-matter bundles, which appeared less swollen or fragmented. Oligodendrocyte cell maturation was prevalent over the 28-day period. Densities of immature OPCs (NG2(+)Olig2(+)) and mature (CC-1(+)Olig2(+)) oligodendrocytes in the peri-hematoma increased dramatically over the first week. Regardless of the maturation state, they increased preferentially inside the white-matter bundles. These results provide evidence that endogenous oligodendrocyte precursors proliferate and differentiate in the peri-hematoma region and have the potential to re-myelinate axon tracts after hemorrhagic stroke.

CT Evolution of Hematoma and Surrounding Hypodensity in a Cadaveric Model of Intracerebral Hemorrhage.

BACKGROUND: The evolution of intracerebral hematoma and perihematoma edema in the ultra-early period on computed tomographic (CT) scans in patients with intracerebral hemorrhage (ICH) is not well understood. We aimed to investigate hematoma and perihematoma changes in "neutral brain" models of ICH. METHODS: One human and five goat cadaveric heads were used as "neutral brains" to provide physical properties of brain without any biological activity or new bleeding. ICH was induced by slow injection of 4 ml of fresh human blood into the right basal ganglia of the goat brains. Similarly, 20 ml of fresh blood was injected deep into the white matter of the human cadaver head in each hemisphere. Serial CT scans of the heads were obtained immediately after hematoma induction and then 1, 3, and 5 hours afterward. Analyze software (AnalyzeDirect, Overland Park, KS, USA) was used to measure hematoma and perihematoma hypodensity volumes in the baseline and follow-up CT scans. RESULTS: The initial hematoma volumes of 11.6 ml and 10.5 ml in the right and left hemispheres of the cadaver brains gradually decreased to 6.6 ml and 5.4 ml at 5 hours, showing 43% and 48% retraction of hematoma, respectively. The volume of the perihematoma hypodensity in the right and left hemisphere increased from 2.6 ml and 2.2 ml in the 1-hour follow-up CT scans to 4.9 ml and 4.4 ml in the 5-hour CT scan, respectively. Hematoma retraction was also observed in all five goat brains ICH models with the mean ICH volume decreasing from 1.49 ml at baseline scan to 1.01 ml at the 5-hour follow-up CT scan (29.6% hematoma retraction). Perihematoma hypodensity was visualized in 70% of ICH in goat brains, with an increasing mean hypodensity volume of 0.4 ml in the baseline CT scan to 0.8 ml in the 5-hour follow-up CT scan. CONCLUSION: Our study demonstrated that substantial hematoma retraction and perihematoma hypodensity occurs in ICH in the absence of any new bleeding or biological activity of surrounding brain. Such observations suggest that active bleeding is underestimated in patients with no or small hematoma expansion and our understanding of perihematoma hypodensity needs to be reconsidered.

A dynamic observation of pathologic and ultrastructural changes of perihematoma in intracerebral hemorrhage patients / 中国神经精神疾病杂志

Background In recent years,some researches had been conducted on the pathologic changes of the secondary injury of perihematoma in animal experiments,but only a few studies had been done on the dynamic pathologic and ultrastructural changes of the perihematoma in ICH patients. The unique contribution of our study is to investigate the dynamic pathologic and ultrastructural changes of the perihematoma in ICH patients and provide significant insights into how the pathophysiology and ultrastructures changed after ICH.Methods The written informed consents were obtained from the ICH patients or their relatives. 30 patients (the supertentorial hemotoma volume＞30 mi and the cerebellar hemotoma volume ＞10 mi) were divided into 8 groups according to the time passed after ICH:＜6 h (6 patients), 6 ～ 12 h (7 patients), 12 ～24 h (5 patients), 24～48 h (3 patients), 48 ～72 h (3 patients), 3 ～4 days group (3 patients), 5 days group (2 patients) and 8 days group ( 1 patient) and subjected to craniotomy for hemotoma evacuation. During the operation for the hemotoma's evacuation, a small amount of tissues that must be removed, which located at 1 cm near the hematoma, were taken as experimental groups; And the same tissues of 7 patients (＜12 h), which were far from the hemotoma on the operational way, were taken as control group. The pathologic and ultrastructral changes were observed.Results The tissues of the control group were almost normal while the damages of the tissues from the experimental groups were slight in ＜6 h groups, more severe after 6h and got to the maximum between 24 ～48 h , recovered gradually after 72 h, became similar to the 6 ～ 12 h group on 5 th day, got better on 8 th day and resembled the 6 h group.Conclusions The injury of the perihematoma occurred in early stage, reached the peak level between 24 and 48 hours after ICH; which was consistent to the clinical nervous functional deficits in the ICH patients.

An Analysis of Factors Related to the Shape of Hypertensive Intracerebral Hematoma and Its Clinical Significance

Eighty three cases of hypertensive intracerebral hemorrhage were retrospectively analyzed with a special emphasis on the shape of the hematoma. The hematomas were classified according to the computerized tomography(CT) findings into three groups as circumscribed hematoma with smooth margin and minimal surrounding edema(Type A). circumscribed hematoma with irregular margin and variable surrounding edema(Type B), and highly destructive hematoma with very irregular margin and usually with severe surrounding edema(Type C). The types of the hematoma were unrelated to the patient's age, blood pressure on arrival, serum triglyceride and cholesterol, liver function(except for SGOT), and coagulation study, and location as seen on CT, but were significantly related to the amount of the hematoma. Type A showed relatively better outcome than type B or type C, and type C invariably showed the poorest outcome.

Study on the relationship between complement activation and inflammatory reaction in tissues of the perihematoma in patients with intracerebral hemorrhage / 临床神经病学杂志

72 h goups, respectively. A few tissues distant from the hematoma on the way into the cranium were taken from the 2 former groups as control. Immunohistochemistry staining and reverse transcription polymerase chain reaction (RT-PCR) were used to detected expression of complement facters C3 ,complement inhibitor (Clusterin),the infiltration of the inflammatory cells, the proliferation of neuroglia cells and the expression of cytokins.Results The immunohistochemistry staining showed that the expression of complement facter C3 got to the peak at 12~72 h (P