Cerebral Hemorrhage: Pathophysiology, Treatment, and Future Directions.

Intracerebral hemorrhage (ICH) is a devastating form of stroke with high morbidity and mortality. This review article focuses on the epidemiology, cause, mechanisms of injury, current treatment strategies, and future research directions of ICH. Incidence of hemorrhagic stroke has increased worldwide over the past 40 years, with shifts in the cause over time as hypertension management has improved and anticoagulant use has increased. Preclinical and clinical trials have elucidated the underlying ICH cause and mechanisms of injury from ICH including the complex interaction between edema, inflammation, iron-induced injury, and oxidative stress. Several trials have investigated optimal medical and surgical management of ICH without clear improvement in survival and functional outcomes. Ongoing research into novel approaches for ICH management provide hope for reducing the devastating effect of this disease in the future. Areas of promise in ICH therapy include prognostic biomarkers and primary prevention based on disease pathobiology, ultra-early hemostatic therapy, minimally invasive surgery, and perihematomal protection against inflammatory brain injury.

Impacts of ABO-incompatible platelet transfusions on platelet recovery and outcomes after intracerebral hemorrhage.

Acute platelet transfusion after intracerebral hemorrhage (ICH) given in efforts to reverse antiplatelet medication effects and prevent ongoing bleeding does not appear to improve outcome and may be associated with harm. Although the underlying mechanisms are unclear, the influence of ABO-incompatible platelet transfusions on ICH outcomes has not been investigated. We hypothesized that patients with ICH who receive ABO-incompatible platelet transfusions would have worse platelet recovery (using absolute count increment [ACI]) and neurological outcomes (mortality and poor modified Rankin Scale [mRS 4-6]) than those receiving ABO-compatible transfusions. In a single-center cohort of consecutively admitted patients with ICH, we identified 125 patients receiving acute platelet transfusions, of whom 47 (38%) received an ABO-incompatible transfusion. Using quantile regression, we identified an association of ABO-incompatible platelet transfusion with lower platelet recovery (ACI, 2 × 103cells per µL vs 15 × 103cells per µL; adjusted coefficient ß, -19; 95% confidence interval [CI], -35.55 to -4.44; P = .01). ABO-incompatible platelet transfusion was also associated with increased odds of mortality (adjusted odds ratio [OR], 2.59; 95% CI, 1.00-6.73; P = .05) and poor mRS (adjusted OR, 3.61; 95% CI, 0.97-13.42; P = .06); however, these estimates were imprecise. Together, these findings suggest the importance of ABO compatibility for platelet transfusions for ICH, but further investigation into the mechanism(s) underlying these observations is required.

Intraventricular Hemorrhage Expansion in the CLEAR III Trial: A Post Hoc Exploratory Analysis.

BACKGROUND: The objective of this study was to evaluate factors associated with intraventricular hemorrhage (IVH) expansion and its association with long-term outcomes. METHODS: We performed a post hoc analysis of the international, multi-center CLEAR III trial (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage) which enrolled IVH patients between September 1, 2009, and January 31, 2015. The exposure was IVH expansion, defined as >1 mL increase in volume between baseline and stability computed tomography scans, before treatment randomization. We assessed factors associated with IVH expansion and secondarily assessed the relationship of IVH expansion with clinical outcomes: composite of death or major disability (modified Rankin Scale score, >3), and mortality alone at 6 months. The relationship of IVH expansion on ventriculoperitoneal shunt placement was additionally explored. Multivariable logistic regression was used for all analyses. RESULTS: Of 500 IVH patients analyzed, the mean age was 59 (±11) years old, 44% were female and 135 (27%) had IVH expansion. In multivariable regression models, factors associated with IVH expansion were baseline parenchymal intracerebral hemorrhage (ICH) volume (adjusted odds ratio [OR], 1.04 per 1 mL increase [95% CI, 1.01-1.08]), presence of parenchymal hematoma expansion: >33% (adjusted OR, 6.63 [95% CI, 3.92-11.24]), time to stability head CT (adjusted OR, 0.71 per 1 hour increase [95% CI, 0.54-0.94]), and thalamic hematoma location (adjusted OR, 1.68 [95% CI, 1.01-2.79]) while additionally adjusting for age, sex, and race. In secondary analyses, IVH expansion was associated with higher odds of poor 6-month outcomes (adjusted OR, 1.84 [95% CI, 1.12-3.02]) but not mortality (OR, 1.40 [95% CI, 0.78-2.50]) after adjusting for baseline ICH volume, thalamic ICH location, age, anticoagulant use, Glasgow Coma Scale score, any withdrawal of care order, and treatment randomization arm. However, there were no relationships of IVH expansion on subsequent ventriculoperitoneal shunt placement (adjusted OR, 1.02 [95% CI, 0.58-1.80]) after adjusting for similar covariates. CONCLUSIONS: In a clinical trial cohort of patients with large IVH, acute hematoma characteristics, specifically larger parenchymal volume, hematoma expansion, and thalamic ICH location were associated with IVH expansion. Given that IVH expansion resulted in poor functional outcomes, exploration of treatment approaches to optimize hemostasis and prevent IVH expansion, particularly in patients with thalamic ICH, require further study. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00784134.

Red Blood Cell Transfusions and Outcomes After Intracerebral Hemorrhage.

BACKGROUND: Low red blood cell (RBC) levels are associated with worse intracerebral hemorrhage (ICH) outcomes. However, relationships of RBC transfusions on ICH outcomes are unclear given the overlap of RBC transfusion, comorbidities, and disease severity. We investigated RBC transfusion relationships on ICH outcomes while accounting for comorbidities and disease severity. METHODS: ICH hospitalizations between 2002 and 2011 and RBC transfusion exposure were identified from the Nationwide Inpatient Sample using ICD-9-CM codes. Logistic regression was used to study the relationship between RBC transfusion on outcomes after adjusting for demographics, baseline comorbidities, and markers of disease severity. Additional sensitivity analyses stratified by comorbidity burden and disease severity were performed. RESULTS: Of 597,046 ICH hospitalizations, RBC transfusions were administered in 22,904 (4%). RBC transfusion was associated with higher odds of in-hospital mortality (adjusted OR: 1.22 [95%CI: 1.10-1.35]). In sensitivity analyses, RBC transfusions resulted in poor outcomes regardless of the comorbidity burden, but attenuation in this relationship was notable with lower comorbidities (adjusted OR 1.43 [95%CI: 1.34-1.51] vs 1.18 [95%CI: 1.10-1.29]). There were no associations of RBC transfusions with poor outcomes in hospitalizations without mechanical ventilation (adjusted OR 0.88 [95%CI: 0.83-1.13]) and in cases requiring ventriculostomy drains (adjusted OR 1.05 [95%CI: 0.97-1.10]). CONCLUSIONS: In a large, nationally representative sample, RBC transfusion was associated with poor ICH outcomes. However, there were variations in this relationship based on comorbidities and disease severity. Additional prospective studies are required to assess direct risks and benefits from RBC transfusions in ICH.

Acute and subacute neurovascular impact of cryptogenic air emboli.

Background: Cerebral air embolism is a rare cause of acute ischemic stroke that is becoming increasingly well-described in the literature. However, the mechanism and severity of this type of injury can vary, with ischemia typically emerging early in the course of care. To the best of our knowledge, delayed ischemia in this setting has not yet been described. Case Description: A stroke code was called for an unresponsive, hospitalized, 75-year-old man. A computerized tomography (CT) scan of the head revealed air within the right greater than left hemispheric cortical veins with loss of sulcation, concerning for developing ischemia, and CT angiography revealed absent opacification of the distal cortical vessels in the right anterior cerebral artery and middle cerebral artery territories. Magnetic resonance imaging (MRI) of the brain was obtained 5.75 h after the patient's last known well-showed small areas of subtle cortical diffusion restriction. Follow-up CT head within 24 h showed near-complete resolution of the air emboli after treatment with 100% fraction of inspired oxygen on mechanical ventilation. Subsequent MRI, performed 4 days after the initial event, showed extensive cortical diffusion restriction and cerebral edema crossing vascular territories. Conclusion: This case highlights that cerebral air emboli can cause delayed ischemia that may not be appreciated on initial imaging. As such, affected patients may require intensive neurocritical care management, close neurologic monitoring, and repeat imaging irrespective of initial radiographic findings.

Characterization of CSF inflammatory markers after hemorrhagic stroke and their relationship to disease severity.

Background: The inflammatory response within the central nervous system is a key driver of secondary brain injury after hemorrhagic stroke, both in patients with intracerebral hemorrhage (ICH) and aneurysmal subarachnoid hemorrhage (aSAH). In this study, we aimed to characterize inflammatory molecules in the blood and cerebrospinal fluid (CSF) of patients within 72 hours of hemorrhage to understand how such molecules vary across disease types and disease severity. Methods: Biological samples were collected from patients admitted to a single-center Neurosciences Intensive Care Unit with a diagnosis of ICH or aSAH between 2014 and 2022. Control CSF samples were collected from patients undergoing CSF diversion for normal pressure hydrocephalus. A panel of immune molecules in the plasma and CSF samples was analyzed using Cytometric Bead Array assays. Clinical variables, including demographics, disease severity, and intensive care unit length of stay were collected. Results: Plasma and/or CSF samples were collected from 260 patients (188 ICH patients, 54 aSAH patients, 18 controls). C-C motif chemokine ligand-2 (CCL2), interleukin-6 (IL-6), granulocyte-colony stimulating factor (G-CSF), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF), were detectable in the CSF within the first 3 days after hemorrhage, and all were elevated compared to plasma. Compared with controls, CCL2, IL-6, IL-8, G-CSF, and VEGF were elevated in the CSF of both ICH and aSAH patients (p<0.01 for all comparisons). VEGF was increased in ICH patients compared to aSAH patients (p<0.01). CCL2, G-CSF, and VEGF in the CSF were associated with more severe disease in aSAH patients only. Conclusions: Within 3 days of hemorrhagic stroke, proinflammatory molecules can be detected in the CSF at higher concentrations than in the plasma. Early concentrations of some pro-inflammatory molecules may be associated with markers of disease severity.

Emergent external ventricular drain placement in patients with factor Xa inhibitor-associated intracerebral hemorrhage after reversal with andexanet alfa.

BACKGROUND: Andexanet alfa (AA), a factor Xa-inhibitor (FXi) reversal agent, is given as a bolus followed by a 2-hour infusion. This long administration time can delay EVD placement in intracerebral hemorrhage (ICH) patients. We sought to evaluate the safety of EVD placement immediately post-AA bolus compared to post-AA infusion. METHODS: We conducted a retrospective study that included adult patients admitted with FXi-associated ICH who received AA and underwent EVD placement The primary outcome was the occurrence of a new hemorrhage (tract, extra-axial, or intraventricular hemorrhage). Secondary outcomes included mortality, intensive care unit and hospital length of stay, and discharge modified Rankin Score. The primary safety outcome was documented thrombotic events. RESULTS: Twelve patients with FXi related ICH were included (EVD placement post-AA bolus, N = 8; EVD placement post-AA infusion, N = 4). Each arm included one patient with bilateral EVD placed. There was no difference in the incidence of new hemorrhages, with one post-AA bolus patient had small, focal, nonoperative extra-axial hemorrhage. Morbidity and mortality were higher in post-AA infusion patients (mRS, post-AA bolus, 4 [4-6] vs. post-AA infusion 6 [5,6], p = 0.24 and post-AA bolus, 3 (37.5 %) vs. post-AA infusion, 3 (75 %), p = 0.54, respectively). One patient in the post-AA bolus group had thrombotic event. There was no difference in hospital LOS (post-AA bolus, 19 days [12-26] vs. post-AA infusion, 14 days [9-22], p = 0.55) and ICU LOS (post-AA bolus, 10 days [6-13] vs. post-AA infusion, 11 days [5-21], p = 0.86). CONCLUSION: We report no differences in the incidence of tract hemorrhage, extra-axial hemorrhage, or intraventricular hemorrhage post-AA bolus versus post-AA infusion. Larger prospective studies to validate these results are warranted.

Cerebral Microbleeds and Acute Hematoma Characteristics in the ATACH-2 and MISTIE III Trials.

BACKGROUND AND OBJECTIVES: To study the relationship between the presence of cerebral microbleeds (CMBs) and acute hematoma characteristics among patients with primary intracerebral hemorrhage (ICH). METHODS: We pooled individual patient data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) trial and the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 (MISTIE III) trial. We included individuals with a brain MRI scan. Exposure was the presence of a CMB. The coprimary outcomes were admission ICH volume and hematoma expansion. Mixed-effects linear and logistic regression models were used, with demographics and comorbid conditions considered fixed effects and the study cohort treated as a random effect. Additional analyses assessed the relationship between CMB topography and number and hematoma characteristics. RESULTS: Of the 1,499 patients with ICH enrolled in the parent trials, 466 (31.1%) were included in this analysis, and 231 (49.6%) patients had CMBs. In adjusted models, presence of CMBs was associated with smaller ICH volume (ß = -0.26, 95% confidence interval [CI] -0.44 to -0.08) and lower odds of hematoma expansion (odds ratio 0.65, 95% CI 0.40-0.95; p = 0.04). The strength of association between CMBs and hematoma characteristics increased with increasing number of CMBs. The location of the CMBs and the severity of leukoaraiosis did not modify these results. DISCUSSION: In a pooled cohort of patients with ICH, our results are consistent with the hypothesis that more severe underlying small vessel disease, as represented by CMBs, leads to smaller baseline hematoma volumes and reduced hematoma expansion. Underlying cerebral small vessel disease may be of prognostic significance after ICH. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT01176565 and NCT01827046. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the presence of microbleeds on MRI is associated with a smaller ICH volume at presentation and a lower rate of hematoma expansion on follow-up imaging.

RCVS: Symptoms, Incidence, and Resource Utilization in a Population-Based US Cohort.

OBJECTIVE: To estimate the incidence of hospitalization for reversible cerebral vasoconstriction syndrome (RCVS), we identified RCVS-related hospital admissions across 11 U.S. states in 2016. METHODS: We tested the validity of ICD-10 code I67.841 in 79 patients with hospital admissions for RCVS or other cerebrovascular diseases at one academic and one community hospital. After determining that this code had a sensitivity of 100% (95% CI, 82-100%) and a specificity of 90% (95% CI, 79-96%), we applied it to administrative data from the Healthcare Cost and Utilization Project on all ED visits and hospital admissions. Age- and sex-standardized RCVS incidence was calculated using census data. Descriptive statistics were used to analyze associated diagnoses. RESULTS: Across 5,067,250 hospital admissions in our administrative data, we identified 222 patients with a discharge diagnosis of RCVS in 2016. The estimated annual age- and sex-standardized incidence of RCVS hospitalization was 2.7 (95% CI, 2.4-3.1) cases per million adults. Many patients had concomitant neurologic diagnoses, including subarachnoid hemorrhage (37%), ischemic stroke (16%), and intracerebral hemorrhage (10%). In the 90 days before the index admission, 97 patients had an ED visit and 34 patients a hospital admission, most commonly for neurologic, psychiatric, and pregnancy-related diagnoses. Following discharge from the RCVS hospital admission, 58 patients had an ED visit and 31 had a hospital admission, most commonly for neurologic diagnoses. CONCLUSIONS: Using population-wide data, we estimated the age- and sex-standardized incidence of hospitalization for RCVS in U.S. adults as approximately 3 per million per year.

A rare case of HIV CNS escape in a patient previously considered a viral controller.

Human immunodeficiency virus (HIV) ribonucleic acid (RNA) levels generally remain undetectable in the cerebrospinal fluid of people living with HIV with peripheral viral suppression. Secondary HIV central nervous system (CNS) escape refers to the rare independent replication of HIV RNA in the central nervous system despite peripheral viral suppression that occurs in the setting of a concomitant non-HIV infection. We describe here a young man with perinatal HIV infection considered a viral controller who developed secondary HIV CNS escape in the setting of a presumed fungal CNS infection.

Low hemoglobin and hematoma expansion after intracerebral hemorrhage.

OBJECTIVE: Studies have independently shown associations of lower hemoglobin levels with larger admission intracerebral hemorrhage (ICH) volumes and worse outcomes. We investigated whether lower admission hemoglobin levels are associated with more hematoma expansion (HE) after ICH and whether this mediates lower hemoglobin levels' association with worse outcomes. METHODS: Consecutive patients enrolled between 2009 and 2016 to a single-center prospective ICH cohort study with admission hemoglobin and neuroimaging data to calculate HE (>33% or >6 mL) were evaluated. The association of admission hemoglobin levels with HE and poor clinical outcomes using modified Rankin Scale (mRS 4-6) were assessed using separate multivariable logistic regression models. Mediation analysis investigated causal associations among hemoglobin, HE, and outcome. RESULTS: Of 256 patients with ICH meeting inclusion criteria, 63 (25%) had HE. Lower hemoglobin levels were associated with increased odds of HE (odds ratio [OR] 0.80 per 1.0 g/dL change of hemoglobin; 95% confidence interval [CI] 0.67-0.97) after adjusting for previously identified covariates of HE (admission hematoma volume, antithrombotic medication use, symptom onset to admission CT time) and hemoglobin (age, sex). Lower hemoglobin was also associated with worse 3-month outcomes (OR 0.76 per 1.0 g/dL change of hemoglobin; 95% CI 0.62-0.94) after adjusting for ICH score. Mediation analysis revealed that associations of lower hemoglobin with poor outcomes were mediated by HE (p = 0.01). CONCLUSIONS: Further work is required to replicate the associations of lower admission hemoglobin levels with increased odds of HE mediating worse outcomes after ICH. If confirmed, an investigation into whether hemoglobin levels can be a modifiable target of treatment to improve ICH outcomes may be warranted.

Prognostic Value of the Neurological Examination in Cardiac Arrest Patients After Therapeutic Hypothermia.

OBJECTIVES: Current prognostication guidelines for cardiac arrest (CA) survivors predate the use of therapeutic hypothermia (TH). The prognostic value and ideal timing of the neurological examination remain unknown in the setting of TH. DESIGN: Patients (N = 291) admitted between 2007 and 2015 to Columbia University intensive care units for TH following CA had neurological examinations performed on days 1, 3, 5, and 7 postarrest. Absent pupillary light response (PLR), absent corneal reflexes (CRs), and Glasgow coma scores motor (GCS-M) no better than extension were considered poor examinations. Poor outcome was recorded as cerebral performance category score ≥3 at discharge and 1 year. Predictive values of examination maneuvers were calculated for each time point. MAIN RESULTS: Among the 137 survivors to day 7, sensitivities and negative predictive values were low at all time points. The PLR had false positive rates (FPRs) of 0% and positive predictive values (PPV) of 100% from day 3 onward. For the CR and GCS-M, the FPRs decreased from day 3 to 5 (9% vs 3%; 21% vs 9%), while PPVs increased (91% vs 96%; 90% vs 95%). Excluding patients who died due to withdrawal of life-sustaining therapy (WLST) did not significantly affect FPRs or PPVs, nor did assessing outcome at 1 year. CONCLUSIONS: A poor neurological examination remains a strong predictor of poor outcome, both at hospital discharge and at 1 year, independent of WLST. Following TH, the predictive value of the examination is insufficient at day 3 and should be delayed until at least day 5, with some additional benefit beyond day 5.

Human CD39+ Treg Cells Express Th17-Associated Surface Markers and Suppress IL-17 via a Stat3-Dependent Mechanism.

Human CD4+ T regulatory cells (Tregs) are a population of phenotypically and functionally diverse cells that downregulate inflammatory and autoimmune responses. As Th17 cells play an important role in the pathogenesis of autoimmune diseases, it is critical to elucidate the mechanisms regulating these cells. In this study, we examined the molecular basis underlying the phenotypic and functional diversity of human Tregs expressing the ectonucleotidase CD39. CD4+CD25hiCD39+ Tregs inhibit the proliferative response and the secretion of IL-17 and IFN-γ of autologous CD4+ T effector cells, while CD4+CD25hiCD39- Tregs only suppress IFN-γ production. We demonstrate that activated human CD4+CD25hiCD39+ Tregs express the Th17-associated surface markers CCR6 and IL-23R, and phosphorylate the transcription factor Stat3. Moreover, suppression of IL-17 by CD4+CD25hiCD39+ Tregs occurs via a Stat3-dependent mechanism as inhibition of Stat3 activation in the CD39+ Tregs reverses their ability to suppress IL-17. CD4+CD25hiCD39- Tregs are not endowed with the ability to inhibit IL-17 as they do not upregulate CCR6 or the IL-23R, and furthermore, they secrete IL-17. Our findings provide the first evidence that human Treg functional diversity is matched to the type of immune response being regulated and reveal a new role for Stat3 in controlling Treg function.

Use of early head CT following out-of-hospital cardiopulmonary arrest.

AIM: Neurological emergencies can lead to cardiac arrest, and post-arrest patients can develop life-threatening neurological abnormalities. This study aims to estimate and characterize the use of early head CT (HCT), and its potential impact on post-resuscitation management. METHODS: This retrospective study analyzed 213 adults who suffered an out-of-hospital cardiac arrest (OHCA) and survived for at least 24h. Demographics were collected and arrest-related variables were documented. Timing of HCT was recorded and if abnormalities were found on HCT within 24h of resuscitation, any resulting changes in management were recorded. Outcome was measured by cerebral performance category at discharge. RESULTS: Only 54% of patients who survived OHCA underwent HCT in the first 24h after resuscitation. Patients who underwent HCT were healthier and had better pre-arrest functional status and shorter duration of arrest. Acute abnormalities were found on 38% of HCT and 34% of these abnormal scans resulted in management changes. CONCLUSIONS: Early HCT is not consistently performed after OHCA and may be heavily influenced by a patient's premorbid status and duration of arrest. Early HCT can demonstrate acute abnormalities that can result in significant changes in patient management.

Unexpected Rapid Improvement and Neurogenic Stunned Myocardium in a Patient With Acute Motor Axonal Neuropathy: A Case Report and Literature Review.

Acute Motor Axonal Neuropathy-type Guillain-Barré Syndrome (GBS) is a subset of GBS with either a rapidly improving or protracted course that was first described in China. We describe a 27-year-old previously healthy woman with weakness that progressed to complete tetraplegia and areflexia within 2 weeks after an upper respiratory illness. A lumbar puncture performed 4 days after onset of neurologic symptoms was inconclusive for GBS, and electromyography revealed complete motor axonal neuropathy. The patient had Mycoplasma pneumoniae in her nares and blood, and several antiganglioside antibodies in her blood. She was treated with plasmapheresis, antibiotics, and physical therapy. Her motor function and reflexes improved rapidly with treatment, and she was able to ambulate within 3 weeks. She also experienced cardiomyopathy, which improved with plasmapheresis. We report a rare case of Mycoplasma pneumonia-associated acute motor axonal neuropathy-type GBS presenting with complete tetraplegia, areflexia, and neurogenic stunned myocardium that rapidly improved with plasmapheresis.

Case report: cytokine and CD4+ T-cell profiles of monozygotic twins with autism and divergent comorbidities and drug treatment.

Autism spectrum disorders are neurodevelopmental disorders that are thought to be caused by a gene-by-environment interaction and in which various immune alterations are reported. We investigate CD4(+) T-cell cytokine profiles and subpopulations in 19-year-old monozygotic twins with autism and different comorbidities. CD4(+) T cells from the twin with epilepsy produce more interferon-gamma, less interleukin-17, and have an increased interferon-γ/interleukin-4 ratio. CD4(+) T cells from the twin with multiple sclerosis exhibit a cytokine profile similar to an age and gender-matched control and a higher percentage of T regulatory (Treg) cells. The twins' mother's T cells produce very high levels of both interleukin-17 and interferon-γ. Cytokine and CD4(+) T-cell abnormalities in the twins could contribute to or be a result of the manifestation of their divergent comorbidities. A proinflammatory, autoimmune-polarized cytokine profile is observed in this unique family with autism.