Circulating Blood Prognostic Biomarker Signatures for Hemorrhagic Cerebral Cavernous Malformations (CCMs).

Cerebral cavernous malformations (CCMs) are a neurological disorder characterized by enlarged intracranial capillaries in the brain, increasing the susceptibility to hemorrhagic strokes, a major cause of death and disability worldwide. The limited treatment options for CCMs underscore the importance of prognostic biomarkers to predict the likelihood of hemorrhagic events, aiding in treatment decisions and identifying potential pharmacological targets. This study aimed to identify blood biomarkers capable of diagnosing and predicting the risk of hemorrhage in CCM1 patients, establishing an initial set of circulating biomarker signatures. By analyzing proteomic profiles from both human and mouse CCM models and conducting pathway enrichment analyses, we compared groups to identify potential blood biomarkers with statistical significance. Specific candidate biomarkers primarily associated with metabolism and blood clotting pathways were identified. These biomarkers show promise as prognostic indicators for CCM1 deficiency and the risk of hemorrhagic stroke, strongly correlating with the likelihood of hemorrhagic cerebral cavernous malformations (CCMs). This lays the groundwork for further investigation into blood biomarkers to assess the risk of hemorrhagic CCMs.

Serum Neuron-Specific Enolase as a Biomarker of Neonatal Brain Injury-New Perspectives for the Identification of Preterm Neonates at High Risk for Severe Intraventricular Hemorrhage.

Neonatal brain injury (NBI) is a critical condition for preterm neonates with potential long-term adverse neurodevelopmental outcomes. This prospective longitudinal case-control study aimed at investigating the levels and prognostic value of serum neuron-specific enolase (NSE) during the first 3 days of life in preterm neonates (<34 weeks) that later developed brain injury in the form of either periventricular leukomalacia (PVL) or intraventricular hemorrhage (IVH) during their hospitalization. Participants were recruited from one neonatal intensive care unit, and on the basis of birth weight and gestational age, we matched each case (n = 29) with a neonate who had a normal head ultrasound scan (n = 29). We report that serum NSE levels during the first three days of life do not differ significantly between control and preterm neonates with NBI. Nevertheless, subgroup analysis revealed that neonates with IVH had significantly higher concentrations of serum NSE in comparison to controls and neonates with PVL on the third day of life (p = 0.014 and p = 0.033, respectively). The same pattern on the levels of NSE on the third day of life was also observed between (a) neonates with IVH and all other neonates (PVL and control; p = 0.003), (b) neonates with II-IV degree IVH and all other neonates (p = 0.003), and (c) between control and the five (n = 5) neonates that died from the case group (p = 0.023). We conclude that NSE could be an effective and useful biomarker on the third day of life for the identification of preterm neonates at high risk of developing severe forms of IVH.

sTWEAK is a leukoaraiosis biomarker associated with neurovascular angiopathy.

OBJECTIVE: Leukoaraiosis (LA) refers to white matter lesions of undetermined etiology associated with the appearance and worsening of vascular pathologies. The aim is to confirm an increased frequency and intensity of LA in symptomatic patients with neurovascular pathology compared with asymptomatic subjects, and its association with circulating serum levels of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK). METHODS: An observational study was conducted in which two groups of patients were compared. Group I (N = 242) comprised of asymptomatic subjects with arterial hypertension and/or diabetes or with a history of transient ischemic attacks, and Group II (N = 382) comprised patients with lacunar stroke or deep hemispheric intracerebral hemorrhage (ICH) of hypertensive origin. Serum levels of sTWEAK were analyzed and correlated with prevalence and intensity of LA according to the Fazekas scale. RESULTS: The prevalence of LA was higher in symptomatic (85.1%) versus asymptomatic patients (62.0%). Logistic regression model showed a significant relation of LA with neurovascular pathologies (OR: 2.69, IC 95%: 1.10-6.59, p = 0.003). When stratified according to the Fazekas scale, LA of grade II (OR: 3.53, IC 95%: 1.10-6.59, p = 0.003) and specially grade III (OR: 4.66, 95% CI: 1.09-19.84, p = 0.037) showed correlation with neurovascular pathologies. Increased sTWEAK levels were found in the symptomatic group in all LA grades (p < 0.0001), and associated with 5.06 times more risk of presenting clinical symptoms (OR: 5.06, 95% CI: 2.66-9.75, p < 0.0001). INTERPRETATION: LA showed a higher prevalence in patients with symptomatic lacunar stroke or deep hemispheric ICH. There is an association between sTWEAK levels and LA degree.

Serum arachidonic acid levels is a predictor of poor functional outcome in acute intracerebral hemorrhage.

BACKGROUND AND AIMS: Correlations between serum levels of polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA) and dihomogammalinolenic acid (DHLA) and outcomes following cardiovascular disease have been reported. This study aimed to investigate the relationship between serum levels of PUFAs (including AA) and functional outcomes among intracerebral hemorrhage (ICH) patients. METHODS: From November 2012 to July 2020, ICH patients within 24 h from onset were enrolled. Patients were divided into a good functional outcome group (modified Rankin Scale [mRS] score at 3 months, 0-3) and a poor functional outcome group (mRS score at 3 months, 4-6). We compared baseline variables between groups. RESULTS: Participants comprised 133 patients (mean age, 60 years), with 106 patients (80%) in the good functional outcome group and 27 patients (20%) in the poor functional outcome group. Higher National Institutes of Health Stroke Scale (NIHSS) score and larger hematoma on admission were more frequent in the poor functional outcome group (median NIHSS score 6 vs. 14, p < 0.001; median hematoma volume, 7.5 ml vs. 13.5 ml, p = 0.07). In terms of serum PUFA levels, only median serum AA level was significantly lower in the poor functional outcome group (212 µg/ml vs. 179 µg/ml, p = 0.002). Multivariate logistic regression analysis showed lower serum AA level was independently associated with poor functional outcome (odds ratio 0.986, 95% confidence interval 0.976-0.996, p = 0.009). CONCLUSION: Lower serum AA level was associated with poor functional outcome in ICH patients. AA may represent an important biomarker of severity among ICH patients.

Extracellular fluid, cerebrospinal fluid and plasma biomarkers of axonal and neuronal injury following intracerebral hemorrhage.

Spontaneous intracerebral hemorrhage (ICH) is the most devastating form of stroke. To refine treatments, improved understanding of the secondary injury processes is needed. We compared energy metabolic, amyloid and neuroaxonal injury biomarkers in extracellular fluid (ECF) from the perihemorrhagic zone (PHZ) and non-injured (NCX) brain tissue, cerebrospinal fluid (CSF) and plasma. Patients (n = 11; age 61 ± 10 years) undergoing ICH surgery received two microdialysis (MD) catheters, one in PHZ, and one in NCX. ECF was analysed at three time intervals within the first 60 h post- surgery, as were CSF and plasma samples. Amyloid-beta (Aß) 40 and 42, microtubule associated protein tau (tau), and neurofilament-light (NF-L) were analysed using Single molecule array (Simoa) technology. Median biomarker concentrations were lowest in plasma, higher in ECF and highest in CSF. Biomarker levels varied over time, with different dynamics in the three fluid compartments. In the PHZ, ECF levels of Aß40 were lower, and tau higher when compared to the NCX. Altered levels of Aß peptides, NF-L and tau may reflect brain tissue injury following ICH surgery. However, the dynamics of biomarker levels in the different fluid compartments should be considered in the study of pathophysiology or biomarkers in ICH patients.

Assessing early erythrolysis and the relationship to perihematomal iron overload and white matter survival in human intracerebral hemorrhage.

AIMS: Iron released from lysed red blood cells within the hematoma plays a role in intracerebral hemorrhage (ICH)-related neurotoxicity. This study utilizes magnetic resonance imaging (MRI) to examine the time course, extent of erythrolysis, and its correlation with perihematomal iron accumulation and white matter loss. METHODS: The feasibility of assessing proportional erythrolysis using T2* MRI was examined using pig blood phantoms with specified degrees of erythrolysis. Fifteen prospectively enrolled ICH patients had MRIs (3-Tesla) at days 1-3, 14, and 30 (termed early, subacute, and late periods, respectively). Measurement was performed on T2*, 1/T2*, and fractional anisotropy (FA) maps. RESULTS: Pig blood phantoms showed a linear relationship between 1/T2* signal and percent erythrolysis. MRI on patients showed an increase in erythrolysis within the hematoma between the early and subacute phases after ICH, almost completing by day 14. Although perihematomal iron overload (IO) correlated with the erythrolysis extent and hematoma volume at days 14 and 30, perihematomal white matter (WM) loss significantly correlated with both, only at day 14. CONCLUSION: MRI may reliably assess the portion of the hematoma that lyses over time after ICH. Perihematomal IO and WM loss correlate with both the erythrolysis extent and hematoma volume in the early and subacute periods following ICH.

Association of Serum IL-6 (Interleukin 6) With Functional Outcome After Intracerebral Hemorrhage.

BACKGROUND AND OBJECTIVES: IL-6 (interleukin 6) is a proinflammatory cytokine and an established biomarker in acute brain injury. We sought to determine whether admission IL-6 levels are associated with severity and functional outcome after spontaneous intracerebral hemorrhage (ICH). METHODS: We performed an exploratory analysis of the recombinant activated FAST trial (Factor VII for Acute ICH). Patients with admission serum IL-6 levels were included. Regression analyses were used to assess the associations between IL-6 and 90-day modified Rankin Scale. In secondary analyses, we used linear regression to evaluate the association between IL-6 and baseline ICH and perihematomal edema volumes. RESULTS: Of 841 enrolled patients, we included 552 (66%) with available admission IL-6 levels (mean age 64 [SD 13], female sex 203 [37%]). IL-6 was associated with poor outcome (modified Rankin Scale, 4-6; per additional 1 ng/L, odds ratio, 1.30 [95% CI, 1.04-1.63]; P=0.02) after adjustment for known predictors of outcome after ICH and treatment group. IL-6 was associated with ICH volume after adjustment for age, sex, and ICH location, and this association was modified by location (multivariable interaction, P=0.002), with a stronger association seen in lobar (ß, 12.51 [95% CI, 6.47-18.55], P<0.001) versus nonlobar (ß 5.32 [95% CI, 3.36-7.28], P<0.001) location. IL-6 was associated with perihematomal edema volume after adjustment for age, sex, ICH volume, and ICH location (ß 1.22 [95% CI, 0.15-2.29], P=0.03). Treatment group was not associated with IL-6 levels or outcome. CONCLUSIONS: In the FAST trial population, higher admission IL-6 levels were associated with worse 90-day functional outcome and larger ICH and perihematomal edema volumes.

A Roadmap for Developing Plasma Diagnostic and Prognostic Biomarkers of Cerebral Cavernous Angioma With Symptomatic Hemorrhage (CASH).

BACKGROUND: Cerebral cavernous angioma (CA) is a capillary microangiopathy predisposing more than a million Americans to premature risk of brain hemorrhage. CA with recent symptomatic hemorrhage (SH), most likely to re-bleed with serious clinical sequelae, is the primary focus of therapeutic development. Signaling aberrations in CA include proliferative dysangiogenesis, blood-brain barrier hyperpermeability, inflammatory/immune processes, and anticoagulant vascular domain. Plasma levels of molecules reflecting these mechanisms and measures of vascular permeability and iron deposition on magnetic resonance imaging are biomarkers that have been correlated with CA hemorrhage. OBJECTIVE: To optimize these biomarkers to accurately diagnose cavernous angioma with symptomatic hemorrhage (CASH), prognosticate the risk of future SH, and monitor cases after a bleed and in response to therapy. METHODS: Additional candidate biomarkers, emerging from ongoing mechanistic and differential transcriptome studies, would further enhance the sensitivity and specificity of diagnosis and prediction of CASH. Integrative combinations of levels of plasma proteins and characteristic micro-ribonucleic acids may further strengthen biomarker associations. We will deploy advanced statistical and machine learning approaches for the integration of novel candidate biomarkers, rejecting noncorrelated candidates, and determining the best clustering and weighing of combined biomarker contributions. EXPECTED OUTCOMES: With the expertise of leading CA researchers, this project anticipates the development of future blood tests for the diagnosis and prediction of CASH to clinically advance towards precision medicine. DISCUSSION: The project tests a novel integrational approach of biomarker development in a mechanistically defined cerebrovascular disease with a relevant context of use, with an approach applicable to other neurological diseases with similar pathobiologic features.

Systemic inflammation status at admission affects the outcome of intracerebral hemorrhage by increasing perihematomal edema but not the hematoma growth.

Acute stress and inflammation responses are associated with worse outcomes in intracerebral hemorrhage (ICH) but the precise mechanisms involved are unclear. We evaluated the effect of neutrophil-to-lymphocyte ratio (NLR) in ICH outcome, with focus on hematoma expansion and early cerebral edema. In a retrospective study, we included all patients with primary ICH admitted to our center within 24-h from symptom onset from January 2014 to February 2015. We retrieved demographic and medical history data, Glasgow Coma Scale scores, blood cell counts, glucose, and C-reactive protein, and calculated NLR. We obtained hematoma volumes by computerized planimetry. Outcomes included independence at 90 days (modified Rankin scale 0-2), mortality at 30 days, significant hematoma expansion (> 33% or > 6 mL) and early cerebral edema causing significant midline shift (> 2.5 mm) at 24 h. We included 135 patients. NLR independently associated with independence at 90 days (adjusted odds ratio (aOR) 0.79, 95% CI 0.67-0.93, p = 0.006) significant cerebral edema (aOR 1.08, 95%CI 1.01-1.15, p = 0.016) but not hematoma expansion (aOR 0.99, 95%CI 0.94-1.04, p = 0.736). The severity of midline shift was positively correlated with NLR (adjusted beta = 0.08, 95% CI 0.05-0.11, p < 0.001). In ICH, an immediate and intense systemic inflammatory response reduces the likelihood of a better functional outcome at 90 days, which is more likely to be explained by perihematomal edema growth than due to a significant hematoma expansion. These findings could have implications in new treatment strategies and trial designs, which endpoints tend to target exclusively hematoma enlargement.

Prognostic significance of serum translocator protein in patients with spontaneous intracerebral hematoma：preliminary findings.

Background: The aim of this study was to measure the level of translocator protein (TSPO) in patients with intracerebral hematoma (ICH) and to determine whether TSPO can predict ICH outcomes.Method: Patients with ICH were recruited at Wujin Hospital Affiliated with Jiangsu University between January 2018 and May 2020. The level of TSPO and inflammatory factors were analyzed by enzyme-linked immunosorbent assay (ELISA). A receiver operating characteristic curve (ROC) analysis was applied to assess the accuracy of TSPO for predicting patient outcomes.Result: The median of TSPO was 2.26 ng/ml. The lower- (46 cases) and higher-(51 cases) TSPO groups were thus divided based on the median value. The perihematomal edema (PHE) volume in the lower TSPO group was 6.3 ± 1.3 ml which was significantly lower than that in higher-TSPO group (14.8 ± 3.5 ml) (p < 0.05). The serum level of the interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) in the higher-TSPO group was significantly higher than that in the lower TSPO group (p < 0.05). The Spearman's correlation found that TSPO concentrations significantly correlated with PHE volume, modified Rankin Scale score (MRS), IL-1ß, IL-6, TNF-α, and CRP concentrations. The area under the ROC (AUC), specificity, sensitivity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and Diagnostic Odds Ratio (DOR) of TSPO was 0.932, 82.1%, 89.9%, 5.02, 0.12, and 40.8, respectively, which was more reliable than other inflammatory factors.Conclusion: The TSPO may a reliable biomarker in predicting the prognosis of ICH patients.

Early Serum Biomarkers for Intensive Care Unit Treatment within the First 24 Hours in Patients with Intracerebral Hemorrhage.

BACKGROUND: The prognostic significance of serum biomarkers in patients with intracerebral hemorrhage (ICH) is not well investigated concerning inhospital mortality (IHM) and cardiopulmonary events within the first 24 hours of intensive care unit (ICU) treatment. The influence of troponin I (TNI) value and cortisol value (CV) on cardiopulmonary events within the first 24 hours of ICU treatment was reported in subarachnoid hemorrhage patients, but not in ICH patients up to now. The aim of this study was to investigate the role of early serum biomarkers on IHM and TNI value and CV on cardiopulmonary events within the first 24 hours of ICU treatment. PATIENTS AND METHODS: A total of 329 patients with spontaneous ICH were retrospectively analyzed. Blood samples were taken on admission to measure serum biomarkers. The TNI value and CV were defined as biomarkers for cardiopulmonary stress. Demographic data, cardiopulmonary parameters, including norepinephrine application rate (NAR) in microgram per kilogram per minute and inspiratory oxygen fraction (FiO2) within the first 24 hours, and treatment regime were analyzed concerning their impact on ICU treatment and in hospital outcome. Binary logistic analysis was used to identify independent prognostic factors for IHM. RESULTS: Patients with initially nonelevated CVs required higher NAR (p = 0.01) and FiO2 (p = 0.046) within the first 24 hours of ICU treatment. Lower cholinesterase level (p = 0.004), higher NAR (p = 0.002), advanced age (p < 0.0001), larger ICH volume (p < 0.0001), presence of intraventricular hemorrhage (p = 0.007) and hydrocephalus (p = 0.009), raised level of C-reactive protein (p = 0.024), serum lactate (p = 0.003), and blood glucose (p = 0.05) on admission were significantly associated with IHM. In a multivariate model, age (odds ratio [OR]: 1.055; 95% confidence interval [CI]: 1.026-1.085; p < 0.0001), ICH volume (OR: 1.016; CI: 1.008-1.025; p < 0.0001), and Glasgow Coma Scale (GCS) score (OR: 0.680; CI: 0.605-0.764; p < 0.0001) on admission as well as requiring NAR (OR: 1.171; CI: 1.026-1.337; p = 0.02) and FiO2 (OR: 0.951; CI: 0.921-0.983, p = 0.003) within the first 24 hours were independent predictors of IHM. CONCLUSION: Higher levels of C-reactive protein, serum lactate, blood glucose, and lower cholinesterase level on admission were significantly associated with IHM. Patients with initially nonelevated CVs required higher NAR and FiO2 within the first 24 hours of ICU treatment. Furthermore, requiring an NAR > 0.5 µg/kg/min or an FiO2 > 0.21 were identified as additional independent predictors for IHM. These results could be helpful to improve ICU treatment in ICH patients.

The presence of leukoaraiosis enhances the association between sTWEAK and hemorrhagic transformation.

OBJECTIVE: To investigate whether elevated serum levels of sTWEAK (soluble tumor necrosis factor-like inducer of apoptosis) might be involved in a higher frequency of symptomatic hemorrhagic transformation (HT) through the presence of leukoaraiosis (LA) in patients with acute ischemic stroke (IS) undergoing reperfusion therapies. METHODS: This is a retrospective observational study. The primary endpoint was to study the sTWEAK-LA-HT relationship by comparing results with biomarkers associated to HT and evaluating functional outcome at 3-months. Clinical factors, neuroimaging variables and biomarkers associated to inflammation, endothelial/atrial dysfunction or blood-brain barrier damage were also investigated. RESULTS: We enrolled 875 patients (mean age 72.3 ± 12.2 years; 46.0% women); 710 individuals underwent intravenous thrombolysis, 87 endovascular therapy and 78 both. HT incidence was 32%; LA presence was 75.4%. Patients with poor functional outcome at 3-months showed higher sTWEAK levels at admission (9844.2 [7460.4-12,542.0] vs. 2717.3 [1489.7-5852.3] pg/mL, P < 0.0001). By means of logistic regression models, PDGF-CC and sTWEAK were associated with mechanisms linked simultaneously to HT and LA. Serum sTWEAK levels at admission ≥6700 pg/mL were associated with an odds ratio of 13 for poor outcome at 3-months (OR: 13.6; CI 95%: 8.2-22.6, P < 0.0001). CONCLUSIONS: Higher sTWEAK levels are independently associated with HT and poor functional outcome in patients with IS undergoing reperfusion therapies through the presence of LA. sTWEAK could become a therapeutic target to reduce HT incidence in patients with IS.

Clinical significance of FSTL 1, Bax, Bcl-2 in acute cerebral infarction and its relationship with hemorrhagic transformation.

OBJECTIVE: Acute cerebral infarction (ACI) is the most common type of acute cerebrovascular disease so far, and its incidence rate has been increasing in recent years. At present, the methods of diagnosing ACI in clinic are extremely complicated, and an effective index that can effectively diagnose ACI is urgently needed in clinic. This study is designed to investigate the clinical significance of Follistatin-like protein 1 (FSTL1), Bax and Bcl-2 in ACI. PATIENTS AND METHODS: A total of 84 cases of ACI patients admitted to our hospital from September 2017 to September 2019 and 90 cases of healthy subjects undergoing physical examination at the same time were selected as the research objects for prospective analysis. The concentrations of FSTL1, Bax and Bcl-2 in the peripheral blood of objects in the two groups were detected to analyze the diagnostic value of FSTL1, Bax and Bcl-2 for ACI, and the correlation of FSTL 1, Bax and Bcl-2 with the infarct size, treatment method and hemorrhagic transformation. Another 20 SD rats were purchased, among which 10 rats were randomly selected for ACI modeling. FSTL1 concentration, Bax and Bcl-2 protein expression in brain tissues of ACI rats and normal rats were detected. RESULTS: FSTL1 and Bax in peripheral blood of ACI patients were higher than those of healthy subjects (p<0.050), and Bcl-2 was lower than those of healthy subjects (p<0.050). It was detected that FSTL1, Bax and Bcl-2 had good diagnostic value for patients with ACI (p<0.001). FSTL1 and Bax decreased while Bcl-2 increased in patients treated with thrombolytic therapy (p<0.050). And FSTL1, Bax and Bcl-2 were closely related to infarct size and hemorrhagic transformation (p<0.050). Logistic regression analysis showed that NIHSS score, atrial fibrillation, infarct volume, FSTL1 and Bax were independent risk factors affecting hemorrhagic transformation in ACI patients (p<0.050), and Bcl-2 was an independent protective factor affecting hemorrhagic transformation in ACI patients (p<0.050). The concentration of FSTL1 and the expression of Bax protein in rat brain tissue were also higher than that in normal rats, while Bcl-2 was lower than that in normal rats (p < 0.001). CONCLUSIONS: FSTL1, Bax and Bcl-2 are involved in the occurrence and development of ACI and are closely related to the hemorrhagic transformation of patients. The mechanism by which FSTL1 promotes the occurrence of ACI might be related to promoting the occurrence of inflammatory responses in the brain tissue of patients or accelerating the apoptosis of neurons.

Alterations in inflammatory markers and clinical outcome after spontaneous intracerebral hemorrhage - Preliminary results.

OBJECTIVE: After an intracerebral hemorrhage, there is an immunological reaction, the specific mechanism of which is not fully understood, that seems to contribute to secondary brain injury. In this study, we investigated alterations of inflammatory markers in the blood and clinical outcome after an intracerebral hemorrhage. METHODS: Between July 2013 and February 2016, we performed a prospective study for which we recruited patients who had suffered an intracerebral hemorrhage. Using various scoring scales we evaluated the neurological state upon admission and discharge, and at one and three months following the ICH. During the hospital stay, various inflammatory markers were examined in blood samples. RESULTS: Out of 132 screened patients, 27 were included (48.2% male, mean age 68 years). We found significantly elevated serum concentrations of interleukin-6 (p=0.006) at the time of admission and throughout days three and five. There were also elevated c-reactive protein and granulocyte-colony stimulating factor concentrations found. The concentrations of these immune parameters showed significant monotonic relationships. The ROC analyses showed a better discrimination for mortality with regard to the percentage of T helper cells than with regard to the ICH volume alone. CONCLUSION: Our results may be regarded as preliminary evidence of the occurrence of inflammation after intracerebral hemorrhage. If there is a relationship between inflammation and clinical outcome remains speculative.

Cryptogenic Intracranial Hemorrhagic Strokes Associated with Hypervitaminosis E and Acutely Elevated α-Tocopherol Levels.

OBJECTIVES: Up to 41% of intracerebral hemorrhages (ICH) are considered cryptogenic despite a thorough investigation to determine etiology. Certain over-the-counter supplements may increase proclivity to bleeding, and we hypothesize that specifically vitamin E may have an association with ICH and acutely elevated serum levels of α-tocopherol. Our aim is to report 3 cases of recently admitted patients with hypervitaminosis E and otherwise cryptogenic ICH. METHODS: At our institution between January and December 2018, 179 patients were admitted with ICH with 73 imputed to be "cryptogenic" (without clear etiology as per Structural vascular lesions, Medication, Amyloid angiopathy, Systemic disease, Hypertension, or Undetermined and Hypertension, Amyloid angiopathy, Tumor, Oral anticoagulants, vascular Malformation, Infrequent causes, and Cryptogenic criteria). Of these, we found 3 (4.1%) clearly admitted to consistent use of vitamin E supplementation for which α-tocopherol levels were checked. We describe the clinical presentation and course of these patients and their etiologic and diagnostic evaluations including neuroimaging and α-tocopherol laboratory data. RESULTS: All patients in this series were consistently consuming higher than recommended doses of vitamin E and developed acute ICH. The first 2 patients both had subcortical (thalamic) intraparenchymal hemorrhages while the third had an intraventricular hemorrhage. Serum α-tocopherol levels in patient A, B, and C were elevated at 30.8, 46.7, and 23.3 mg/L, respectively (normal range 5.7-19.9 mg/L) with a mean of 33.6 mg/L. No clear alternate etiologies to their ICH could be conclusively determined despite thorough workups. CONCLUSIONS: In patients with cryptogenic ICH, clinicians should consider hypervitaminosis E and check serum α-tocopherol level during admission. Reviewing the patient's pharmacologic history, including over-the-counter supplements such as vitamin E, may help identify its association, and its avoidance in the future may mitigate risk. With its known vitamin K antagonism, hypo-prothrombinemic effect, cytochrome p-450 interaction, and antiplatelet activity, vitamin E may not be as benign as presumed. Its consumption in nonrecommended doses may increase ICH risk, which may be underestimated and under-reported.

Application of P(jv-a) CO2 in monitoring cerebral oxygen supply-demand balance in injured brain.

Transcranial Doppler sonography (TCD) assayed cerebral blood flow (CBF) may vary between different intracranial pathologies. Blood gas analysis of the jugular bulb provides a novel way to estimate the global relationship between CBF and oxygen metabolism. In this study, 25 patients with brain trauma, spontaneous intracerebral hemorrhage, and acute cerebral infarction were recruited. Jugular venous oxygen saturation (SjvO2) increased significantly at different time points after hyperventilation (p < 0.05). A negative correlation between the partial pressure of CO2 between jugular venous bulb and radial artery blood (P(jv-a)CO2) and CBF could be observed in acute brain injury and spontaneous intracerebral hemorrhage groups, while P(jv-a)CO2 and CBF show positive correlation in acute cerebral infarction group. Our results suggest that serial P(jv-a)CO2 analysis combing with SjvO2 can be utilized to monitor the change of CBF for patients undergoing craniocerebral surgery.

Increased plasma plasmin-α2-plasmin inhibitor complex levels correlate with postoperative rebleeding after endoscopic surgery for spontaneous intracerebral hemorrhage.

BACKGROUND: Postoperative rebleeding (PR) is one of the most severe complications of endoscopic surgery, often performed to remove spontaneous intracerebral hemorrhage (sICH). However, the risk factors for PR remain unclear. OBJECTIVE: This study retrospectively investigated whether increased preoperative plasma plasmin-α2-plasmin inhibitor complex (PIC) levels, indicating activation of fibrinolysis, are associated with PR. METHODS: A total of 101 patients underwent endoscopic surgery to evacuate sICH at our institution from January 2010 to June 2019, and 79 patients who underwent examinations of plasma PIC levels at admission with available radiographical data were included. Correlations between PR and increased plasma PIC levels were retrospectively evaluated. RESULTS: PR occurred in eight patients (10.1%), and high PIC levels (≥ 4 or 6 µg/ml) were significantly associated with PR. The sensitivities employing high PIC levels of ≥ 4 µg/ml and ≥ 6 µg/ml were both 0.63, and the specificities using the same PIC levels were 0.86 and 0.92, respectively. Multivariable analyses showed that high plasma PIC levels of ≥ 4 µg/ml (odds ratio (OR), 12.77; 95% confidence interval (CI), 1.65-98.77; p = 0.02) or ≥ 6 µg/ml (OR, 18.33; 95% CI, 2.32-144.82; p = 0.006) were independent predictors of PR. CONCLUSIONS: This study found that increased plasma PIC levels were associated with PR following the endoscopic evacuation of sICHs, indicating that increased plasma PIC levels could be potentially used to predict PR. Further studies are needed to establish new surgical strategies and adjuvant treatments to improve surgical outcomes in patients with sICH prone to PR.

Increased perihematomal neuron autophagy and plasma thrombin-antithrombin levels in patients with intracerebral hemorrhage: An observational study.

Animal studies have demonstrated that autophagy was involved in neuronal damage after intracerebral hemorrhage (ICH). Several studies showed thrombin-antithrombin (TAT) plasma levels were elevated in patients with ICH. In this study, we aimed to evaluate if autophagy occurred in patients with ICH; and the relationship between the severity of brain injury and plasma TAT levels.A novel tissue harvesting device was used during hematoma removal surgery to collect loose fragments of tissue surrounding the affected brain area in 27 ICH patients with hematoma volumes of >30 mL in the basal ganglia. Control tissues were obtained from patients who underwent surgery for arteriovenous malformation (n = 25). Transmission electron microscopy (TEM) and immunohistochemistry for autophagy-related proteins were used to evaluate the ultrastructural and morphologic cellular characteristics; and the extent of autophagy in the recovered tissue specimens. Stroke severity was assessed by using the Glasgow Coma Scale (GCS) and the National Institutes of Health Stroke Scale (NIHSS). An enzyme-linked immunosorbent assay (ELISA) was used to measure plasma TAT levels.Transmission electron microscopy showed autophagosomes and autolysosomes exist in neurons surrounding the hematoma, but not in the control tissues. The number of cells containing autophagic vacuoles correlated with the severity of brain injury. Immunohistochemistry showed strong LC3, beclin 1, and cathepsin D staining in ICH tissue specimens. Plasma TAT levels correlated positively with autophagic cells and ICH severity (P < .01).Autophagy was induced in perihematomal neurons after ICH. Autophagy and plasma TAT levels correlated positively with severity of brain injury. These results suggest that autophagy and increased plasma TAT levels may contribute to the secondary damage in ICH patients.

Low-density lipoprotein cholesterol and risk of intracerebral hemorrhage: A prospective study.

OBJECTIVE: To prospectively examine the association between low-density lipoprotein (LDL) cholesterol (LDL-C) concentrations and intracerebral hemorrhage (ICH) risk. METHODS: The current cohort study included 96,043 participants (mean age 51.3 years) who were free of stroke, myocardial infarction, and cancer at baseline (2006). Serum LDL-C concentrations were assessed in 2006, 2008, 2010, and 2012. Cumulative average LDL-C concentrations were calculated from all available LDL-C data during that period. Incident ICH was confirmed by review of medical records. RESULTS: We identified 753 incident ICH cases during 9 years of follow-up. The ICH risk was similar among participants with LDL concentrations of 70 to 99 mg/dL and those with LDL-C concentrations ≥100 mg/dL. In contrast, participants with LDL-C concentrations <70 mg/dL had a significantly higher risk of developing ICH than those with LDL-C concentrations of 70 to 99 mg/dL; adjusted hazard ratios were 1.65 (95% confidence interval [CI] 1.32-2.05) for LDL-C concentrations of 50 to 69 mg/dL and 2.69 (95% CI 2.03-3.57) for LDL-C concentrations <50 mg/dL. CONCLUSIONS: We observed a significant association between lower LDL-C and higher risk of ICH when LDL-C was <70 mg/dL, and the association became nonsignificant when LDL-C ≥70 mg/dL. These data can help determination of the ideal LDL range in patients who are at increased risk of both atherosclerotic disease and hemorrhagic stroke and guide planning of future lipid-lowering studies.

Neutrophil-lymphocyte ratio predicts the outcome of intracerebral hemorrhage: A meta-analysis.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) is increasingly recognized as a systemic inflammation factor. It has been used as a predictor for clinical outcomes in cancers. However, its relationship with intracerebral hemorrhage (ICH) is still disputed. We sought to evaluate the prognostic role of NLR in ICH. METHODS: We searched PubMed, Cochrane Library, Medline, and EMBASE for potentially relevant articles from inception to April 8, 2018. Efficacy outcomes included major disability at 90 days, short-term mortality or in-hospital mortality. Odds ratio (OR) with 95% confidence interval (95% CI) were pooled to assess the association between NLR and ICH. RESULTS: A total of 7 trials with 2176 patients were included in this meta-analysis. It revealed that higher NLR had a higher risk of major disability at 90 days (OR: 2.20; 95% CI: 1.27-3.81) and higher mortality at short-term (OR: 1.31; 95% CI: 1.02-1.68) in ICH; without statistically significant association with in-hospital mortality (OR: 1.02; 95% CI: 0.91-1.15). CONCLUSIONS: Our meta-analysis proved that high NLR was a predictor of major disability and mortality at short term in ICH patients, but not a predictor of in-hospital mortality.