Highlight
– Early cerebral edema in cerebral venous thrombosis (CVT) can be classified into global, cytotoxic, and vasogenic subtypes using admission neuroimaging.
– Cytotoxic and global cerebral edema independently predict worse 6-month functional outcomes.
– Cytotoxic edema is associated with increased in-hospital mortality risk.
– Global cerebral edema prolongs hospital stay, indicating a more severe clinical course.
Study Background
Cerebral venous thrombosis is an uncommon form of stroke characterized by thrombosis in the cerebral venous system, leading to impaired venous drainage, elevated intracranial pressure, and potentially brain injury. A common but poorly defined neuroimaging feature in CVT is cerebral edema, which can complicate disease progression and influence outcomes. Traditional CT and MRI imaging reveal heterogeneous edema patterns but the clinical relevance of distinct edema subtypes—global cerebral edema, cytotoxic edema, and vasogenic edema—has not been clearly elucidated. Determining these subtypes and their prognostic implications is essential to refine risk stratification and treatment strategies beyond anticoagulation, potentially guiding adjunctive therapies to improve patient outcomes.
Study Design
This retrospective cohort study analyzed data from the CLOT-VENUS (Collaboration on Cerebral Venous Thrombosis) registry, which combines international CVT patient records from two major stroke centers in the United States and Mexico over two decades (2004–2024). The study included 394 adult patients with acute CVT who underwent admission neuroimaging (MRI and/or CT). Cerebral edema patterns were independently reviewed and categorized into three subtypes: global cerebral edema (diffuse swelling involving large brain regions), cytotoxic edema (cellular injury-related swelling), and vasogenic edema (extracellular fluid accumulation due to blood-brain barrier disruption).
The primary outcome was the 6-month modified Rankin Scale (mRS) score assessed as an ordinal shift, signifying overall functional disability. Secondary outcomes comprised ordinal mRS scores at hospital discharge, dichotomous poor functional outcomes (mRS 3-6 vs. 0-2 and mRS 2-6 vs. 0-1), in-hospital mortality, 6-month mortality, and length of hospital stay (LOS). Multivariable logistic regression models controlled for confounders such as demographics and baseline clinical characteristics to isolate the effect of edema subtypes on outcomes.
Key Findings
The cohort (mean age 42.7 years; 65.5% female) exhibited cerebral edema in 220 patients (55.8%), classified as cytotoxic edema (32.5%), global cerebral edema (25.6%), or vasogenic edema (24.9%).
At hospital discharge, patients with global cerebral edema had a dramatically increased odds of worse functional outcomes (adjusted odds ratio [aOR] 2.79; 95% confidence interval [CI], 1.83–4.27; p < 0.001), and cytotoxic edema also significantly increased odds of worse mRS scores (aOR 1.89; 95% CI, 1.27–2.80; p = 0.002). Vasogenic edema did not show a significant independent effect on discharge mRS scores in multivariable analysis.
At 6-month follow-up, both global cerebral edema (aOR 1.83; 95% CI, 1.19–2.81; p = 0.006) and cytotoxic edema (aOR 1.92; 95% CI, 1.28–2.88; p = 0.002) remained strong independent predictors of worse functional status as measured by ordinal mRS shift.
Regarding mortality, cytotoxic edema significantly elevated the risk of in-hospital death (aOR 3.17; 95% CI, 1.22–8.96; p = 0.021). Notably, global cerebral edema was associated with a longer median hospital stay by approximately two days (p = 0.014), reflecting more prolonged or complicated inpatient courses.
The study did not find a statistically significant impact of vasogenic edema on mortality or functional outcomes after adjusting for confounders, suggesting a potentially less deleterious role compared to cytotoxic and global edema types.
Expert Commentary
This comprehensive international registry analysis advances understanding of cerebral edema heterogeneity in CVT, underscoring the clinical importance of distinguishing cytotoxic and global edema subtypes. Cytotoxic edema, indicative of irreversible cellular injury, portends higher mortality and worse recovery, aligning with pathophysiologic concepts of neuronal death due to ischemia or venous congestion. Global cerebral edema likely reflects extensive brain swelling and increased intracranial pressure with detrimental secondary effects on perfusion and neural function.
The findings advocate for early, nuanced neuroimaging assessment in CVT, which could stratify patients for adjunctive therapies targeting edema management, intracranial pressure control, or neuroprotection alongside standard anticoagulation. Early identification of high-risk edema subtypes may facilitate tailored interventions to mitigate secondary brain injury.
However, limitations include the retrospective design, potential for imaging classification biases, and lack of standardized edema quantification or longitudinal imaging. The focus on major stroke centers may reduce the generalizability to broader practice settings. Prospective studies with protocolized imaging and therapeutic interventions are needed to confirm causality and evaluate targeted treatment benefits.
Conclusion
The CLOT-VENUS registry analysis reveals that cytotoxic and global cerebral edema subtypes present early after CVT independently associate with worse functional outcomes and increased mortality risk. Vasogenic edema appears less impactful on prognosis. These insights reinforce the importance of early cerebral edema subtype identification using neuroimaging as a prognostic biomarker and potential therapeutic target. Future prospective research should evaluate whether these edema subtypes can guide adjunctive management strategies beyond anticoagulation to improve patient outcomes and reduce morbidity and mortality in cerebral venous thrombosis.
Funding and Clinicaltrials.gov
The study was funded and supported by the participating institutions of the CLOT-VENUS registry. No clinical trial registration number was reported for this retrospective cohort study.
References
1. Brito A, Cruz-Criollo L, Galecio-Castillo M, et al. Early Cerebral Edema Subtypes and Functional Outcome in Patients With Cerebral Venous Thrombosis: Insights From the CLOT-VENUS Registry. Neurology. 2026 Jun 25;107(2):e218259. PMID: 42348805.
2. Stam J. Thrombosis of the cerebral veins and sinuses. N Engl J Med. 2005;352(17):1791-8.
3. Coutinho JM, Ferro JM, Canhão P, et al. Cerebral venous thrombosis: A practical guide. Pract Neurol. 2015 Feb;15(1):19-25.
4. Lin L, Xu A, Yuan Z, et al. Cytotoxic and vasogenic edema in ischemic stroke: Correlation of diffusion-weighted imaging and brain water content. J Cereb Blood Flow Metab. 2020;40(9):1836-1841.
5. Guo Y, Wu G, Chen Y, et al. Early Brain Edema and Prognosis in Acute Stroke: A Systematic Review and Meta-Analysis. Neurol Res. 2021;43(9):798-807.