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.

Continuous irrigation with thrombolytics for intraventricular hemorrhage: case-control study.

Intraventricular hemorrhage (IVH) is a complication of a spontaneous intracerebral hemorrhage. Standard treatment is with external ventricular drain (EVD). Intraventricular thrombolysis may improve mortality but does not improve functional outcomes. We present our initial experience with a novel irrigating EVD (IRRAflow) that automates continuous irrigation with thrombolysis.Single-center case-control study including patients with IVH treated with EVD compared to IRRAflow. We compared standard demographics, treatment, and outcome parameters between groups. We developed a brain phantom injected with a human clot and assessed clot clearance using EVD/IRRAflow approaches with CT imaging.Twenty-one patients were treated with standard EVD and 9 patients with IRRAflow. Demographics were similar between groups. Thirty-three percent of patients with EVD also had at least one dose of t-PA and 89% of patients with IRRAflow received irrigation with t-PA (p = 0.01). Mean drain days were 8.8 for EVD versus 4.1 for IRRAflow (p = 0.02). Days-to-clearance of ventricular outflow was 5.8 for EVD versus 2.5 for IRRAflow (p = 0.02). Overall clearance was not different. Thirty-seven percent of EVD patients achieved good outcome (mRS ≥ 3) at 90 days versus 86% of IRRAflow patients (p = 0.03). Assessing only t-PA, reduction in mean days-to-clearance (p = 0.0004) and ICU days (p = 0.04) was observed. In the benchtop model, the clot treated with IRRAflow and t-PA showed a significant reduction of volume compared to control.Irrigation with IRRAflow and t-PA is feasible and safe for patients with IVH. Improving clot clearance with IRRAflow may result in improved clinical outcomes and should be incorporated into randomized trials.

A Large Lambl's Excrescence Causing Embolic Stroke in a Young Patient: A Case Report and Review of Literature.

Lambl's excrescences (LEs) are thin, filiform and hypermobile strands that develop at the valvular coaptation sites of the heart. Since first described in 1856 by Vilém Dusan Lambl, there has been an increasing number of reports of central and peripheral emboli arising from cardiac LEs. LEs have been linked to ischemic strokes irrespective of age and comorbidities. We report one of the youngest reported cases in literature of an embolic stroke in a 25-year-old woman caused by a LE. A comprehensive workup was performed that revealed a large aortic valve LE. The patient was discharged on dual anti-platelet therapy with outpatient cardiology follow-up for surveillance echocardiograms. We then surveyed the literature and reviewed case reports and observational studies of LEs linked to systemic emboli. We found that most LEs are present on left-sided high-pressure valves especially the ventricular aspect of the aortic valves and that most reported cases of cerebral embolism had aortic valve LEs. The management of cardioembolic stroke secondary to LEs remains unclear. LEs have not been identified as a definite etiology of cardioembolic strokes warranting the need for large-scale studies to help guide the management of cardiac LEs in the setting of ischemic stroke.

Progressive Disruption of Sphingosine-1-Phosphate Receptor 1 Correlates with Blood-Brain Barrier Leakage in A Rat Model of Chronic Hypoxic Hypoperfusion.

Endothelial dysfunction and blood-brain barrier (BBB) leakage have been suggested as a fundamental role in the development of cerebral small vessel disease (SVD) pathology. However, the molecular and cellular mechanisms that link cerebral hypoxic hypoperfusion and BBB disruption remain elusive. Sphingosine-1-phosphate (S1P) regulates the BBB integrity by binding to its receptor isoform 1 (S1PR1) on endothelial cells. This study tested the hypothesis that hypoxic hypoperfusion triggers capillary endothelial S1PR1 disruption, which compromises BBB integrity and leads to SVD-related neuropathological changes, using a chronic hypoxic hypoperfusion model with BBB dysfunction. Spontaneously hypertensive rat stroke-prone underwent unilateral carotid artery occlusion (UCAO) followed by a Japanese permissive diet (JPD) for up to 9 weeks. Selective S1PR1 agonist SEW2871 was used to activate S1PR1. Significant progressive reduction of S1PR1 was detected in rat brains from 4 to 9 weeks following UCAO/JPD onset, which was also detected in cerebral vasculature in human SVD. S1PR1 activation by SEW2871 significantly reduced lesions in both white and grey matter and ameliorated cerebral blood flow. SEW2871 reversed the loss of endothelial S1PR1 and tight junction proteins, and significantly attenuated UCAO/JPD induced accumulation of neuronal phosphorylated tau. This protective role of SEW2871 is associated with promotion of Akt phosphorylation and inhibition of S1PR2/Erk1/2 activation. Our data suggest S1PR1 signalling as a potential molecular mechanistic basis that links hypoxic hypoperfusion with BBB damage in the neuropathological cascades in SVD. The reversal of BBB disruption through pharmacological intervention of S1PR1 signalling likely reveals a novel therapeutic target for SVD.