Mild Hypoxia Accelerates Cerebral Cavernous Malformation Disease Through CX3CR1-CX3CL1 Signaling.

BACKGROUND: Heterogeneity in the severity of cerebral cavernous malformations (CCMs) disease, including brain bleedings and thrombosis that cause neurological disabilities in patients, suggests that environmental, genetic, or biological factors act as disease modifiers. Still, the underlying mechanisms are not entirely understood. Here, we report that mild hypoxia accelerates CCM disease by promoting angiogenesis, neuroinflammation, and vascular thrombosis in the brains of CCM mouse models. METHODS: We used genetic studies, RNA sequencing, spatial transcriptome, micro-computed tomography, fluorescence-activated cell sorting, multiplex immunofluorescence, coculture studies, and imaging techniques to reveal that sustained mild hypoxia via the CX3CR1-CX3CL1 signaling pathway influences cell-specific neuroinflammatory interactions, contributing to heterogeneity in CCM severity. RESULTS: Histological and expression profiles of CCM neurovascular lesions (Slco1c1-iCreERT2;Pdcd10fl/fl; Pdcd10BECKO) in male and female mice found that sustained mild hypoxia (12% O2, 7 days) accelerates CCM disease. Our findings indicate that a small reduction in oxygen levels can significantly increase angiogenesis, neuroinflammation, and thrombosis in CCM disease by enhancing the interactions between endothelium, astrocytes, and immune cells. Our study indicates that the interactions between CX3CR1 and CX3CL1 are crucial in the maturation of CCM lesions and propensity to CCM immunothrombosis. In particular, this pathway regulates the recruitment and activation of microglia and other immune cells in CCM lesions, which leads to lesion growth and thrombosis. We found that human CX3CR1 variants are linked to lower lesion burden in familial CCMs, proving it is a genetic modifier in human disease and a potential marker for aggressiveness. Moreover, monoclonal blocking antibody against CX3CL1 or reducing 1 copy of the Cx3cr1 gene significantly reduces hypoxia-induced CCM immunothrombosis. CONCLUSIONS: Our study reveals that interactions between CX3CR1 and CX3CL1 can modify CCM neuropathology when lesions are accelerated by environmental hypoxia. Moreover, a hypoxic environment or hypoxia signaling caused by CCM disease influences the balance between neuroinflammation and neuroprotection mediated by CX3CR1-CX3CL1 signaling. These results establish CX3CR1 as a genetic marker for patient stratification and a potential predictor of CCM aggressiveness.

Pathologic Features of Brain Hemorrhage After Radiation Treatment: Case Series with Somatic Mutation Analysis.

BACKGROUND: Radiation treatment for diseases of the brain can result in hemorrhagic adverse radiation effects. The underlying pathologic substrate of brain bleeding after irradiation has not been elucidated, nor potential associations with induced somatic mutations. METHODS: We retrospectively reviewed our department's pathology database over 5 years and identified 5 biopsy specimens (4 patients) for hemorrhagic lesions after brain irradiation. Tissues with active malignancy were excluded. Samples were characterized using H&E, Perl's Prussian Blue, and Masson's Trichrome; immunostaining for B-cells (anti-CD20), T-cells (anti-CD3), endothelium (anti-CD31), macrophages (anti-CD163), α-smooth muscle actin, and TUNEL. DNA analysis was done by two panels of next-generation sequencing for somatic mutations associated with known cerebrovascular anomalies. RESULTS: One lesion involved hemorrhagic expansion among multifocal microbleeds that had developed after craniospinal irradiation for distant medulloblastoma treatment. Three bleeds arose in the bed of focally irradiated arteriovenous malformations (AVM) after confirmed obliteration. A fifth specimen involved the radiation field distinct from an irradiated AVM bed. From these, 2 patterns of hemorrhagic vascular pathology were identified: encapsulated hematomas and cavernous-like malformations. All lesions included telangiectasias with dysmorphic endothelium, consistent with primordial cavernous malformations with an associated inflammatory response. DNA analysis demonstrated genetic variants in PIK3CA and/or PTEN genes but excluded mutations in CCM genes. CONCLUSIONS: Despite pathologic heterogeneity, brain bleeding after irradiation is uniformly associated with primordial cavernous-like telangiectasias and disruption of genes implicated in dysangiogenesis but not genes implicated as causative of cerebral cavernous malformations. This may implicate a novel signaling axis as an area for future study.

Antithrombotic Therapy in Cerebral Cavernous Malformations: A Systematic Review, Meta-Analysis, and Network Meta-Analysis.

BACKGROUND: Cerebral cavernous malformations are complex vascular anomalies in the central nervous system associated with a risk of intracranial hemorrhage. Traditional guidelines have been cautious about the use of antithrombotic therapy in this patient group, citing concerns about potential bleeding risk. However, recent research posits that antithrombotic therapy may actually be beneficial. This study aims to clarify the association between antithrombotic therapy, including antiplatelet and anticoagulant medications, and the risk of intracranial hemorrhage in patients with cerebral cavernous malformations. METHODS AND RESULTS: A comprehensive literature search was conducted in PubMed, Web of Science, and Scopus databases, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Nine single-center, nonrandomized cohort studies involving 2709 patients were included. Outcomes were analyzed using random-effects model, and a network meta-analysis was conducted for further insight. Of the 2709 patients studied, 388 were on antithrombotic therapy. Patients on antithrombotic therapy had a lower risk of presenting with intracranial hemorrhage (odds ratio [OR], 0.56 [95% CI, 0.45-0.7]; P<0.0001). In addition, the use of antithrombotic therapy was associated with lower risk of intracranial hemorrhage from a cerebral cavernous malformation on follow-up (OR, 0.21 [95% CI, 0.13-0.35]; P<0.0001). A network meta-analysis revealed a nonsignificant OR of 0.73 (95% CI, 0.23-2.56) when antiplatelet therapy was compared with anticoagulant therapy. CONCLUSIONS: Our study explores the potential benefits of antithrombotic therapy in cerebral cavernous malformations. Although the analysis suggests a possible role for antithrombotic agents, it is critical to note that the evidence remains preliminary. Fundamental biases in study design, such as ascertainment and assignment bias, limit the weight of our conclusions. Therefore, our findings should be considered hypothesis-generating and not definitive for clinical practice change.

Association Between Hematoma Volume and Risk of Subsequent Ischemic Stroke: A MISTIE III and ATACH-2 Analysis.

BACKGROUND: Nontraumatic intracerebral hemorrhage (ICH) is independently associated with a long-term increased risk of major arterial ischemic events. While the relationship between ICH location and ischemic risk has been studied, whether hematoma volume influences this risk is poorly understood. METHODS: We pooled individual patient data from the MISTIE III (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation Phase 3) and the ATACH-2 (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2) trials. The exposure was hematoma volume, treated as a continuous measure in the primary analysis, and dichotomized by the median in the secondary analyses. The outcome was a symptomatic, clinically overt ischemic stroke, adjudicated centrally within each trial. We evaluated the association between hematoma volume and the risk of an ischemic stroke using Cox regression analyses after adjustment for demographics, vascular comorbidities, and ICH characteristics. RESULTS: Of 1470 patients with ICH, the mean age was 61.7 (SD, 12.8) years, and 574 (38.3%) were female. The median hematoma volume was 17.3 mL (interquartile range, 7.2-35.7). During a median follow-up of 107 days (interquartile range, 91-140), a total of 30 ischemic strokes occurred, of which 22 were in patients with a median ICH volume of ≥17.3 mL and a cumulative incidence of 4.6% (95% CI, 3.1-7.1). Among patients with a median ICH volume <17.3 mL, there were 8 ischemic strokes with a cumulative incidence of 3.1% (95% CI, 1.7-6.0). In primary analyses using adjusted Cox regression models, ICH volume was associated with an increased risk of ischemic stroke (hazard ratio, 1.02 per mL increase [95% CI, 1.01-1.04]). In secondary analyses, ICH volume of ≥17.3 mL was associated with an increased risk of ischemic stroke (hazard ratio, 2.5 [95% CI, 1.1-7.2]), compared with those with an ICH volume <17.3 mL. CONCLUSIONS: In a heterogeneous cohort of patients with ICH, initial hematoma volume was associated with a heightened short-term risk of ischemic stroke.

Transcriptomic signatures of individual cell types in cerebral cavernous malformation.

Cerebral cavernous malformation (CCM) is a hemorrhagic neurovascular disease with no currently available therapeutics. Prior evidence suggests that different cell types may play a role in CCM pathogenesis. The contribution of each cell type to the dysfunctional cellular crosstalk remains unclear. Herein, RNA-seq was performed on fluorescence-activated cell sorted endothelial cells (ECs), pericytes, and neuroglia from CCM lesions and non-lesional brain tissue controls. Differentially Expressed Gene (DEG), pathway and Ligand-Receptor (LR) analyses were performed to characterize the dysfunctional genes of respective cell types within CCMs. Common DEGs among all three cell types were related to inflammation and endothelial-to-mesenchymal transition (EndMT). DEG and pathway analyses supported a role of lesional ECs in dysregulated angiogenesis and increased permeability. VEGFA was particularly upregulated in pericytes. Further pathway and LR analyses identified vascular endothelial growth factor A/ vascular endothelial growth factor receptor 2 signaling in lesional ECs and pericytes that would result in increased angiogenesis. Moreover, lesional pericytes and neuroglia predominantly showed DEGs and pathways mediating the immune response. Further analyses of cell specific gene alterations in CCM endorsed potential contribution to EndMT, coagulation, and a hypoxic microenvironment. Taken together, these findings motivate mechanistic hypotheses regarding non-endothelial contributions to lesion pathobiology and may lead to novel therapeutic targets. Video Abstract.

Role of Rho-Associated Kinase in the Pathophysiology of Cerebral Cavernous Malformations.

Cerebral cavernous malformations (CCMs) are vascular lesions characterized by a porous endothelium. The lack of a sufficient endothelial barrier can result in microbleeds and frank intracerebral hemorrhage. A primary mechanism for lesion development is a sequence variant in at least 1 of the 3 CCM genes (CCM1, CCM2, and CCM3), which influence various signaling pathways that lead to the CCM phenotype. A common downstream process associated with CCM gene loss of function involves overactivation of RhoA and its effector Rho-associated kinase (ROCK). In this study, we review RhoA/ROCK-related mechanisms involved in CCM pathophysiology as potential therapeutic targets. Literature searches were conducted in PubMed using combinations of search terms related to RhoA/ROCK and CCMs. In endothelial cells, CCM1, CCM2, and CCM3 proteins normally associate to form the CCM protein complex, which regulates the functions of a wide variety of protein targets (e.g., MAP3K3, SMURF1, SOK-1, and ICAP-1) that directly or indirectly increase RhoA/ROCK activity. Loss of CCM complex function and increased RhoA/ROCK activity can lead to the formation of stress fibers that contribute to endothelial junction instability. Other RhoA/ROCK-mediated pathophysiologic outcomes include a shift to a senescence-associated secretory phenotype (primarily mediated by ROCK2), which is characterized by endothelial cell migration, cell cycle arrest, extracellular matrix degradation, leukocyte chemotaxis, and inflammation. ROCK represents a potential therapeutic target, and direct (fasudil, NRL-1049) and indirect (statins) ROCK inhibitors have demonstrated various levels of efficacy in reducing lesion burden in preclinical models of CCM. Current (atorvastatin) and planned (NRL-1049) clinical studies will determine the efficacy of ROCK inhibitors for CCM in humans, for which no US Food and Drug Administration-approved or EU-approved pharmacologic treatment exists.

Catheter Tract Hemorrhages and Intracerebral Hemorrhage Outcomes in the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Trial.

BACKGROUND AND OBJECTIVES: Factors associated with external ventricular catheter tract hemorrhage (CTH) are well studied; whether CTH adversely influence outcomes after intracerebral hemorrhage (sICH), however, is poorly understood. We therefore sought to evaluate the association between CTH and sICH outcomes. METHODS: We performed a post hoc analysis of the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage trial. The exposure was CTH and evaluated on serial computed tomography scans between admission and randomization (approximately 72 hours). The primary outcomes were a composite of death or major disability (modified Rankin Score >3) and mortality alone, both assessed at 6 months. Secondary outcomes were functional outcomes at 30 days, permanent cerebrospinal fluid (CSF) shunt placement, any infection, and ventriculitis. We performed logistic regression adjusted for demographics, comorbidities, sICH characteristics, and treatment assignment, for all analyses. RESULTS: Of the 500 patients included, the mean age was 59 (SD, ±11) years and 222 (44%) were female. CTH occurred in 112 (22.4%) patients and was more common in minority patients, those on prior antiplatelet therapy, and patients who had more than 1 external ventricular drain placed. The end of treatment intraventricular hemorrhage volume was higher among patients with CTH (11.7 vs 7.9 mL, P = .01), but there were no differences in other sICH characteristics or the total duration of external ventricular drain. In multivariable regression models, CTH was not associated with death or major disability (odds ratio, 0.7; 95% CI: 0.4-1.2) or death alone (odds ratio, 0.8; 95% CI, 0.5-1.4). There were no relationships between CTH and secondary outcomes including 30-day functional outcomes, permanent CSF shunt placement, any infection, or ventriculitis. CONCLUSION: Among patients with sICH and large intraventricular hemorrhage, CTH was not associated with poor sICH outcomes, permanent CSF shunt placement, or infections. A more detailed cognitive evaluation is needed to inform about the role of CTH in sICH prognosis.

Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage, Part I: Event Rates and Clinical Outcome.

BACKGROUND: Cerebral cavernous malformation with symptomatic hemorrhage (SH) are targets for novel therapies. A multisite trial-readiness project (https://www.clinicaltrials.gov; Unique identifier: NCT03652181) aimed to identify clinical, imaging, and functional changes in these patients. METHODS: We enrolled adult cerebral cavernous malformation patients from 5 high-volume centers with SH within the prior year and no planned surgery. In addition to clinical and imaging review, we assessed baseline, 1- and 2-year National Institutes of Health Stroke Scale, modified Rankin Scale, European Quality of Life 5D-3 L, and patient-reported outcome-measurement information system, Version 2.0. SH and asymptomatic change rates were adjudicated. Changes in functional scores were assessed as a marker for hemorrhage. RESULTS: One hundred twenty-three, 102, and 69 patients completed baseline, 1- and 2-year clinical assessments, respectively. There were 21 SH during 178.3 patient years of follow-up (11.8% per patient year). At baseline, 62.6% and 95.1% of patients had a modified Rankin Scale score of 1 and National Institutes of Health Stroke Scale score of 0 to 4, respectively, which improved to 75.4% (P=0.03) and 100% (P=0.06) at 2 years. At baseline, 74.8% had at least one abnormal patient-reported outcome-measurement information system, Version 2.0 domain compared with 61.2% at 2 years (P=0.004). The most common abnormal European Quality of Life 5D-3 L domains were pain (48.7%), anxiety (41.5%), and participation in usual activities (41.4%). Patients with prospective SH were more likely than those without SH to display functional decline in sleep, fatigue, and social function patient-reported outcome-measurement information system, Version 2.0 domains at 2 years. Other score changes did not differ significantly between groups at 2 years. The sensitivity of scores as an SH marker remained poor at the time interval assessed. CONCLUSIONS: We report SH rate, functional, and patient-reported outcomes in trial-eligible cerebral cavernous malformation with SH patients. Functional outcomes and patient-reported outcomes generally improved over 2 years. No score change was highly sensitive or specific for SH and could not be used as a primary end point in a trial.

Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage, Part II: Biomarkers and Trial Modeling.

BACKGROUND: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cerebral cavernous malformations. We assessed their prospective changes in a multisite trial-readiness project. METHODS: Patients with cavernous malformation and symptomatic hemorrhage (SH) in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of the SH lesion were acquired at baseline and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined criteria for recurrent SH or asymptomatic change. Sample size calculations for hypothesized therapeutic effects were conducted. RESULTS: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH (P=0.019). Annual QSM increase by ≥6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with asymptomatic change during the same epoch and 3.82× more frequently than clinical events. DCEQP change had lower sensitivity for SH and asymptomatic change than QSM change and greater variance. A trial with the smallest sample size would detect a 30% difference in QSM annual change during 2 years of follow-up in 34 or 42 subjects (1 and 2 tailed, respectively); power, 0.8, α=0.05. CONCLUSIONS: Assessment of QSM change is feasible and sensitive to recurrent bleeding in cavernous malformations. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the US Food and Drug Administration of QSM as a biomarker of drug effect on bleeding in cavernous malformations. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03652181.

Mechanistic Evaluation of Diffusion Weighted Hyperintense Lesions After Large Spontaneous Intracerebral Hemorrhage: A Subgroup Analysis of MISTIE III.

BACKGROUND: Ischemic lesions on diffusion weighted imaging (DWI) are common after acute spontaneous intracerebral hemorrhage (ICH) but are poorly understood for large ICH volumes (> 30 mL). We hypothesized that large blood pressure drops and effect modification by cerebral small vessel disease markers on magnetic resonance imaging (MRI) are associated with DWI lesions. METHODS: This was an exploratory analysis of participants in the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 trial with protocolized brain MRI scans within 7 days from ICH. Multivariable logistic regression analysis was performed to assess biologically relevant factors associated with DWI lesions, and relationships between DWI lesions and favorable ICH outcomes (modified Rankin Scale 0-3). RESULTS: Of 499 enrolled patients, 300 had MRI at median 7.5 days (interquartile range 7-8), and 178 (59%) had DWI lesions. The incidence of DWI lesions was higher in patients with systolic blood pressure (SBP) reduction ≥ 80 mm Hg in first 24 h (76%). In adjusted models, factors associated with DWI lesions were as follows: admission intraventricular hematoma volume (p = 0.03), decrease in SBP ≥ 80 mm Hg from admission to day 1 (p = 0.03), and moderate-to-severe white matter disease (p = 0.01). Patients with DWI lesions had higher odds of severe disability at 1 month (p = 0.04), 6 months (p = 0.036), and 12 months (p < 0.01). No evidence of effect modification by cerebral small vessel disease on blood pressure was found. CONCLUSIONS: In patients with large hypertensive ICH, white matter disease, intraventricular hemorrhage volume, and large reductions in SBP over the first 24 h were independently associated with DWI lesions. Further investigation of potential hemodynamic mechanisms of ischemic injury after large ICH is warranted.

Single-nucleus DNA sequencing reveals hidden somatic loss-of-heterozygosity in Cerebral Cavernous Malformations.

Cerebral Cavernous Malformations (CCMs) are vascular malformations of the central nervous system which can lead to moderate to severe neurological phenotypes in patients. A majority of CCM lesions are driven by a cancer-like three-hit mutational mechanism, including a somatic, activating mutation in the oncogene PIK3CA, as well as biallelic loss-of-function mutations in a CCM gene. However, standard sequencing approaches often fail to yield a full complement of pathogenic mutations in many CCMs. We suggest this reality reflects the limited sensitivity to identify low-frequency variants and the presence of mutations undetectable with bulk short-read sequencing. Here we report a single-nucleus DNA-sequencing approach that leverages the underlying biology of CCMs to identify lesions with somatic loss-of-heterozygosity, a class of such hidden mutations. We identify an alternative genetic mechanism for CCM pathogenesis and establish a method that can be repurposed to investigate the genetic underpinning of other disorders with multiple somatic mutations.

Cerebral small vessel disease modifies outcomes after minimally invasive surgery for intracerebral haemorrhage.

BACKGROUND: Minimally invasive surgery (MIS) for spontaneous supratentorial intracerebral haemorrhage (ICH) is controversial but may be beneficial if end-of-treatment (EOT) haematoma volume is reduced to ≤15 mL. We explored whether MRI findings of cerebral small vessel disease (CSVD) modify the effect of MIS on long-term outcomes. METHODS: Prespecified blinded subgroup analysis of 288 subjects with qualified imaging sequences from the phase 3 Minimally Invasive Surgery Plus Alteplase for Intracerebral Haemorrhage Evacuation (MISTIE) trial. We tested for heterogeneity in the effects of MIS and MIS+EOT volume ≤15 mL on the trial's primary outcome of good versus poor function at 1 year by the presence of single CSVD features and CSVD scores using multivariable models. RESULTS: Of 499 patients enrolled in MISTIE III, 288 patients had MRI, 149 (51.7%) randomised to MIS and 139 (48.3%) to standard medical care (SMC). Median (IQR) ICH volume was 42 (30-53) mL. In the full MRI cohort, there was no statistically significant heterogeneity in the effects of MIS versus SMC on 1-year outcomes by any specific CSVD feature or by CSVD scores (all Pinteraction >0.05). In 94 MIS patients with EOT ICH volume ≤15 mL, significant reduction in odds of poor outcome was found with cerebral amyloid angiopathy score <2 (OR, 0.14 (0.05-0.42); Pinteraction=0.006), absence of lacunes (OR, 0.37 (0.18-0.80); Pinteraction=0.02) and absence of severe white matter hyperintensities (WMHs) (OR, 0.22 (0.08-0.58); Pinteraction=0.03). CONCLUSIONS: Following successful haematoma reduction by MIS, we found significantly lower odds of poor functional outcome with lower total burden of CSVD in addition to absence of lacunes and severe WMHs. CSVD features may have utility for prognostication and patient selection in clinical trials of MIS.

mTORC1 Inhibitor Rapamycin Inhibits Growth of Cerebral Cavernous Malformation in Adult Mice.

BACKGROUND: Cerebral cavernous malformations (CCMs) are vascular malformations that frequently cause stroke. CCMs arise due to loss of function in one of the genes that encode the CCM complex, a negative regulator of MEKK3-KLF2/4 signaling in vascular endothelial cells. Gain-of-function mutations in PIK3CA (encoding the enzymatic subunit of the PI3K (phosphoinositide 3-kinase) pathway associated with cell growth) synergize with CCM gene loss-of-function to generate rapidly growing lesions. METHODS: We recently developed a model of CCM formation that closely reproduces key events in human CCM formation through inducible CCM loss-of-function and PIK3CA gain-of-function in mature mice. In the present study, we use this model to test the ability of rapamycin, a clinically approved inhibitor of the PI3K effector mTORC1, to treat rapidly growing CCMs. RESULTS: We show that both intraperitoneal and oral administration of rapamycin arrests CCM growth, reduces perilesional iron deposition, and improves vascular perfusion within CCMs. CONCLUSIONS: Our findings further establish this adult CCM model as a valuable preclinical model and support clinical testing of rapamycin to treat rapidly growing human CCMs.

Minimally Invasive Surgery With Thrombolysis for Intracerebral Hemorrhage Evacuation: Bayesian Reanalysis of a Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Bayesian analysis of randomized controlled trials (RCTs) can extend the value of trial data beyond interpretations based on conventional p value-based binary cutoffs. We conducted an exploratory post hoc Bayesian reanalysis of the minimally invasive surgery with thrombolysis for intracerebral hemorrhage (ICH) evacuation (MISTIE-3) trial and derived probabilities of potential intervention effect on functional and survival outcomes. METHODS: MISTIE-3 was a multicenter phase 3 RCT designed to evaluate the efficacy and safety of the MISTIE intervention. Five hundred and six adults (18 years or older) with spontaneous, nontraumatic, supratentorial ICH of ≥30 mL were randomized to receive either the MISTIE intervention (n = 255) or standard medical care (n = 251). We provide Bayesian-derived estimates of the effect of the MISTIE intervention on achieving a good 365-day modified Rankin Scale score (mRS score 0-3) as relative risk (RR) and absolute risk difference (ARD), and the probabilities that these treatment effects are greater than prespecified thresholds. We used 2 sets of prior distributions: (1) reference priors, including minimally informative, enthusiastic, and skeptical priors, and (2) data-derived prior distribution, using a hierarchical random effects model. We additionally evaluated the potential effects of the MISTIE intervention on 180-day and 30-day mRS and 365-, 180-, and 30-day mortality using data-derived priors. RESULTS: The Bayesian-derived probability that MISTIE intervention has any beneficial effect (RR >1) on achieving a good 365-day mRS score was 70% using minimally informative prior, 87% with enthusiastic prior, 68% with skeptical prior, and 73% with data-derived prior. However, these probabilities were ≤55% for RR >1.10 and 0% for RR >1.52 across a range of priors. The probabilities of achieving RR >1 for 180- and 30-day mRS scores are 65% and 80%, respectively. Furthermore, the probabilities of achieving RR <1 for 365-, 180-, and 30-day mortality are 93%, 98%, and 99%, respectively. DISCUSSION: Our exploratory analyses indicate that across a range of priors, the Bayesian-derived probability of MISTIE intervention having any beneficial effect on 365-day mRS for patients with ICH is between 68% and 87%. These analyses do not change the frequentist-based interpretation of the trial. However, unlike the frequentist p values, which indirectly evaluate treatment effects and only provide an arbitrary binary cutoff (such as 0.05), the Bayesian framework directly estimates the probabilities of potential treatment effects. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov/ct2/show/NCT01827046. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that minimally invasive surgery (MIS) + recombinant tissue plasminogen activator (rt-PA) does not significantly improve functional outcome in patients with ICH. However, this study lacks the precision to exclude a potential benefit of MIS + rt-PA.

Inflammatory Mechanisms in a Neurovascular Disease: Cerebral Cavernous Malformation.

Cerebral cavernous malformation (CCM) is a common cerebrovascular malformation causing intracranial hemorrhage, seizures, and focal neurologic deficits. A unique CCM lesional inflammatory microenvironment has been shown to influence the clinical course of the disease. This review addresses the inflammatory cell infiltrate in the CCM lesion and the role of a defined antigen-driven immune response in pathogenicity. We summarize immune mechanisms associated with the loss of the CCM gene and disease progression, including the potential role of immunothrombosis. We also review evidence of circulating inflammatory biomarkers associated with CCM disease and its clinical activity. We articulate future directions for this research, including the role of individual cell type contributions to the immune response in CCM, single cell transcriptomics of inflammatory cells, biomarker development, and therapeutic implications. The concepts are applicable for developing diagnostic and treatment strategies for CCM and for studying other neurovascular diseases.

Underlying intracranial atherosclerotic disease is associated with worse outcomes in acute large vessel occlusion undergoing endovascular thrombectomy.

BACKGROUND: Data on large vessel occlusion (LVO) management due to intracranial atherosclerotic disease (ICAD) are scarce. OBJECTIVE: To compare clinical outcomes between patients with ICAD and those without ICAD following mechanical thrombectomy (MT). METHODS: We performed a retrospective analysis of consecutive patients who underwent MT for LVO in a large academic comprehensive stroke center, and compared in-hospital mortality, 90-day mortality, favorable functional outcome at 90 days, and symptomatic intracranial hemorrhage (ICH) using chi-squared tests and multivariate logistic regression analyses. We defined ICAD as observable plaque at occlusion site post-thrombectomy. RESULTS: Among 215 patients (mean age 67.1 ± 16.0 years; 60.5% female; 83.6% Black, median NIHSS score 16), ICAD was present in 38 patients (17.7%). Diabetes and dyslipidemia were more common in those with ICAD (57.9% vs. 38.4%, p = 0.027 and 29.0% vs. 14.7%, p = 0.035, respectively). Substantial reperfusion (TICI ≥2b) was achieved less often (84.2% vs. 94.4%, p = 0.031) but symptomatic ICH was also less common in ICAD patients (0% vs. 9.0%, p = 0.081). In-hospital and 90-day mortality were more common (36.8% vs. 15.8%, p = 0.003 and 52.6% vs. 26.6%, p = 0.002, respectively) and favorable functional outcome (mRS 0-2) at 90 days was less common (7.9% vs. 33.9%, p = 0.001) in ICAD patients. After adjusting for prognostic variables, ICAD was independently associated with in-hospital mortality (OR=4.1, 95% CI 1.7-9.7), 90-day mortality (OR=3.7, 95% CI 1.6-8.6), and poor functional outcome at 90 days (OR=5.5, 95% CI 1.6-19.4). CONCLUSION: Symptomatic ICAD in a predominantly African American cohort is associated with increased odds of mortality and poor functional outcome at 90 days in patients with LVO undergoing MT.

Cavernous Angioma Symptomatic Hemorrhage (CASH) Trial Readiness II: Imaging Biomarkers and Trial Modeling.

Background: Quantitative susceptibility mapping (QSM) and dynamic contrast enhanced quantitative perfusion (DCEQP) MRI sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cavernous angiomas. We assessed their prospective changes in cavernous angiomas with symptomatic hemorrhage (CASH) in a multisite trial readiness project ( clinicaltrials.gov NCT03652181 ). Methods: Patients with CASH in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of CASH lesion were acquired at baseline, and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined lesional symptomatic hemorrhage (SH) or asymptomatic change (AC). Sample size calculations for hypothesized therapeutic effects were conducted. Results: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH (p= 0.019). Annual QSM increase by ≥ 6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with AC during the same epoch, and 3.82 times more frequently than clinical events. DCEQP change had lower sensitivity for SH and AC than QSM change, and greater variance. A trial with smallest sample size would detect a 30% difference in QSM annual change in 34 or 42 subjects (one and two-tailed, respectively), power 0.8, alpha 0.05. Conclusions: Assessment of QSM change is feasible and sensitive to recurrent bleeding in CASH. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the U.S. F.D.A. of QSM as a biomarker of drug effect in CASH.

Impact of socioeconomics and race on clinical follow-up and trial enrollment and adherence in cerebral cavernous malformation.

OBJECTIVES: Cerebral cavernous malformation (CCM) affects more than a million Americans but advanced care for symptomatic lesions and access to research studies is largely limited to referral academic centers MATERIALS AND METHODS: A cohort of CCM patients screened for research studies at an accredited center of excellence for CCM was analyzed. Demographics, lesion location, history of hemorrhage, insurance type and area of deprivation index (ADI) were collected. Primary outcomes were clinical follow-up within a year from initial evaluation, and enrollment and adherence in clinical trials among eligible subjects RESULTS: A majority (52.8%) of CCM patients evaluated had a high socioeconomic status (SES) (ADI 1-3), and only 11.5% were African American. Patients who had a symptomatic bleed were more likely to follow-up (p=0.01), and those with brainstem lesion were more likely to enroll/adhere in a clinical trial (p=0.02). Rates of clinical follow-up were similar across different ADI groups, insurance coverage and race. Patients who were uninsured/self-paying, and African Americans were more likely to decline/drop from clinical trials (OR 2.4, 95% CI 0.46-10.20 and OR 2.2, 95% CI 0.33-10.75, respectively), but differences were not statistically significant CONCLUSIONS: Access of disadvantaged patients to center of excellence care and research remains limited despite geographic proximity to their community. Patients with lower SES and African Americans are as likely to follow-up clinically, but there were trends of differences in enrollment/adherence in clinical trials. Mitigation efforts should target systemic causes of low access to specialized care among uninsured and African American patients.