Cytotoxic Edema and Intra-parenchymal Hemorrhage: A Mediated Pathway to Mortality and Functional Outcome in Cerebral Venous Sinus Thrombosis- A sub-analysis of the CLOT-VENUS Registry

Abstract Cytotoxic edema (CE) is a radiographic marker of early tissue injury in cerebral venous thrombosis (CVT) associated with poor outcomes, yet its mechanistic pathway remains unclear. We investigated whether intraparenchymal hemorrhage (IPH) mediates the association between CE and outcomes. We conducted a retrospective cohort study using the multicenter CLOT-VENUS registry, including acute CVT patients treated at two Comprehensive Stroke Centers in the USA and Mexico (2004–2024). CE was defined as hyperintensities around IPH or venous infarct with DWI restricted diffusion and corresponding low ADC, confirming true restricted diffusion. IPH was defined as hemorrhagic transformation of venous infarction or intracerebral hemorrhage on GRE MRI and/or NCCT. Mediation analyses assessed whether IPH mediated CE associations with in-hospital mortality and functional outcomes. Among 394 patients (mean age 42.7 years; 65.5% female), 128 (32.5%) demonstrated CE and 111(30.2%) IPH. CE was associated with in-hospital mortality (aOR 2.63, 95% CI 1.01–7.12) and poor 6-month mRS (aOR 1.71, 95% CI 1.06–2.74). CE was associated with IPH, which in turn was associated with mortality (aOR 8.73, 95% CI 2.93–30.45) and poor mRS (aOR 1.96, 95% CI 1.18–3.25). Adjustment for IPH rendered the CE-outcome associations non-significant. IPH accounted for 76.8% of CE’s effect on mortality and 83.8% on 6-month mRS. Our findings suggest that IPH likely mediates the effect of CE on outcomes in CVT. Although the temporal sequence could not be confirmed, the results underscore the value of early CE detection for timely intervention.