Association of Quality of Life Domains and Clinical Symptoms in Patients With Familial Cerebral Cavernous Malformation.

Background: Familial cerebral cavernous malformation (fCCM) is characterized by multiple brain lesions affecting quality of life. PROMIS-29 (Patient-Reported Outcomes Measurement Information System 29) is a quality of life survey validated in some neurological diseases but not in fCCM. We assessed the reliability, validity, and association of PROMIS-29 in fCCM with clinical symptoms and with the modified Rankin Scale.

Common and distinct circulating microRNAs in four neurovascular disorders.

Background: Familial cerebral cavernous malformations (FCCM), Sturge-Weber Syndrome (SWS), and hereditary hemorrhagic telangiectasia (HHT) are driven by genetic mutations causing varying vascular dysmorphism and risk of brain bleeding. Cerebral microbleeds (CMBs) are associated with the aging process with less characterized genetic drivers. This study hypothesizes that common and distinct circulating microRNAs (miRNAs) can reflect mechanisms of vascular dysmorphism and bleeding, which can serve as potential biomarkers in clinical contexts.

Identifying features of prior hemorrhage in cerebral cavernous malformations on quantitative susceptibility maps: a machine learning pilot study.

Features of new bleeding on conventional imaging in cerebral cavernous malformations (CCMs) often disappear after several weeks, yet the risk of rebleeding persists long thereafter. Increases in mean lesional quantitative susceptibility mapping (QSM) ≥ 6% on MRI during 1 year of prospective surveillance have been associated with new symptomatic hemorrhage (SH) during that period. The authors hypothesized that QSM at a single time point reflects features of hemorrhage in the prior year or potential bleeding in the subsequent year.

Guidelines for the Diagnosis and Clinical Management of Cavernous Malformations of the Brain and Spinal Cord: Consensus Recommendations Based on a Systematic Literature Review by the Alliance to Cure Cavernous Malformation Clinical Advisory Board Experts Panel.

Background And Objectives: Despite many publications about cavernous malformations (CMs), controversy remains regarding diagnostic and management strategies. To update evidence-based guidelines for the clinical management of brain and spinal cord CMs.

Methods: The Alliance to Cure CMs, the patient support group in the United States advocating on behalf of patients and research in CM, convened a multidisciplinary writing group comprising expert CM clinicians to help summarize the existing literature related to the clinical care of CM, focusing on 5 topics: (1) epidemiology and natural history, (2) genetic testing and counseling, (3) diagnostic criteria and imaging standards, (4) neurosurgical considerations, and (5) neurological considerations.

A Systematic Review of MicroRNAs in Hemorrhagic Neurovascular Disease: Cerebral Cavernous Malformations as a Paradigm.

Hemorrhagic neurovascular diseases, with high mortality and poor outcomes, urge novel biomarker discovery and therapeutic targets. Micro-ribonucleic acids (miRNAs) are potent post-transcriptional regulators of gene expression. They have been studied in association with disease states and implicated in mechanistic gene interactions in various pathologies.

Safety and efficacy of atorvastatin for rebleeding in cerebral cavernous malformations (AT CASH EPOC): a phase 1/2a, randomised placebo-controlled trial.

Background: Cerebral cavernous malformations (CCMs) carry a high risk of rebleeding after symptomatic haemorrhage, with serious clinical sequelae. Atorvastatin was shown to prevent CCM growth and bleeding in animal models. We aimed to assess the safety and efficacy of atorvastatin on rebleeding in patients with CCMs after a symptomatic haemorrhage.

Circulating molecules reflect imaging biomarkers of hemorrhage in cerebral cavernous malformations.

Increases in mean lesional iron content by quantitative susceptibility mapping (QSM) by ≥6% and/or vascular permeability by dynamic contrast enhanced quantitative perfusion (DCEQP) by ≥40% on MRI have been associated with new symptomatic hemorrhage (SH) in cerebral cavernous malformations (CCMs). It is not known if plasma biomarkers can reflect these changes within the lesion proper. This cohort study enrolled 46 CCM patients with SH in the prior year.

Intracerebral Hemorrhage: Keep It Simple.

The quotation, attributed to Confucius many centuries ago, in our opinion, applies to the evolving story of defining a primary surgical treatment for spontaneous intracerebral hemorrhage. The precise quote is: "Keep it simple and focus on what matters. Don't let yourself be overwhelmed.

Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations.

Cerebral cavernous malformations (CCMs) are anomalies of the cerebral vasculature. Loss of the CCM proteins CCM1/KRIT1, CCM2, or CCM3/PDCD10 trigger a MAPK-Krüppel-like factor 2 (KLF2) signaling cascade, which induces a pathophysiological pattern of gene expression. The downstream target genes that are activated by KLF2 are mostly unknown.

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.

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.

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.

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.

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 (, , and ), which influence various signaling pathways that lead to the CCM phenotype.

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.

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.

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.

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.

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 (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.

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.

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 ).

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

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.